Antimicrobials

Peptides, 2004 Apr, 25(4), 675 - 83
The interaction of an antimicrobial decapeptide with phospholipid vesicles; Choi MJ et al.; Previously, by using combinatorial peptide libraries, we have identified activity-optimized decapeptide (KSL, KKVVFKVKFK-NH(2)), which exhibited a broad spectrum of the activity against bacteria and fungi without hemolytic activity . In order to examine lipid requirements and to understand the mode of KSL action, we investigated interactions of the peptide with vesicles consisting of various lipid compositions . KSL increased the permeability of negatively charged but not zwitterionic phospholipid membranes, and the leakage was independent on the size of encapsulated molecules (calcein, 1-aminonaphthalene-3,6,8-trisulfonic acid (ANTS)/N,N'-p-xylene bis(pyridinium) bromide (DPX), and fluorescein isothiocyanate (FITC)-dextran with different molecular weight), indicating that the peptide did not form pores or channels in this leakage process . KSL ability to permeabilize vesicles with negatively charged surface was dramatically reduced upon the addition of zwitterionic phospholipid rather than cholesterol, which revealed that the surface charge of lipid membranes played a major role in the activity and selectivity of KSL . Moreover, KSL diastereomer did not increase the permeability of negatively charged vesicles, indicating that the secondary structure of KSL was also required for membrane perturbation activity . Interestingly, KSL had an ability to cause aggregation and subsequent fusion of the acidic vesicles, which seemed to be related to the biological action . Structural studies performed by circular dichroism (CD) spectroscopy indicated that in the presence of acidic vesicles, the beta sheet structure of KSL must be required for the ability to (1) induce a leakage of dye from the acidic vesicles (2) to fuse the acidic vesicles .

Mol Microbiol, 2004 Jun, 52(5), 1291 - 302
Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst; Ng VH et al.; Reactive nitrogen species (RNS) play an essential role in host defence against Mycobacterium tuberculosis (MTB) in the mouse model of tuberculosis (TB), as evidenced by the increased susceptibility of mice deficient in the inducible isoform of nitric oxide synthase (NOS2) . In contrast, the role of reactive oxygen species (ROS) in protection against MTB is less clear, and mice defective in the ROS-generating phagocyte NADPH oxidase (Phox) are relatively resistant . This suggests that MTB might possess efficient mechanisms to evade or counter the phagocyte oxidative burst, effectively masking the impact of this host defence mechanism . In order to assess the role of ROS detoxification pathways in MTB virulence, we generated a katG null mutant of MTB, deficient in the KatG catalase-peroxidase-peroxynitritase, and evaluated the mutant's ability to replicate and persist in macrophages and mice . Although markedly attenuated in wild-type C57Bl/6 mice and NOS2(-/-) mice, the DeltakatG MTB strain was indistinguishable from wild-type MTB in its ability to replicate and persist in gp91(Phox-/-) mice lacking the gp91 subunit of NADPH oxidase . Similar observations were made with murine bone marrow macrophages infected ex vivo: growth of the DeltakatG MTB strain was impaired in macrophages from C57Bl/6 and NOS2(-/-) mice, but indistinguishable from wild-type MTB in gp91(Phox-/-) macrophages . These results indicate that the major role of KatG in MTB pathogenesis is to catabolize the peroxides generated by the phagocyte NADPH oxidase; in the absence of this host antimicrobial mechanism, KatG is apparently dispensable.

J Nat Prod, 2004 May, 67(5), 811 - 6
Tolaasins A--E, five new lipodepsipeptides produced by Pseudomonas tolaasii; Bassarello C et al.; Pseudomonas tolaasii, the causal organism of brown blotch disease of Agaricus bisporus and of the yellowing of Pleurotus ostreatus, was shown to produce in culture tolaasin I (1), tolaasin II (2), and five other minor metabolites, tolaasins A, B, C, D, and E (3-7) . These compounds were demonstrated to be important in the development of the disease symptoms . This paper reports on the structural elucidation, based essentially on NMR studies and MS spectra, and biological activity of the above lipodepsipeptides (3-7) . All the above analogues showed differences in the peptide moiety, as observed in other lipodepsipeptides of bacterial origin, and maintained the beta-hydroxyoctanoyl phi chain at the N-terminus, except tolaasin A, in which the acyl moiety was a gamma-carboxybutanoyl phi moiety . Among the target microorganisms used (fungi, yeast, and bacteria) the Gram-positive bacteria were the most sensitive, although the antimicrobial activity appeared to be correlated to the structural modification in the different analogues . The structure-activity relationships of these toxins are discussed.

Ageing Res Rev, 2004 Jan, 3(1), 31 - 54
HIV infection and advanced age emerging epidemiological, clinical, and management issues; Manfredi R; While the mean age of HIV/AIDS patients at first diagnosis is progressively rising, no updated epidemiological estimates, controlled clinical data, and randomized therapeutic trials, are available regarding clinical and laboratory response to antiretroviral therapy, safety of anti-HIV compounds and their associations, potential drug-drug interactions, short- and long-term toxicity, consequences on underlying disorders, or interactions with concomitant pharmacological regimens, in the elderly . The life expectancy of HIV-infected persons treated with highly active antiretroviral therapy (HAART) now approximates that of general population matched for age, while also AIDS definition itself has lost most of its epidemiological and clinical significance, thanks to the immunoreconstitution resulting from the large-scale use of potent HAART regimens . The increased survival of HIV-infected patients, the late recognition of other subjects with missed or delayed diagnosis are responsible for a further expected rise of mean age of HIV-infected individuals, so that the patient population aged 60-70 years or more is expected to increase in coming years . Unfortunately, the majority of therapeutic trials involving antiretroviral therapy, as well as antimicrobial chemoprophylaxis for AIDS-related opportunistic complications, have advanced age and/or concurrent end-organ disorders among main exclusion criteria, or the design of these studies does not allow to extrapolate data regarding older patients, compared with younger ones . The very limited data presently available seem to demonstrate that HAART has a virological efficacy in the elderly comparable with that of younger adults, but immunological recovery is often slower and blunted, although several studies clearly demonstrated that thymic function is preserved until late adult age . When facing an HIV-infected patient with advanced age, health care givers have to pay careful attention to eventual end-organ disorders, all possible pharmacological interactions, overlapping toxicity due to concurrent drug administration . All these issues may significantly interfere with HAART activity, patient's adherence to prescribed medications, and frequency and severity of untoward effects . The guidelines of antiretroviral therapy and those of treatment and prophylaxis of AIDS-related diseases deserve appropriate updates, paralleling the increasing mean age of HIV-infected population . Moreover, epidemiological figures need an increased focus on older age, while clinical trials specifically targeting on the elderly population are mandatory to have reliable data on all aspects of HAART administration in advanced age.

Int J Food Microbiol, 2004 Jun 15, 93(3), 267 - 79
Characterization of an E2-type colicin and its application to treat alfalfa seeds to reduce Escherichia coli O157:H7; Nandiwada LS et al.; Several outbreaks of Escherichia coli O157:H7 infections have been associated with contaminated alfalfa seeds . A recently isolated E . coli strain Hu194 was capable of inhibiting 22 strains of E . coli O157:H7 and this inhibition was mediated by the production of a colicin named Hu194 . The objectives of this study were to test the efficacy of treating alfalfa seeds with colicin Hu194 against E . coli O157:H7 strains, and to characterize this antimicrobial protein . Significant reductions (approximately 5 log CFU ml-1) in the viable cell counts of strains 43890 and 43895 were observed after 1-day incubation with semi-crude colicin, and after 2 days for strain 3081 . Strain 43890 was successfully eliminated (5 log CFU g-1) from inoculated alfalfa seeds after soaking in a colicin suspension at a concentration of 10,000 AU/g . Treatment of alfalfa seeds inoculated with strains 43895 and 3081 required 20-fold higher concentrations of colicin Hu194 to achieve as much as 3 log CFU g-1 reductions . The genes encoding the colicin Hu194 operon were located on a 6 kb plasmid, and the sequence analysis revealed that this colicin was an E-type DNAse . From the sequence data, the estimated molecular masses of colicin Hu194, its immunity protein and lysis protein were 61.3, 10.0 and 4.8 kDa, respectively . Based on DNA and protein sequence comparisons with other E-type colicin, colicin Hu194 belonged to the type E2-colicin cluster . However, cross-immunity tests between E-group colicins suggested that Hu194 colicin was divergent from the previously characterized E2 colicins.

Phytother Res, 2004 Apr, 18(4), 339 - 41
The antimicrobial activity of essential oils of Hypericum scabrum, Hypericum scabroides and Hypericum triquetrifolium; Kizil G et al.; The essential oils of Hypericum scabrum, Hypericum scabroides and Hypericum triquetrifolium were studied for the first time for their antimicrobial activity against nine organisms . All the essential oils exhibited some broad spectrum antibacterial activity, at a concentration of 80 microg/mL . The essential oils of Hypericum species showed antibacterial activity against the tested organisms and a yeast .

J Agric Food Chem, 2004 Jun 2, 52(11), 3530 - 5
chemical composition, plant genetic differences, antimicrobial and antifungal activity investigation of the essential oil of Rosmarinus officinalis L; Angioni A et al.; The chemical composition of the essential oil of the Sardinian Rosmarinus officinalis L . obtained by hydro distillation and steam\hydro distillation was studied using GC-FID and MS . Samples were collected at different latitude and longitude of Sardinia (Italy) . The yields ranged between 1.75 and 0.48% (v/w, volume/dry-weight) . A total of 30 components were identified . The major compounds in the essential oil were alpha-pinene, borneol, (-) camphene, camphor, verbenone, and bornyl-acetate . Multivariate analysis carried out on chemical molecular markers, with the appraisal of chemical, pedological, and random amplified polymorphic DNA data, allows four different clusters to be distinguished . The antimicrobial and antifungal tests showed a weak activity of Sardinian rosemary . On the other hand, an inductive effect on fungal growth, especially toward Fusarium graminearum was observed.

J Agric Food Chem, 2004 Jun 2, 52(11), 3309 - 12
In vitro antioxidant, antimicrobial, and antiviral activities of the essential oil and various extracts from herbal parts and callus cultures of Origanum acutidens; Sokmen M et al.; The essential oil and various extracts obtained from Origanum acutidens and methanol extracts (MeOH) from callus cultures have been evaluated for their antioxidative, antimicrobial, and antiviral properties . The essential oil exhibited strong antimicrobial activity with a significant inhibitory effect against 27 (77%) of the 35 bacteria, 12 (67%) of the 18 fungi, and a yeast tested and moderate antioxidative capacity in DPPH and beta-carotene/linoleic acid assays . GC and GC-MS analyses of the oil resulted in the identification of 38 constituents, carvacrol being the main component . The MeOH extracts obtained from herbal parts showed better antioxidative effect than that of butylated hydroxytoluene (BHT), whereas callus cultures also exhibited interesting antioxidative patterns . Concerning antiviral activity, none of the extracts inhibited the reproduction of influenza A/Aichi virus in MDCK cells . The MeOH extracts from herbal parts inhibited the reproduction of HSV-1, and also callus cultures exerted slight antiherpetic effect.

J Am Acad Orthop Surg, 2004 May-Jun, 12(3), 155 - 63
Spinal epidural abscess in adults; Bluman EM et al.; Spinal epidural abscess is a potentially life-threatening disease that can cause paralysis by the accumulation of purulent material in the epidural space . Although modern diagnostic and management methods have improved the prognosis, morbidity and mortality remain significant . Outcome usually is determined by the rapidity of the diagnosis and initiation of appropriate treatment . A high index of suspicion is warranted when a patient presents with spinal pain or a neurologic deficit in conjunction with fever or an elevated erythrocyte sedimentation rate . Gadolinium-enhanced magnetic resonance imaging should be done in suspected cases to localize and define the abscess . For spinal epidural abscess associated with neurologic compromise, the treatment of choice is emergent surgical decompression and debridement (with or without spinal stabilization), followed by long-term antimicrobial therapy . In the absence of a neurologic deficit, medical management is an alternative to surgery when the risk of neurologic complications is low based on the location and morphology of the abscess, immune status of the patient, and virulence of the organism.

J Pept Sci, 2004 May, 10(5), 304 - 11
Antinematodal effect of antimicrobial peptide, PMAP-23, isolated from porcine myeloid against Caenorhabditis elegans; Park Y et al.; The antinematodal activity and mechanism of a 23-mer antimicrobial peptide, PMAP-23, derived from pig myeloid was investigated . PMAP-23 displayed a strong antinematodal activity against the eggs and worms of Caenorhabditis elegans . To investigate the antinematodal mechanism of PMAP-23, fluorescence activated flow cytometry and confocal laser scanning microscopy were performed . C . elegans treated with PMAP-23 showed higher fluorescence intensity by propidium iodide (PI) staining than normal cells . Confocal microscopy showed that the peptide was localized in the egg's shell and cell membrane . The action of the peptide against C . elegans membranes was examined by testing the membrane disrupting activity using liposome (PC/PS; 3:1, w/w) . The result suggests that PMAP-23 may exert its antinematodal activity by disrupting the structure of the cell membrane via pore formation or via direct interaction with the lipid bilayers.

J Pept Sci, 2004 May, 10(5), 298 - 303
Structure-antiviral activity relationships of cecropin A-magainin 2 hybrid peptide and its analogues; Lee DG et al.; In order to elucidate the structure-antiviral activity relationship of cecropin A (1-8)-magainin 2 (1-12) (termed CA-MA) hybrid peptide, several analogues with amino acid substitutions were synthesized . In a previous study, it was shown that serine at position 16 in CA-MA hybrid peptide was very important for antimicrobial activity . Analogues were designed to increase the hydrophobic property by substituting a hydrophobic amino acid residue (S --> A, V, F or W, position 16) in the CA-MA hybrid peptide . In this study, the structure-antiviral activity relationships of CA-MA and its analogues were investigated . In particular, substitution of Ser with a hydrophobic amino acid, Val, Phe or Trp at position 16 caused a dramatic increase in the virus-cell fusion inhibitory activity . These results suggested that the hydrophobicity at position 16 in the hydrophobic region of CA-MA is important for potent antiviral activity.

Acta Crystallogr D Biol Crystallogr, 2004 Jun, 60(Pt 6), 1121 - 4 Epub 2004 May 21.
Purification, characterization and preliminary crystallographic studies of a novel plant defensin from Pachyrrhizus erosus seeds; Song X et al.; Defensins are small cysteine-rich antimicrobial peptides that are widely distributed in plants, insects and mammals . As potent defenders in protecting plants from pathogenic fungal attack, plant defensins are presumed to play an important role in the innate immunity of plants and are expected to find applications in the production of transgenic crops . A novel plant defensin protein SPE10 from Pachyrrhizus erosus seeds was purified and partially sequenced . Crystallization screening using the hanging-drop vapour-diffusion method resulted in two crystal forms, from one of which a diffraction data set was collected to 0.98 A resolution . The crystal belongs to space group P2(1), with unit-cell parameters a = 32.71, b = 28.11, c = 54.85 angstroms, beta = 103.78 degrees . Preliminary crystallographic studies revealed two subunits in the asymmetric unit .

Fitoterapia, 2004 Jun, 75(3-4), 409 - 11
Antimicrobial activity of Memecylon malabaricum leaves; Hullatti KK et al.; The petroleum ether, chloroform and methanol extracts of Memecylon malabaricum leaves were tested for antimicrobial activity . Only methanol extract has shown activity against bacteria both Gram (+) and Gram (-), and fungi .

Fitoterapia, 2004 Jun, 75(3-4), 395 - 7
Antimicrobial activity of the macrofungus Pholiota adiposa; Dulger B; The 60% methanolic extract of Pholiota adiposa exhibited antimicrobial activity .

Fitoterapia, 2004 Jun, 75(3-4), 368 - 70
Antimicrobial and cytotoxic activities of the fruit essential oil of Xylopia aethiopica from Nigeria; Asekun OT et al.; The fruits essential oil of Xylopia aethiopica showed activity against four microorganisms and cytotoxicity to carcinoma cells (Hep-2 cell line) at 5 mg/ml concentration .

Bioorg Med Chem, 2004 Jun 15, 12(12), 3135 - 9
Synthesis and in vitro antimicrobial activities of 2-hydroxy-6-methyl-7-(arylamino)-1,7-dihydropurin-8-ones; Sharma P et al.; A number of 2-hydroxy-6-methyl-7-(arylamino)-1,7-dihydropurin-8-ones have been synthesized . 3-Oxo-2-(arylhydrazono)butyric acid ethyl ester were acetylated and treated with triethyl amine and formamide in presence of 1,4-dioxane to yield N-(5-acetyl-4-ethoxy-2-oxo-2,5-dihydro-imidazol-1-yl)-N-arylacetamide, which on refluxation with urea and freshly prepared sodium ethoxide yielded the title compound . All the newly synthesized compounds have been characterized by spectroscopic and elemental analysis data . The synthesized compounds were screened against a representative panel of susceptible and resistant Gram-positive and Gram-negative bacteria using a standard antibiotic drug purinthol as control . Quantitative structure-activity relationship has also been interpreted in terms of correlation of biological activity with molecular refractive index parameters (M(R)) and Hammett substituent constant (sigma).

Biochim Biophys Acta, 2004 Jun 1, 1699(1-2), 221 - 7
Identification and structural analysis of the antimicrobial domain in hipposin, a 51-mer antimicrobial peptide isolated from Atlantic halibut; Birkemo GA et al.; Hipposin is a potent 51-mer antimicrobial peptide (AMP) from Atlantic halibut with sequence similarity to parasin (19-mer catfish AMP), buforin I (39-mer toad AMP), and buforin II (an active 21-mer fragment of buforin I), suggesting that the antimicrobial activity of these peptides might all be due to a common antimicrobial sequence motif . In order to identify the putative sequence motif, the antimicrobial activity of hipposin fragments against 20 different bacteria was compared to the activity of hipposin, parasin and buforin II . Neither parasin nor the 19-mer parasin-like fragment HIP(1-19) (differs from parasin in only three residues) that is derived from the N-terminal part (residues 1-19) of hipposin had marked antimicrobial activity . In contrast, the fragment HIP(16-36) (identical to buforin II) that is derived from the middle part of hipposin (residues 16-36) had such activity, indicating that this part of hipposin contained an antimicrobial sequence motif . The activity was enhanced when the parasin-like N-terminal sequence was also present, as the fragment HIP(1-36) which consists of residues 1-36 in hipposin was more potent than HIP(16-36) . Extending HIP(1-36) with three C-terminal residues-thereby constructing the buforin I-like peptide HIP(1-39) (differs from buforin I in only three residues)-increased the activity further . Also, the presence of the C-terminal part of hipposin (residues 40-51) increased the activity, as hipposin was clearly the most potent of all the peptides that were tested . Circular dichroism structural analysis of the peptides revealed that they were all non-structured in aqueous solution . However, trifluoroethanol and the membrane-mimicking entities dodecylphosphocholine micelles and negatively charged liposomes induced (amphiphilic) alpha-helical structuring in hipposin . Judging from the structuring of the individual fragments, the tendency for alpha-helical structuring appeared to be greater in the C-terminal and the buforin II-like middle region of hipposin than in the parasin-like N-terminal region.

Lancet, 2004 May 22, 363(9422), 1683 - 8
Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial; Brooks WA et al.; BACKGROUND: Pneumonia is a leading cause of morbidity and mortality in young children . Early reversal of severity signs--chest indrawing, hypoxia, and tachypnoea--improves outcome . We postulated that zinc, an acute phase reactant, would shorten duration of severe pneumonia and time in hospital . METHODS: In a double-blind placebo-controlled clinical trial in Matlab Hospital, Bangladesh, 270 children aged 2-23 months were randomised to receive elemental zinc (20 mg per day) or placebo, plus the hospital's standard antimicrobial management, until discharge . The outcomes were time to cessation of severe pneumonia (no chest indrawing, respiratory rate 50 per min or less, oxygen saturation at least 95% on room air) and discharge from hospital . Discharge was allowed when respiratory rate was 40 per minute or less for 24 consecutive hours while patients were maintained only on oral antibiotics . FINDINGS: The group receiving zinc had reduced duration of severe pneumonia (relative hazard {RH}=0.70, 95% CI 0.51-0.98), including duration of chest indrawing (0.80, 0.61-1.05), respiratory rate more than 50 per min (0.74, 0.57-0.98), and hypoxia (0.79, 0.61-1.04), and overall hospital duration (0.75, 0.57-0.99) . The mean reduction is equivalent to 1 hospital day for both severe pneumonia and time in hospital . All effects were greater when children with wheezing were omitted from the analysis . INTERPRETATION: Adjuvant treatment with 20 mg zinc per day accelerates recovery from severe pneumonia in children, and could help reduce antimicrobial resistance by decreasing multiple antibiotic exposures, and lessen complications and deaths where second line drugs are unavailable.

J Colloid Interface Sci, 2004 Jul 1, 275(1), 177 - 82
Silver nanoparticles as antimicrobial agent: a case study on E . coli as a model for Gram-negative bacteria; Sondi I et al.; The antimicrobial activity of silver nanoparticles against E . coli was investigated as a model for Gram-negative bacteria . Bacteriological tests were performed in Luria-Bertani (LB) medium on solid agar plates and in liquid systems supplemented with different concentrations of nanosized silver particles . These particles were shown to be an effective bactericide . Scanning and transmission electron microscopy (SEM and TEM) were used to study the biocidal action of this nanoscale material . The results confirmed that the treated E . coli cells were damaged, showing formation of "pits" in the cell wall of the bacteria, while the silver nanoparticles were found to accumulate in the bacterial membrane . A membrane with such a morphology exhibits a significant increase in permeability, resulting in death of the cell . These nontoxic nanomaterials, which can be prepared in a simple and cost-effective manner, may be suitable for the formulation of new types of bactericidal materials.

Microbes Infect, 2004 May, 6(6), 536 - 41
Induced expression of the antimicrobial peptide melittin inhibits experimental infection by Mycoplasma gallisepticum in chickens; Lazarev VN et al.; The in vivo action of the antimicrobial peptide melittin, expressed from a recombinant plasmid vector, on chickens experimentally infected with Mycoplasma gallisepticum was studied . The plasmid vector pBI/mel2/rtTA includes the melittin gene under the control of an inducible tetracycline-dependent human cytomegalovirus promoter and the gene coding for the trans-activation protein rtTA . Aerosol administration of the vector, followed by infecting the chickens with M . gallisepticum 1226, is shown to inhibit development of infection . The inhibitory action was confirmed by a complex of clinical, pathomorphological, histological and serological studies, and also by comparing the M . gallisepticum reisolation frequency from the respiratory tract and internal organs . The data suggest that plasmid vectors expressing genes of antimicrobial peptides can be considered as potential agents for the prevention and treatment of mycoplasma infections in poultry farming.

Trends Biotechnol, 2004 Jun, 22(6), 286 - 94
The contribution of farm animals to human health; Kues WA et al.; Farm animals and their products have a longstanding and successful history of providing significant contributions to human nutrition, clothing, facilitation of labour, research, development and medicine and have thus been essential in improving life expectancy and human health . With the advent of transgenic technologies the potential of farm animals for improving human health is growing and many areas remain to be explored . Recent breakthroughs in reproductive technologies, such as somatic cloning and in vitro embryo production, and their merger with molecular genetic tools, will further advance progress in this field . Here, we have summarized the contribution of farm animals to human health, covering the production of antimicrobial peptides, dietary supplements or functional foods, animals used as disease models and the contribution of animals to solving urgent environmental problems and challenges in medicine such as the shortage of human cells, tissues and organs and therapeutic proteins . Some of these areas have already reached the level of preclinical testing or commercial application, others will be further advanced only when the genomes of the animals concerned have been sequenced and annotated . Provided the necessary precautions are being taken, the transmission of pathogens from animals to humans can be avoided to provide adequate security . Overall, the promising perspectives of farm animals and their products warrant further research and development in this field.

Pediatr Clin North Am, 2004 Jun, 51(3), 819 - 27, xii
Anomalies, abnormalities, and care of the umbilicus; Pomeranz A; This article discusses various anomalies and abnormalities of the umbilical cord and issues related to cord care . The issue of screening newborns with an isolated single umbilical artery for renal abnormalities is addressed . The clinical presentation of infants with omphalomesenteric and urachal duct remants along with the more common umbilical granuloma is reviewed . All three of these abnormalities can present with a wet or draining cord . The need for umbilical cord treatment with antimicrobial/antiseptic agents versus dry cord care is discussed, as are serious infections that involve the cord.

Insect Mol Biol, 2004 Jun, 13(3), 283 - 91
Transcriptional regulation in cowpea bruchid guts during adaptation to a plant defence protease inhibitor; Moon J et al.; Cowpea bruchid, when fed on a diet containing the soybean cysteine protease inhibitor soyacystatin N (scN), activates an array of counter-defence genes to adapt to the negative effects of the inhibitor and regain its normal rate of feeding and development . A collection of 1920 cDNAs was obtained by differential subtraction with cDNAs prepared from guts of the 4th instar larvae of scN-adapted (reared on scN-containing diet) and scN-unadapted (reared on regular scN-free diet) cowpea bruchids . Subsequent expression profiling using DNA microarray and Northern blot analyses identified ninety-four transcript species from this collection that are responsive to dietary scN . scN-adapted insects induced genes encoding protein and carbohydrate digestive enzymes, probably to help meet their carbon and nitrogen requirements . Up-regulation of antimicrobial and detoxification protein genes may represent a generalized defence response . Genes down-regulated by scN reflected physiological adjustments of the cowpea bruchids to scN challenge . A large portion of the responsive genes, presumably involved in carrying out the counter-defence response, were of unknown function . The full-length cDNA of an scN-inducible cathepsin B-like cysteine protease was obtained . Its transcriptional response to scN during larval development contrasts with the pattern of the cathepsin L family, the major digestive enzymes . These results suggest cathepsin B-like cysteine proteases may play a crucial role in cowpea bruchid adaptation to dietary scN.

Biochemistry, 2004 Jun 1, 43(21), 6393 - 403
Effect of drastic sequence alteration and D-amino acid incorporation on the membrane binding behavior of lytic peptides; Papo N et al.; The amphipathic alpha-helix is a common motif found in many cell lytic peptides including antimicrobial peptides . We have recently shown that significantly altering the amphipathic structure of a lytic peptide by reshuffling its sequence and/or replacing a few l-amino acids with their D-enantiomers did not significantly affect the antimicrobial activity of the peptides nor their ability to bind and permeate negatively charged (PE/PG) membranes . However, a pronounced effect was observed regarding their hemolytic activity and their ability to bind and permeate zwitterionic (PC/Cho) membranes . To shed light on these findings, here we used surface plasmon resonance (SPR) with mono- and bilayer membranes . We found that the L-amino acid (aa) peptides bound 10-25-fold stronger to PC/Cho bilayers compared with monolayers, whereas the diastereomers bound similarly to both membranes . A two-state reaction model analysis of the data indicated that this difference is due to the insertion of the L-aa peptides into the PC/Cho bilayers, whereas the diastereomers are surface-localized . In contrast, only an approximately 2-fold difference was found with negatively charged membranes . Changes in the amphipathicity markedly affected only the insertion of the L-aa peptides into PC/Cho bilayers . Furthermore, whereas the all-L-aa peptides bound similarly to the PC/Cho and PE/PG membranes, the diastereomers bound approximately 100-fold better to PE/PG compared with PC/Cho membranes, and selectivity was determined only in the first binding step . The effect of the peptides on the lipid order determined by using ATR-FTIR studies supported these findings . Besides shedding light on the mode of action of these peptides, the present study demonstrates SPR as a powerful tool to differentiate between non-cell-selective compared with bacteria-selective peptides, based on differences in their membrane binding behavior.

Clin Infect Dis, 2004 Jun 1, 38(11), 1570 - 8 Epub 2004 May 13.
Clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in asian countries: a study by the Asian Network for Surveillance of Resistant Pathogens; Song JH et al.; To evaluate the clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in Asian countries, we performed a prospective observational study of 233 cases of adult pneumococcal pneumonia in 9 Asian countries from January 2000 to June 2001 . Among 233 isolates, 128 (55%) were not susceptible to penicillin (25.3% were intermediately susceptible, and 29.6% were resistant) . Clinical severity of pneumococcal pneumonia was not significantly different between antibiotic-resistant and antibiotic-susceptible groups . Mortality rates among patients with pneumococcal pneumonia caused by penicillin-, cephalosporin-, or macrolide-resistant strains were not higher than those with antibiotic-susceptible pneumococcal pneumonia . Bacteremia and mechanical ventilation were significant risk factors for death, but any kind of antibiotic resistance was not associated with increased mortality due to pneumococcal pneumonia . Outcome of pneumococcal pneumonia was not significantly affected by drug resistance, and current antimicrobial regimens are mostly effective in the treatment of pneumococcal pneumonia, despite the widespread emergence of in vitro resistance.

Orthopade, 2004 Jul, 33(7), 822 - 8
{Guidelines on antimicrobial therapy in situations of periprosthetic THR infection}; Frommelt L; Periprosthetic infection is nowadays a rare complication in artificial joint replacement . The infection of joint prostheses is a foreign body associated infection at the site of bone tissue which is difficult to treat with antimicrobial agents . Apart from cases with early, non-established infections, the surgical removal of the foreign material and radical debridement of bone and soft tissue is necessary . The surgical revision is performed preferentially using a one or two stage exchange of the prosthesis . In some cases, only the removal of the prosthesis is necessary . In these cases, a pseudoarthroplasty or an arthrodesis without definitely implanted foreign material is performed . Amputation is carried out if all other forms of revision have failed . All of these surgical procedures are accomplished by antimicrobial therapy, whether systemically administered and/or topically by drug delivery systems . Controlled studies for the comparison of one and two stage exchange procedures are not currently available . For the therapy of periprosthetic infection, an infectious disease specialist who is experienced in this area is needed in addition to an experienced surgical team . Thus, the therapy of these infections should be performed exclusively in centres of competence.

Methods Mol Biol, 2004, 268, 317 - 30
Flavonoids from Argentine Tagetes (Asteraceae) with antimicrobial activity; Tereschuk ML et al.; The flavonoids, constituting one of the most numerous and widespread groups of natural plant constituents, are important to humans not only because they contribute to plant colors but also because many members are physiologically active . These low-molecular-weight substances, found in all vascular plants, are phenylbenzopyrones . Over 4000 structures have been identified in plant sources, and they are categorized into several groups . Primarily recognized as pigments responsible for the autumnal burst of hues and the many shades of yellow, orange, and red in flowers and food, the flavonoids are found in fruits, vegetables, nuts, seeds, stems, flowers, and leaves as well as tea and wine and are important constituents of the human diet . They are prominent components of citrus fruits and other food sources . Flavonols (quercetin, myricetin, and kaempferol) and flavones (apigenin and luteolin) are the most common phenolics in plant-based foods . Quercetin is also a predominant component of onions, apples, and berries . Such flavanones as naringin are typically present in citrus fruit, and flavanols, particularly catechin, are present as catechin gallate in such beverages as green or black tea and wine . Some major sources of flavonoids are outlined in Table 1 . The daily intake of flavonoids in humans has been estimated to be approx 25 mg/d, a quantity that could provide pharmacologically significant concentrations in body fluids and tissues, assuming good absorption from the gastrointestinal tract.Biological activity of flavonoids was first suggested by Szent-Gyorgyi 1938, who reported that citrus peel flavonoids were effective in preventing the capillary bleeding and fragility associated with scurvy . The broad spectrum of biological activity within the group and the multiplicity of actions displayed by a certain individual members make the flavonoids one of the most promising classes of biologically active compounds.

Methods Mol Biol, 2004, 268, 281 - 8
Testing disinfectants in the food factory: phenol coefficient method; Herrera AG; Contamination of foods by the environment has direct public health and keeping quality significance . The food factory environment (with raw materials and processing) governs the numbers and types of microorganisms in finished products . Use of the appropriate sampling procedures permits us to discover the magnitude and type of contamination . Microbiological sampling allows objective evaluation of the disinfectants and the sanitation practices and procedures used in the food factory.Disinfectants are antimicrobial pesticides that are primarily used on inanimate surfaces (such as floors, walls, and countertops) to kill infectious bacteria, fungi, and viruses . Antimicrobial pesticides are substances used to kill or suppress the growth of harmful microorganisms on inanimate objects and surfaces . Products intended for the control of microorganisms in or on people or animals are considered drugs, not pesticides, and are therefore regulated by the Food and Drug Administration (FDA) . Antimicrobial pesticides are divided into two broad use categories: 1 . Non-public health products include those used to control the growth of algae, odor-causing bacteria, and microorganisms causing spoilage, deterioration, and fouling of materials . Examples include antimicrobials used in cooling towers, paints, and paper products . 2 . Public health products are intended to control microorganisms infectious to people . Examples include sterilants, which are used to destroy or eliminate all forms of microbial life including fungi, viruses, and all forms of bacteria and their spores; disinfectants, which are used to destroy or irreversibly inactivate infectious fungi and bacteria, but not necessarily their spores; and sanitizers, which are used to reduce, but not necessarily eliminate microorganisms . Examples range from sterilants used to treat surgical instruments to disinfectants applied to hospital floors, walls, and bed linens and sanitizers used on carpets or in laundry additives.

Methods Mol Biol, 2004, 268, 153 - 61
Viability of amoebae, fungal conidia, and yeasts: rapid assessment by flow cytometry; Noble-Wang JA et al.; Conventional methods for the evaluation of antimicrobials and disinfecting solutions with microorganisms involve culture-based techniques, which are time-consuming and underestimate the number of viable organisms . Rapid detection and viability measurements of microorganisms in homogenous and heterogenous microbial populations have been greatly enhanced by recent advances in the use of fluorescent stains in flow cytometry (FCM) . FCM has been applied to enumerate, differentiate, and identify microorganisms, determine protein and DNA content of cells, analyze the physiological state of individual cells, and analyze the interaction of drugs, antibiotics, and antimicrobials with microbial cells . Four physiological states of cells can be distinguished by FCM: (1) reproductively viable, (2) metabolically active, (3) intact, and (4) permeabilized.FCM permits a rapid and quantitative measurement of the optical characteristics of cells as they pass through, in a single file, a focused beam of light . As cells are carried within a fast-flowing fluid stream and through the focus of exciting light, three parameters are measured: forward angle light scatter, side angle light scatter, and fluorescence emitted by dyes that have specific interaction with intracellular components of individual cells . FCM data that are presented in histogram and dot plots can be generated to give information on a variety of properties of interest among cells in the population as a whole.FCM offers major advantages in multiparameter data acquisition and multivariate data analysis, high-speed analysis, and cell-sorting capabilities . Disadvantages may be associated with the cost, which is usually over 100,000 (US Dollars) for a typical laser-based flow cytometer with just analyzing capabilities . Another disadvantage is that skilled personnel are usually required to operate these complex instruments so as to get optimum performance . A schematic overview of flow cytometry is presented in Fig . 1.

Antimicrob Agents Chemother, 2004 Jun, 48(6), 2132 - 9
Interaction of antimycobacterial drugs with the anti-Mycobacterium avium complex effects of antimicrobial effectors, reactive oxygen intermediates, reactive nitrogen intermediates, and free fatty acids produced by macrophages; Sano K et al.; The profiles of the interaction of antimycobacterial drugs with macrophage (MPhi) antimicrobial mechanisms have yet to be elucidated in detail . We examined the effects of various antimycobacterial drugs on the anti-Mycobacterium avium complex (MAC) antimicrobial activity of reactive oxygen intermediates (ROIs), especially of an H(2)O(2)-halogen (H(2)O(2)-Fe(2+)-NaI)-mediated bactericidal system, reactive nitrogen intermediates (RNIs), and free fatty acids (FFAs), which are known as central antimicrobial effectors of host MPhis against mycobacterial pathogens . We have found that certain drugs, such as rifampin (RIF), rifabutin (RFB), isoniazid (INH), clofazimine (CLO), and some fluoroquinolones, strongly or moderately reduced the anti-MAC activity of the H(2)O(2)-Fe(2+)-NaI system, primarily by inhibiting the generation of hypohalite ions and in part by interfering with the halogenation reaction of bacterial cell components due to the H(2)O(2)-Fe(2+)-NaI system . This phenomenon is specific to the H(2)O(2)-Fe(2+)-NaI system, since these drugs did not reduce the anti-MAC activity of RNIs and FFAs . From the perspective of the chemotherapy of MAC infections, the present findings indicate an important possibility that certain antimycobacterial drugs, such as rifamycins (RIF and RFB), INH, CLO, and also some types of fluoroquinolones, may interfere with the ROI-mediated antimicrobial mechanisms of host MPhis against intracellular MAC organisms.

Antimicrob Agents Chemother, 2004 Jun, 48(6), 1983 - 8
The action of bismuth against Helicobacter pylori mimics but is not caused by intracellular iron deprivation; Bland MV et al.; Helicobacter pylori is highly susceptible to bismuth, a heavy metal with antimicrobial activity linked to its effect on bacterial iron uptake . Three strains of H . pylori were analyzed for indicators of iron limitation following exposure to the MIC of colloidal bismuth subcitrate (MIC(CBS)) . Similar morphologic and outer membrane changes were observed following growth in iron-limiting medium and at the MIC(CBS) that inhibited the growth of all three strains . These changes, which were also observed for iron-limited bacteria, were alleviated by the addition of iron to the cultures . H . pylori ATP levels, reduced in iron-limiting medium, were below the limits of detection in two of the three strains following exposure to bismuth . The addition of iron partially restored bacterial ATP levels in these two strains, although not to normal concentrations . In contrast, exposure of the same strains to the MIC(CBS) failed to deplete intracellular levels of iron, which were significantly reduced by culturing in iron-limiting medium . Thus, the antimicrobial effect of bismuth and of iron limitation on H . pylori may be similar . However, the respective mechanisms of intracellular action would appear to be mediated by different pathways within the cell.

Biotechnol Appl Biochem, 2004 Jun, 39(Pt 3), 339 - 45
Recombinant antimicrobial peptides efficiently produced using novel cloning and purification processes; Metlitskaia L et al.; Endogenous antimicrobial peptides are ubiquitous components of animal and plant host defences . These peptides, usually cationic and amphipathic, kill target cells rapidly and are efficacious against antibiotic-resistant and clinically relevant pathogens . A practical challenge in the development of cationic peptides as therapeutics is to meet the production requirements for large quantities of highly purified drug substance at competitive costs . While chemical peptide synthesis can be used to manufacture cationic peptides, we have developed cost-effective methods for recombinant production by expressing fusion proteins comprised of multiple copies of the peptides . The fusion proteins accumulate in Escherichia coli inclusion bodies and constitute over 50% of the total cellular proteins . Active antimicrobial peptides are released by chemical reagents and purified by chromatography, combining both standard and novel approaches . Challenges of industrial-scale manufacturing of therapeutics were considered in the development of this process.

J Am Vet Med Assoc, 2004 May 15, 224(10), 1634 - 9
Efficacy of ceftiofur hydrochloride sterile suspension administered parenterally for the treatment of acute postpartum metritis in dairy cows; Chenault JR et al.; OBJECTIVE: To evaluate the efficacy of ceftiofur hydrochloride sterile suspension administered parenterally for treatment of acute postpartum metritis (APM) in dairy cows . DESIGN: Multilocation, randomized block, field trial . ANIMALS: 406 cows in the first 14 days postpartum . PROCEDURE: Cows with rectal temperatures > or = 39.5 degrees C (103.1 degrees F) without clinical signs of respiratory or gastrointestinal tract disease and with a fetid vaginal discharge were allocated randomly in blocks of 3 to 3 treatment groups: sterile saline (0.9% NaCl) solution administered at a dosage of 2 mL/45.4 kg (2 mL/100 lb), SC or IM, once daily for 5 days (control); or ceftiofur hydrochloride administered at a dosage of 1.1 or 2.2 mg of ceftiofur equivalents (CE)/kg (0.5 or 1 mg/lb, respectively), SC or IM, once daily for 5 days . Cows were evaluated on days 6, 10, and 14, and clinical cure or failure to cure was determined . Clinical cure was defined as no additional antimicrobial treatment administered, rectal temperature < 39.5 degrees C, and absence of a fetid vaginal discharge . RESULTS: On day 14, clinical cure rates were 77%, 65%, and 62% for the 2.2 mg of CE/kg, 1.1 mg of CE/kg, and control groups, respectively . No significant differences were detected in clinical cure rates between control and treatment groups on day 10 or 6 . CONCLUSIONS AND CLINICAL RELEVANCE: Ceftiofur hydrochloride administered at a dosage of 2.2 mg of CE/kg, SC or IM, once daily for 5 days was efficacious for treatment of APM in dairy cows.

Am J Infect Control, 2004 May, 32(3), 161 - 9
Survey of oral care practices in US intensive care units; Binkley C et al.; BACKGROUND: Research has shown that oral care involving toothbrushes and topical antimicrobials improves the oral health of medically compromised patients and may reduce the incidence of nosocomial infections including pneumonia . This survey research was undertaken to determine the type and frequency of oral care in intensive care units (ICUs) in the United States and the attitudes, beliefs, and knowledge of health care workers . METHODS: A randomly selected survey of 102 ICUs within the continental United States participated with 556 respondents; 97% of respondents were registered nurses . MEASUREMENTS: Frequency and type of oral care provided, attitudes and beliefs, and knowledge and training in oral care were measured . RESULTS: Ninety-two percent of respondents perceived oral care to be a high priority . The primary methods of oral care involved the use of foam swabs, moisturizers, and mouthwash . Toothbrushes and toothpaste were used infrequently by almost 80% of respondents . The majority of nurses indicated a need for research-proven oral care standards and desired to learn more . CONCLUSIONS: In this random sample of ICUs, oral care methods were not consistent with current research and oral care protocols . The translation of oral care research into practice in the ICU may improve the quality of care and decrease the incidence of ventilator-associated pneumonia.

Caries Res, 2004 May-Jun, 38(3), 286 - 93
Sugar alcohols: what is the evidence for caries-preventive and caries-therapeutic effects?
Van Loveren C.
The most widely used sugar alcohols are: xylitol, sorbitol, mannitol, maltitol, lactitol and the products Lycasin and Palatinit . It is often claimed that xylitol is superior to the other sugar alcohols for caries control . This paper examines clinical studies on the caries-preventive and therapeutic effects of sugar alcohols with emphasis on sorbitol and xylitol . It is concluded that chewing sugar-free gum 3 or more times daily for prolonged periods of time may reduce caries incidence irrespective of the type of sugar alcohol used . It may be sufficient to do this only on school days . Sucking xylitol-containing candies or tablets may have a similar effect as chewing xylitol chewing gum . Clinical trials suggest greater caries reductions from chewing gums sweetened with xylitol than from gums sweetened with sorbitol . However, the superiority of xylitol was not confirmed in 2 out of 4 clinical trials comparing the caries-preventive effect of xylitol- with sorbitol-sweetened gums . The caries-preventive effects of polyol-containing gums and candies seem to be based on stimulation of the salivary flow, although an antimicrobial effect cannot be excluded . There is no evidence for a caries-therapeutic effect of xylitol . These conclusions are in line with those of recent reviews and with the conclusions of the Scientific Committee on Medicinal Products and Medical Devices of the EU Commission .

Caries Res, 2004 May-Jun, 38(3), 247 - 53
Salivary proteins: protective and diagnostic value in cariology?
Van Nieuw Amerongen A, Bolscher JG, Veerman EC.
Saliva is essential for a lifelong conservation of the dentition . Various functions of saliva are implicated in the maintenance of oral health and the protection of our teeth: (i) The tooth surface is continuously protected against wear by a film of salivary mucins and proline-rich glycoprotein . (ii) The early pellicle proteins, proline-rich proteins and statherin, promote remineralization of the enamel by attracting calcium ions . (iii) Demineralization is retarded by the pellicle proteins, in concert with calcium and phosphate ions in saliva and in the plaque fluid . (iv) Several salivary (glyco)proteins prevent the adherence of oral microorganisms to the enamel pellicle and inhibit their growth . (v) The salivary bicarbonate/carbonate buffer system is responsible for rapid neutralization of acids . An overview is presented on the major antimicrobial systems in human saliva . Not only the well-known major salivary glycoproteins, including mucins, proline-rich glycoprotein and immunoglobulins, but also a number of minor salivary (glyco)proteins, including agglutinin, lactoferrin, cystatins and lysozyme, are involved in the first line of defense in the oral cavity . Besides, small cationic antimicrobial peptides, e.g . defensins, cathelicidin and the histatins, have come into focus . These are potentially suited as templates for the design of a new generation of antibiotics, since they kill a broad spectrum of microorganisms, while hardly evoking resistance, in contrast to the classical antibiotics .

Caries Res, 2004 May-Jun, 38(3), 223 - 9
Antimicrobials in future caries control? A review with special reference to chlorhexidine treatment; Twetman S; The aim of this paper was to examine recent evidence for the effect of the antibacterial approach to prevent and control caries with special reference to the use of chlorhexidine (CHX) . Existing information from the mid 1990s provided limited evidence for the effectiveness of CHX gels, rinses and toothpaste in preventing caries in permanent teeth of children and adolescents . An updated literature search on CHX intervention in controlled clinical trials from 1995 to May 2003 unveiled 22 studies covering over 4,500 patients with clinical caries as end point . The vast majority (n = 21) were dealing with CHX-containing varnishes . Since the studies exhibited disparities in design, diagnosis and intervention, the findings were subgrouped with respect to caries type and localization . According to the ranking system of the Swedish Council on Technology Assessment in Health Care, the evidence for an anticaries effect of CHX varnishes was rated as inconclusive for caries-active schoolchildren and adolescents with regular fluoride exposure . Regarding fissure caries, a preventive effect of CHX varnishes was demonstrated in 4 studies out of 5 when compared to no treatment in children with low fluoride exposure . The evidence for arresting root caries in dry-mouth patients and frail elderly subjects was inconclusive . In conclusion, the evidence from the recent literature was inconclusive for the use of CHX varnishes for caries prevention in risk groups .

MMWR Morb Mortal Wkly Rep, 2004 May 21, 53(19), 407 - 10
Fatal cases of Rocky Mountain spotted fever in family clusters--three states, 2003; Centers for Disease Control and Prevention (CDC); Rocky Mountain spotted fever (RMSF), a tickborne infection caused by Rickettsia rickettsii and characterized by a rash, has a case-fatality rate as high as 30% in certain untreated patients . Even with treatment, hospitalization rates of 72% and case-fatality rates of 4% have been reported . This report summarizes the clinical course of three fatal cases of RMSF in children and related illness in family members during the summer of 2003 . These cases underscore the importance of 1) prompt diagnosis and appropriate antimicrobial therapy in patients with RMSF to prevent deaths and 2) consideration of RMSF as a diagnosis in family members and contacts who have febrile illness and share environmental exposures with the patient.

Vet Ther, 2004 Spring, 5(1), 60 - 74
Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle; Nowakowski MA et al.; The pharmacokinetics of the new triamilide antibiotic tulathromycin was investigated in two cattle studies . Following a single subcutaneous injection, the drug was rapidly absorbed and bioavailability was excellent . High and persistent levels of the drug in lung tissue were observed as well . These attributes are advantageous for an antimicrobial drug indicated for the treatment of bacterial and mycoplasmal respiratory diseases in cattle.

J Med Microbiol, 2004 Jun, 53(Pt 6), 535 - 8
Helicobacter pylori: antibiotic resistance and eradication rates in Suffolk, UK, 1991-2001; Cameron EA et al.; Helicobacter pylori infection causes a number of gastrointestinal diseases and its current treatment is based on multidrug regimes including acid suppression and antimicrobials . The success of these regimes is determined by a number of factors including antibiotic resistance, which varies widely but is an increasing problem . Local data are important in establishing the most cost-effective eradication regime . Data have been collected prospectively on antibiotic resistance at Ipswich Hospital (Suffolk, UK) in all consecutive isolates of H . pylori from 1991 to 2001 . The success of regimes consisting of a proton pump inhibitor, amoxycillin and metronidazole (PPI/A/M) has also been evaluated in patients found positive on serological testing in primary care using urea breath testing . Overall, metronidazole resistance was found in 31.7 % of isolates and clarithromycin resistance in 5.3 % . A significant increase in metronidazole resistance from 29.1 to 37.0 % (P = 0.022) and a decrease in clarithromycin resistance from 10.3 to 3.8 % (P = 0.014) was seen over the study period . Metronidazole resistance was significantly more common in women (P < 0.001) and young patients (P < 0.001) . Eradication with PPI/A/M was successful in 89.9 % of patients and did not change significantly over the study period . Eradication rates were lower in young patients (P < 0.001) . Whilst metronidazole resistance is increasing in Suffolk, this does not seem to have a significant effect on eradication rates . Metronidazole-based regimes are still effective first-line treatments in most patients.

J Inorg Biochem, 2004 Jun, 98(6), 1151 - 9
Equilibrium characterization of the As(III)-cysteine and the As(III)-glutathione systems in aqueous solution; Rey NA et al.; Some arsenic compounds were the first antimicrobial agents specifically synthesized for the treatment of infectious diseases such as syphilis and trypanosomiasis . More recently, arsenic trioxide has been shown to be efficient in the treatment of acute promyelocytic leukemia . The exact mechanism of action has not been elucidated yet, but it seems to be related to arsenic binding to vicinal thiol groups of regulatory proteins . Glutathione is the major intracellular thiol and plays important roles in the cellular defense and metabolism . This paper reports on a study of the interactions between arsenic(III) and either cysteine or glutathione in aqueous solution . The behavior observed for the As(III)-glutathione system is very similar to that of As(III)-cysteine . In both cases, the formation of two complexes in aqueous solution was evidenced by NMR and electronic spectroscopies and by potentiometry . The formation constants of the cysteine complexes {As(H(-1)Cys)(3)}, log K = 29.84(6), and {As(H(-2)Cys)(OH)(2)}(-), log K = 12.01(9), and of the glutathione complexes {As(H(-2)GS)(3)}(3-), log K = 32.0(6), and {As(H(-3)GS)(OH)(2)}(2-), log K = 10(3) were calculated from potentiometric and spectroscopic data . In both cases, the {As(HL)(3)} species, in which the amine groups are protonated, predominate from acidic to neutral media, and the {As(L)(OH)(2)} species appear in basic medium (the charges were omitted for the sake of simplicity) . Spectroscopic data clearly show that the arsenite-binding site in both complexes is the sulfur atom of cysteine . In the {As(L)(OH)(2)} species, the coordination sphere is completed by two hydroxyl groups . In both cases, arsenic probably adopts a trigonal pyramidal geometry . Above pH 10, the formation of {As(OH)(2)O}(-) excludes the thiolates from arsenic coordination sites . At physiological pH, almost 80% of the ligand is present as {As(HL)(3)}.

Bioorg Med Chem Lett, 2004 Jun 21, 14(12), 3165 - 8
Structure-based design, synthesis, and antimicrobial activity of purine derived SAH/MTA nucleosidase inhibitors; Tedder ME et al.; The structure-based design, synthesis, and biological activity of novel inhibitors of S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described . Using 6-substituted purine and deaza purines as the core scaffolds, a systematic and structure guided series of modifications provided low nM inhibitors with broad-spectrum antimicrobial activity.

Bioorg Med Chem Lett, 2004 Jun 21, 14(12), 3069 - 72
The synthesis and antimicrobial evaluation of a new series of isoxazolinyl oxazolidinones; Weidner-Wells MA et al.; A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide {3+2} dipolar cycloaddition reaction . These compounds were screened against a panel of susceptible and resistant Gram-positive organisms . Several analogs from this series were comparable to or more potent than linezolid in vitro.

Br J Dermatol, 2004 May, 150(5), 904 - 9
Involvement of granulysin-producing T cells in the development of superficial microbial folliculitis; Oono T et al.; BACKGROUND: Granulysin is a recently identified antimicrobial protein expressed on cytotoxic T cells, natural killer (NK) cells and NKT cells . It has been shown that granulysin contributes to the defence mechanisms against mycobacterial infection . Superficial microbial folliculitis is a common skin disease . In a previous report, we showed that, as a first line of defence, alpha-defensin, a human neutrophil peptide, and beta-defensin (human beta-defensin-2) were expressed in infiltrating neutrophils and in lesional epidermal keratinocytes, respectively, in superficial folliculitis . As we also observed many infiltrating lymphocytes in lesional dermis, we hypothesized that infiltrating lymphocytes may possess antimicrobial substances, such as granulysin, and play a role in the defence mechanism as a second line of defence . OBJECTIVES: Seven specimens of superficial microbial folliculitis diagnosed clinically and histologically were examined by means of immunohistochemistry . To identify the phenotype of cells expressing granulysin, confocal laser microscopic examination was performed . RESULTS: A dense lymphoid cell infiltrate was observed in pustules, in the perivascular regions . A large number of these lymphoid cells were positive for granulysin . Phenotypically, cells consisted of CD3+ T cells, CD8+ T cells and UCHL-1+ T cells . CD20+ cells and CD56+ cells were not observed . Microscopic examination with a confocal laser showed that the lymphocytes producing granulysin were CD3+ and CD4+ T cells but not CD8+ T cells . CONCLUSIONS: We showed that many granulysin-bearing T cells infiltrated affected follicles and perilesional dermis in superficial microbial folliculitis . However, few granulysin-positive lymphoid cells were observed in sterile pustular lesions . Our observations indicated that adaptive immunity such as granulysin, a lymphocyte-produced antimicrobial protein, may play an important role in the cutaneous defence mechanism.

Bioconjug Chem, 2004 May-Jun, 15(3), 530 - 5
Promotion of peptide antimicrobial activity by fatty acid conjugation; Chu-Kung AF et al.; Three peptides, YGAA{KKAAKAA}(2) (AKK), KLFKRHLKWKII (SC4), and YG{AKAKAAKA}(2) (KAK), were conjugated with lauric acid and tested for the effect on their structure, antibacterial activity, and eukaryotic cell toxicity . The conjugated AKK and SC4 peptides showed increased antimicrobial activity relative to unconjugated peptides, but the conjugated KAK peptide did not . The circular dichroism spectrum of AKK showed a significantly larger increase in its alpha-helical content in the conjugated form than peptide KAK in a solution containing phosphatidylethanolamine/phosphotidylglycerol vesicles, which mimics bacterial membranes . The KAK and AKK peptides and their corresponding fatty acid conjugates showed little change in their structure in the presence of phosphatidylcholine vesicles, which mimic the cell membrane of eukaryotic cells . The hemolytic activity of the KAK and AKK peptides and conjugates was low . However, the SC4 fatty acid conjugate showed a large increase in hemolytic activity and a corresponding increase in helical content in the presence of phosphatidylcholine vesicles . These results support the model of antimicrobial peptide hemolytic and antimicrobial activity being linked to changes in secondary structure as the peptides interact with lipid membranes . Fatty acid conjugation may improve the usefulness of peptides as antimicrobial agents by enhancing their ability to form secondary structures upon interacting with the bacterial membranes.

Aust Vet J, 2004 Apr, 82(4), 223 - 7
Survey for papillomatous digital dermatitis in Australian dairy cattle; Milinovich GJ et al.; OBJECTIVE: To determine whether Treponema-associated papillomatous digital dermatitis (PDD) occurs in Australian dairy cattle . DESIGN: Mail-out questionnaire and histological and bacteriological examination of biopsy tissue from suspect PDD lesions . PROCEDURE: The questionnaire was mailed to 375 veterinarians to evaluate their knowledge of PDD, determine if they had observed the disease in Australian dairy cattle, and to request biopsy material from suspicious cases . Biopsies were examined for histological and bacteriological evidence of PDD, including for the presence of spirochaetes . RESULTS: Eighty-eight replies to the questionnaire were received (23.5%) . Of 52 respondents who were aware of PDD as a possible cause of lameness, 26 reported observing the condition in Australian cattle . Of 32 respondents who were unaware of the condition, 6 reported observing lesions that might have been PDD . The majority of reports of PDD-like lesions came from the southern Australian states, the condition occurring during periods of high rainfall and proving responsive to topical or parenteral application of antimicrobials . Biopsies from five erosive lesions showed histological similarity to PDD whereas biopsies from five proliferative lesions were consistent with chronic inflammation, fibroma or cutaneous papilloma . The presence of spirochaetes was not demonstrated in any of the lesions by histological or bacteriological methods . CONCLUSION: Anecdotal reports and analysis of biopsy material confirm that a condition similar to PDD does occur sporadically in dairy cattle in southern Australia . However, this condition has so far not been shown to be associated with the presence of spirochaetes in the lesions.

Immunogenetics, 2004 Jun, 56(3), 170 - 7 Epub 2004 May 18.
Bioinformatic discovery and initial characterisation of nine novel antimicrobial peptide genes in the chicken; Lynn DJ et al.; Antimicrobial peptides (AMPs) are essential components of innate immunity in a range of species from Drosophila to humans and are generally thought to act by disrupting the membrane integrity of microbes . In order to discover novel AMPs in the chicken, we have implemented a bioinformatic approach that involves the clustering of more than 420,000 chicken expressed sequence tags (ESTs) . Similarity searching of proteins-predicted to be encoded by these EST clusters-for homology to known AMPs has resulted in the in silico identification of full-length sequences for seven novel gallinacins (Gal-4 to Gal-10), a novel cathelicidin and a novel liver-expressed antimicrobial peptide 2 (LEAP-2) in the chicken . Differential gene expression of these novel genes has been demonstrated across a panel of chicken tissues . An evolutionary analysis of the gallinacin family has detected sites-primarily in the mature AMP-that are under positive selection in these molecules . The functional implications of these results are discussed.

Pediatr Surg Int, 2004 Jun, 20(6), 402 - 7 Epub 2004 May 18.
Advances in the treatment of oesophageal atresia over three decades: the 1970s and the 1990s; Orford J et al.; Oesophageal atresia management has evolved alongside the development of paediatric surgery . An analysis of a 30-year prospective collection of oesophageal atresia cases treated at the Royal Alexandra Hospital for Children, NSW, Australia is presented . There has been a dramatic change in the surgical approach . Fewer infants are undergoing operations of cervical oesophagostomy, gastrostomy and oesophageal replacement . More, including fragile infants, are surviving with a repaired native oesophagus . Fewer infants are suffering morbidity secondary to anastomotic leak . The progression in treatment has been enabled by improved neonatal support due to advances in neonatology, neonatal anaesthesia, nutritional support and antimicrobial therapy . Oesophageal atresia treatment and outcome has changed markedly over three decades . Cooperative multi-centre database development is now required to provide data in order to further refine treatment for clinical challenges that remain.

Proc Natl Acad Sci U S A, 2004 May 25, 101(21), 8233 - 8 Epub 2004 May 17.
A gene cluster for secondary metabolism in oat: implications for the evolution of metabolic diversity in plants; Qi X et al.; The evolution of the ability to synthesize specialized metabolites is likely to have been key for survival and diversification of different plant species . Oats (Avena spp.) produce antimicrobial triterpenoids (avenacins) that protect against disease . The oat beta-amyrin synthase gene AsbAS1, which encodes the first committed enzyme in the avenacin biosynthetic pathway, is clearly distinct from other plant beta-amyrin synthases . Here we show that AsbAS1 has arisen by duplication and divergence of a cycloartenol synthase-like gene, and that its properties have been refined since the divergence of oats and wheat . Strikingly, we have also found that AsbAS1 is clustered with other genes required for distinct steps in avenacin biosynthesis in a region of the genome that is not conserved in other cereals . Because the components of this gene cluster are required for at least four clearly distinct enzymatic processes (2,3-oxidosqualene cyclization, beta-amyrin oxidation, glycosylation, and acylation), it is unlikely that the cluster has arisen as a consequence of duplication of a common ancestor . Although clusters of paralogous genes are common in plants (e.g., gene clusters for rRNA and specific disease resistance), reports of clusters of genes that do not share sequence relatedness and whose products contribute to a single selectable function are rare {Gierl, A . & Frey, M . (2001) Planta 213, 493-498} . Taken together, our evidence has important implications for the generation of metabolic diversity in plants.

Arch Dermatol, 2004 May, 140(5), 563 - 6
Acaricidal activity of Melaleuca alternifolia (tea tree) oil: in vitro sensitivity of sarcoptes scabiei var hominis to terpinen-4-ol; Walton SF et al.; OBJECTIVE: To compare the acaricidal activity of Melaleuca alternifolia (tea tree) oil (TTO) and some of its individual active components on the itch mite Sarcoptes scabiei var hominis . DESIGN: In vitro acaricide sensitivity assessment . SETTING: The Menzies School of Health Research laboratory, located near the Infectious Diseases Ward of the Royal Darwin Hospital, Australia, where patients are admitted and treated for crusted scabies . PARTICIPANTS: Scabies mites (S scabiei var hominis) were collected from a 20-year-old Aboriginal woman admitted to the Royal Darwin Hospital with crusted scabies.Interventions Within 3 hours of collection, scabies mites were placed in continuous direct contact with the TTO products and control acaricides and were observed at regular intervals . MAIN OUTCOME MEASURES: Percentage of mites dead at regular observation intervals between 5 minutes and 24 hours during continuous exposure to the TTO products and acaricides . RESULTS: The 5% TTO and active component terpinen-4-ol were highly effective in reducing mite survival times . Statistically significant differences in mite survival curves were observed for 5% TTO, 2.1% terpinen-4-ol, 5% permethrin, and ivermectin (100 microg/g of Emulsifying Ointment British Pharmacopoeia 88) . In vivo effectiveness was also observed . CONCLUSIONS: Documentation of resistance against antiectoparasitic compounds is increasing . Reported S scabiei treatment failures with lindane, crotamiton, and benzyl benzoate, as well as likely emerging resistance to 5% permethrin and oral ivermectin, are of concern and advocate for the identification and development of novel acaricidal drugs . Tea tree oil is a membrane-active biocide extracted from the tree M alternifolia . It is a principal antimicrobial in a wide range of pharmaceuticals sold in Australia, with the main active component being oxygenated terpenoids . The results suggest that TTO has a potential role as a new topical acaricide and confirm terpinen-4-ol as the primary active component.

FEBS Lett, 2004 May 21, 566(1-3), 301 - 6
The cyclic antimicrobial peptide RTD-1 induces stabilized lipid-peptide domains more efficiently than its open-chain analogue; Abuja PM et al.; The effects of a mammalian cyclic antimicrobial peptide, rhesus theta defensin 1 (RTD-1) and its open chain analogue (oRTD-1), on the phase behaviour and structure of model membrane systems (dipalmitoyl phosphatidylcholine, DPPC and dipalmitoyl phosphatidylglycerol, DPPG) were studied . The increased selectivity of RTD-1 for anionic DPPG over zwitterionic DPPC was shown by differential scanning calorimetry . RTD-1, at a molar peptide-lipid ratio of 1:100, induced considerable changes in the phase behaviour of DPPG, but not of DPPC . The main transition temperature, Tm, was unchanged, but additional phase transitions appeared above Tm . oRTD-1 induced similar effects . However, the effects were not observable below a peptide:lipid molar ratio of 1:50, which correlates with the weaker biological activity of oRTD-1 . Small- and wide-angle X-ray scattering revealed for DPPG the appearance of additional structural features induced by RTD-1 above Tm, which were interpreted as correlated lamellar structures, with increased order of the fatty acyl side chains of the lipid . It is proposed that after initial electrostatic interaction of the cationic rim of the peptide with the anionic DPPG headgroups, leading to stabilized lipid-peptide clusters, the hydrophobic face of the peptide assists in its interaction with the fatty acyl side chains eventually leading to membrane disruption.

Int J Cancer, 2004 Jul 10, 110(5), 695 - 700
Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma; Wu MS et al.; Genes involved in regulating antimicrobial immunity and inflammation may modulate the risk of Helicobacter pylori-associated diseases . IL-1 and TNF-alpha are major cytokines detected in H . pylori-infected tissues . We aimed to determine the role of gene polymorphisms for these cytokines and their receptors in 2 distinct H . pylori-related gastric malignancies, adenocarcinoma (GAC) and maltoma . Genotyping for IL-1beta (-31 C/T, -511 C/T), TNF-alpha (-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C), TNFR1 (-383 A/C) and TNFR2 (196 G/T) was undertaken for 70 patients with maltoma and 204 patients with noncardia GAC and compared to 210 unrelated healthy controls . Genotype frequencies showed no differences among patients with GAC or maltoma and controls for IL-1beta, TNFR1 or TNFR2 . The TNF-alpha -857 T variant was significantly underrepresented in maltoma compared to controls (6.4% vs . 14.3%, p = 0.018), conferring a 3-fold decrease in risk (OR = 0.33, 95% CI 0.15-0.75) . Comparison of allele frequencies between GAC and controls failed to show any statistical significance for TNF-alpha polymorphisms . We concluded that TNF-alpha -857 T itself or a neighboring gene may modify the risk of maltoma . The differences in genetic background as well as divergent clinicopathologic features between GAC and maltoma support the notion that fundamental mechanistic differences exist in these 2 well-defined H . pylori-related malignancies .

Klin Mikrobiol Infekc Lek, 2004 Apr, 10(2), 73 - 9
{Antimicrobial prophylaxis in surgery}; Stastnik M; Antimicrobial prophylaxis is an important factor influencing the risk of infection at the spot of surgical interventions (SSI) . SSIs are the most important nosocomial infections of hospitalized surgical patients; they are responsible for increases of 10 to 20 % in the total costs of treatment . The efficacy of antimicrobial prophylaxis hinges on four basic factors . The first is a correctly indicated prophylaxis (in surgical operations with a confirmed reduction of SSI risk after prophylaxis and/or in cases of surgical operations, where a possible early or organ SSI could have tragic consequences) . The second factor is the choice of the best possible antimicrobial for a specific indication . The third factor is the best possible time for the administration of prophylaxis (in most indications at the beginning of anaesthesia) . The fourth factor influencing the efficacy of prophylaxis is its administration for only the absolutely minimum time period necessary (in most indications best is a single administration, possibly including a second peroperative ATB dose) . The high rate of errors in the actual practice of prophylaxis and the confirmed efficacy of implementing local recommendations indicate that it is absolutely necessary to define national and local recommendations for antimicrobial prophylaxis, to ensure that surgeons adhere to these recommendations and to initiate SSI surveillance in the Czech Republic.

Med Klin (Munich), 2004 May 15, 99(5), 251 - 60
{Infectious diseases-Part II: New agents, resistances, and treatment strategies}; Salzberger B et al.; A number of new antimicrobial agents have been licensed in the last years, most prominently a number of new antiviral and antimycotic agents . The development of new antibacterial agents has slowed down, new agents are mainly targeted at a small but rapidly growing number of patients infected with bacteria resistant to the current antibiotics.The rates of resistance against antibiotics are rapidly rising, especially for gram-positive cocci and, in addition, for gram-negative nosocomial agents . Rising rates of resistances are further present in chronic viral infections, e . g., HIV infection . Instruments to monitor and minimize the rates of resistances are necessary.Important changes are to be found in a number of infectious complications . For patients with sepsis a new therapeutic principle, drocretogrin, has been found to reduce mortality . Additionally, low-dose corticosteroids in selected patients, close control of blood sugar and other interventions have shown to be effective . Corticosteroids have proven to be effective as well in the reduction of complications in adults with bacterial meningitis, most pronounced in pneumococcal meningitis . With new drugs licensed for the treatment of malaria and changes in the epidemiology, the guidelines for therapy and prevention have been reformulated.

Clin Rev Allergy Immunol, 2004 Apr, 26(2), 115 - 25
Toll-like receptors and immune response in allergic disease; Gangloff SC et al.; Allergic reactions are dominated by the preferential development of specific Th2 responses against innocuous antigens in atopic individuals . This can reflect alterations in innate immune mechanisms . Toll-like receptors (TLRs) have evolved as key molecules in innate and adaptive immunity . Their activation by structurally distinct exogenous or endogenous ligands present at the cell microenvironment plays a critical role in antimicrobial defense . The global view is that TLR activation induces antigen-presenting cells to produce cytokines that favor Th1-type immune responses, suggesting that it might prevent the development of deleterious Th2 responses in allergy . On the basis of epidemiological studies and recent data, it has been established that TLRs play a role in the development of Th2 responses . However, more information is needed to fully understand the mechanism of TLR involvement and the implication of immune cells that express TLRs in the Th1/Th2 cytokine profiles . Several TLRs, such as TLR9, TLR7, and TLR8, can be considered as good target candidates . Some TLR ligands, such as CpG DNA, are effective adjuvants, strong inducers of both IL-5 and eosinophilia downregulation . They are also potential links to allergen epitopes that could provide new allergen-specific immunotherapy regimens for the treatment of allergic disorders.

FEMS Immunol Med Microbiol, 2004 Jun 1, 41(2), 141 - 8
Anti-complement effects of lactoferrin-derived peptides; Samuelsen O et al.; Lactoferrin is an important biological molecule with many functions such as modulation of the inflammatory response, iron metabolism and antimicrobial defense . One effect of lactoferrin is the inhibition of the classical complement pathway . This study reports that antimicrobial peptides derived from the N-terminal region from both human and bovine lactoferrin, lactoferricin H and lactoferricin B, respectively, inhibit the classical complement pathway . No inhibitory effect of these peptides was observed on the alternative complement pathway in an AP50 assay . However, lactoferricin B reduced the inhibitory properties of serum against Escherichia coli in a concentration dependent manner . These results suggest that the N-terminal region of lactoferrin is the important part in the inhibition of complement activation and that these peptides possess other important properties than their antimicrobial effect.

Burns, 2004 Jun, 30(4), 329 - 33
Effects of cytokines and heat shock on defensin levels of cultured keratinocytes; Bick RJ et al.; Burns have been associated with high levels of circulating pro-inflammatory cytokines which promote systemic inflammatory response syndrome (SIRS), immunosuppression and sepsis for which no effective treatment is currently available . Defensins, a family of cationic naturally occurring antimicrobial peptides, are considered important components of the innate immune system and enhance adaptive immunity . This study examines the effects of pro-inflammatory cytokines, interleukin-1beta (IL-1beta), gamma-interferon (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) on human beta-defensin-2 (HBD-2) levels in cultured keratinocytes . We also examined the effects of heat shock at 42 degrees C . The results demonstrate that only TNFalpha shows significant induction of HBD-2 but this induction was not sustained in the long-term . In addition, endogenous levels of defensin were significantly reduced by exposure to heat shock . The keratinocytes also responded to IL-1beta by becoming hypertrophic . These results indicate that stress-related, pro-inflammatory cytokines can induce keratinocytes to synthesize HBD-2, while heat shock appears to reduce its production . These experiments give us further insight into the role of natural antimicrobial peptides under conditions of stress.

Can Vet J, 2004 Apr, 45(4), 309 - 11
Availability and estimates of veterinary antimicrobial use in British Columbia; Fraser E et al.; The amount of antimicrobial use is a significant selection pressure that alters the frequency of antimicrobial resistance . This paper summarizes attempts to estimate the weight of antimicrobial purchases in British Columbia for use in animals . The data reported here do not capture all sources of veterinary antimicrobial use in British Columbia . This paper highlights how information deficits on veterinary drug use complicate the development of an evidence-based policy framework for combating antimicrobial resistance.

Tumori, 2004 Jan-Feb, 90(1), 132 - 5
The development of pulmonary adenocarcinoma in a patient with Job's syndrome, a rare immunodeficiency condition; Oztop I et al.; The hyperimmunoglobulin E (HIE) (Job's) syndrome often has it onset in childhood and is characterized by markedly elevated serum IgE levels, chronic dermatitis and recurrent pyogenic infections . Lymphoid malignancies have most commonly been associated with this syndrome while the first case in the literature of carcinoma associated with HIE syndrome was a squamous cell carcinoma of the vulva, described by Clark et al . in 1998 . We observed a male patient with Job's syndrome diagnosed at age three who presented with bone pain and a metastatic epithelial tumor of the bone revealed by biopsy . Diagnostic procedures aimed at detecting the primary site showed multiple mediastinal lymph nodes with lung and liver metastases on computed tomography scans and an extradural spinal metastasis at the upper thoracic level on magnetic resonance imaging . Although the patient refused a bronchoscopic procedure, a diagnosis of pulmonary adenocarcinoma was established on the basis of sputum cytology and the clinical aspects of tumor extent . Intravenous corticosteroids and palliative radiotherapy were given for the spinal metastasis . Palliative chemotherapy could not be started because of the patient's poor performance status as well as nosocomial fungal pneumonia and pseudomonal urogenital infection with bacteremia . Despite the antifungal and broad-spectrum antimicrobial treatments, the patient died of pseudomonal sepsis.

Hepatogastroenterology, 2004 May-Jun, 51(57), 822 - 4
Living-related liver transplantation in a patient with end-stage hepatolithiasis and a biliary-bronchial fistula; Hirohashi K et al.; Liver transplantation in patients with end-stage hepatolithiasis is complicated by the high incidence of the suppurative cholangitis and systemic infection . A 43-year-old Korean-Japanese woman with hepatolithiasis, biliary cirrhosis, suppurative cholangitis, and biliary-bronchial fistula underwent living-related liver transplantation (LRLT) using a right lobe graft of her sister . The risk of infection was minimized by preoperative percutaneous transhepatic biliary drainage initiated 2 months before transplantation . The native liver was resected en bloc with the extrahepatic bile ducts and the infected section of the right hemidiaphragm . Opportunistic infection was prevented by limiting antimicrobial therapy to the interval from preoperative day 3 to postoperative day 4 . Immunosuppressive agents were given below standard dose . The postoperative course following LRLT was uncomplicated, and hepatic function was good . Careful management of infection and adequate graft size are essential for successful LRLT in patients with end-stage hepatolithiasis.

Arch Environ Health, 2003 Jul, 58(7), 433 - 41
Chronic sinusitis: defective T-cells responding to superantigens, treated by reduction of fungi in the nose and air; Dennis DP; In this study, the author used endoscopic sinus photography to study the effects of reduction of fungi in the nose, and in environmental air, on the sinus mucosa of 639 patients diagnosed with chronic rhinosinusitis . Sinus mucosal photographs were taken before and after reduction of fungal load in the nose and air, to determine if there was an optimum environmental air fungal load associated with sinus mucosal recovery to normal appearance . Systemic symptoms associated with fungal exposure, which resolved when fungus was removed from the patient and the environmental air and reappeared with recurrent environmental fungal exposure, are also discussed and are termed systemic fungal symptoms . Interventions consisted of nasal fungal load reduction with normal saline nasal irrigations and antimicrobial nasal sprays, and environmental air fungal load reduction with high-efficiency particulate air (HEPA) filtration in combination with ionizers or evaporation of a solution of botanical extract . Main outcome measures were obtained with environmental air 1-hr gravity-plate fungal colony counts, laser air particle counts, and endoscopic sinus photography . Blood levels of immunoglobulins IgG and IgE for 7 common molds were also determined . After intervention, 94% of patients who used antimicrobial nasal sprays and who reduced their environmental fungal air count to 0-4 colonies per 1-hr agar gravity-plate exposure (n = 365) exhibited normal sinus mucosa by endoscopic exam . Environmental air fungal counts that exceeded 4 colonies resulted in sinus mucosal abnormalities ranging from edema, to pus and/or nasal polyps at higher counts . Neutralization of allergy, and/or surgery, were used as appropriate following implementation of environmental measures . On the basis of these observations, as well as detailed clinical experience and a review of the current literature, the author hypothesizes that the pathogenesis of chronic rhinosinusitis, allergic fungal sinusitis, and systemic fungal symptoms is a genetic defect at the variable beta chain helper T-cell receptor (TCR Vbeta) site which requires the presence of an antigen (fungus) . Chronic sinusitis patients who have recurring exposure to environmental air that contains fungal concentrations in excess of 4 colonies per 1-hr agar plate exposure appear to have an increased risk of persistent chronic sinusitis and/or systemic symptoms, regardless of the medical treatment provided.

Harefuah, 2004 Feb, 143(2), 121 - 5, 166
{Bacteriophages as antibacterial agents}; Shasha SM et al.; Bacteriophages are viruses that only infect bacteria . They have played an important role in the development of molecular biology and have been used as anti-bacterial agents . Since their independent discovery by Twort and d'Herelle, they have been extensively used to prevent and treat bacterial infections, mainly in Eastern Europe and the former Soviet Union . In western countries this method has been sporadically employed on humans and domesticated animals . However, the discovery and widespread use of antibiotics, coupled with doubts about the efficacy of phage therapy, led to an eclipse in the use of phage in medicine . The emergence of antibiotic resistant bacteria, especially strains that are multiply resistant, has resulted in a renewed interest in alternatives to conventional drugs . One of the possible replacements for antibiotics is the use of bacteriophages as antimicrobial agents . This brief review aims to describe the history of bacteriophage and early clinical studies on their use in bacterial disease prophylaxis and therapy, and discuss the advantages and disadvantages of bacteriophage in this regard.

J Infect Dis, 2004 Jun 1, 189(11), 2129 - 38 Epub 2004 May 10.
Sphingosine 1-phosphate induces antimicrobial activity both in vitro and in vivo; Garg SK et al.; Sphingosine 1-phosphate (S1P), a polar sphingolipid metabolite, is involved in a wide spectrum of biological processes, including Ca(++) mobilization, cell growth, differentiation, motility, and cytoskeleton organization . Here, we show a novel role of S1P in the induction of antimicrobial activity in human macrophages that leads to the intracellular killing of nonpathogenic Mycobacterium smegmatis and pathogenic M . tuberculosis . Such activity is mediated by host phospholipase D, which favors the acidification of mycobacteria-containing phagosomes . Moreover, when it was intravenously injected in mycobacteria-infected mice, S1P reduced mycobacterial growth and pulmonary tissue damage . These results identify S1P as a novel regulator of the host antimicrobial effector pathways.

J Hosp Infect, 2004 May, 57(1), 44 - 51
The procedures of hygiene to control hospital-acquired diarrhoea in paediatric wards: a multicentre audit; Jusot JF et al.; An audit was carried out in paediatric wards to study the compliance of healthcare workers (HCWs) to the procedures recommended for the control of hospital-acquired diarrhoea . Thirty-two paediatric wards in the southeast of France participated on a voluntary basis in this prospective observational study after completing a self-administered questionnaire recording measures of hygiene . All the observations were made by the same investigator and focused on preventive procedures: use of single room, handwashing, hand disinfection, overclothing, single-use gloves and masks . Two hundred and seventy patient-HCW contacts were observed, including mainly diapering, temperature measurement, collection of blood sample and catheter care . The isolation of patients in a single room and use of gowns by HCWs were significantly associated with diarrhoea . Whereas handwashing before care was performed by HCWs in more than 95% of all the procedures, the compliance in the use of disposable gloves by HCWs was only of 39.4% for technical procedures (including those with potential exposure to blood) and 20.3% for diapering or temperature measurement . A substantial agreement between reported and observed measures of hygiene was observed for handwashing before contact and hand disinfection with antimicrobial soap before contact . In contrast, this agreement was moderate for use of single room, handwashing after contact, overclothing and wearing disposable gloves after a diaper change . Despite the excellent compliance of HCWs to handwashing, clearer recommendations for the indication and use of disinfectants and disposable gloves are urgently needed.

Immunity, 2004 May, 20(5), 637 - 49
Monomeric and polymeric gram-negative peptidoglycan but not purified LPS stimulate the Drosophila IMD pathway; Kaneko T et al.; Insects depend solely upon innate immune responses to survive infection . These responses include the activation of extracellular protease cascades, leading to melanization and clotting, and intracellular signal transduction pathways inducing antimicrobial peptide gene expression . In Drosophila, the IMD pathway is required for antimicrobial gene expression in response to gram-negative bacteria . The exact molecular component(s) from these bacteria that activate the IMD pathway remain controversial . We found that highly purified LPS did not stimulate the IMD pathway . However, lipid A, the active portion of LPS in mammals, activated melanization in the silkworm Bombyx morii . On the other hand, the IMD pathway was remarkably sensitive to polymeric and monomeric gram-negative peptidoglycan . Recognition of peptidoglycan required the stem-peptide sequence specific to gram-negative peptidoglycan and the receptor PGRP-LC . Recognition of monomeric and polymeric peptidoglycan required different PGRP-LC splice isoforms, while lipid A recognition required an unidentified soluble factor in the hemolymph of Bombyx morii.

Curr Infect Dis Rep, 2004 Jun, 6(3), 187 - 190
Nebulization of Antibiotics in Management of Sinusitis; Vaughan WC; Chronic sinusitis with recurrent acute infections continues to be a significant medical problem . Even after aggressive medical and surgical management, some patients continue to have recurrent infections . These infections are often multidrug-resistant . Topical delivery of medications into body cavities has been practiced for decades . Recently, the use of prescription antibiotic, antifungal, and anti-inflammatory topical medications has increased for sinus patients . This article examines emerging data on nebulized antimicrobials for patients with sinusitis.

Cent Eur J Public Health, 2004 Mar, 12 Suppl, S57 - 9
Biological activity of 2-hydroxythiobenzanilides and related compounds; Kubicova L et al.; Thiobenzanilides substituted in thioacyl moiety with one or more hydroxy groups are interesting for their biological effects depending on the substitution pattern . New findings in mechanisms of action of 2-hydroxybenzanilides insert 2-hydroxybenzanilides and their analogues, e.g . substituted thiobenzanilides, among interesting compounds in the development of new potential antimicrobial drugs . The present review paper with 32 references links up with our previous communications which reviewed biological activity of 2-hydroxybenzanilides and related compounds, and includes the research of mono-, di-, and trihydroxythiobenzanilides carried out in the last period.

Am J Vet Res, 2004 May, 65(5), 610 - 5
Effect of danofloxacin and tilmicosin on body temperatures of beef calves with pneumonia experimentally induced by inoculation with Mannheimia haemolytica; Fajt VR et al.; OBJECTIVE: To examine effects of danofloxacin and tilmicosin on continuously recorded body temperature in beef calves with pneumonia experimentally induced by inoculation of Mannheimia haemolytica . ANIMALS: 41 Angus-cross heifers (body weight, 160 to 220 kg) without a recent history of respiratory tract disease or antimicrobial treatment, all from a single ranch . PROCEDURE: Radiotransmitters were implanted intravaginally in each calf . Pneumonia was induced intrabronchially by use of logarithmic-phase cultures of M . haemolytica . At 21 hours after inoculation, calves were treated with saline (0.9% NaCl) solution, danofloxacin, or tilmicosin . Body temperature was monitored from 66 hours before inoculation until 72 hours after treatment . Area under the curve (AUC) of the temperature-time plot and mean temperature were calculated for 3-hour intervals and compared among treatment groups . RESULTS: The AUCs for 3-hour intervals did not differ significantly among treatment groups for any of the time periods . Analysis of the mean temperature for 3-hour intervals revealed significantly higher temperatures at most time periods for saline-treated calves, compared with temperatures for antimicrobial-treated calves; however, we did not detect significant differences between the danofloxacin- and tilmicosin-treated calves . The circadian rhythm of temperatures before exposure was detected again approximately 48 hours after bacterial inoculation . CONCLUSIONS AND CLINICAL RELEVANCE: Danofloxacin and tilmicosin did not differ in their effect on mean body temperature for 3-hour intervals but significantly decreased body temperature, compared with body temperature in saline-treated calves . Normal daily variation in body temperature must be considered in the face of respiratory tract disease during clinical evaluation of feedlot cattle.

Orthopade, 2004 Apr, 33(4), 397 - 404
{Special aspects of implant-associated infection in orthopedic surgery . From the pathophysiology to custom-tailored prevention strategies}; Schierholz JM et al.; One of the most important risk factors in orthopedic surgery is implant-associated infection . Adhesion and colonization mediated implant infections are extremely resistant to antibiotics and host defences and frequently persist until the biomaterial or foreign body is removed, which is standard therapy . Tissue damage caused by surgery and foreign body implantation increases the susceptibility to infections, activates host defences and stimulates the generation of inflammatory mediators including radicals that are further aggravated by bacterial activity and toxins . Nearly one third of implant-related infections can be prevented by strictly following established infection control guidelines . However, a significant number of implant-associated infections remains . The escape of bacteria from host defence and antibiotic therapy makes the development of infection-resistant materials as anti-microbial drug delivery systems feasible . This concept consists of the sustained delivery of antimicrobial drugs into the local microenvironment of implants avoiding systemic side effects exceeding usual systemic concentrations by magnitudes of order.

Intensive Care Med, 2004 Aug, 30(8), 1557 - 63 Epub 2004 May 13.
Variation of infected cell count in bronchoalveolar lavage and timing of ventilator-associated pneumonia; Dupont H et al.; OBJECTIVES: The aim of this study was to evaluate and compare the accuracy of the percentage of infected cells (%IC) in bronchoalveolar lavage (BAL) for ventilator-associated pneumonia (VAP) diagnosis according to its onset from the initiation of mechanical ventilation . PATIENTS: One hundred and eight patients admitted to a surgical ICU were retrospectively included (1999-2001) . A total of 171 cases of VAP were diagnosed on clinical, biological, chest X-ray and BAL results (threshold >/=10(4 )cfu/ml) . RESULTS: The %IC significantly decreased with the timing of VAP diagnosis: 12.2+/-12.1% for VAP occurring less than 7 days after the initiation of mechanical ventilation, 7.4+/-9.2% for VAP occurring between 7 and 15 days and 4.8+/-6.4% for VAP after 15 days ( p=0.0002), despite the same number of elements and proportion of polymorphonuclear neutrophils in BAL . In addition, a relationship between the %IC and the pathogen responsible for VAP was observed for P . aeruginosa {higher for VAP <7 days than for VAP 7-15 days ( p=0.01) and VAP >15 days ( p=0.006)} and S . aureus {lower for VAP >15 days than VAP 7-15 days ( p=0.04) and VAP <7 days ( p=0.04)} . Furthermore, the %IC in BAL was lower in patients undergoing antimicrobial therapy than in patients without antibiotics ( p=0.04) . Three factors were independently associated with the %IC: quantitative culture of BAL (beta=0.42, p<0.0001), ongoing antimicrobial therapy (beta= -0.21, p=0.003) and onset of VAP (beta= -0.17, p=0.01) . CONCLUSIONS: A relationship between the %IC in BAL, duration of ventilation, quantitative culture of BAL and ongoing antimicrobial therapy has been proved in this study . The %IC for VAP diagnosis may not be accurate in patients with ongoing antibiotics and late onset infections (>7 days).

Inform Prim Care, 2004, 12(1), 19 - 26
Changing public attitudes to antibiotic prescribing: can the internet help?
Madle G, Kostkova P, Mani-Saada J, Weinberg J, Williams P.
INTRODUCTION: Antimicrobial resistance is a global problem with serious implications for modern medicine . Education of the public is essential for reducing patient pressure on GPs and subsequent inappropriate prescribing . Evaluation of educational interventions is necessary to assess their impact on public knowledge and attitudes . The aim of this study was to evaluate the effect of a health information website, part of the National electronic Library of Infection, on user knowledge and attitudes . METHOD: Questionnaires testing user knowledge and attitudes before and after using the website . RESULTS: There were significant improvements in knowledge about the use of antibiotics and antibiotic resistance . Expectations that antibiotics should be prescribed were significantly reduced after using the website . Health professionals showed a significantly greater knowledge about antibiotics and were less likely to expect antibiotics to be prescribed for acute otitis media than non-health professionals before using the website . There was no significant difference between the knowledge of these groups after using the website, but non-health professionals continued to have higher expectations of antibiotics being prescribed than health professionals . CONCLUSIONS: Health information websites can play a significant role in influencing public knowledge and attitudes . Further research is needed to investigate how people learn from these interventions and to determine their long-term impact on public attitudes and subsequent behaviour.

Annu Rev Biophys Biomol Struct, 2004, 33, 95 - 118
Structure, molecular mechanisms, and evolutionary relationships in DNA topoisomerases; Corbett KD et al.; Topoisomerases are enzymes that use DNA strand scission, manipulation, and rejoining activities to directly modulate DNA topology . These actions provide a powerful means to effect changes in DNA supercoiling levels, and allow some topoisomerases to both unknot and decatenate chromosomes . Since their initial discovery over three decades ago, researchers have amassed a rich store of information on the cellular roles and regulation of topoisomerases, and have delineated general models for their chemical and physical mechanisms . Topoisomerases are now known to be necessary for the survival of cellular organisms and many viruses and are rich clinical targets for anticancer and antimicrobial treatments . In recent years, crystal structures have been obtained for each of the four types of topoisomerases in a number of distinct conformational and substrate-bound states . In addition, sophisticated biophysical methods have been utilized to study details of topoisomerase reaction dynamics and enzymology . A synthesis of these approaches has provided researchers with new physical insights into how topoisomerases employ chemistry and allostery to direct the large-scale molecular motions needed to pass DNA strands through each other.

Drugs, 2004, 64(10), 1091 - 124
QT prolongation with antimicrobial agents: understanding the significance; Owens RC Jr; Cardiac toxicity has been relatively uncommon within the antimicrobial class of drugs, but well described for antiarrhythmic agents and certain antihistamines . Macrolides, pentamidine and certain antimalarials were traditionally known to cause QT-interval prolongation, and now azole antifungals, fluoroquinolones and ketolides can be added to the list . Over time, advances in preclinical testing methods for QT-interval prolongation and a better understanding of its sequelae, most notably torsades de pointes (TdP), have occurred . This, combined with the fact that five drugs have been removed from the market over the last several years, in part because of QT-interval prolongation-related toxicity, has elevated the urgency surrounding early detection and characterisation methods for evaluating non-antiarrhythmic drug classes . With technological advances and accumulating literature regarding QT prolongation, it is currently difficult or overwhelming for the practising clinician to interpret these data for purposes of formulary review or for individual patient treatment decisions . Certain patients are susceptible to the effects of QT-prolonging drugs . For example, co-variates such as gender, age, electrolyte derangements, structural heart disease, end organ impairment and, perhaps most important, genetic predisposition, underlie most if not all cases of TdP . Between and within classes of drugs there are important differences that contribute to delayed repolarisation (e.g . intrinsic potency to inhibit certain cardiac ion currents or channels, and pharmacokinetics) . To this end, a risk stratification scheme may be useful to rank and compare the potential for cardiotoxicity of each drug . It appears that in most published cases of antimicrobial-associated TdP, multiple risk factors are present . Macrolides in general are associated with a greater potential than other antimicrobials for causing TdP from both a pharmacodynamic and pharmacokinetic perspective . The azole antifungal agents also can be viewed as drugs that must be weighed carefully before use since they also have both pharmacodynamic and pharmacokinetic characteristics that may trigger TdP . The fluoroquinolones appear less likely to be associated with TdP from a pharmacokinetic perspective since they do not rely on cytochrome P450 (CYP) metabolism nor do they inhibit CYP enzyme isoforms, with the exception of grepafloxacin and ciprofloxacin . Nonetheless, patient selection must be carefully made for all of these drugs . For clinicians, certain responsibilities are assumed when prescribing antimicrobial therapy: (i) appropriate use to minimise resistance; and (ii) appropriate patient and drug selection to minimise adverse event potential . Incorporating information learned regarding QT interval-related adverse effects into the drug selection process may serve to minimise collateral iatrogenic toxicity.

Int J Tuberc Lung Dis, 2004 Feb, 8(2), 253 - 9
A microplate indicator-based method for determining the susceptibility of multidrug-resistant Mycobacterium tuberculosis to antimicrobial agents; Morcillo N et al.; SETTING: Reference Laboratory, Buenos Aires Province Tuberculosis Control Program, Dr Cetrangolo Hospital, Argentina . OBJECTIVE: To obtain a rapid, inexpensive method of determining minimal inhibitory concentrations (MIC) of several drugs acting on multidrug-resistant Mycobacterium tuberculosis (MDR-TB), a colorimetric, microplate-based assay (M-MTT) was developed . DESIGN: One hundred and one clinical isolates were studied . Drugs were placed in a microtiter plate, and several two fold dilutions were made in situ . Kanamycin, capreomycin, ethionamide, para-aminosalicylic acid and clarithromycin were tested in a range concentration of 8.0-0.25 microg/ml, cycloserine 60.0-1.9 microg/ml, clofazimine 3.0-0.10 microg/ml, levofloxacin 4.0-0.13 microg/ml and rifabutin 1.0-0.13 microg/ml . General indicator 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) at 5.0 mg/ml was used for visualising cellular growth and viability . The proportion method with Middlebrook 7H11 was used as the gold standard . RESULTS: MICs by M-MTT were obtained at on average 8 days and correlated with those obtained using the proportion method . In our conditions, the total cost of MIC determination for nine drugs was 5.00 US dollars . CONCLUSION: M-MTT could be used as a simple, rapid, low-cost technology to test the susceptibility of MDR-TB strains to several second-line and alternative drugs, with the objective of orienting future treatment regimens.

Cell Tissue Res, 2004 Jun, 316(3), 391 - 401 Epub 2004 May 11.
Earthworm leukocyte populations specifically harbor lysosomal enzymes that may respond to bacterial challenge; Engelmann P et al.; Earthworm leukocytes (coelomocytes) are responsible for innate cellular immune functions such as phagocytosis and encapsulation against parasites and pathogens . Microbial killing results from the combined action of the phagocytic process with humoral immune factors such as agglutinins (e.g., lectins), lysosomal enzymes (e.g., acid phosphatase, lysozyme), and various cytotoxic and antimicrobial molecules . There is also evidence of weak adaptive immune responses against foreign transplants . This study focused on aspects of the innate immune response . First, anti-human acid phosphatase (anti-AcP) polyclonal antibody characterized different acid hydrolase patterns in coelomocytes . Second, flow cytometry identified a strongly immunoreactive coelomocyte population . Third, ultrastructural and cytochemical analyses revealed acid phosphatase in discrete granules (lysosomes) of effector hyaline and granular coelomocytes but not in mature chloragocytes . Coelomocytes were exposed to bacteria to assess how phagocytosis influences: (a) the production of acid phosphatase using Western blot, and (b) release of acid phosphatase using ELISA from cell-free coelomic fluid . Fourth, after phagocytosis, acid phosphatase levels differed between controls and experimentals . Fifth, we found a 39-kDa molecule that reacted intensely with anti-AcP . Our results suggest that effector earthworm coelomocytes may not eliminate pathogens only by phagocytosis but also by extracellular lysis.

Otolaryngol Head Neck Surg, 2004 May, 130(5 Suppl), S95 - 118
Clinical practice guideline: Otitis media with effusion; Rosenfeld RM et al.; The clinical practice guideline on otitis media with effusion (OME) provides evidence-based recommendations on diagnosing and managing OME in children . This is an update of the 1994 clinical practice guideline "Otitis Media With Effusion in Young Children," which was developed by the Agency for Healthcare Policy and Research (now the Agency for Healthcare Research and Quality) . In contrast to the earlier guideline, which was limited to children aged 1 to 3 years with no craniofacial or neurologic abnormalities or sensory deficits, the updated guideline applies to children aged 2 months through 12 years with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae . The American Academy of Pediatrics, American Academy of Family Physicians, and American Academy of Otolaryngology-Head and Neck Surgery selected a subcommittee composed of experts in the fields of primary care, otolaryngology, infectious diseases, epidemiology, hearing, speech and language, and advanced practice nursing to revise the OME guideline . The subcommittee made a strong recommendation that clinicians use pneumatic otoscopy as the primary diagnostic method and distinguish OME from acute otitis media (AOM) . The subcommittee made recommendations that clinicians should (1) document the laterality, duration of effusion, and presence and severity of associated symptoms at each assessment of the child with OME; (2) distinguish the child with OME who is at risk for speech, language, or learning problems from other children with OME and more promptly evaluate hearing, speech, language, and need for intervention in children at risk; and (3) manage the child with OME who is not at risk with watchful waiting for 3 months from the date of effusion onset (if known), or from the date of diagnosis (if onset is unknown) . The subcommittee also made recommendations that (4) hearing testing be conducted when OME persists for 3 months or longer, or at any time that language delay, learning problems, or a significant hearing loss is suspected in a child with OME; (5) children with persistent OME who are not at risk should be reexamined at 3- to 6-month intervals until the effusion is no longer present, significant hearing loss is identified, or structural abnormalities of the eardrum or middle ear are suspected; and (6) when a child becomes a surgical candidate, tympanostomy tube insertion is the preferred initial procedure . Adenoidectomy should not be performed unless a distinct indication exists (nasal obstruction, chronic adenoiditis); repeat surgery consists of adenoidectomy plus myringotomy, with or without tube insertion . Tonsillectomy alone or myringotomy alone should not be used to treat OME . The subcommittee made negative recommendations that (1) population-based screening programs for OME not be performed in healthy, asymptomatic children and (2) antihistamines and decongestants are ineffective for OME and should not be used for treatment; antimicrobials and corticosteroids do not have long-term efficacy and should not be used for routine management . The subcommittee gave as options that (1) tympanometry can be used to confirm the diagnosis of OME and (2) when children with OME are referred by the primary clinician for evaluation by an otolaryngologist, audiologist, or speech-language pathologist, the referring clinician should document the effusion duration and specific reason for referral (evaluation, surgery), and provide additional relevant information such as history of AOM and developmental status of the child . The subcommittee made no recommendations for (1) complementary and alternative medicine as a treatment for OME based on a lack of scientific evidence documenting efficacy and (2) allergy management as a treatment for OME based on insufficient evidence of therapeutic efficacy or a causal relationship between allergy and OME . Last, the panel compiled a list of research needs based on limitations of the evidence reviewed . The purpose of this guideline is to inform clinicians of evidence-based methods to identify methods to identify, monitor, and manage OME in children aged 2 months through 12 years . The guideline may not apply to children older than 12 years because OME is uncommon and the natural history is likely to differ from younger children who experience rapid developmental change . The target population includes children with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae . The guideline is intended for use by providers of health care to children, including primary care and specialist physicians, nurses and nurse practitioners, physician assistants, audiologists, speech-language pathologists, and child development specialists . The guideline is applicable to any setting in which children with OME would be identified, monitored, or managed . This guideline is not intended as a sole source of guidance in evaluating children with OME . Rather, it is designed to assist primary care and other clinicians by providing an evidence-based framework for decision-making strategies . It is not intended to replace clinical judgment or establish a protocol for all children with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

Clin Diagn Lab Immunol, 2004 May, 11(3), 599 - 607
Enhanced surfactant protein and defensin mRNA levels and reduced viral replication during parainfluenza virus type 3 pneumonia in neonatal lambs; Grubor B et al.; Defensins and surfactant protein A (SP-A) and SP-D are antimicrobial components of the pulmonary innate immune system . The purpose of this study was to determine the extent to which parainfluenza type 3 virus infection in neonatal lambs alters expression of sheep beta-defensin 1 (SBD-1), SP-A, and SP-D, all of which are constitutively transcribed by respiratory epithelia . Parainfluenza type 3 viral antigen was detected by immunohistochemistry (IHC) in the bronchioles of all infected lambs 3 days postinoculation and at diminished levels 6 days postinoculation, but it was absent 17 days postinoculation . At all times postinoculation, lung homogenates from parainfluenza type 3 virus-inoculated animals had increased SBD-1, SP-A, and SP-D mRNA levels as detected by fluorogenic real-time reverse transcriptase PCR . Protein levels of SP-A in lung homogenates detected by quantitative-competitive enzyme-linked immunosorbent assay and protein antigen of SP-A detected by IHC were not altered . These studies demonstrate that parainfluenza type 3 virus infection results in enhanced expression of constitutively transcribed innate immune factors expressed by respiratory epithelia and that this increased expression occurs concurrently with decreased viral replication.

BMC Ecol . 2004 May 11;4(1):7.
Resistance of rumen bacteria murein to bovine gastric lysozyme; Dominguez-Bello MG et al.; BACKGROUND: Lysozymes, enzymes mostly associated with defence against bacterial infections, are mureinolytic . Ruminants have evolved a gastric c type lysozyme as a digestive enzyme, and profit from digestion of foregut bacteria, after most dietary components, including protein, have been fermented in the rumen . In this work we characterized the biological activities of bovine gastric secretions against membranes, purified murein and bacteria . RESULTS: Bovine gastric extract (BGE) was active against both G+ and G- bacteria, but the effect against Gram- bacteria was not due to the lysozyme, since purified BGL had only activity against Gram+ bacteria . We were unable to find small pore forming peptides in the BGE, and found that the inhibition of Gram negative bacteria by BGE was due to an artefact caused by acetate . We report for first time the activity of bovine gastric lysozyme (BG lysozyme) against pure bacterial cultures, and the specific resistance of some rumen Gram positive strains to BGL . CONCLUSIONS: Some Gram+ rumen bacteria showed resistance to abomasum lysozyme . We discuss the implications of this finding in the light of possible practical applications of such a stable antimicrobial peptide.

J Am Acad Nurse Pract . 2004 Apr;16(4):146, 148, 150 passim.
Appropriate outpatient macrolide use in community-acquired pneumonia; Gotfried MH; PURPOSE: To review current guidelines concerning the outpatient management of community-acquired pneumonia (CAP), to discuss antibiotic resistance and its relation to outcomes, and to define the appropriate use of newer macrolides in CAP . DATA SOURCES: Comprehensive review of the scientific literature, comparison of published clinical practice guidelines, and expert opinion . CONCLUSIONS: Despite increasing knowledge regarding its etiology and pathogenesis, CAP remains the seventh leading cause of death in the United States . Although 80% of all patients with CAP are treated as outpatients, over 1 million hospital admissions due to CAP occur each year . From an employer perspective, total annual employer costs were fivefold greater for patients with pneumonia than for those who were not affected . Appropriate antimicrobial choices should lead to improved outcomes . Reports of increasing resistance of pathogens associated with CAP, increasing frequency of atypical pathogens, and the availability of an increasing number of antimicrobials have made treatment decisions more involved . IMPLICATIONS FOR PRACTICE: In an effort to improve outcomes, several guidelines have been published recommending appropriate antimicrobial agents to treat CAP in different patient populations . All guidelines base treatment recommendations on the hospitalization status of the patient, and all agree that coverage of atypical pathogens as part of an initial empirical regimen is important . Comorbidity and modifying factors that may increase the risk of infection with resistant organisms also are taken into account . Controversy exists regarding the use of newer macrolides versus newer fluoroquinolones as initial empirical therapy . The applicability of the reported increasing resistance of common pneumonia pathogens to outcomes in regimens containing newer macrolides is a subject of debate . Defining appropriate antimicrobial use in different patient groups should help achieve better outcomes and allay the development of resistance.

Fertil Steril, 2004 May, 81(5), 1357 - 65
Preclinical evaluation of magainin-A as a contraceptive antimicrobial agent; Clara A et al.; OBJECTIVE: To evaluate the safety and contraceptive efficacy of magainin-A in monkeys . DESIGN: Controlled laboratory study . SETTING: Department of Immunology, National Institute for Research in Reproductive Health, Parel, Mumbai, India . ANIMAL(S): Male and female bonnet monkeys (Macaca radiata) . INTERVENTION(S): Animals were treated intravaginally with 1 mg of magainin-A before attempted conception, as well as daily for 14 days to assess local and systemic toxicity . MAIN OUTCOME MEASURE(S): Suitability of magainin-A for the control of pregnancy and sexually transmitted infections . RESULT(S): Complete sperm immobilization was observed within 20 seconds after the exposure to magainin-A (800-1,000 microg) in vitro . Intravaginal administration of 1 mg of magainin-A blocked conception in monkeys . When magainin-A was administered intravaginally for 14 consecutive days, no treatment-related abnormalities were observed in menstrual cycle length, vaginal epithelial cell morphology, and hematologic/serum biochemical profiles . The peptide inhibited the growth of sexually transmitted infection-causing pathogens but not HIV-1 and HIV-2 . Conclusion(s): Magainin-A can be used as an effective and safe intravaginal contraceptive compound with additional protection against sexually transmitted infection-causing pathogens.

FEBS Lett, 2004 May 7, 565(1-3), 171 - 5
Ion channel-like activity of the antimicrobial peptide tritrpticin in planar lipid bilayers; Salay LC et al.; The cationic peptide tritrpticin (VRRFPWWWPFLRR, Trp3) has a broad action spectrum, acting against Gram-positive and Gram-negative bacteria, as well as some fungi, while also displaying hemolytic activity . We have studied the behavior of Trp3 in planar lipid bilayers (or black lipid membrane - BLM) and were able to demonstrate its ion channel-like activity . Channel-like activity was observed in negatively charged azolectin BLM as a sudden appearance of discrete current fluctuations upon application of a constant voltage across the membrane . Trp3 formed large conductance channels (500-2000 pS) both at positive and negative potentials . In azolectin bilayers, the predominant ion-channel activity was characterized by very regular and discrete current steps (corresponding to openings) of uniform amplitude, which exhibited relatively long residence times (of the order of seconds) . Occasionally, multiple conductance steps were observed, indicating the simultaneous presence of more than one open pore . In bilayers of zwitterionic diphytanoylphosphatidyl choline (DPhPC) Trp3 also showed ion-channel activity, but in a much less frequent and less prominent way . Studies of ion selectivity indicated that Trp3 forms a cation-selective channel . These results should contribute to the understanding of the molecular interactions and mechanism of action of Trp3 in lipid bilayers and biological membranes.

FEBS Lett, 2004 May 7, 565(1-3), 65 - 9
The insect antimicrobial peptide, L-pyrrhocoricin, binds to and stimulates the ATPase activity of both wild-type and lidless DnaK; Chesnokova LS et al.; Recent reports have indicated that insect antimicrobial peptides kill bacteria by inhibiting the molecular chaperone DnaK . It was proposed that the antimicrobial peptide, all-L-pyrrhocoricin (L-PYR), binds to two sites on DnaK, the conventional substrate-binding site and the multi-helical C-terminal lid, and that inhibition of DnaK comes about from the lid mode of binding . In this report, we show using two different assays that L-PYR binds to and stimulates the ATPase activity of both wild-type and a lidless variant of DnaK . Our study shows that L-PYR interacts with DnaK much like the all-L NR (NRLLLTG) peptide, which is known to bind in the conventional substrate-binding site of DnaK . L-PYR antimicrobial activity is thus a consequence of the competitive inhibition of bacterial DnaK.

Biochim Biophys Acta, 2004 May 6, 1698(2), 239 - 50
Structure-activity relationships for the beta-hairpin cationic antimicrobial peptide polyphemusin I; Powers JP et al.; The solution structure of polyphemusin I was determined using (1)H-NMR spectroscopy . Polyphemusin I was found to be an amphipathic, beta-hairpin connected by a type I' beta-turn . The 17 low-energy structures aligned very well over the beta-sheet region while both termini were poorly defined due in part to a hinge-like region centred in the molecule about arginine residues 6 and 16 . Conversely, a linear analogue, PM1-S, with all cysteines simultaneously replaced with serine was found to be dynamic in nature, and a lack of medium and long-range NOEs indicated that this molecule displayed no favoured conformation . Circular dichroism (CD) spectroscopy confirmed that in solution, 50% trifluoroethanol (TFE) and in the presence of liposomes, PM1-S remained unstructured . The antimicrobial activity of PM1-S was found to be 4- to 16-fold less than that of polyphemusin I and corresponded with a 4-fold reduction in bacterial membrane depolarization . Both peptides were able to associate with lipid bilayers in a similar fashion; however, PM1-S was completely unable to translocate model membranes while polyphemusin I retained this activity . It was concluded that the disulfide-constrained, beta-sheet structure of polyphemusin I is required for maximum antimicrobial activity . Disruption of this structure results in reduced antimicrobial activity and completely abolishes membrane translocation indicating that the linear PM1-S acts through a different antimicrobial mechanism.

Curr Med Chem, 2004 May, 11(10), 1345 - 59
Proanthocyanidins in health care: current and new trends; Cos P et al.; Polyphenolic compounds are widely distributed in higher plants and are an integral part of the human diet . Recent interest in these substances has been stimulated by their potential health benefits, which are believed to arise mainly from their antioxidant activity . In the past years, the antioxidant activity of flavonoids has been studied in detail . An important but often overlooked group of polyphenols is that of the proanthocyanidins . Therefore, the present review is focused mainly on the antioxidant activity of proanthocyanidins and its relevancy in vivo . The three most important mechanisms of their antioxidant action will be discussed, i.e . free radical scavenging activity, chelation of transition metals, and inhibition of enzymes . In addition, the protective role of proanthocyanidins against lipid peroxidation and peroxynitrite, as well as their antimicrobial properties will be discussed . To study the in vivo relevancy of the proanthocyanidin activities, the knowledge of their pharmacokinetic parameters is crucial . Although bioavailability and metabolism data on polyphenols in general and proanthocyanidins in particular are still largely unavailable, the first reports indicate that at least monomers and smaller oligomeric procyanidins are absorbed . There is also considerable scientific and public interest in the important role that antioxidants may play in health care, e.g . by acting as cancer chemopreventive and anti-inflammatory agents and by reducing risk of cardiovascular mortality . Each of these aspects will be discussed, with special attention to the role of proanthocyanidins on apoptosis, gene expression and transcription factors, such as NF-kappa B.

Anim Health Res Rev, 2003 Dec, 4(2), 73 - 93
Molecular genetic methods in the veterinary clinical bacteriology laboratory: current usage and future applications; Cai HY et al.; In the last 5 years, numerous molecular methods have been published for the detection and characterization of bacteria in the field of veterinary medicine . PCR has been the most commonly used technology . Although not currently used for clinical veterinary diagnosis, new technologies such as liquid-phase hybridization, real-time PCR, pathogen load determination and DNA/protein microarray have been described and have many possible applications in the clinical bacteriology laboratory because of their sensitivity and efficiency . This review describes the basic principles and application of recently published DNA-based molecular techniques for the purpose of veterinary clinical bacteriological diagnosis . It covers advances in probe hybridization technology, DNA/RNA amplification techniques and other molecular detection methods, including 16S rRNA analysis for bacterial characterization and DNA microarrays for bacterial detection . The review briefly summarizes the application of molecular methods for the diagnosis of specific important bacterial infections of animals, and for other animal pathogens that are slow or difficult to isolate in the clinical bacteriology laboratory . In addition, the molecular detection of antimicrobial resistance genes and of bovine mastitis pathogens is briefly described and current commercially available tests are listed.

Pharmacoepidemiol Drug Saf, 2004 May, 13(5), 323 - 31
Banning antimicrobial growth promoters in feedstuffs does not result in increased therapeutic use of antibiotics in medicated feed in pig farming; Arnold S et al.; OBJECTIVE: We analysed prescription patterns for medicated feedstuffs to find out whether the ban on nutritive antimicrobial growth promotion introduced in Switzerland in 1999 had caused an increase in the therapeutic use of antimicrobial agents given orally to piglets and fattening pigs . METHODS: From 1996 to 2001, a total of 6427 prescriptions were evaluated for medicated pig feed delivered to pig farms in the Swiss canton of St Gall . Prescribed daily doses (PDD) were derived for 14 active ingredients . The overall amount and the potency of antimicrobial agents were measured in relation to the size of the pig population (PDD/population) . RESULTS: The use of antimicrobial agents decreased between 1996 (1200 kg) and 1999 (708 kg) and increased thereafter from 779 kg in 2000 to 936 kg in 2001 . The PDD/population (6.1 in 1996 and 3.6 in 1999) remained low (3.3 in 2000 and 3.4 in 2001) . The difference between the two parameters can be explained by changes in prescribing patterns, namely a reduction in antimicrobial therapy of respiratory diseases in fattening pigs and a shift to antimicrobial treatment of gastrointestinal-tract infections in piglets using drugs with a high PDD .

Biol Pharm Bull, 2004 May, 27(5), 710 - 3
Evaluation of in vitro antimicrobial and in vivo cytotoxic properties of some novel titanium-based coordination complexes; Sheikh C et al.; The aim of the present study was to determine the antimicrobial and cytotoxic activities of eight novel titanium(III) based coordination complexes {Ti(Pht)(2)(DL-serine)(2), S(1)}, {Ti(Pht)(2)(glycine)(2), S(2))}, {Ti(Pht)(2)(cystine)(2), S(3)}, {Ti(Pht)(2)(DL-leucine)(2), S(4)}, {Ti(Suc)(2)(L-leucine)(2), S(5)}, {Ti(Suc)(2)(cystine)(2), S(6)}, {Ti(Suc)(2)(cystein)(2), S(7)} and {Ti(Suc)(2)(DL-serine)(2), S(8)} against several gram-positive and -negative bacteria, fungi and brine shrimp nauplii . The investigation showed that almost all of the complexes were moderately active against tested bacteria and fungi at high concentration (200 microg/disc) compared with the standard antibiotic, amoxicillin and the antifungal agent, nystatin . In vivo lethality bioassay experiment showed that only S(7) and S(8) among the complexes had better cytotoxic effect than standard gallic acid . The LC(50) values of these two complexes were found to be 1.00 and 1.21 microg/ml, respectively . Thus the results suggest that only two complexes (S(7), S(8)) among the titanium(III) based coordination complexes show the anticancer properties comparable to the standard cytotoxic agent, and further studies of these two complexes may be helpful for their clinical implication.

Microbiology, 2004 May, 150(Pt 5), 1539 - 46
Evolution of multi-resistance plasmids in Australian clinical isolates of Escherichia coli; Sherley M et al.; Plasmids allow the movement of genetic material, including antimicrobial resistance genes, between bacterial species and genera . They frequently mediate resistance to multiple antimicrobials and can result in the acquisition by a pathogen of resistance to all or most clinically relevant antimicrobials . Unfortunately, there are still large gaps in our understanding of how new multi-resistance plasmids evolve . Five Australian clinical institutions collaborated in this study of multi-resistance plasmids in clinical isolates of Escherichia coli . We characterized 72 resistance plasmids in terms of the antimicrobial resistance profile they conferred, their size and their incompatibility group . Restriction fragment length polymorphisms were used to determine the genetic relationships between the plasmids . Relationships between the host cells were determined using multi-locus enzyme electrophoresis . A lack of correlation between the evolutionary history of the host cells and their plasmids suggests that the horizontal transfer of resistance plasmids between strains of E . coli is common . The resistance plasmids were very diverse, with a wide range of resistance profiles and a lack of discrete evolutionary lineages . Multi-resistance plasmids did not evolve via the co-integrative capture of smaller resistance plasmids; rather, the roles of recombination and the horizontal movement of mobile genetic elements appeared to be most important.

Pediatr Infect Dis J, 2004 May, 23(5), 399 - 405
Azithromycin compared with beta-lactam antibiotic treatment failures in pneumococcal infections of children; Gonzalez BE et al.; OBJECTIVE: To determine whether treatment failures occurred more commonly with azithromycin than with beta-lactam antibiotics in children who developed invasive pneumococcal disease within 30 days of receiving prior antimicrobial therapy . METHODS: Retrospective review of medical records of children evaluated at Texas Children's Hospital between 1996 and 2002 who had received antimicrobials (azithromycin or a beta-lactam antibiotic) and developed invasive pneumococcal disease within 30 days . Treatment failure was defined as invasive pneumococcal infection that occurred while taking antimicrobials or within 3 days of stopping azithromycin treatment or 1 day of stopping beta-lactam treatment . Penicillin and azithromycin susceptibilities were determined and categorized according to National Committee for Clinical Laboratory Standards guidelines . RESULTS: We identified 21 and 33 children with similar demographic features who had developed invasive pneumococcal disease within 1 month of receiving azithromycin or a beta-lactam antibiotic, respectively . Eleven (52%) children in the azithromycin group and 11 (33%) in the beta-lactam group met the definition for treatment failures (P = 0.34) . Eight treatment failures while receiving azithromycin were caused by pneumococci with the macrolide-resistant (M) phenotype, 2 with the macrolide-, lincosamide- and streptogramin B-resistant (MLSB) phenotype and 1 by a macrolide-susceptible organism . In the beta-lactam group 7 had a penicillin-resistant isolate, 3 had an intermediately susceptible isolate and 1 had a susceptible isolate . CONCLUSIONS: Our study suggests that treatment failures among patients who developed invasive disease within 30 days of receiving an antimicrobial occur as frequently in patients who receive beta-lactam antibiotics as in those who receive azithromycin . Furthermore macrolide resistant organisms are not more likely to be recovered after a macrolide treatment failure than a penicillin-nonsusceptible isolate being recovered after a beta-lactam treatment failure (P = 1.0).

J Clin Microbiol, 2004 May, 42(5), 2258 - 60
Accuracy and appropriateness of antimicrobial susceptibility test reporting for bacteria isolated from blood cultures; Diekema DJ et al.; Accurate antimicrobial susceptibility testing (AST) and appropriate reporting of AST results for pathogens isolated from blood cultures are critical functions of the microbiology laboratory . We studied AST performance and reporting from positive blood cultures at hospital microbiology laboratories in Iowa . One hundred sixteen episodes of bacteremia from 14 participating hospitals were examined . We detected AST or identification errors for 18 episodes (16%) and judged reporting of AST results to be inappropriate for 38 episodes (33%) . Further study is necessary to determine the impact of testing errors and suboptimal reporting of results on the management of bloodstream infection.

Am J Gastroenterol, 2004 May, 99(5), 894 - 904
Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease; Forsberg G et al.; OBJECTIVES: Exposure to gliadin and related prolamins and appropriate HLA-DQ haplotype are necessary but not sufficient for contracting celiac disease (CD) . Aberrant innate immune reactions could be contributing risk factors . Therefore, jejunal biopsies were screened for bacteria and the innate immune status of the epithelium investigated . METHODS: Children with untreated, treated, challenged CD, and controls were analyzed . Bacteria were identified by scanning electron microscopy . Glycocalyx composition and mucin and antimicrobial peptide production were studied by quantitative RT-PCR, antibody and lectin immunohistochemistry . RESULTS: Rod-shaped bacteria were frequently associated with the mucosa of CD patients, with both active and inactive disease, but not with controls . The lectin Ulex europaeus agglutinin I (UEAI) stained goblet cells in the mucosa of all CD patients but not of controls . The lectin peanut agglutinin (PNA) stained glycocalyx of controls but not of CD patients . mRNA levels of mucin-2 (MUC2), alpha-defensins HD-5 and HD-6, and lysozyme were significantly increased in active CD and returned to normal in treated CD . Their expression levels correlated to the interferon-gamma mRNA levels in intraepithelial lymphocytes . MUC2, HD-5, and lysozyme proteins were seen in absorptive epithelial cells . beta-defensins hBD-1 and hBD-2, carcinoembryonic antigen (CEA), CEA cell adhesion molecule-1a (CEACAM1a), and MUC3 were not affected . CONCLUSIONS: Unique carbohydrate structures of the glycocalyx/mucous layer are likely discriminating features of CD patients . These glycosylation differences could facilitate bacterial adhesion . Ectopic production of MUC2, HD-5, and lysozyme in active CD is compatible with goblet and Paneth cell metaplasia induced by high interferon-gamma production by intraepithelial lymphocytes.

J Endocrinol, 2004 May, 181(2), 347 - 54
Brevinin-1 and multiple insulin-releasing peptides in the skin of the frog Rana palustris; Marenah L et al.; Few studies have comprehensively examined amphibian granular gland secretions for novel insulinotropic peptides . This study involved isolation and characterisation of biologically active peptides from the skin secretions of Rana palustris frogs . Crude secretions obtained by mild electrical stimulation from the dorsal skin surface were purified by reversed-phase HPLC on a semipreparative Vydac C18 column, yielding 80 fractions . These fractions were assayed for insulin-releasing activity using glucose-responsive BRIN-BD11 cells . Acute 20 min incubations were performed in Krebs Ringer bicarbonate buffer supplemented with 5.6 mmol/l glucose in the absence (control) and presence of various fractions . Fractions 29-54 and fractions 68-75 showed significant 2.0-6.5-fold increases in insulin-releasing activity (P<0.001) . The fractions showing most prominent insulinotropic activity were further purified to single homogeneous peaks, which, on testing, evoked 1.5-2.8-fold increases in insulin release (P<0.001) . The structures of the purified peptides were determined by mass spectrometry and N-terminal amino acid sequencing . Electrospray ionisation ion-trap mass spectrometry analysis revealed molecular masses of 2873.5-8560.4 Da . Sufficient material was isolated to determine the primary amino acid sequence of the 2873.5 Da peptide, revealing a 27 amino acid sequence, ALSILRGLEKLAKMGIALTNCKATKKC, repressing palustrin-1c . The database search for this peptide showed a 48% homology with brevinin-1, an antimicrobial peptide isolated from various Rana species, which itself stimulated insulin release from BRIN-BD11 cells in a concentration-dependent manner . In conclusion, the skin secretions of R . palustris frogs contain a novel class of peptides with insulin-releasing activity that merit further investigation.

Am J Health Syst Pharm, 2004 Apr 15, 61(8), 787 - 92
Pharmacist involvement in antimicrobial use at rural community hospitals in four Western states; Stevenson KB et al.; PURPOSE: Pharmacist involvement in antimicrobial use at small rural hospitals in four Western states was studied . METHODS: Surveys were mailed in July 2000 to hospitals with a daily patient census of <150 in Idaho, Nevada, Utah, and eastern Washington . RESULTS: Seventy-seven (77%) of 100 hospitals returned completed surveys . Only 5% of the hospitals had onsite pharmacists 24 hours per day . An onsite pharmacist was present for a median of 26 hours per week in hospitals without 24-hour pharmacist coverage (range, 0-116 hr/wk) . Many hospitals (71%) had policies for monitoring or controlling antimicrobial use, but only 28% had a system capable of monitoring compliance with such policies . Few hospitals had systems for recommending changes in antimicrobial selection on the basis of susceptibility test results (27%) or for monitoring physician compliance with dosage recommendations by pharmacists (21%) . Onsite pharmacist hours were significantly associated with pharmacists being involved in the initial ordering of antibiotics and providing active oversight of antimicrobial use . There was a negative correlation between onsite pharmacist hours and use of third-generation cephalosporins and carbapenems . CONCLUSION: A survey showed that rural hospital pharmacists in four Western states spent relatively little time monitoring and influencing antimicrobial prescribing.

Tunis Med, 2004 Jan, 82 Suppl 1, 136 - 45
{Aortic infectious endocarditis on native valve}; Fekih M et al.; Between 1990 and 2002, 32 patients with mean age of 34 years has been treated for an aortic infective endocarditis on native valve . All the patients had recognised heart disease before developing the infection . 24 patients are operated for aortic valve replacement . The hospital mortality was 15.6% (5 patients) . The mean follow-up was 47.4 months . The survival rate was 75% . Aortic infective endocarditis remains a serious affection with poor prognosis, despite the contribution of echocardiography and advances in antimicrobial therapy and cardiac surgery . Significants morbidity and mortality are usually caused by sequele of the disease rather than by the infection itself.

Clin Infect Dis, 2004 May 1, 38(9), 1298 - 303 Epub 2004 Apr 15.
Shiga toxin-producing Escherichia coli infection; Thorpe CM; Large-scale outbreaks of Shiga toxin-producing Escherichia coli (STEC) infection have revealed the great disease-causing potential of this organism, especially among children and elderly persons . Approximately 5%-10% of people with STEC infection will develop hemolytic-uremic syndrome (HUS), approximately 10% of those who develop HUS will die or have permanent renal failure, and up to 50% of those who develop HUS will develop some degree of renal impairment . Important concepts in understanding the pathogenesis and prevention of STEC-associated HUS are emerging, although no specific therapy yet exists . Optimal management of STEC infection includes intravenous hydration, avoidance of antimotility agents and antimicrobials, and monitoring for sequelae . Antimicrobials may have a potentially harmful role, possibly by inducing intestinal production of Shiga toxin during the diarrheal phase of illness . A recent clinical trial evaluating an intraluminal Shiga toxin-binding agent to ameliorate HUS showed no improvement in outcome . Interventions to prevent HUS from developing in STEC-infected children are under investigation . Prevention of exposure to STEC remains important, and animal vaccines to prevent stool shedding of STEC among food animals are in development.

Clin Infect Dis, 2004 May 1, 38(9), 1287 - 92 Epub 2004 Apr 15.
Are antimicrobial-impregnated catheters effective? Don't throw out the baby with the bathwater; Crnich CJ et al.; The antimicrobial-impregnated central venous catheter (CVC) has been the most intensively studied technology for the prevention of CVC-related bloodstream infections (BSIs) over the past 30 years . Although more than a dozen randomized trials have shown significant benefit, authors of an analysis published in a recent issue of Clinical Infectious Diseases have raised questions about the efficacy of antimicrobial-impregnated CVCs because of perceived defects in the experimental design of the studies and statistical analyses of the data . They have further argued that even if this technology might be effective in preventing CVC-related BSI, its cost-effectiveness is questionable . Although most of the studies scrutinized by the authors of this analysis indeed had shortcomings, we believe that their analysis unjustifiably downplays a large body of research that has demonstrated a consistent reduction in CVC-related BSI and a clear-cut cost-effectiveness associated with the use of antimicrobial-impregnated CVCs.

Clin Infect Dis, 2004 May 1, 38(9), 1279 - 86 Epub 2004 Apr 14.
Trends in antimicrobial drug development: implications for the future; Spellberg B et al.; The need for new antimicrobial agents is greater than ever because of the emergence of multidrug resistance in common pathogens, the rapid emergence of new infections, and the potential for use of multidrug-resistant agents in bioweapons . Paradoxically, some pharmaceutical companies have indicated that they are curtailing anti-infective research programs . We evaluated the United States Food and Drug Administration (FDA) databases of approved drugs and the research and development programs of the world's largest pharmaceutical and biotechnology companies to document trends in the development of new antimicrobial agents . FDA approval of new antibacterial agents decreased by 56% over the past 20 years (1998-2002 vs . 1983-1987) . Projecting future development, new antibacterial agents constitute 6 of 506 drugs disclosed in the developmental programs of the largest pharmaceutical and biotechnology companies . Despite the critical need for new antimicrobial agents, the development of these agents is declining . Solutions encouraging and facilitating the development of new antimicrobial agents are needed.

Intensive Care Med, 2004 May, 30(5), 844 - 52 Epub 2004 Feb 04.
Value of the clinical pulmonary infection score for the identification and management of ventilator-associated pneumonia; Luyt CE et al.; OBJECTIVE: To evaluate the potential ability of an algorithm based on the clinical pulmonary infection score (CPIS) to identify and treat patients with bacterial ventilator-associated pneumonia (VAP) compared to a strategy based on quantitative cultures of bronchoscopic specimens . DESIGN: Retrospective cohort study . SETTING: Thirty-one critical care units across France . PATIENTS: Two hundred and one patients clinically suspected of having VAP who had been included in the "invasive strategy" group of the French multicenter randomized trial and for whose quantitative cultures bronchoscopic specimens were obtained . CPIS was determined retrospectively, based on data that had been collected for the initial study . INTERVENTIONS: None . MEASUREMENTS AND RESULTS: The clinical pulmonary infection score was determined on days 1 and 3, and compared in patients identified as having developed VAP or not, as defined by bronchoscopic specimen culture results . On day 3 138 of the 201 patients (69%) had a CPIS of more than 6 that would have required prolonged antimicrobial therapy based on the algorithm . In contrast, based on bronchoscopy, only 88 (44%) patients were considered to have VAP (kappa coefficient for concordance between the two strategies, 0.33) . While the sensitivity of CPIS more than 6 on day 3 for identifying VAP was 89%, its specificity was only 47%, leading to potentially unnecessary treatment of 60 (53%) of the 113 patients without VAP as diagnosed by bronchoscopy . CONCLUSION: A strategy based on the CPIS to decide which patients with suspected VAP should receive prolonged administration of antibiotics would appear to over-prescribe these agents, as compared to a strategy based on bronchoscopy.

P R Health Sci J, 2004 Mar, 23(1), 25 - 33
Antibiotics in older adults; Rodriguez-Julbe MC et al.; Antibiotics are frequently prescribed in the older person, the dosification needs special care, since the pharmacokinetic parameters changes with aging and the side effects can be different in the older person . The creatinine clearance changes and we must modify the way we prescribe such antibiotics to the elderly, calculating . The variety of antibiotics now available led us to consider this paper in which we have presented the antimicrobial agents that can be considered in the treatment of the older person . We present several groups: the penicillins, cephalosporins, monobactams, carbapenems and betalactamase inhibitors or the great betalactam group . Other trimetroprin-sulfame-thoxazole, the newer macrolides (azithromycin and clarithromycin) as well as the aminoglycosides, vancomycin, clindamycin, metroridazole . The indications and contraindications are presented and reviewed.

J Int Acad Periodontol, 2004 Apr, 6(2), 63 - 7
The effects of manuka honey on plaque and gingivitis: a pilot study; English HK et al.; Research has shown that manuka honey has superior antimicrobial properties that can be used with success in the treatment of wound healing, peptic ulcers and bacterial gastro-enteritis . Studies have already shown that manuka honey with a high antibacterial activity is likely to be non-cariogenic . The current pilot study investigated whether or not manuka honey with an antibacterial activity rated UMF 15 could be used to reduce dental plaque and clinical levels of gingivitis . A chewable "honey leather" was produced for this trial . Thirty volunteers were randomly allocated to chew or suck either the manuka honey product, or sugarless chewing gum, for 10 minutes, three times a day, after each meal . Plaque and gingival bleeding scores were recorded before and after the 21-day trial period . Analysis of the results indicated that there were statistically highly significant reductions in the mean plaque scores (0.99 reduced to 0.65; p=0.001), and the percentage of bleeding sites (48% reduced to 17%; p=0.001), in the manuka honey group, with no significant changes in the control group . Conclusion: These results suggest that there may be a potential therapeutic role for manuka honey confectionery in the treatment of gingivitis and periodontal disease.

J Am Vet Med Assoc, 2004 May 1, 224(9), 1467 - 70, 1453-4
Ultrasonographic diagnosis of septic arthritis secondary to porcupine quill migration in a dog; Brisson BA et al.; A 7-year-old castrated male German Shepherd Dog was evaluated for lethargy, icterus, and sepsis . Porcupine quills had been removed from the dog's face 1 month prior to examination; progressive right forelimb lameness had developed soon after removal of the quills . Septic arthritis of the right elbow joint was diagnosed and was unresponsive to antimicrobial and anti-inflammatory treatments . At the time of referral, the dog had developed endocarditis, septicemia, and disseminated intravascular coagulation . Via ultrasonography, a foreign body consistent with a porcupine quill was detected in the medial portion of the right humeroradial joint . The dog did not respond to initial supportive treatment and died as a result of cardiac arrest . Postmortem examination confirmed the presence of a quill in the medial compartment of the right elbow joint and severe acute endocarditis with septic emboli to the kidneys and spleen . Ultrasonographic examination should be considered as a diagnostic tool when septic arthritis secondary to a foreign body is suspected in dogs.

J Biol Chem, 2004 Jul 16, 279(29), 30433 - 9 Epub 2004 Apr 30.
Solution structure of spheniscin, a beta-defensin from the penguin stomach; Landon C et al.; Recently two beta-defensins, named spheniscins, have been isolated from the stomach content of the king penguin (Aptenodytes patagonicus), which is capable of preserving food for several weeks during egg incubation (Thouzeau, C., Le Maho, Y., Froget, G., Sabatier, L., Le Bohec, C., Hoffmann, J . A., and Bulet, P . (2003) J . Biol . Chem . 278, 51053-51058) . It has been proposed that, in combination with other antimicrobial peptides, spheniscins may be involved in this long term preservation of food in the bird's stomach . To draw some structure/function features, the three-dimensional structure in aqueous solution of the most abundant spheniscin (Sphe-2) was determined by two-dimensional NMR and molecular modeling techniques . The overall fold of Sphe-2 includes a three-stranded antiparallel beta-sheet stabilized by three disulfide bridges with a pairing typical of beta-defensins . In addition, the N-terminal segment shows helical features on most structures . Sphe-2 is highly cationic, and its surface displays a hydrophobic patch . Comparative modeling revealed that this patch is preserved in avian defensins . The activity of Sphe-2 against a pathogenic Gram-positive strain was retained in vitro in the conditions of osmolarity found in penguin stomach content and also in different salt concentrations and compositions up to those reported for seawater . Comparison with structurally related mammalian beta-defensins showed that the hydrophobic patch is not preserved in mammalian beta-defensins and that the high cationicity of Sphe-2 is presumably the critical factor for its retained activity in high salt concentrations . Such peculiarities, in addition to a broad activity spectrum, suggest that penguin defensins may represent interesting probes for the design of highly efficient antibiotics to fight off pathogens that develop in relatively salt-rich body fluids.

Fish Shellfish Immunol, 2004 Apr, 16(4), 513 - 25
Molecular cloning and expression analysis of Ch-penaeidin, an antimicrobial peptide from Chinese shrimp, Fenneropenaeus chinensis; Kang CJ et al.; A new member of antimicrobial peptide genes of the penaeidin family, Ch-penaeidin, has been cloned from the haemocytes of Chinese shrimp, Fenneropenaeus chinensis, by reverse transcription PCR (RT-PCR), 3'-rapid amplification of cDNA end (3'-RACE) and smart cDNA methods . The Ch-penaeidin cDNA was 655 bp and the open reading frame of the cDNA encoded a 71 amino acid peptide . Ch-penaeidin contained a putative NH2-terminal signal sequence (1-19) followed by a mature peptide (20-71) . The sequence identity with other penaeidins from Litopenaeus vannamei and Litopenaeus setiferus is between 48% and 71% . The signal sequence of Ch-penaeidin is almost completely identical to that of other penaeidins, while differing relatively in the N-terminal domain of the mature peptide . Ch-penaeidin was designated as a novel member of class penaeidin 3 according to phylogenetic analysis . The mature peptide, with a predicted molecular weight of 5589.32 Da, and a pI of 9.77, has eight positively charged amino acids and no negatively charged amino acids . The expression and distribution of Ch-penaeidin in unchallenged shrimps were studied by RT-PCR, Northern blot and in situ hybridisation . The results showed that the Ch-penaeidin transcripts were detected in haemocytes (granular haemocytes), heart, gill, intestine, and subcuticular epithelia of the shrimp, and that Ch-penaeidin was constitutively expressed mainly in haemocytes.

J Biochem Mol Toxicol, 2004, 18(2), 107 - 14
Effect of alpha-tocopherol and N-acetylcysteine on benzoyl peroxide toxicity in human keratinocytes; Bellei E et al.; Benzoyl peroxide is a free-radical generating compound widely used in the polymer industry and also in pharmaceuticals as antimicrobial agent to treat acne . However, benzoyl peroxide causes irritation and contact dermatitis in about 1% of patients . Concern over the use of this compound is motivated by the demonstration that it can also act as skin tumor promoter in mice . In addition, benzoyl peroxide induces DNA strand breaks in many cells, including keratinocytes . Benzoyl peroxide toxicity is presumably mediated by the formation of reactive free radicals and by the consumption of intracellular antioxidants.In this work we investigated the effect of both the lipophilic antioxidant alpha-tocopherol and the hydrophilic thiol donor N-acetylcysteine (NAC) in human keratinocyte line HaCaT exposed to benzoyl peroxide . A protective effect against benzoyl peroxide cytotoxicity was achieved when cells were grown on a alpha-tocopherol layer . On the contrary, the addition of alpha-tocopherol dissolved in ethanol had a pro-oxidant effect, leading to an enhancement of benzoyl peroxide toxicity . Cytotoxicity was also reduced adding NAC to the culture medium; the presence of both NAC and alpha-tocopherol exerts a synergistic cytoprotection .

Photochem Photobiol Sci, 2004 May, 3(5), 436 - 50 Epub 2004 Feb 12.
Photodynamic therapy: a new antimicrobial approach to infectious disease?
Hamblin MR, Hasan T.
Photodynamic therapy (PDT) employs a non-toxic dye, termed a photosensitizer (PS), and low intensity visible light which, in the presence of oxygen, combine to produce cytotoxic species . PDT has the advantage of dual selectivity, in that the PS can be targeted to its destination cell or tissue and, in addition, the illumination can be spatially directed to the lesion . PDT has previously been used to kill pathogenic microorganisms in vitro, but its use to treat infections in animal models or patients has not, as yet, been much developed . It is known that Gram-(-) bacteria are resistant to PDT with many commonly used PS that will readily lead to phototoxicity in Gram-(+) species, and that PS bearing a cationic charge or the use of agents that increase the permeability of the outer membrane will increase the efficacy of killing Gram-(-) organisms . All the available evidence suggests that multi-antibiotic resistant strains are as easily killed by PDT as naive strains, and that bacteria will not readily develop resistance to PDT . Treatment of localized infections with PDT requires selectivity of the PS for microbes over host cells, delivery of the PS into the infected area and the ability to effectively illuminate the lesion . Recently, there have been reports of PDT used to treat infections in selected animal models and some clinical trials: mainly for viral lesions, but also for acne, gastric infection by Helicobacter pylori and brain abcesses . Possible future clinical applications include infections in wounds and burns, rapidly spreading and intractable soft-tissue infections and abscesses, infections in body cavities such as the mouth, ear, nasal sinus, bladder and stomach, and surface infections of the cornea and skin.

Photochem Photobiol Sci, 2004 May, 3(5), 412 - 8 Epub 2004 Feb 05.
Lethal photosensitisation of oral bacteria and its potential application in the photodynamic therapy of oral infections; Wilson M; Chemical antibacterial agents are increasingly being used in prophylactic and therapeutic regimes for dental plaque-related diseases, which are among the most common human infections . As these agents are difficult to maintain at a therapeutic concentration in the oral cavity and can be rendered ineffective by resistance development in the target organisms, there is a need to develop alternative antimicrobial approaches . Bacteria and other microbes can be sensitised to light through prior treatment with a chemical photosensitising agent . Lethal photosensitisation of a wide range of bacteria responsible for caries, periodontal diseases and root canal infections has been demonstrated using red light in conjunction with a number of photosensitisers, including Toluidine Blue, phthalocyanines and chlorins . The advantages of this approach are that bacteria can be eradicated in very short periods of time (seconds or minutes), resistance development in the target bacteria is unlikely and damage to adjacent host tissues and disruption of the normal microflora can be avoided . This approach may be a useful alternative to antibiotics and antiseptics in eliminating cariogenic and periodontopathogenic bacteria from disease lesions and for the disinfection of root canals . Not only would this be of benefit for the treatment of these diseases but, by replacing the antimicrobial agents that are currently used for such purposes, it would help to conserve our dwindling supply of antimicrobial agents that are effective in the treatment of serious systemic infections.

Nat Cell Biol, 2004 May, 6(5), 458 - 64
An epididymis-specific beta-defensin is important for the initiation of sperm maturation; Zhou CX et al.; Although the role of the epididymis, a male accessory sex organ, in sperm maturation has been established for nearly four decades, the maturation process itself has not been linked to a specific molecule of epididymal origin . Here we show that Bin1b, a rat epididymis-specific beta-defensin with antimicrobial activity, can bind to the sperm head in different regions of the epididymis with varied binding patterns . In addition, Bin1b-expressing cells, either of epididymal origin or from a Bin1b-transfected cell line, can induce progressive sperm motility in immotile immature sperm . This induction of motility is mediated by the Bin1b-induced uptake of Ca(2+), a mechanism that has a less prominent role in maintaining motility in mature sperm . In vivo antisense experiments show that suppressed expression of Bin1b results in reduced binding of Bin1b to caput sperm and in considerable attenuation of sperm motility and progressive movement . Thus, beta-defensin is important for the acquisition of sperm motility and the initiation of sperm maturation.

Pediatrics, 2004 May, 113(5), 1412 - 29
Otitis media with effusion; American Academy of Family Physicians; American Academy of Otolaryngology-Head and Neck Surgery; American Academy of Pediatrics Subcommittee on Otitis Media With Effusion; The clinical practice guideline on otitis media with effusion (OME) provides evidence-based recommendations on diagnosing and managing OME in children . This is an update of the 1994 clinical practice guideline "Otitis Media With Effusion in Young Children," which was developed by the Agency for Healthcare Policy and Research (now the Agency for Healthcare Research and Quality) . In contrast to the earlier guideline, which was limited to children 1 to 3 years old with no craniofacial or neurologic abnormalities or sensory deficits, the updated guideline applies to children aged 2 months through 12 years with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae . The American Academy of Pediatrics, American Academy of Family Physicians, and American Academy of Otolaryngology-Head and Neck Surgery selected a subcommittee composed of experts in the fields of primary care, otolaryngology, infectious diseases, epidemiology, hearing, speech and language, and advanced-practice nursing to revise the OME guideline . The subcommittee made a strong recommendation that clinicians use pneumatic otoscopy as the primary diagnostic method and distinguish OME from acute otitis media . The subcommittee made recommendations that clinicians should 1) document the laterality, duration of effusion, and presence and severity of associated symptoms at each assessment of the child with OME, 2) distinguish the child with OME who is at risk for speech, language, or learning problems from other children with OME and more promptly evaluate hearing, speech, language, and need for intervention in children at risk, and 3) manage the child with OME who is not at risk with watchful waiting for 3 months from the date of effusion onset (if known) or diagnosis (if onset is unknown) . The subcommittee also made recommendations that 4) hearing testing be conducted when OME persists for 3 months or longer or at any time that language delay, learning problems, or a significant hearing loss is suspected in a child with OME, 5) children with persistent OME who are not at risk should be reexamined at 3- to 6-month intervals until the effusion is no longer present, significant hearing loss is identified, or structural abnormalities of the eardrum or middle ear are suspected, and 6) when a child becomes a surgical candidate (tympanostomy tube insertion is the preferred initial procedure) . Adenoidectomy should not be performed unless a distinct indication exists (nasal obstruction, chronic adenoiditis); repeat surgery consists of adenoidectomy plus myringotomy with or without tube insertion . Tonsillectomy alone or myringotomy alone should not be used to treat OME . The subcommittee made negative recommendations that 1) population-based screening programs for OME not be performed in healthy, asymptomatic children, and 2) because antihistamines and decongestants are ineffective for OME, they should not be used for treatment; antimicrobials and corticosteroids do not have long-term efficacy and should not be used for routine management . The subcommittee gave as options that 1) tympanometry can be used to confirm the diagnosis of OME and 2) when children with OME are referred by the primary clinician for evaluation by an otolaryngologist, audiologist, or speech-language pathologist, the referring clinician should document the effusion duration and specific reason for referral (evaluation, surgery) and provide additional relevant information such as history of acute otitis media and developmental status of the child . The subcommittee made no recommendations for 1) complementary and alternative medicine as a treatment for OME, based on a lack of scientific evidence documenting efficacy, or 2) allergy management as a treatment for OME, based on insufficient evidence of therapeutic efficacy or a causal relationship between allergy and OME . Last, the panel compiled a list of research needs based on limitations of the evidence reviewed . The purpose of this guideline is to inform clinicians of evidence-based methods to identify, monitor, and manage OME in children aged 2 months through 12 years . The guideline may not apply to children more than 12 years old, because OME is uncommon and the natural history is likely to differ from younger children who experience rapid developmental change . The target population includes children with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae . The guideline is intended for use by providers of health care to children, including primary care and specialist physicians, nurses and nurse practitioners, physician assistants, audiologists, speech-language pathologists, and child-development specialists . The guideline is applicable to any setting in which children with OME would be identified, monitored, or managed . This guideline is not intended as a sole source of guidance in evaluating children with OME . Rather, it is designed to assist primary care and other clinicians by providing an evidence-based framework for decision-making strategies . It is not intended to replace clinical judgment or establish a protocol for all children with this condition and may not provide the only appropriate approach to diagnosing and managing this problem.

Int J Antimicrob Agents, 2004 May, 23(5), 494 - 7
Impact of tazobactam pharmacokinetics on the antimicrobial effect of piperacillin-tazobactam combinations; Liu Q et al.; Pharmacokinetic-pharmacodynamic (PK-PD) modelling was used to study the impact of the pharmacokinetics of tazobactam on the antimicrobial effect of piperacillin-tazobactam combinations . An in vitro experiment using a novel dilution system was performed to compare the effects of two conditions of the combination therapy against Escherichia coli ATCC35218, a beta-lactamase producing bacterium . Both conditions simulated the same initial concentrations of piperacillin and tazobactam, but different elimination half-lives for tazobactam . The killing and regrowth kinetics of E . coli clearly indicated that there is a difference in the antimicrobial effects when there is a difference in the pharmacokinetics of tazobactam in the combination therapy . The results show that for equal piperacillin exposure, different tazobactam half-lives will have a significant effect on antimicrobial outcome.

Int J Antimicrob Agents, 2004 May, 23(5), 438 - 45
Changes before and after a policy to restrict antimicrobial usage in upper respiratory infections in Taiwan; Ho M et al.; The Bureau of National Health Insurance (BNHI) of Taiwan issued a new reimbursement regulation effective from 1 February 2001 forbidding the use of antimicrobials in ambulatory patients with upper respiratory infections (URI) without evidence of bacterial infection . We evaluated the effect of this regulation by analysing changes in the types of infections diagnosed and the amount of antibiotics prescribed in 1999, 2000 and 2001 . Between 1999 and 2001, antimicrobials for respiratory infections decreased from 18.0 to 9.97 DDD/1000 per day or by 44.6% (P=0.0000+) . Antimicrobials for URI decreased from 8.32 in 1999 to 3.28 DDD/1000 per day in 2001 or by 60.6% (P=0.0000+); from 2000 to 2001 the decrease was 55.8% . Reduction of antimicrobials for URI from 1999 to 2001 accounted for 62.8% of the reduction of antimicrobials in respiratory infections or 51.3% of the total reduction of antimicrobials . Reduction in aminopenicillins was responsible for most of the decrease.

Biochem Biophys Res Commun, 2004 May 28, 318(2), 397 - 404
Cooperativity in the binding of the cationic biocide polyhexamethylene biguanide to nucleic acids; Allen MJ et al.; The interaction between the broad-spectrum antimicrobial agent, polyhexamethylene biguanide (PHMB), and various nucleic acids was investigated . Titration of either single- or double-stranded 100-bp DNA, or mixed-molecular weight marker DNA, or tRNA with PHMB caused precipitation of a complex between nucleic acid and PHMB in which the nucleotide/biguanide ratio was always close to unity . Binding of PHMB was highly cooperative, with apparent Hill coefficients 10.3-14.6 . When a fluorescent derivative of PHMB was titrated with increasing amounts of nucleic acid, all four forms of nucleic acid caused strong polarisation of fluorescence, demonstrating the association with PHMB . The intensity and broad-spectrum binding of PHMB to all forms of nucleic acid has significant implications for the mechanism of action of this biocide.

Regul Pept, 2004 Jul 15, 119(3), 199 - 207
Effects of a chromogranin-derived peptide (CgA 47-66) in the writhing nociceptive response induced by acetic acid in rats; Ghia JE et al.; Chromogranin A (CgA) is an acidic protein identified within a large variety of endocrine cells . Colocalized with catecholamines in chromaffin cells, CgA is a prohormone precursor of small biologically active peptides . Vasostatin (CgA 1-76) is the most conserved fragment of CgA and chromogranin A 47-66 peptide (CgA 47-66) possesses potent antimicrobial activities . The aim of this study was to test the hypothesis that CgA 47-66 may be involved in mechanisms modulating nociception . Thus, we used acetic acid (AA) which produces a delayed inflammatory response and episodes of abdominal writhing, a marker of pain, when injected intraperitoneally (i.p.) to rats . Administration (i.p.) of CgA 47-66 induced specific opposite dose-dependent effects depending on concentration . That is, CgA 47-66 below 0.5 mg/kg produced antinociceptive effects, whereas at 2 mg/kg it produced a marked pronociceptive effect . The latter effect was blocked by diltiazem and indomethacin . CgA 47-66-induced antinociceptive effects on AA-induced responses were reversed when the corticotropin-releasing factor (CRF) antagonist alpha-helical CRF 9-41 was i.p . injected to animals prior to AA and CgA 47-66 administration . The administration of i.p . calcitonin gene-related peptide (CGRP) or substance P (SP) evoked dose-dependent abdominal writhing; this effect was abolished when CgA 47-66 was injected . The present data suggest, for the first time, that a fragment of CgA, CgA 47-66, possesses potent antinociceptive effects at low doses . Although the mechanism triggered by this peptide is unknown, CRF receptors are likely to be involved.

J Ethnopharmacol, 2004 Apr, 91(2-3), 361 - 5
Memory enhancing activity of Glycyrrhiza glabra in mice; Dhingra D et al.; In the traditional system of medicine, the roots and rhizomes of Glycyrrhiza glabra (family: Leguminosae) have been employed clinically for centuries for their anti-inflammatory, antiulcer, expectorant, antimicrobial and anxiolytic activities . The present study was undertaken to investigate the effects of Glycyrrhiza glabra (popularly known as liquorice) on learning and memory in mice . Elevated plus-maze and passive avoidance paradigm were employed to test learning and memory . Three doses (75, 150 and 300 mg/kg p.o.) of aqueous extract of Glycyrrhiza glabra were administered for 7 successive days in separate groups of animals . The dose of 150 mg/kg of the aqueous extract of liquorice significantly improved learning and memory of mice . Furthermore, this dose significantly reversed the amnesia induced by diazepam (1 mg/kg i.p.) and scopolamine (0.4 mg/kg i.p.) . Anti-inflammatory and antioxidant properties of liquorice may be contributing favorably to the memory enhancement effect . Since scopolamine-induced amnesia was reversed by liquorice, it is possible that the beneficial effect on learning and memory was due to facilitation of cholinergic-transmission in mouse brain . However, further studies are necessitated to identify the exact mechanism of action . In the present investigation, Glycyrrhiza glabra has shown promise as a memory enhancing agent in all the laboratory models employed.

Curr Med Res Opin, 2004 Apr, 20(4), 555 - 63
Efficacy of 750-mg, 5-day levofloxacin in the treatment of community-acquired pneumonia caused by atypical pathogens; Dunbar LM et al.; BACKGROUND: Current recommended durations for treatment of atypical community-acquired pneumonia (CAP) range from 10 to 21 days . However, antibiotics such as the fluoroquinolones may allow for effective, short-course regimens . OBJECTIVE: This study evaluated the efficacy of 750 mg levofloxacin for 5 days compared to a 500-mg, 10-day levofloxacin regimen for the treatment of atypical CAP . METHODS: A randomized, active-controlled, double-blind, multicenter study was conducted within the United States . Of the 528 patients enrolled in the study, 149 were diagnosed with CAP due to Legionella pneumophila, Chlamydia pneumoniae, or Mycoplasma pneumoniae . Patients' baseline symptoms were re-evaluated on Day 3 of therapy . Clinical efficacy and resolution of CAP symptoms were evaluated at the posttherapy visit (7-14 days after the last dose of active drug) . RESULTS: This report represents a subgroup analysis of a previous clinical study . Among the 123 clinically evaluable patients diagnosed with atypical CAP (26 patients were unevaluable), the clinical success rates were 95.5% (63 of 66 patients) for the 750-mg group and 96.5% (55 of 57 patients) for the 500-mg group (95% CI for success rate of the 500-mg group minus that of the 750-mg group, -6.8 to 8.8) . At the poststudy evaluation (31-38 days after treatment began), relapse occurred in </= 2% of patients in either treatment group . Among patients diagnosed with atypical CAP, the 750-mg therapy resulted in more rapid symptom resolution, with a significantly greater proportion of patients experiencing resolution of fever by Day 3 of therapy (p = 0.031) . CONCLUSION: The 750-mg, 5-day course of levofloxacin was at least as effective as the 500-mg, 10-day regimen for atypical CAP . Additionally, the 750-mg, short-course levofloxacin therapy may reduce total antimicrobial drug usage and more rapidly relieve pneumonia symptoms.

Mycopathologia, 2004 Feb, 157(2), 155 - 61
Nocardia beijingensis, is a pathogenic bacterium to humans: the first infectious cases in Thailand and Japan; Kageyama A et al.; Nocardia beijingensis, a recently established new species, is an isolate from soil in China . During our taxonomic studies on 450 nocardial clinical isolates in Thailand and Japan, 17 strains from Thailand and 1 strain from Japan were found to have a similar physiological characteristic to those of N . beijingensis, such as a drug susceptibility pattern to three antimicrobial agents . Our phylogenetic studies on these 18 strains by 16S rRNA gene sequence analysis confirmed that these strains belong to N . beijingensis species . Phylogenetically, these newly isolated N . beijingensis strains were found to be classified into two distinct clades: one is a Japanese clade and other is a Chinese clade, including a reference strain and 17 Thai strains . This is the first report of human infection due to N . beijingensis strains, and we propose that the bacterium be categorized as an opportunistic infectious group regardless of its original isolation from soil.

Scand J Infect Dis, 2004, 36(3), 198 - 203
Diagnostic value of bronchoalveolar lavage in community-acquired pneumonia in a routine setting: a study on patients treated in a Finnish university hospital; Hohenthal U et al.; Only a few previous studies have focused on the use or bronchoalveolar lavage (BAL) in patients with community-acquired pneumonia (CAP) . Our aim was to evaluate the diagnostic value of BAL in CAP in a routine clinical setting . 71 disease episodes were retrospectively analysed . The patients had undergone BAL for serious or slowly responding pneumonia . All procedures were performed during antimicrobial treatment of the patient . BAL fluid was cultivated for bacteria, fungi, and viruses . In 68 episodes, 1 or several specific polymerase chain reaction tests were performed . Only 1 (1.3%) quantitative bacterial culture was considered diagnostic for CAP, and indicated a change of antimicrobial treatment . The diagnostic yield increased to 9.8% when other methods were used . A respiratory virus was the only aetiology in 3 (6.0%) patients . In slowly responding pneumonia, also hospital-acquired pathogens and malignancies were identified, resulting in a total diagnostic yield of 20.0% . Thus, even when a large array of diagnostic assays was applied, the value of BAL in pretreated patients with CAP was very small, and its therapeutic implications minimal . In a subgroup of slowly responding pneumonia, the procedure was of some usefulness even after commencement of antimicrobial treatment.

Ned Tijdschr Geneeskd, 2004 Apr 10, 148(15), 725 - 8
{Summary of the practice guideline 'Acute cough' from the Dutch College of General Practitioners}; van Balen JA et al.; In most cases acute cough has an infectious, often viral, cause . When the coughing lasts longer than 3 weeks, the diagnosis has to be reconsidered . The effectiveness of cough medicines has not been proven . For the management of acute cough it is important to distinguish between non-serious and serious lower respiratory tract infections . A serious lower respiratory tract infection is: a lower respiratory tract infection with a higher risk of a complicated course: when pneumonia is suspected, in infants and the elderly, and in patients with relevant co-morbidity . The prescription of antibiotics for acute cough is not useful in the majority of the patients; antimicrobial therapy can be indicated, but only in the case of lower respiratory tract infections with a higher risk of a complicated course . Specific management has to be considered in the case of: whooping cough, bronchiolitis and croup . In the case of pneumonia, antimicrobial therapy is indicated; follow-up is necessary . In the case of moderate to severe croup, a single dose of corticosteroids is recommended.

Mo Med, 2004 Mar-Apr, 101(2), 128 - 31
Ordering errors by first-year residents: evidence of learning from mistakes; Walling HW et al.; OBJECTIVE AND DESIGN: To study patterns of ordering errors, we reviewed charts of patients cared for by first-year residents at our community-based teaching hospital . RESULTS: In month one, 39 of 1248 orders (3.1%) were rated as errors . In contrast, 9 of 1072 orders (0.84%) in month six were rated as errors (p < 0.001) . Of the 48 errors identified, 36 (75%) related to medications (choice, dose, route, frequency, or duration) . Over half (53%) of these errors involved antimicrobials, pulmonary medications, or diabetes-related drugs . For all errors, half (24/48) were identified by attending physicians, with hospital support staff noting most of the remaining errors (43.8%) . Errors were ultimately corrected by the first-year resident in over half of the cases (52%); attending physicians corrected 16 of 39 errors (41%) in month one but only one of nine errors (11%) in month six . Errors by first-year residents were primarily attributed to inattention (45.8%) or deficits in clinical knowledge (43.8%) . No adverse effects resulted from any of the ordering errors identified . Primary consequences of errors included inconvenience to staff (50%), delay in treatment or diagnosis (31.3%), or receiving unneeded medication (18.8%) . CONCLUSIONS: The number of medical errors decreases with experience . Our results highlight the importance of clinical supervision during the initial months of training.

MLO Med Lab Obs, 2004 Apr, 36(4), 12 - 6, 21-2; quiz 24-5
Bacterial resistance: how to detect three types; Shima SM et al.; Antimicrobial susceptibility testing in the clinical laboratory is becoming more complex . We can no longer be concerned with simply determining accurate susceptibilities . Microbiologists must now possess knowledge of bacterial-resistance mechanisms and implement procedures to reliably detect them . The traditional susceptibility test will most likely need to be supplemented with testing methods and software that allow for phenotypic identification of resistance mechanisms . Resistance mechanisms can be present in apparently susceptible bacterial populations . Accurate identification of these mechanisms will help to control emergence of new resistance by encouraging use of the most appropriate antibiotics.

Cells Tissues Organs, 2004, 176(4), 187 - 94
Apocrine glands in the eyelid of primates contribute to the ocular host defense; Stoeckelhuber M et al.; Apocrine glands of Moll are regular components of primate eyelids . We studied the distribution and localization of these glands in three different primate species, the common marmoset, the rhesus monkey, and the hamadryas baboon . In addition, we tested the primate glands of Moll with antibodies against antimicrobial proteins, cytoskeletal proteins and the androgen receptor . The glands of Moll differ in abundance and distribution in different monkeys . In the common marmoset, a representative of the New World monkeys, Platyrrhini, the apocrine glands are frequently found at the lid margin and in the overlying epidermis of the lid . In the rhesus monkey and the hamadryas baboon, representatives of Old World monkeys, Catarrhini, apocrine glands are rarer and located predominantly at the margin of the lid . The immunohistochemical analysis indicates the presence of a variety of antimicrobial proteins, e.g . lysozyme, beta-defensin-2, adrenomedullin, lactoferrin, and IgA, in these glands . Interestingly, there are basically no androgen receptors in the nuclei of apocrine glands at the lid margin in all three monkey species . In the common marmoset, however, androgen receptors are found in apocrine glands of the overlying epidermis of the lid . We speculate that the glands of Moll are derived from apocrine glands as found in the skin of the entire body in New World monkeys which developed at the lid margins of higher primates and humans into specialized glands secreting agents of host defense in the eye .

Proc Natl Acad Sci U S A, 2004 May 11, 101(19), 7363 - 8 Epub 2004 Apr 26.
Multidimensional signatures in antimicrobial peptides; Yount NY et al.; Conventional analyses distinguish between antimicrobial peptides by differences in amino acid sequence . Yet structural paradigms common to broader classes of these molecules have not been established . The current analyses examined the potential conservation of structural themes in antimicrobial peptides from evolutionarily diverse organisms . Using proteomics, an antimicrobial peptide signature was discovered to integrate stereospecific sequence patterns and a hallmark three-dimensional motif . This striking multidimensional signature is conserved among disulfide-containing antimicrobial peptides spanning biological kingdoms, and it transcends motifs previously limited to defined peptide subclasses . Experimental data validating this model enabled the identification of previously unrecognized antimicrobial activity in peptides of known identity . The multidimensional signature model provides a unifying structural theme in broad classes of antimicrobial peptides, will facilitate discovery of antimicrobial peptides as yet unknown, and offers insights into the evolution of molecular determinants in these and related host defense effector molecules.

J Antimicrob Chemother, 2004 Jun, 53(6), 902 - 5 Epub 2004 Apr 29.
Towards targeted prescribing: will the cure for antimicrobial resistance be specific, directed therapy through improved diagnostic testing?
Peterson LR, Dalhoff A.
The discovery of antimicrobial agents was one of the major events of the twentieth century . However, with the 'antibiotic era' barely five decades old, we are now faced with the global problem of emerging resistance in virtually all pathogens . Guidelines and admonishments to improve prescribing have had little effect . At this point, in the twenty-first century, we are on the threshold of another era of discovery-that of molecular diagnostics . We postulate that the development and use of new molecular microbiological testing, coupled with an ever-improving understanding of how best to use these precious drugs in the treatment of infection, offers the greatest hope yet for physician prescribing that can retard, or perhaps even reduce, the development of drug resistance in many microbial species . This diagnostic advance could preserve the utility of antimicrobial agents well into the future for the benefit of all people.

J Antimicrob Chemother, 2004 Jun, 53(6), 971 - 4 Epub 2004 Apr 29.
Antimicrobial activity of clofazimine is not dependent on mycobacterial C-type phospholipases; Bopape MC et al.; We have used a phospholipase C (PLC)-deletion mutant (plcABC) of the H37Rv strain of Mycobacterium tuberculosis (MTB), as well as a plcA-insertion mutant of Mycobacterium smegmatis, to investigate the possible involvement of PLCs in clofazimine-mediated inhibition of mycobacterial K(+) transport and growth . Inactivation of the PLCs of MTB and insertion of the plcA gene into M . smegmatis resulted in a substantial reduction and increase in hydrolysis of phosphatidylcholine (PC), respectively . However, both the mutant and wild-type strains of MTB and M . smegmatis were equally sensitive to the inhibitory effects of clofazimine on K(+) uptake and growth . These observations demonstrate that the PLCs of MTB are not involved in the antimicrobial activity of clofazimine.

J Antimicrob Chemother, 2004 Jun, 53(6), 1109 - 11 Epub 2004 Apr 29.
Defined daily doses of antimicrobials reflect antimicrobial prescriptions in ambulatory care; Monnet DL et al.; BACKGROUND: Data on actual antimicrobial prescriptions are rarely made available and the World Health Organization (WHO) recommends using the number of defined daily doses (DDDs) as a measurement unit for inter-country comparisons of antimicrobial use in outpatients . However, because antimicrobials are given for limited periods of time and the DDDs may not represent the doses used in practice, this measurement unit has been blamed for poorly reflecting the number of antimicrobial prescriptions in outpatients . METHODS: For 11 out of 15 European countries, data on national outpatient sales of antimicrobials and on antimicrobial prescriptions to outpatients in 1997 were purchased from the Institute for Medical Statistics (IMS) Health . For two additional countries, i.e . Sweden and Denmark, similar data were obtained from the National Corporation of Swedish Pharmacies and the Danish Medicines Agency, respectively . The relationships between the number of DDDs and the number of prescriptions, on the one hand, and the antimicrobial use density (DDD per 1000 inhabitant-days) and the prescription rate (prescriptions per 1000 inhabitants), on the other hand, were assessed with the two-tailed Spearman coefficient for non-parametric correlations . RESULTS: The number of DDDs, as defined by the WHO, and the number of prescriptions of antimicrobials to outpatients in European countries in 1997 were strongly correlated . Similarly, the antimicrobial use density and the prescription rate in these countries were strongly correlated . These relationships were found for total systemic antimicrobials and for all major antimicrobial classes . CONCLUSION: Our results confirm the relevance of the number of DDDs per 1000 inhabitant-days as a measurement unit to compare outpatient antimicrobial use among countries or regions.

Med J Aust, 2004 May 3, 180(9), 455 - 8
Impact of an electronic antibiotic advice and approval system on antibiotic prescribing in an Australian teaching hospital; Grayson ML et al.; The impact of a computer-based infectious diseases electronic antibiotic advice and approval system ("IDEA(3)S") was assessed as an alternative to a labour-intensive, phone-based approval system . IDEA(3)S-based approvals replaced 48% of all approvals for the most frequently requested antimicrobial agents (ceftriaxone/cefotaxime, vancomycin) and were associated with stable overall rates of antimicrobial use . Antibiotic prescribing for community-acquired pneumonia was 76% concordant with IDEA(3)S recommendations, and clinical acceptance of IDEA(3)S was excellent . Successful implementation required a coordinated, evidence-based approach between clinicians, pharmacists and hospital administration, together with ongoing staff education and feedback of results . IDEA(3)S is a useful new adjunct to routine clinician consultation to support appropriate antibiotic prescribing for a number of common indications in hospitals.

Natl Med J India, 2004 Jan-Feb, 17(1), 10 - 6
New drugs in India over the past 15 years: analysis of trends; Ghosh A et al.; BACKGROUND: New drugs are appearing in the Indian pharmaceutical market every day . To study the trends we analysed the pattern of new drug approvals and introductions in India over the past 15 years (1988-2002) . METHODS: Lists of new drugs approved by the Drugs Controller General of India, released half-yearly, were obtained and entered into a computer database . Additional information, such as anatomical therapeutic chemical coding, availability status till 31 December 2002 and source were added to this database before analysing overall time trends and the situation in individual therapeutic categories . RESULTS: Excluding unrecognized and compound formulations and 28 veterinary products, 396 drugs were approved for clinical use during this period . Of these, 315 have also been launched in the market and 5 were subsequently withdrawn . Nervous system-related drugs accounted for the largest number of approvals (82), followed by antimicrobials (73) and cardiovascular drugs (57) . Five new antimalarials have emerged but other tropical diseases have been mostly ignored . Eleven vaccines have been added . CONCLUSION: There has been a sharp spurt in the annual number of approvals and introductions . The proliferation of brands and fixed-dose combinations has kept pace with the introduction of new molecules . Unfortunately, most new drugs are not major therapeutic advances . In the context of this rapid proliferation, meeting the information needs of prescribers, establishing an effective nationwide pharmacovigilance system and reorienting the focus of pharmacology education--from information provision to development of self-learning and critical judgement skills-are some issues for concern.

J Wound Care, 2004 Apr, 13(4), 154 - 5
Colloidal silver as an antimicrobial agent: fact or fiction?
van Hasselt P, Gashe BA, Ahmad J.
OBJECTIVE: Colloidal silver preparations are marketed on the internet as omnipotent antimicrobial agents, but scientific support for these claims is lacking . This study reports the results of in vitro tests of colloidal silver's antimicrobial activity against several pathogenic or non-pathogenic microorganisms . METHOD: Three samples of colloidal silver were tested: one available commercially on the internet (silver concentration of 22 ppm) and two samples (concentrations of 403 and 413 ppm) which were prepared in our laboratory using standard chemical methods . RESULTS: In an agar-well diffusion assay none of the three colloidal silver solutions had any effect on the growth of the test organisms . All tested bacterial strains were sensitive to ciprofloxacin . Colloidal silver 22 ppm showed no bactericidal activity in phenol coefficient tests . CONCLUSION: As the tested colloidal silver solutions did not show any antimicrobial effect in vitro on the microorganisms, claims of colloidal silver's antimicrobial potency are misleading and there is no place for it as an antiseptic.

Planta Med, 2004 Mar, 70(3), 272 - 6
Antimicrobial activity of 3-O-acyl-(-)-epicatechin and 3-O-acyl-(+)-catechin derivatives; Park KD et al.; As an exploratory investigation of antimicrobial promoting compounds, 3- O-acyl-(-)-epicatechins and 3- O-acyl-(+)-catechins possessing various aromatic groups and aliphatic chains of varying length from C4 to C16 for increasing lipophilicity were synthesized and tested for antimicrobial activities against Gram-positive, Gram-negative bacteria and fungi . The (-)-epicatechin and (+)-catechin derivatives comprised of aromatic groups increased activity and derivatives with acyl chain groups of carbon atoms in the close vicinity of C8 to C10 showed strong antimicrobial activity (MIC = 2 - 8 microg/ml) against Gram-positive bacteria and weak activity against fungi . However, the activity decreased when the carbon chain length of the substituents was too short (C4 to C6) or too long (C16) . These results suggest that the presence of lipophilic substituents with moderate sizes might be crucial for the optimal antimicrobial activity.

Ann Pharmacother, 2004 Jun, 38(6), 1031 - 8 Epub 2004 Apr 27.
Antimicrobial-associated renal tubular acidosis; Hemstreet BA; OBJECTIVE: To review the literature documenting the association of various antimicrobial medications with the development of renal tubular acidosis (RTA) . DATA SOURCES: A search of the English literature via MEDLINE (1966-November 2003) and International Pharmaceutical Abstracts (1970-November 2003) was conducted to identify human reports of RTA associated with various drugs from all available classes of antimicrobial agents . Major search terms included renal tubular acidosis, acidosis, antibiotics, and antimicrobials . Bibliographies of selected articles were also searched to identify additional reports of RTA . STUDY SELECTION AND DATA EXTRACTION: Case reports, observational studies, and experimental studies documenting the association of any antimicrobial agent with the development of RTA were included . DATA SYNTHESIS: Antimicrobial-associated RTA is a relatively uncommon adverse effect, with most reports involving amphotericin B, trimethoprim/sulfamethoxazole, and outdated tetracycline . These agents may induce RTA either through direct tubular toxicity or as a function of their pharmacologic action . The time course for the development of RTA varies depending on the antimicrobial utilized . In most instances, RTA is reversible; however, some patients may experience prolonged recovery after the offending agent is removed . CONCLUSIONS: Given that antimicrobial-associated RTA is a relatively uncommon adverse effect, review of the patient's drug regimen may reveal these agents as otherwise unrecognized causes of RTA . Likewise, underlying causes of RTA other than medications must be ruled out . Diagnosing antimicrobial-induced RTA may be difficult, given many of these agents may be used in combination and some are intrinsically nephrotoxic.

Ann Pharmacother, 2004 Jun, 38(6), 996 - 8 Epub 2004 Apr 27.
Rash associated with piperacillin/tazobactam administration in infectious mononucleosis; LeClaire AC et al.; OBJECTIVE: To report a case of piperacillin/tazobactam-induced rash in a patient with infectious mononucleosis . CASE SUMMARY: A 25-year-old white man developed a rash while receiving piperacillin/tazobactam 3.375 g intravenously every 6 hours and gentamicin for osteomyelitis complicating a left femur fracture secondary to a motorcycle accident . Due to progression of the rash following additional doses of piperacillin/tazobactam during hospitalization, the patient's antimicrobial regimen was changed to vancomycin and meropenem . Subsequently, a mononucleosis spot test was positive, and both Epstein-Barr virus (EBV) immunoglobulin (Ig) G and IgM antibodies were positive . The rash rapidly resolved with the discontinuation of piperacillin/tazobactam . DISCUSSION: Although the development of rash following the administration of several different antimicrobials, especially ampicillin, has been previously reported, this is the first report of piperacillin/tazobactam-induced rash in infectious mononucleosis . The rash is generally self-limiting and usually resolves within days of discontinuing the causative antimicrobial agent . An altered drug metabolism or an immune-mediated process has been suggested as the potential mechanism for rash development . CONCLUSIONS: Prior reports of antimicrobial-induced rash in infectious mononucleosis and a positive laboratory diagnosis of EBV in our patient with no history of penicillin allergy support the identification of piperacillin/tazobactam as the inducer of the rash . According to the Naranjo probability scale, the association of piperacillin/tazobactam with the rash was classified as probable.

J Virol, 2004 May, 78(10), 4976 - 82
The plant virus Tomato Spotted Wilt Tospovirus activates the immune system of its main insect vector, Frankliniella occidentalis; Medeiros RB et al.; Tospoviruses have the ability to infect plants and their insect vectors . Tomato spotted wilt virus (TSWV), the type species in the Tospovirus genus, infects its most important insect vector, Frankliniella occidentalis, the western flower thrips (WFT) . However, no detrimental effects on the life cycle or cytopathological changes have been reported in the WFT after TSWV infection, and relatively few viral particles can be observed even several days after infection . We hypothesized that TSWV infection triggers an immune response in the WFT . Using subtractive cDNA libraries to probe WFT DNA macroarrays, we found that the WFT's immune system is activated by TSWV infection . The activated genes included (i) those encoding antimicrobial peptides, such as defensin and cecropin; (ii) genes involved in pathogen recognition, such as those encoding lectins; (iii) those encoding receptors that activate the innate immune response, such as Toll-3; and (iv) those encoding members of signal transduction pathways activated by Toll-like receptors, such as JNK kinase . Transcriptional upregulation of these genes after TSWV infection was confirmed by Northern analysis, and the kinetics of the immune response was measured over time . Several of the detected genes were activated at the same time that viral replication was first detected by reverse transcription-PCR . To our knowledge, this is the first report of the activation of an insect vector immune response by a plant virus . The results may lead to a better understanding of insects' immune responses against viruses and may help in the future development of novel control strategies against plant viruses, as well as human and animal viruses transmitted by insect vectors.

J Biochem (Tokyo), 2004 Mar, 135(3), 297 - 304
Perinerin, a novel antimicrobial peptide purified from the clamworm Perinereis aibuhitensis grube and its partial characterization; Pan W et al.; A novel antimicrobial peptide was isolated and partially characterized from the homogenate of an Asian marine clamworm, Perinereis aibuhitensis Grube . This novel peptide, named Perinerin, was purified to homogeneity by heparin-affinity column and reverse-phase HPLC, and biologically tested with a MTS-PMS colorimetric assay . Perinerin consists of 51 amino acid residues and structurally appears to be highly basic and hydrophobic . It shows marked activity in vitro against both Gram-negative and Gram-positive bacteria and fungi, which indicates a bactericidal effect as well . Perinerin appears to be constitutively present and its sequence is novel among all other known antimicrobial peptides . These results suggest that Perinerin has the potential to serve as a convenient "evaluation marker" for studying alterations in the biochemistry of the host, particularly with respect to environmental changes . In addition, the MTS-PMS colorimetric assay examination of antimicrobial activity appears to be superior to existing methods and may offer more general application in the search for new antibiotic molecules.

Vet Immunol Immunopathol, 2004 May, 99(1-2), 127 - 32
Equine beta-defensin-1: full-length cDNA sequence and tissue expression; Davis EG et al.; beta-Defensins are cysteine-rich endogenously produced antimicrobial peptides that play an important role in innate immune defense . Although, previous investigations have identified beta-defensins in several mammalian species, no reports have identified equine beta-defensins . Using a strategy of database searching for expressed sequence tags (EST) we identified putative expression of equine beta-defensins in hepatic tissue . Based on this information, sequence specific primers were designed for the equine gene enabling the identification of the full-length cDNA sequence of equine beta-defensin-1 . Comparative analyses showed that equine beta-defensin-1 has 46-52% amino-acid identity with other beta-defensins, sharing the greatest identity with porcine beta-defensin-1 . Complete conservation of cysteine residues was maintained between the species evaluated, and RT-PCR analysis revealed diverse mRNA tissue expression for equine beta-defensin-1 . These data extend the repertoire of equine antimicrobial peptides and expand our understanding of equine innate immunity .

Aliment Pharmacol Ther, 2004 May 1, 19(9), 1009 - 17
Primary Helicobacter pylori resistance to metronidazole and clarithromycin in the Finnish population; Koivisto TT et al.; AIM: To systematically determine Helicobacter pylori primary antimicrobial resistance in Finland and the associated demographic and clinical features . METHODS: A total of 342 adult patients referred for gastroscopy at 23 centres in different parts of Finland and positive for the rapid biopsy urease test were recruited . Clinical and demographic data were collected via a structured questionnaire . Patients with positive H . pylori culture and successful antibiotic sensitivity determination by the E-test method (n = 292) were included in the present analysis . RESULTS: The study population consisted of 134 men and 158 women, mean age 56 years (95% CI, 55-58 years) . Resistance to metronidazole was 38% (110 of 292) and to clarithromycin 2% (seven of 292) . Resistance to metronidazole was higher in women than in men (48% vs . 25%, P < 0.001) . Previous use of antibiotics for gynaecological infections predicted metronidazole resistance (P = 0.01), and previous use of antibiotics for respiratory (P = 0.02) and dental infections (P = 0.02) the clarithromycin resistance . We observed no major geographical variations in metronidazole resistance . CONCLUSIONS: The primary metronidazole resistance of H . pylori was 38% and was common in women previously treated for gynaecological infections . Primary clarithromycin resistance was uncommon (2%) and may associate with previous dental and respiratory infections.

Clin Microbiol Infect, 2004 May, 10(5), 473 - 97
Report from the European Conference on the Role of Research in Combating Antibiotic Resistance, 2003; Cornaglia G et al.; Europe has been at the forefront of efforts to control antibiotic resistance, and this globally important health care problem has prompted numerous recommendations for action at both the national and international levels . Starting in 2002, research on antimicrobial resistance has been considered to be one of the specific objectives of the Sixth Framework Programme (FP6) within the European Union . This report summarises the plenary presentations, as well as the findings of six Working Groups covering specific areas of antibiotic resistance, given at a conference in November 2003 entitled 'The Role of Research in Combating Antibiotic Resistance', co-organised by the European Union and the European Society for Clinical Microbiology and Infectious Diseases, and held in Rome under the patronage of the Italian government.

J Agric Food Chem, 2004 May 5, 52(9), 2479 - 84
New method for the determination of benzoic and sorbic acids in commercial orange juices based on second-order spectrophotometric data generated by a pH gradient flow injection technique; Marsili NR et al.; Two widely employed antimicrobials, benzoic and sorbic acids, were simultaneously determined in commercial orange juices employing a combination of a flow injection system with pH gradient generation, diode array spectrophotometric detection, and chemometric processing of the recorded second-order data . Parallel factor analysis and multivariate curve resolution-alternating least-squares were used for obtaining the spectral profiles of sample components and concentration profiles as a function of pH, including provisions for managing rank-deficient data sets . An appropriately designed calibration with a nine-sample set of binary mixtures of standards, coupled to the use of the second-order advantage offered by the applied chemometric techniques, allowed quantitation of the analytes in synthetic test samples and also in commercial orange juices, even in the presence of unmodeled interferents (with relative prediction errors of 8.7% for benzoic acid and 2.5% for sorbic acid) . No prior separation or sample pretreatment steps were required . The comparison of results concerning commercial samples with a laborious reference technique yielded satisfactory statistical indicators (recoveries were 99.0% for benzoic acid and 101.4% for sorbic acid).

J Pept Sci, 2004 Mar, 10(3), 173 - 7
Isolation of allicepin, a novel antifungal peptide from onion (Allium cepa) bulbs; Wang HX et al.; From the bulbs of the onion Allium cepa, a novel antifungal peptide distinct from the antimicrobial peptide previously reported from onion seeds was isolated . The antifungal peptide, designated allicepin, was purified with a procedure that involved aqueous extraction, ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel and FPLC-gel filtration on Superdex 75 . Allicepin was unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue gel . The molecular weight of allicepin was estimated to be 10 K by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration on Superdex 75 . Allicepin exerted an inhibitory activity on mycelial growth in several fungal species including Botrytis cinerea, Fusarium oxysporum, Mycosphaerella arachidicola and Physalospora piricola.

J Med Liban, 2002 Sep-Dec, 50(5-6), 211 - 5
Survey of antimicrobial prophylaxis for surgical procedures in Lebanese hospitals; Azzam R et al.; Antimicrobial prophylaxis (AMP) is an effective measure to prevent the surgical site infection (SSI) . This prospective survey of three months describe the adequacy of AMP in 10 acute care hospitals (affiliated to the Lebanese University, Faculty of Medical Sciences) based on international guidelines for only three parameters, digestive, orthopaedic and vascular surgery . Out of 964 surgical procedures, 916 (95%) were eligible for AMP, of which 767 (84%) received one or several antibiotics . Cefazolin was frequently prescribed (49%), followed by beta-lactamase-inhibitor/penicillin (18%), cefuroxime (17%), ceftriaxone (7%) and vancomycin (0.1%) . In compliance with current US guidelines on indication, choice of drug, duration and time of first dose administration, AMP was given for only 32% of the procedures . Duration of AMP was < or = 24 hours in 35% and exceeded 48 hours in 57% . A single dose of prophylaxis was given to 26%, 12% receive an additional dose and 62% receive more than 2 doses . The first dose was administered within 30 min before operation in 92% of procedures . We conclude that AMP in Lebanese hospitals was fairly adequate in terms of respecting indications for selected surgical procedures . Improvement could be made by reducing the duration of prophylaxis and avoiding the use of broad-spectrum antibiotics.

J Am Vet Med Assoc, 2004 Apr 15, 224(8), 1312 - 6
Outcome and complications associated with treatment of pemphigus foliaceus in dogs: 43 cases (1994-2000); Gomez SM et al.; OBJECTIVE: To identify factors affecting prognosis, outcome, and complications associated with pemphigus foliaceus in dogs . DESIGN: Retrospective study . ANIMALS: 43 dogs with pemphigus foliaceus . PROCEDURE: Medical records were reviewed for signalment, age at diagnosis, duration to diagnosis, body area affected, initial immunosuppressive regimens and concurrent use of antimicrobials and sucralfate or histamine receptor 2 blocking agent, adverse effects of treatment, duration of treatment, number of visits for follow-up care, cause of death, and credentials of the veterinarians responsible for continued care . RESULTS: The case fatality rate was 60.5% . Factors significantly correlated with survival time included concurrent use of antimicrobials during initiation of immunosuppressive treatment and a lower number of adverse effects to treatment . Treatment times lasting more than 10 months from diagnosis correlated significantly with survival . CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with or prophylactic use of antimicrobials may be warranted during initial immunosuppressive treatment . The inverse correlation between survival time and number of adverse treatment effects was not unexpected because it was reflective of the owners' decision to euthanatize their dogs and of corticosteroid-related secondary diseases . Survival beyond the tenth month of treatment predicted long-term survival, which suggests that dogs require careful management during the early months of treatment.

J Dent Res, 2004 May, 83(5), 425 - 8
Nanocrystalline tetracalcium phosphate cement; Gbureck U et al.; Calcium hydroxide cements can lack long-term stability and achieve sustained release by matrix-controlled diffusion of hydroxyl ions . Tetracalcium phosphate (TTCP) hydrolyzes slowly to form calcium hydroxide and a thin insoluble apatite layer that prevents further reaction . In this study, mechanical amorphization was used to create a setting calcium-hydroxide-releasing cement from TTCP . The effect of high-energy ball milling of TTCP on the mechanical properties of the cement was investigated . X-ray diffraction data were used to determine the phase composition of the set cements . An accelerated in vitro test compared pH of water after prolonged boiling of nanocrystalline TTCP cements and a calcium salicylate material . As milling time increased, cement compressive strength and degree of conversion increased . Hydroxyl ion release from the cement was comparable with that from a calcium salicylate material . This new cement system offers the antimicrobial potential of calcium salicylate materials combined with the long-term stability of insoluble apatite cements.

Cytokine Growth Factor Rev, 2004 Apr-Jun, 15(2-3), 169 - 94
The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppression; Kalvakolanu DV; Cytokines and vitamins play a central role in controlling neoplastic cell growth . The interferon (IFN) family of cytokines regulates antiviral, anti-tumor, antimicrobial, differentiation, and immune responses in mammals . Significant advances have been made with respect to IFN-induced signal transduction pathways and antiviral responses . However, the IFN-induced anti-tumor actions are poorly defined . Although IFNs themselves inhibit tumor growth, combination of IFNs with retinoids (a class of Vitamin A related compounds) strongly potentiates the IFN-regulated anti-tumor action in a number of cell types . To define the molecular mechanisms involved in IFN/retinoid (RA)-induced apoptosis we have employed a genetic approach and identified several critical genes . In this review, I provide the current picture of IFN- RA- and IFN/RA-regulated growth suppressive pathways . In particular, I focus on a novel set of genes, the genes-associated with retinoid-interferon induced mortality (GRIM) . GRIMs may be novel types of tumor suppressors, useful as biological response markers and potentially novel targets for drug development.

Free Radic Biol Med, 2004 May 15, 36(10), 1259 - 69
p38 MAPK associated with stereoselective priming by grepafloxacin on O2- production in neutrophils; Niwa M et al.; Grepafloxacin is an asymmetric fluoroquinolone derivative which possesses high tissue penetrability as well as strong, broad-spectrum antimicrobial activities . We recently found that grepafloxacin induced a priming effect on neutrophil respiratory burst induced by N-formylmethionylleucylphenylalanine . In this report, we elucidate the precise mechanism of the priming by grepafloxacin . The R(+) enantiomer of grepafloxacin induced a more potent priming effect than did S(-)-grepafloxacin . R(+)-Grepafloxacin also produced a more potent translocation of both p47- and p67-phox proteins to membrane fractions of neutrophils . Grepafloxacin-induced primed superoxide generation was significantly inhibited by pretreatment with PD169316 and SB203580, p38 mitogen-activated protein kinase (MAPK) inhibitors, but not with PD98059, a specific inhibitor of the upstream kinase that activates p44/42 MAPK, or SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (JNK) . Grepafloxacin strongly phosphorylated p38 MAP kinase but not p44/42 MAPK or JNK . R(+)-Grepafloxacin showed more potent phosphorylation of p38 MAPK than did S(-)-grepafloxacin, in a time- and concentration-dependent manner . PD169316 significantly inhibited R(+)-grepafloxacin-induced translocation of p47-phox protein to the membrane fraction . Interestingly, grepafloxacin stereospecifically bound to the membrane fractions of neutrophils . These results strongly suggest that grepafloxacin stereospecifically primes neutrophil respiratory burst, and p38 MAPK activation is closely related to the grepafloxacin priming.

J Hosp Infect, 2004 Apr, 56 Suppl 2, S6 - 9
European norms in hand hygiene; Rotter ML; In the area of hand hygiene, European Norms exist, or are under development, with regard to protective gloves and for assessing the antimicrobial efficacy of hand disinfectants . Important norms for gloves are EN 420 (General requirements), EN 374 (Protective gloves against chemicals and microorganisms) and EN 455 (Medical gloves for single use) . A suspension test for the demonstration of bactericidal activity (prEN 12054) is obligatory for hand disinfectants in all fields of application; a test to prove activity against yeasts applies only to hygienic hand rub . (Optional) Claims for virucidal activities can be substantiated by prEN 1476 and, in future, for mycobactericidal capacity by a test which is still under development . In vivo tests exist for post-contamination treatments, hygienic hand wash and hygienic hand rub (EN 1499 and EN 1500 respectively), and for the preoperative surgical hand rub/wash (prEN 12791) . The two former tests employ artificially contaminated hands, the latter test is done with clean hands . All in vivo tests use reference hand treatments (with unmedicated soap or 2-propanol 60% (vol.) or 1-propanol 60% (vol.), respectively) against the results of which are compared with those achieved with the product under test and with the same volunteers . An antiseptic soap needs to be significantly more efficacious than unmedicated soap, a product for hygienic hand rub must not be inferior to the reference treatment with 2-propanol, and a surgical hand disinfectant must not cause a smaller bacterial reduction than the reference preparation with 1-propanol, immediately, and after 3 h . An (optional) claim for sustained activity of a surgical disinfectant needs to be demonstrated by achieving a significantly stronger bacterial reduction after 3 h than the reference preparation.

Biomaterials, 2004 Sep, 25(20), 5013 - 21
Biological performance of a novel synthetic furanone-based antimicrobial; Baveja JK et al.; Infection of medical devices causes significant morbidity and mortality and considerable research effort has been directed at solving this problem . The aim of this study was to assess the biological performance of a novel furanone compound that has potential as an anti-infective coating for medical devices . This study examined in vitro leukocyte response following exposure to the antibacterial 3-(1'-bromohexyl)-5-dibromomethylene-2(5H)-furanone and assessed the tissue response following subcutaneous implantation of the furanone compound covalently bound to polystyrene (PS) . Peripheral human blood was exposed to furanones in solution for 1h and flow cytometry used to analyse viability and changes in expression of surface receptors CD11b/CD18 and CD44 . Flow cytometry results from propidium iodide stained cell suspensions suggested that the leukocytes were viable after exposure to furanones in whole blood . No significant difference was found in the expression of CD11b/CD18 and CD44 between the furanone exposed samples and the negative control for neutrophils suggesting that the furanones themselves do not activate these leukocytes . The positive control lipopolysaccharide significantly up-regulated CD11b/CD18 and slightly down-regulated CD44 on both PMNs and monocytes . In vivo studies of the tissue response to furanone covalently bound to PS showed that there was no significant difference in cellularity of capsules surrounding the disk and no significant increase in myeloperoxidase expression . These results demonstrate negligible acute inflammatory response to synthetic brominated antibacterial furanones . Future studies will focus on chronic responses and examination of in vivo efficacy.

Emerg Infect Dis, 2004 Mar, 10(3), 522 - 5
Adherence barriers to antimicrobial treatment guidelines in teaching hospital, the Netherlands; Mol PG et al.; To optimize appropriate antimicrobial use in a university hospital and identify barriers hampering implementation strategies, physicians were interviewed regarding their opinions on antimicrobial policies . Results indicated that effective strategies should include regular updates of guidelines that incorporate the views of relevant departments and focus on addressing senior staff and residents because residents do not make independent decisions in a teaching-hospital setting.

J Gerontol Nurs, 2004 Apr, 30(4), 14 - 23; quiz 54-5
Pneumonia in the long-term care setting: etiology, management, and prevention; Coleman PR; 1.Nursing-home acquired pneumonia (NHAP) is a major cause of death and disability among elderly nursing home residents, despite the availability of new antimicrobials and diagnostic techniques . 2 . Elderly individuals with NHAP have vague clinical presentations and unique institutional limitations can lead to delays in diagnosis, treatment, and poor resident outcomes . 3 . Successful management of the resident with pneumonia includes choice of antibiotic therapy, excellent nursing care, and thoughtful consideration of treatment setting . 4 . Preventive strategies to reduce the risk of NHAP include attention to vaccination status and oral hygiene care to reduce bacterial colonization of potential respiratory pathogens.

Infect Control Hosp Epidemiol, 2004 Apr, 25(4), 308 - 12
Compliance with local guidelines for antibiotic prophylaxis in surgery; Pons-Busom M et al.; OBJECTIVES: To describe the development and implementation of a local protocol for antibiotic prophylaxis in surgery and to assess compliance with these guidelines using a computer-based system . DESIGN: One 5-week prospective period (phase 1) followed by three 1-week, cross-sectional assessments (phases 2, 3, and 4) . SETtING: Pharmacy of a 350-bed acute care teaching hospital in Barcelona, Spain . METHODS: In phase 1, 395 forms for antibiotic prescribing delivered to the pharmacy were reviewed . Nonadherence was defined as the prescription of an antibiotic (or doses) different from what the protocol specified . In phases 2, 3, and 4, antibiotic prescribing forms for all elective procedures (630 patients) performed during 1-week periods were analyzed . RESULTS: A total of 1,047 patients (mean age, 58.9 +/- 17.3 years) were included . Cefazolin was administered in 41% of procedures . Overall compliance with antibiotic prescribing forms was 83.3% . There was a statistically significant increase in compliance with guidelines throughout the four phases of the study, from 80.3% in phase 1 to 87.8% in phase 4 (P < .042), as well as adherence to completing forms for surgical procedures, from 51% in phase 2 to 77.6% in phase 4 (P < .001) . The main reason for non-adherence was that some procedures had not been included in the protocol in phase 2 . CONCLUSION: Surgeons sensitized to the implementation of local antibiotic prophylaxis guidelines showed a high degree of compliance with them, using both the procedure established for antibiotic prescribing and the antimicrobials recommended for particular operations

Infect Control Hosp Epidemiol, 2004 Apr, 25(4), 302 - 7
Compliance with guidelines on antibiotic prophylaxis in total hip replacement surgery: results of a retrospective study of 416 patients in a teaching hospital; Bedouch P et al.; OBJECTIVE: To assess compliance of anesthesiologist practices in antibiotic prophylaxis during total hip replacement (THR) surgery with the French Society of Anesthesiology and Intensive Care consensus-based guidelines . DESIGN: Retrospective review of medical records . Compliance of anesthesiologist practices with the guidelines was assessed according to antibiotic prophylaxis use, antimicrobial agent, dosage of first injection, time from first dose to incision, and total duration of antibiotic prophylaxis . SETTING: Orthopedic surgery wards in a 2,200-bed French teaching hospital . PATIENTS: A random sample of 416 patients undergoing THR from January 1999 to December 2000 . RESULTS: Three hundred eighty-six (93%) of the sampled medical records were usable . Antibiotic prophylaxis was used for 366 (95%) of the patients . Total duration of prophylaxis did not exceed 48 hours in 98% (359 of 366) of the patients . Drug selection complied with national guidelines in 259 (71%) of the patients . Dosage and timing of the first injection were appropriate in 98% (290 of 296) and 80% (236 of 296) of the patients, respectively, who received one of the recommended antibiotics . Overall, 53% (203 of 386) of the patients met all five criteria . In multivariate analysis, there was a significant anesthesiologist effect on overall compliance with the guidelines (likelihood ratio chi-square with 9 degrees of freedom, 25.7; P < .01) . Undergoing surgery during 2000 was the only patient characteristic associated with an increased rate of appropriate practices (adjusted OR, 1.56; CI95 1.02-2.38) . CONCLUSION: The overall compliance rate should be improved by disseminating the guidelines and the results of this study following audit and feedback.

J Plant Res, 2004 Apr, 117(2), 155 - 62 Epub 2004 Feb 13.
Use of Scots pine seedling roots as an experimental model to investigate gene expression during interaction with the conifer pathogen Heterobasidion annosum (P-type); Li G et al.; The root-rot fungus Heterobasidion annosum is a major pathogen of woody trees in temperate regions of the world . In this study, seedling root of Scots pine was used as an experimental model to investigate gene expression in conifer trees during challenge with H . annosum . Initial cellular and histochemical studies have established the systems and indicated the key sequence of events during the infection process . Also, to correlate histochemical observations with the time-dependent pattern of events in host gene expression, a transcriptome profiling of a selected set of host genes from a pine-root subtraction cDNA library was conducted . Differential screening of the subset of genes arrayed on nylon membrane with cDNA probes made from seedling roots infected for 1, 3, 7 and 15 days revealed a number of up-regulated genes {disease-resistance gene analog, antimicrobial peptide (AMP) gene homolog etc.} following inoculation . The results also showed strong expression of genes involved in cell defense and protein synthesis at the early stages of the infection (3-7 days) with a decline at late stages of infection (15 days) . The decline in expression of key defense genes at late stages of infection correlated well with the period of vascular colonization and subsequent loss of root turgor . Northern analyses with two of the major induced genes (AMP homolog and disease-resistance gene analog) indicated a several-fold increase in host gene expression following infection . In addition, a particular single gene (thaumatin-like protein) was consistently expressed throughout the four sampling periods of the experiment . BlastX analyses revealed that the Scots-pine thaumatin-like gene shared 51-77% sequence homology with other thaumatin-like proteins in GenBank . The importance of these results in tree defense and use of conifer seedling root in host-parasite interaction in forest trees is discussed.

J Endod, 2004 May, 30(5), 359 - 61
Effect of propolis on human fibroblasts from the pulp and periodontal ligament; Al-Shaher A et al.; Propolis, a flavonoid-rich product of honey comb, exhibits antibacterial and anti-inflammatory properties . In this study, we examined the tolerance of fibroblasts of the periodontal ligament (PDL) and dental pulp to propolis and compared with that of calcium hydroxide in vitro . Cells from human dental pulp and PDL were obtained from healthy third molars and subjected to various concentrations of propolis (0-20 mg/ml) and calcium hydroxide (0-250 mg/ml) . The cell viability after propolis treatment was analyzed by crystal violet staining of the cells followed by spectrophotometric analysis . Data revealed that exposure of PDL cells or pulp fibroblasts to 4 mg/ml or lower concentrations of propolis resulted in >75% viability of cells . On the contrary, calcium hydroxide 0.4 mg/ml was cytotoxic and <25% of the cells were found to be viable . Further investigations may find propolis to be a possible alternative for an intracanal antimicrobial agent.

J Vet Med Sci, 2004 Mar, 66(3), 319 - 22
Effects of antimicrobial peptides derived from the beetle Allomyrina dichotoma defensin on mouse peritoneal macrophages stimulated with lipopolysaccharide; Motobu M et al.; We previously reported that synthetic peptides, RLYLRIGRR-NH2 (peptide A) and RLRLRIGRR-NH2 (peptide B), derived from the beetle Allomyrina dichotoma defensin, showed antimicrobial activity against both Gram-positive and negative bacteria and suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) mRNA expression in a murine macrophage cell line . In this study, inhibitory effects of these peptides in LPS-induced mouse peritoneal macrophage activation were investigated . The supplement of peptide A to macrophages cultured with LPS resulted in a significant decrease in nitric oxide and TNF-alpha production . Furthermore, NF-kappaB activation was also blocked by addition of peptide A . These results indicated that peptide A blocked macrophage activation induced by LPS.

J Vet Med Sci, 2004 Mar, 66(3), 307 - 9
In vitro susceptibility of 21 antimicrobial agents to 37 isolates of Brachyspira hyodysenteriae isolated from pigs in Okinawa Prefecture; Uezato K et al.; The in vitro susceptibilities to 21 antimicrobial agents, of 37 isolates of Brachyspira (B.) hyodysenteriae isolated from pigs in Okinawa meat center and a pig farm in Okinawa Prefecture, Japan, were determined by the agar dilution method . Carbadox was the most active of all the agents tested against the isolates (MIC: <0.003 to 0.05) . All the isolates were highly susceptible to olaquindox, tiamulin, dimetridazole, efrotomycin and valnemulin with MICs ranging from </=0.1 to 1.6 microg/ml . Penicillins, chloramphenicol, tetracyclines, terdecamycin and streptomycin were also active against the isolates . Most isolates were resistant to lincomycin, avilamycin and macrolides (with the exception of terdecamycin).

Cochrane Database Syst Rev . 2004;(2):CD001832.
Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis; Prasad K et al.; BACKGROUND: Antibiotic therapy for suspected acute bacterial meningitis (ABM) needs to be started immediately, even before the results of cerebrospinal fluid culture and antibiotic sensitivity are available . It is not clear whether the available evidence supports the choice of third generation cephalosporins over the conventional antibiotic combination of ampicillin and chloramphenicol . Immediate institution of effective treatment through intravenous route may reduce death and disability in survivors . OBJECTIVES: The objective of this review is to determine the effectiveness and safety of the third generation cephalosporins and conventional treatment with penicillin/ampicillin-chloramphenicol in patients with community-acquired acute bacterial meningitis . SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2003) which contains the Cochrane Acute Respiratory Infections Group trials register, MEDLINE (January 1966 to November 2003), and EMBASE (January 1990 to November 2003) . We also searched the reference list of review articles and textbook chapters and contacted experts for any unpublished trials . SELECTION CRITERIA: Randomised controlled trials comparing ceftriaxone or cefotaxime with conventional antibiotics as empirical therapy of acute bacterial meningitis . DATA COLLECTION AND ANALYSIS: Two independent reviewers applied the study selection criteria, assessed methodological quality and extracted data . MAIN RESULTS: Eighteen trials included 993 patients in the analysis . The kappa (chance-corrected agreement) between the observers in study selection and data extraction was substantial . There was no heterogeneity of results among the studies in any outcome except diarrhoea . There was no statistically significant difference between the groups in the risk of death (risk difference -1%; 95% confidence interval (CI) -4% to +3%), risk of deafness (risk difference -4%; 95% CI -9% to +1%), risk of treatment failure (risk difference -2%; 95% CI -5% to +2%) . However, there were significantly decreased risk of culture positivity of CSF after 10-48 hours (risk difference -6%; 95% CI -11% to 0%) and statistically significant increased in the risk of diarrhoea between the groups (risk difference +8%; 95% CI +3% to +13%) with the third generation cephalosporins . The risk of neutropenia and skin rash were not significantly different between the two groups . However, all the studies have been conducted in the eighties except two, which have been conducted in 1993 and 1996 . REVIEWERS' CONCLUSIONS: Although the review shows no clinically important difference between ceftriaxone or cefotaxime and conventional antibiotics, the studies are done decades ago and may not apply to current routine practice . However, in situations where ceftriaxone or cefotaxime are not available or affordable, ampicillin-chloramphenicol combination may be used as an alternative . The antimicrobial resistance pattern against various antibiotics needs to be closely monitored in developing as well as developed countries . The factors determining overuse of antibiotics in developing countries and educational interventions to limit such practice are priority area for research in developing countries.

Antimicrob Agents Chemother, 2004 May, 48(5), 1548 - 52
Broth microdilution susceptibility testing for Leptospira spp; Murray CK et al.; Leptospirosis in humans has traditionally been treated with penicillin or doxycycline . The choice of therapy offered at the time of initial patient presentation is often empirical, as definitive diagnosis can take weeks . Determining the activity of numerous antimicrobial agents against a wide range of Leptospira serovars may broaden empirical therapeutic options . Various antimicrobials have been shown to be active against a limited number of serovars in in vitro studies, chiefly by the use of broth macrodilution techniques . We developed a broth microdilution technique using the commercially available growth indicator alamarBlue . MICs produced by this technique were compared to MICs and minimal bactericidal concentrations produced by the traditional broth macrodilution technique . The internal validity of our methods was assessed with 11 runs over numerous days with a single isolate of Leptospira interrogans serovar Icterohaemorrhagiae . By either method, the MICs for these internal-validity runs fell within 2 dilutions of each other for more than 90% of antimicrobials . A broader application of these two techniques included 12 serovars (including seven species) of Leptospira and six antimicrobials (penicillin G, doxycycline, chloramphenicol, erythromycin, cefotaxime, and ciprofloxacin) . Observed reproducibility fell within 2 dilutions for 99% of the duplicate result sets for the MIC microdilution method, compared to 89% for the MIC macrodilution method . The macrodilution method tended to have a higher MIC at which 90% of the isolates were inhibited (MIC(90)) than did the microdilution method, but the MIC(90)s of both methods were within 2 dilutions of each other for all six drugs . The macrodilution and microdilution techniques produced similar results, with microdilution allowing a faster, more streamlined method of producing MIC results.

Kansenshogaku Zasshi, 2004 Jan, 78(1), 22 - 31
{Disinfection of water of remove Legionella species: evaluation of an antimicrobial ceramic}; Sasahara T et al.; To evaluate the efficacy of an antimicrobial ceramic for killing Legionella strains in vitro, bacteria were exposed to the ceramic soaked in PBS at 25 degrees C or 42 degrees C . The number of L . pneumophila began to decrease significantly after 4 h of exposure at 25 degrees C and reached < 10 log cfu/ml after 12 h . A similar significant decrease was also observed after exposure at 42 degrees C . Furthermore, it was found that the antimicrobial ceramic showed bactericidal activity against six strains of Legionella isolated from various water sources, including L . pneumophila (serotype 1-4), L . micdadei, and L . dumoffii, after 24 h of exposure . The antimicrobial activity against L . pneumophila of the supernatant obtained by soaking the ceramic in PBS for 24 h was also assessed . Bactericidal activity of this supernatant was also noted . Analysis of the supernatant by ICP-MS resulted in the detection of eight metals (Mg, Al, Ca, Mn, Zn, Sr, Ag, and Ba) at a maximum concentration of 2.5 mg/l . When reconstituted PBS was made with all eight metals at the same concentrations as in the supernatant, the reconstituted PBS containing Ag alone and all metals showed significantly bactericidal activity against L . pneumophila, but PBS with only one metal component except Ag or a combination of Ag with Zn and/or Ca did not . These findings suggest that the antimicrobial ceramic possesses strong bactericidal activity against Legionella species and that eight metals released from the ceramic have a synergistic bactericidal effect against Legionella . When the antimicrobial ceramic was placed in hot spring water or cooling tower water instead of PBS, the number of L . pneumophila in the water decreased to < 10 log cfu/ml after 24 h of exposure and the bactericidal activity persisted for 5 weeks . These results indicate that the antimicrobial ceramic can be used to eradicate Legionella species contaminating various water sources.

Phytother Res, 2004 Mar, 18(3), 230 - 2
Extracts from St John's Wort and their antimicrobial activity; Avato P et al.; In an effort to carry out a more in-depth investigation on the antimicrobial properties of H . perforatum, we have assayed different extracts (MeOH; petroleum ether; CHCl(3) and EtOAc) from the aerial parts of the plant against selected microorganisms . Growth inhibition was observed only for Gram-positive bacteria, B . subtilis and B . cereus being the most susceptible to the tested drugs . The Hypericum extract obtained with EtOAc was the most active . The main constituents of this extract, as determined by HPLC analysis, were flavonoids, hypericins and hyperforins . Incubation of the selected microorganisms with the pure chemicals resulted in a significant inhibition of their growth by hypericin, hyperforin and its stable dicyclohexilammonium salt . Flavonoids appeared inactive at all .

J Mass Spectrom, 2004 Apr, 39(4), 351 - 60
Metabolites of an orally active antimicrobial prodrug, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime, identified by liquid chromatography/tandem mass spectrometry; Zhou L et al.; DB75 (2,5-bis(4-amidinophenyl)furan) is a promising antimicrobial agent against African trypanosomiasis and Pneumocystis carinii pneumonia . However, it suffers from poor oral activity in rodent models for both infections . In contrast, a novel prodrug of DB75, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), has excellent oral activity . DB289 is currently undergoing clinical investigation as a candidate drug to treat primary stage African trypanosomiasis and Pneumocystis carinii pneumonia . In this study, metabolites of DB289 formed after incubation with freshly isolated rat hepatocytes were characterized using liquid chromatography/ion trap mass spectrometry . Administration of DB289 and octadeuterated DB289 in a 1 : 1 mixture greatly facilitated metabolite identification by providing isotope patterns with twin ions separated by 8 m/z units in the ratio 1 : 1, in the extracted ion chromatograms of molecular ions and in the product ion mass spectra of metabolites . Ten metabolites were identified . Series of O-demethylations and N-dehydroxylations led to the metabolic activation of DB289 to DB75 with the production of four intermediate phase I metabolites . Phase II glucuronidation and sulfation led to the formation of four glucuronide and one sulfate metabolites .

Ophthalmic Res, 2004 May-Jun, 36(3), 139 - 44
Determination of nontoxic concentrations of piperacillin/tazobactam for intravitreal application . An electroretinographic, histopathologic and morphometric analysis; Ozkiris A et al.; BACKGROUND: To investigate the highest nontoxic intravitreal dose of piperacillin/tazobactam in rabbits . MATERIAL AND METHODS: Forty New Zealand white albino rabbits were used in this study . The rabbits were divided into four equal groups (10 rabbits in each) and the right eyes were treated with 0.1 ml intravitreal injections of 1,000 microg piperacillin/tazobactam in group 1, 500 microg in group 2, 250 microg in group 3, and 100 microg in group 4 . The left eyes served as controls and were injected with 0.1 ml of saline solution . Ganzfeld electroretinogram (ERG) was performed on all eyes before and after 4 weeks of intravitreal injections . Then, the rabbits were killed and the eyes were enucleated for histopathological evaluation of the retina . Retinal sections were evaluated by morphometric analyses on cell counts of ganglion cell layer and thickness of the various retinal layers . RESULTS: Baseline ERGs were similar among the groups (p > 0.05) . After 4 weeks of injection, there were a reduction of the b-wave amplitude and extension of the b-wave implicit time in photopic and scotopic ERGs in group 1 and group 2 when compared with controls (for each, p < 0.001) . Intravitreal injection of 100 and 250 microg piperacillin/tazobactam did not cause any deterioration of the b-wave of ERGs throughout the follow-up period of 4 weeks (for each, p > 0.05) . After morphometric analysis of retinal sections in all groups, there were no statistically significant differences in the mean number of surviving ganglion cells, thickness of the whole retina and the inner plexiform layer compared with controls (p > 0.05) . CONCLUSION: 250 microg/0.1 ml piperacillin/tazobactam is the highest nontoxic dose to the normal retinas of adult albino rabbits as intravitreal injection . Piperacillin/tazobactam may be a new, potentially important drug in the treatment of endophthalmitis as it has a broad antimicrobial spectrum .

J Biol Chem, 2004 Jul 23, 279(30), 30973 - 82 Epub 2004 Apr 21.
Molecular characterization of two novel antibacterial peptides inducible upon bacterial challenge in an annelid, the leech Theromyzon tessulatum; Tasiemski A et al.; Two novel antimicrobial peptides named theromacin and theromyzin were isolated and characterized from the coelomic liquid of the leech Theromyzon tessulatum . Theromacin is a 75-amino acid cationic peptide containing 10 cysteine residues arranged in a disulfide array showing no similarities with other known antimicrobial peptides . Theromyzin is an 86-amino acid linear peptide and constitutes the first anionic antimicrobial peptide observed in invertebrates . Both peptides exhibit activity directed against Gram-positive bacteria . Theromacin and theromyzin cDNAs code precursor molecules containing a putative signal sequence directly followed by the mature peptide . The enhancement of theromacin and theromyzin mRNA levels has been observed after blood meal ingestion and upon bacterial challenge . In situ hybridization revealed that both genes are expressed in large fat cells in contact with coelomic cavities . Gene products were immunodetected in large fat cells, in intestinal epithelia, and at the epidermis level . In addition, a rapid release of the peptides into the coelomic liquid was observed after bacterial challenge . The presence of antimicrobial peptide genes in leeches and their expression in a specific tissue functionally resembling the insect fat body provide evidence for the first time of an antibacterial response in a lophotrochozoan comparable to that of holometabola insects.

Infect Immun, 2004 May, 72(5), 2772 - 9
Differential regulation of beta-defensin gene expression during Cryptosporidium parvum infection; Zaalouk TK et al.; Invasion of enterocytes by pathogenic microbes evokes both innate and adaptive immune responses, and microbial pathogens have developed strategies to overcome the initial host immune defense . beta-Defensins are potentially important endogenous antibiotic-like effectors of innate immunity expressed by intestinal epithelia . In this study, the interplay between the enteric protozoan parasite Cryptosporidium parvum and host epithelial beta-defensin expression was investigated . Using human and murine models of infection, we demonstrated that C . parvum infection differentially regulates beta-defensin gene expression . Downregulation of murine beta-defensin-1 mRNA and protein was observed in both in vitro and in vivo models of infection . Infection of the human colonic HT29 cell line with the parasite resulted in differential effects on various members of the defensin gene family . Partial reduction in human beta-defensin-1 (hBD-1), induction of hBD-2, and no effect on hBD-3 gene expression was observed . Recombinant hBD-1 and hBD-2 peptides exhibited significant antimicrobial activity against C . parvum sporozoites in vitro . These findings demonstrate that C . parvum infection of enterocytes may affect the expression of various defensins in different ways and suggest that the overall outcome of the effect of antimicrobial peptides on early survival of the parasite may be complex.

Infect Immun, 2004 May, 72(5), 2477 - 83
Differential regulation of DAP12 and molecules associated with DAP12 during host responses to mycobacterial infection; Aoki N et al.; DAP12 and its associating molecules MDL-1, TREM-1, and TREM-2 are the recently identified immune regulatory molecules, expressed primarily on myeloid cells including monocytes/macrophages, dendritic cells, NK cells, and neutrophils . However, little is known about the regulation of their expression during host antimicrobial responses . We have investigated the effect of pulmonary mycobacterial infection and type 1 cytokines on the expression of these molecules both in vivo and in vitro . While DAP12 was constitutively expressed at high levels in the lungs, the MDL-1, TREM-1, and TREM-2 molecules were inducible during mycobacterial infection . Their kinetic expression was correlated with that of the type 1 cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) . In primary lung macrophage cultures, high constitutive levels of DAP12 and TREM-2 were not modulated by mycobacterial or type 1 cytokine exposure . In contrast, expression of both MDL-1 and TREM-1 was markedly induced by mycobacterial infection and such induction was inhibited by concurrent exposure to IFN-gamma . On mycobacterial infection of TNF-alpha(-/-) and IFN-gamma(-/-) mice in vivo or their lung macrophages in vitro, TNF-alpha was found to be critical for mycobacterially induced MDL-1, but not TREM-1, expression whereas IFN-gamma negatively regulated mycobacterially induced MDL-1 and TREM-1 expression . Our findings thus suggest that DAP12 and its associating molecules are differentially regulated by mycobacterial infection and type 1 cytokines and that MDL-1- and TREM-1-triggered DAP12 signaling may play an important role in antimicrobial type 1 immunity.

J Antimicrob Chemother, 2004 Jun, 53(6), 906 - 17 Epub 2004 Apr 21.
Antimicrobial resistance: a microbial risk assessment perspective; Snary EL et al.; The emergence of antimicrobial-resistant microorganisms in both humans and food animals is a growing concern . Debate has centred on links between antimicrobial use in the production of food animals and the emergence of resistant organisms in the human population . Consequently, microbial risk assessment (MRA) is being used to facilitate scientific investigations of the risks related to the food chain, including quantification of uncertainty and prioritization of control strategies . MRA is a scientific tool that can be used to evaluate the level of exposure and the subsequent risk to human health relating to a specific organism or particular type of resistance . This paper reviews the recent applications of MRA in the area of antimicrobial resistance, and in particular, it focuses on the methods, assumptions and data limitations . Since MRA outputs are dependent on the quality of data inputs used in their development, we aim to promote the generation of good quality data by describing the properties that data should ideally possess for MRA and by highlighting the benefit of data generation specifically for inclusion in MRAs.

Arch Dis Child Fetal Neonatal Ed, 2004 May, 89(3), F229 - 35
Diagnostic markers of infection in neonates; Ng PC; Diagnostic markers of infection are useful indicators of neonatal sepsis . Serial measurements of infection markers can improve diagnostic sensitivity, and the use of multiple markers can enhance diagnostic accuracy . Current evidence suggests that promising markers may be useful for early termination of antimicrobial treatment, but none of the current diagnostic tests are sensitive and specific enough to influence the clinical decision for withholding antibiotic treatment at the onset of suspected infection.

Expert Opin Biol Ther, 2004 Apr, 4(4), 543 - 9
Antimicrobial peptides and the skin; Bardan A et al.; In recent years, hundreds of naturally occurring peptide antibiotics have been discovered based on their ability to inhibit the growth of microbial pathogens . These antimicrobial peptides (AMPs) participate in the innate immune response by providing a rapid first-line defence against infection . This review discusses the biology and clinical relevance of the two major families of AMPs, cathelicidins and defensins, with emphasis on their function in mammalian skin and their association with skin pathology . Current evidence shows that cathelicidins and defensins act as both natural antibiotics and as signalling molecules that activate host cell processes involved in immune defence and tissue repair . Alterations in the expression pattern of AMPs have been associated with a variety of pathological processes . Ongoing and future studies are likely to implicate AMPs in several unexplained human inflammatory disorders and to provide novel therapeutic approaches for the treatment of these diseases.

Genet Mol Res, 2004 Mar 31, 3(1), 167 - 80
DNA repair in Chromobacterium violaceum; Duarte FT et al.; Chromobacterium violaceum is a Gram-negative beta-proteobacterium that inhabits a variety of ecosystems in tropical and subtropical regions, including the water and banks of the Negro River in the Brazilian Amazon . This bacterium has been the subject of extensive study over the last three decades, due to its biotechnological properties, including the characteristic violacein pigment, which has antimicrobial and anti-tumoral activities . C . violaceum promotes the solubilization of gold in a mercury-free process, and has been used in the synthesis of homopolyesters suitable for the production of biodegradable polymers . The complete genome sequence of this organism has been completed by the Brazilian National Genome Project Consortium . The aim of our group was to study the DNA repair genes in this organism, due to their importance in the maintenance of genomic integrity . We identified DNA repair genes involved in different pathways in C . violaceum through a similarity search against known sequences deposited in databases . The phylogenetic analyses were done using programs of the PHILYP package . This analysis revealed various metabolic pathways, including photoreactivation, base excision repair, nucleotide excision repair, mismatch repair, recombinational repair, and the SOS system . The similarity between the C . violaceum sequences and those of Neisserie miningitidis and Ralstonia solanacearum was greater than that between the C . violaceum and Escherichia coli sequences . The peculiarities found in the C . violaceum genome were the absence of LexA, some horizontal transfer events and a large number of repair genes involved with alkyl and oxidative DNA damage.

Genet Mol Res, 2004 Mar 31, 3(1), 102 - 16
Tolerance to stress and environmental adaptability of Chromobacterium violaceum; Hungria M et al.; Chromobacterium violaceum is a Gram-negative bacterium, abundant in a variety of ecosystems in tropical and subtropical regions, including the water and borders of the Negro River, a major component of the Amazon Basin . As a free-living microorganism, C . violaceum is exposed to a series of variable conditions, such as different sources and abundance of nutrients, changes in temperature and pH, toxic compounds and UV rays . These variations, and the wide range of environments, require great adaptability and strong protective systems . The complete genome sequencing of this bacterium has revealed an enormous number and variety of ORFs associated with alternative pathways for energy generation, transport-related proteins, signal transduction, cell motility, secretion, and secondary metabolism . Additionally, the limited availability of iron in most environments can be overcome by iron-chelating compounds, iron-storage proteins, and by several proteins related to iron metabolism in the C . violaceum genome . Osmotically inducible proteins, transmembrane water-channel, and other membrane porins may be regulating the movement of water and maintaining the cell turgor, activities which play an important role in the adaptation to variations in osmotic pressure . Several proteins related to tolerance against antimicrobial compounds, heavy metals, temperature, acid and UV light stresses, others that promote survival under starvation conditions, and enzymes capable of detoxifying reactive oxygen species were also detected in C . violaceum . All these features together help explain its remarkable competitiveness and ability to survive under different types of environmental stress.

J Orthop Res, 2004 May, 22(3), 671 - 7
Bactericidal activity of antimicrobial coated polyurethane sleeves for external fixation pins; Forster H et al.; This study was conducted to assess the potential of gentamicin coated polyurethane sleeves to inhibit bacterial colonization on external fixation pins and wires . These antimicrobial sleeves have been designed to be fitted over the pins and wires, at the time of surgery, as a prophylactic approach to combat the major complication of external fixation treatment, pin tract infection . Elution testing was conducted to estimate the amount of gentamicin released into the pin tract . These gentamicin concentrations were compared to the gentamicin minimal inhibitory concentration (MIC) level for common pin tract pathogens . Elution testing revealed that the gentamicin coated polyurethane sleeves released significant quantities of the antibiotic for up to 26 weeks . The initial bolus release was characterized by predicted pin tract gentamicin concentrations of >80 microg/ml at the 2 h and 1 day elution time points . These amounts of gentamicin, delivered directly to the pin tract, are far beyond those that could be achieved via oral or intravenous administration . Furthermore, the expected concentration of gentamicin in the pin tract remained above the National Committee for Clinical Laboratory Standards (NCCLS) MIC breakpoint of 4 microg/ml, {Performance standards for antimicrobial susceptibility testing: twelfth informational supplement M100-S12, NCCLS, Wayne, PA, 2002}, for at least 20 weeks . Data from the SENTRY antimicrobial surveillance program (1997-2002) established a high level of bactericidal activity for gentamicin, with 83.1% of the common pin tract pathogen isolates found to be susceptible to the antibiotic . The initial burst and subsequent long-term sustained local delivery of effective amounts of gentamicin from the antimicrobial sleeves would be expected to inhibit bacterial colonization on external fixation pins and wires . This inhibition of bacterial colonization should substantially reduce the incidence of pin tract infection, and improve the overall outcome and cost effectiveness of external fixation fracture management.

Nat Genet, 2004 May, 36(5), 481 - 5 Epub 2004 Apr 18.
An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice; Roy CN et al.; Inflammation influences iron balance in the whole organism . A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation) . Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia) . Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia . Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release . Hamp is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD . Mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia . These data suggest a previously unidentified role for Hfe in innate immunity and ACD.

Biochemistry, 2004 Apr 27, 43(16), 4696 - 702
Structure of thermolysin cleaved microcin J25: extreme stability of a two-chain antimicrobial peptide devoid of covalent links; Rosengren KJ et al.; The structure of a two-chain peptide formed by the treatment of the potent antimicrobial peptide microcin J25 (MccJ25) with thermolysin has been characterized by NMR spectroscopy and mass spectrometry . The native peptide is 21 amino acids in size and has the remarkable structural feature of a ring formed by linkage of the side chain of Glu8 to the N-terminus that is threaded by the C-terminal tail of the peptide . Thermolysin cleaves the peptide at the Phe10-Val11 amide bond, but the threading of the C-terminus through the N-terminal ring is so tight that the resultant two chains remain associated both in the solution and in the gas phases . The three-dimensional structure of the thermolysin-cleaved peptide derived using NMR spectroscopy and simulated annealing calculations has a well-defined core that comprises the N-terminal ring and the threading C-terminal tail . In contrast to the well-defined core, the newly formed termini at residues Phe10 and Val11 are disordered in solution . The C-terminal tail is associated to the ring both by hydrogen bonds stabilizing a short beta-sheet and by hydrophobic interactions . Moreover, unthreading of the tail through the ring is prevented by the bulky side chains of Phe19 and Tyr20, which flank the octapeptide ring . This noncovalent two-peptide complex that has a remarkable stability in solution and in highly denaturing conditions and that survives in the gas phase is the first example of such a two-chain peptide lacking disulfide or interchain covalent bonds.

J Mol Biol, 2004 Feb 27, 336(4), 903 - 15
Crystal structure of chorismate synthase: a novel FMN-binding protein fold and functional insights; Ahn HJ et al.; Chorismate synthase catalyzes the conversion of 5-enolpyruvylshikimate 3-phosphate to chorismate in the shikimate pathway, which represents an attractive target for discovering antimicrobial agents and herbicides . Chorismate serves as a common precursor for the synthesis of aromatic amino acids and many aromatic compounds in microorganisms and plants . Chorismate synthase requires reduced FMN as a cofactor but the catalyzed reaction involves no net redox change . Here, we have determined the crystal structure of chorismate synthase from Helicobacter pylori in both FMN-bound and FMN-free forms . It is a tetrameric enzyme, with each monomer possessing a novel "beta-alpha-beta sandwich fold" . Highly conserved regions, including several flexible loops, cluster together around the bound FMN to form the active site . The unique FMN-binding site is formed largely by a single subunit, with a small contribution from a neighboring subunit . The isoalloxazine ring of the bound FMN is significantly non-planar . Our structure illuminates the essential functional roles played by the cofactor.

Ceska Slov Farm, 2004 Mar, 53(2), 73 - 9
{Biological availability of ophthalmic drugs . 1 . Increasing drug permeability in the cornea}; Masteikova R et al.; Most eye diseases are treated by topical administration of ophthalmic preparations . Low ophthalmic bioavailability is due to a number of physiological and physicochemical factors . The main obstacle to the penetration of active ingredients to the eye is the layered character of the cornea . Formulation of ophthalmic preparations enabling easier penetration of this biological barrier thus ranks among the most effective ways of improving bioavailability . Penetrability of the cornea can be increased by the following methods: a) adjustment of the actual acidity in such a way that pH of the preparation makes it possible to produce the optimal portion of non-ionized particles; b) incorporation of absorption enhancers (non-ionic tensides, salts of bile acids, some antimicrobial substances, EDTA, cyclodextrins, etc.) into the composition of the preparation, and c) production of prodrugs or ionic pairs.

Postgrad Med, 2004 Apr, 115(4), 79 - 84
HIV and sexually transmitted diseases . Latest views on synergy, treatment, and screening; Klausner JD et al.; While STDs have an important impact on HIV transmission, experimental intervention studies demonstrating that STD control reduces HIV incidence have had mixed results . STDs can impact the clinical management of patients infected with HIV by increasing both viral load and HIV infectiousness . The clinical management of STDs is a dynamic field that has seen the advent of new diagnostic assays as well as changes in susceptibility to and availability of antimicrobial agents . As a result, excellence in HIV medical care requires physicians to be current in STD medicine . Physicians who care for patients with HIV infection should be familiar with recent guidelines recommending routine risk assessment and STD screening in these patients.

Arch Pharm (Weinheim), 2004 May, 337(5), 281 - 8
Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives; Aytemir MD et al.; In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity . Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline . The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis . Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits . The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method . Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-{4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl}-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour . 2-{4-(4-Chloro-phenyl)-piperazin-1-ylmethyl}-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not . Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.

Clin Infect Dis, 2004 Apr 15, 38(8), 1159 - 66 Epub 2004 Apr 05.
Immune reconstitution in HIV-infected patients; Hirsch HH et al.; The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of potent antiretroviral therapies (ARTs), which have enabled sustained suppression of HIV replication and recovery of CD4 T cell counts . Knowledge of the function of CD4 T cells in immune reconstitution was derived from large clinical studies demonstrating that primary and secondary prophylaxis against infectious agents, such as Pneumocystis jirovecii (Pneumocystis carinii), Mycobacterium avium complex, cytomegalovirus, and other pathogens, can be discontinued safely once CD4 T cell counts have increased beyond pathogen-specific threshold levels (usually >200 CD4 T cells/mm3) for 3-6 months . The downside of immune reconstitution is an inflammatory syndrome occurring days to months after the start of ART, with outcomes ranging from minimal morbidity to fatal progression . This syndrome can be elicited by infectious and noninfectious antigens . Microbiologically, the possible pathogenic pathways involve recognition of antigens associated with ongoing infection or recognition of persisting antigens associated with past (nonreplicating) infection . Specific antimicrobial therapy, nonsteroidal anti-inflammatory drugs, and/or steroids for managing immune reconstitution syndrome should be considered.

Clin Infect Dis, 2004 Apr 15, 38(8), 1141 - 9 Epub 2004 Mar 30.
Risk factors for ventilator-associated pneumonia: from epidemiology to patient management; Bonten MJ et al.; Risk factors for the development of ventilator-associated pneumonia (VAP), as identified in epidemiological studies, have provided a basis for testable interventions in randomized trials . We describe how these results have influenced patient treatment . Single interventions in patients undergoing intubation have focused on either reducing aspiration of oropharyngeal secretions, modulation of colonization (in either the oropharynx, the stomach, or the whole digestive tract), use of systemic antimicrobial prophylaxis, or ventilator circuit changes . More recently, multiple simultaneously implemented interventions have been used . In general, routine measures to decrease oropharyngeal aspiration and antibiotic-containing prevention strategies appear to be the most effective, and the latter were associated with improved rates of patient survival in recent trials . These benefits must be balanced against the widespread fear of emergence of antibiotic resistance . In hospital settings with low baseline levels of antibiotic resistance, however, the benefits to patient outcome may outweigh this fear of resistance . In settings with high levels of antibiotic resistance, combined approaches of non-antibiotic using strategies and education programs might be most beneficial.

Z Gastroenterol, 2004 Apr, 42(4), 333 - 8
{The role of defensins in the pathogenesis of chronic-inflammatory bowel disease}; Schmid M et al.; Defensins are endogenous antimicrobial peptides with a broad activity spectrum . Even at micromolar concentrations gramnegative and grampositive bacteria, but also mycobacteria, as well as fungi (candida), viruses (herpes) and protozoa (giardia lamblia) are destroyed . As part of the innate immune system defensins are expressed by the intestinal epithelium and contribute to the maintenance of the mucosal barrier . This barrier appears to be defective in inflammatory bowel diseases since on one hand, the immune response is directed against the "normal" luminal bacterial flora and on the other hand, mucosal adherent and invasive bacteria have been observed in these diseases . A defective defensin expression may well explain these phenomena . Indeed, Crohn's disease of the terminal ileum, especially if associated with a NOD2 mutation, is characterised by a diminished alpha-defensin (human defensin 5 and 6) expression, and in inflamed Crohn's colitis, in contrast to ulcerative colitis, the beta-defensin (human beta-defensins 2 and 3) response is reduced . Through a deficient chemical mucosal barrier this defect could lead to increased bacterial invasion into the intestinal mucosa and might well explain an adequate inflammatory response . Although the final proof that this deficient defensin response leads to a reduced antibacterial activity of the intestinal mucosa is still lacking, the most plausible concept of pathogenesis of Crohn's disease is a defensin deficiency syndrome.

Drugs Today (Barc), 1998 Feb, 34(2), 107 - 23
Current concepts in the antimicrobial therapy of community-acquired pneumonia; Cunha BA; The majority of community-acquired pneumonias (CAPs) are caused by typical bacterial pathogens, i.e., S . pneumoniae, H . influenzae or M . catarrhalis . Atypical pneumonias, i.e., legionnaires' disease, C . pneumoniae pneumonia and M . pneumoniae pneumonia are less common in frequency than typical bacterial pathogens, but are of considerable public health and therapeutic importance . The newest therapeutic considerations in CAP are related to monotherapy versus combination therapy, parenteral versus oral therapy, minimizing the emergence of penicillin-resistant pneumococci and an appreciation that comorbid factors in antibiotic selection are unimportant . Monotherapy using a respiratory quinolone or doxycycline covers both typical and atypical causes of CAPs and is equally efficacious and less expensive than double drug therapy . Except in patients unable to take oral medications/those in CCUs, patients with CAP may be started on i.v . antibiotic therapy, but should be switched to oral therapy after 48 hours/clinical defervescence . The combination of 2 days of i.v . therapy plus 12 days of oral therapy has been shown to be as effective as 14 days of i.v . therapy . The use of doxycycline or respiratory quinolones may forestall or eliminate the emergence of highly penicillin-resistant pneumococci, and, for this reason, these agents probably should be used preferentially over beta-lactam antibiotics to treat CAPs . The status of the host's immune system, particularly intact splenic function, and the underlying condition of the cardiorespiratory system are the critical factors in predicting mortality, morbidity, complications and hospital stay . However, antibiotic selection is not affected by comorbidities, and antibiotics should not be changed or added to the usual therapy of CAP because of comorbid factors . Multiple drug therapy does not improve the outcome, which is a function of underlying host factors . (c) 1998 Prous Science . All rights reserved.

Eur J Pharm Biopharm, 2004 May, 57(3), 489 - 93
Antimicrobial safety of a preservative-free nasal multiple-dose drug administration system; Klocker N et al.; Recent technical developments in metered-dose pumps allow preservative-free nasal drug application with multiple-dose systems, avoiding the cytotoxic and allergic problems of preservatives . The use of the 3K System as a representative of those systems is demonstrated as microbiologically safe and without risk for the user and for the product during shelf life, under challenge up to 24 weeks, as well as under worst-case conditions with heavy bacterial contamination on the outlet surface . Therefore, the authors assess preservative-free pump systems as the new gold standard for mucosal drug application.

J Bacteriol, 2004 May, 186(9), 2673 - 81
Conditional lethal amber mutations in essential Escherichia coli genes; Herring CD et al.; The essential genes of microorganisms encode biological functions important for survival and thus tend to be of high scientific interest . Drugs that interfere with essential functions are likely to be interesting candidates for antimicrobials . However, these genes are hard to study genetically because knockout mutations in them are by definition inviable . We recently described a conditional mutation system in Escherichia coli that uses a plasmid to produce an amber suppressor tRNA regulated by the arabinose promoter . This suppressor was used here in the construction of amber mutations in seven essential E . coli genes . Amber stop codons were introduced as "tagalong" mutations in the flanking DNA of a downstream antibiotic resistance marker by lambda red recombination . The drug marker was removed by expression of I-SceI meganuclease, leaving a markerless mutation . We demonstrate the method with the genes frr, gcpE, lpxC, map, murA, ppa, and rpsA . We were unable to isolate an amber mutation in ftsZ . Kinetics of cell death and morphological changes were measured following removal of arabinose . As expected given the wide range of cellular mechanisms represented, different mutants showed widely different death curves . All of the mutations were bactericidal except the mutation in gcpE, which was bacteriostatic . The strain carrying an amber mutation in murA was by far the most sensitive, showing rapid killing in nonpermissive medium . The MurA protein is critical for peptidoglycan synthesis and is the target for the antibiotic fosfomycin . Such experiments may inexpensively provide valuable information for the identification and prioritization of targets for antibiotic development.

Ann Clin Microbiol Antimicrob . 2004 Apr 17;3(1):4.
Prior antimicrobial therapy in the hospital and other predisposing factors influencing the usage of antibiotics in a pediatric critical care unit; Briassoulis G et al.; BACKGROUND: The aim of this study was to determine whether prior antimicrobial therapy is an important risk factor for extended antimicrobial therapy among critically ill children . To evaluate other predisposing factors influencing the usage of antibiotics in a pediatric intensive care unit (PICU) setting . To examine the relationship between the extent of antimicrobial treatment and the incidence of nosocomial infections and outcome . METHODS: This prospective observational cohort study was conducted at a university-affiliated teaching hospital (760 beds) in Athens . Clinical data were collected upon admission and on each consecutive PICU day . The primary reason for PICU admission was recorded using a modified classification for mutually exclusive disease categories . All administered antibiotics to the PICU patients were recorded during a six-month period . Microbiological and pharmacological data were also collected over this period . The cumulative per patient and the maximum per day numbers of administered antibiotics, as well as the duration of administration were related to the following factors: Number of antibiotics which the patients were already receiving the day before admission, age groups, place of origin, the severity of illness, the primary disease and its complications during the course of hospitalization, the development of nosocomial infections with positive cultures, the presence of chronic disease or immunodeficiency, various interventional techniques (mechanical ventilation, central catheters), and PICU outcome . RESULTS: During a six-month period 174 patients were admitted to the PICU and received antibiotics for a total of 950 days (62.3% of the length of stay days) . While in PICU, 34 patients did not receive antimicrobial treatment (19.5%), 69 received one antibiotic (39.7%), 42 two (24.1%), 17 three (9.8%), and 12 more than three (6.9%) . The number of antibiotics prescribed in PICU or at discharge did not differ from that at admission . Indications for receiving antibiotics the day before admission and throughout during hospitalization into PICU were significantly correlated . Although the cumulative number of administered antibiotics did not correlate with mortality (9.8%), it was significantly related to the severity scoring systems PRISM (p <.001), TISS (p <.002) and was significantly related to the number of isolated microorganisms (p <.0001) . Multiple regression analysis demonstrated that independent determinants of the cumulative number of antibiotics were: prior administration of antibiotics, presence of a bloodstream infection, positive bronchial cultures, immunodeficiency, and severity of illness . CONCLUSION: Prior antimicrobial therapy should be recognized as an important risk factor for extended antimicrobial therapy among critically ill children . Severity of illness, immunodeficiency, and prolonged length of stay are additional risk factors.

Arch Pharm Res, 2004 Mar, 27(3), 314 - 8
Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells; Kim SS et al.; Microglia are the major inflammatory cells in the central nervous system and become activated in response to brain injuries such as ischemia, trauma, and neurodegenerative diseases including Alzheimer's disease (AD) . Moreover, activated microglia are known to release a variety of proinflammatory cytokines and oxidants such as nitric oxide (NO) . Minocycline is a semisynthetic second-generation tetracycline that exerts anti-inflammatory effects that are completely distinct form its antimicrobial action . In this study, the inhibitory effects of minocycline on NO and prostaglandin E2 (PGE2) release was examined in lipopolysaccharides (LPS)-challenged BV2 murine microglial cells . Further, effects of minocycline on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression levels were also determined . The results showed that minocycline significantly inhibited NO and PGE2 production and iNOS and COX-2 expression in BV2 microglial cells . These findings suggest that minocycline should be evaluated as potential therapeutic agent for various pathological conditions due to the excessive activation of microglia.

Clin Pharmacokinet, 2004, 43(6), 405 - 15
Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages; Pea F et al.; OBJECTIVE: To define the optimal dosage regimen of teicoplanin that ensures early therapeutically relevant trough concentrations (C(min)) {>10 mg/L at 24 hours and possibly close to 20 mg/L at 48 hours} in patients with acute leukaemia who develop febrile neutropenia after chemotherapy . DESIGN: Prospective observational pharmacokinetic study . PARTICIPANTS: Adult patients (n = 33) with normal renal function previously treated with antineoplastic chemotherapy because of acute lymphocytic or acute nonlymphocytic leukaemia, and subsequently developing febrile neutropenia treated with empirical antimicrobial therapy . DESIGN: First, the standard dosage group (n = 11) was administered standard loading and maintenance doses of teicoplanin (400 mg every 12 hours for three doses followed by 400 mg once daily) . Blood samples were collected at defined times as part of routine monitoring and assessed for teicoplanin plasma concentration by fluorescence polarisation immunoassay . Secondly, the high dosage group (n = 22) received a high loading regimen (800 + 400 mg 12 hours apart on day 1, 600 + 400mg 12 hours apart on day 2) followed by a high maintenance regimen (400 mg every 12 hours) from day 3 on.RESULTS: In the standard dosage group, no patient had the recommended teicoplanin C(min) of >or=10 mg/L within the first 72 hours, and only five of the 11 patients (45%) had a C(min) of >or=10 mg/L after 120 hours . No patient had a C(min) of >or=20 mg/L . In the high dosage group, teicoplanin C(min) averaged >or=10 mg/L within 24 hours, and this value was achieved within 48 hours in all but one patient . Of note, C(min) at 72 hours exceeded 20 mg/L in ten of the 22 patients (45%) . No patient experienced significant impairment of renal function . CONCLUSIONS: In this patient group, therapeutically relevant C(min) may be achieved very early in the treatment period with loading doses of 12 mg/kg and 6 mg/kg 12 hours apart on day 1, and 9 mg/kg and 6 mg/kg 12 hours apart on day 2, regardless of renal function . Subsequently, in patients with normal renal function a maintenance dosage of 6 mg/kg every 12 hours may be helpful in ensuring C(min) close to 20 mg/L . Assessment of C(min) after 48-72 hours may be useful to individualise teicoplanin therapy . Factors increasing volume of distribution and/or renal clearance of teicoplanin (fluid load, hypoalbuminaemia, leukaemic status) may explain the need for higher dosages.

Aust Vet J, 2003 Aug, 81(8), 480 - 7
The medicine and epidemiology of bovine respiratory disease in feedlots; Cusack PM et al.; Bovine Respiratory Disease (BRD) results from a complex, multifactorial interaction of stressors, animal susceptibility, and respiratory pathogens . The infectious agents associated with BRD are ubiquitous among cattle populations . Typically, one or a combination of stressors are necessary to initiate BRD . Prevention of BRD should, therefore, address management procedures to minimise stressors . Administration of vaccines against BRD agents may help reduce the incidence of BRD but is unlikely to eliminate the condition . The effectiveness of antimicrobials in the treatment of BRD depends primarily on early recognition and treatment . The use of antioxidant vitamins, minerals or other agents in the prevention and treatment of BRD warrants further research.

Bacteriol Virusol Parazitol Epidemiol, 2002 Jul-Dec, 47(3-4), 173 - 8
{Resistance phenotypes circulating in nosocomial high risk departments}; Licker M et al.; OBJECTIVES: Between November 2001-January 2002 we collected 406 samples from patients hospitalized in Intensive Care adults and new-borns Unit (ICU) . The aim was to observe the colonization and infection status with bacteria that may have nosocomial potential and to establish circulating phenotypes in ICUs . METHODS: The identification was performed by API (bioMerieux) method, and we have performed the antimicrobial susceptibility tests by both: API method and by Kirby-Bauer disc-diffusion test . RESULTS: We isolated 295 strains with nosocomial potential: 34 MRSA strains, 23 MRCNS strains, 29 ESBL producing gram negative rods, etc . CONCLUSIONS: We observed the presence of multiple drug resistant bacteria which play an important roll in both: massive colonization of patients and in the etiology of nosocomial infections . This leads us to the conclusion that antibiotic resistance pattern should be interpreted by the bacteriologist and a consistent policy concerning the use of antimicrobial drugs in hospital settings should be instituted.

Boll Chim Farm, 2004 Jan-Feb, 143(1), 34 - 9
Synthesis of some thiazolyl and thiadiazolyl derivatives of 4(3H)-quinazolinone as anti-inflammatory-antimicrobial agents; Bekhit AA et al.; This paper describes the synthesis of four series of 4(3H)-quinazolinone derivatives . The first series was prepared by cyclization of the intermediate 3-aryl-2-substituted thiocarbamoylhydrazonomethyl-4(3H)-quinazolinones 2a,b with ethyl bromoacetate to afford the corresponding thiazolidinonyl derivatives 3a,b . The second series were prepared by the cyclization of the intermediate 2a,b with phenacyl bromide or 4-substituted phenacyl bromide giving rise to thiazolinyl derivatives 4a-f . Furthermore, the thiazolidinonyl derivatives 5a,b were obtained by reaction of the intermediate 2a,b with thioglycolic acid . On the other hand, heating the intermediate 2a,b with acetic anhydride afforded the corresponding thiadiazolinyl derivatives 6a,b . Some of the synthesized compounds showed promising anti-inflammatory-antimicrobial activities.

Mar Biotechnol (NY) . 2004 Apr 19; {Epub ahead of print}
Sustainable Production of Bioactive Compounds by Sponges-Cell Culture and Gene Cluster Approach: A Review; Muller WE et al.; Sponges (phylum Porifera) are sessile marine filter feeders that have developed efficient defense mechanisms against foreign attackers such as viruses, bacteria, or eukaryotic organisms . Protected by a highly complex immune system, as well as by the capacity to produce efficient antiviral compounds (e.g., nucleoside analogues), antimicrobial compounds (e.g., polyketides), and cytostatic compounds (e.g., avarol), they have not become extinct during the last 600 million years . It can be assumed that during this long period of time, bacteria and microorganisms coevolved with sponges, and thus acquired a complex common metabolism . It is suggested that (at least) some of the bioactive secondary metabolites isolated from sponges are produced by functional enzyme clusters, which originated from the sponges and their associated microorganisms . As a consequence, both the host cells and the microorganisms lost the ability to grow independently from each other . Therefore, it was-until recently-impossible to culture sponge cells in vitro . Also the predominant number of "symbiotic bacteria" proved to be nonculturable . In order to exploit the bioactive potential of both the sponge and the "symbionts," a 3D-aggregate primmorph culture system was established; also it was proved that one bioactive compound, avarol/avarone, is produced by the sponge Dysidea avara . Another promising way to utilize the bioactive potential of the microorganisms is the cloning and heterologous expression of enzymes involved in secondary metabolism, such as the polyketide synthases.

J Infus Nurs, 2004 Mar-Apr, 27(2), 79 - 84
Judicious use of antimicrobials in the critical care setting; Horner M; This article reviews the judicious use of antibiotics in an intensive care setting . Risk factors for both infection and antimicrobial resistance are discussed . Various methods hospitals can apply to promote the optimal use of antibiotics also are reviewed . These methods include empiric therapy, antibiotic cycling, treatment guidelines and protocols, and antibiotic susceptibility monitoring.

Clin Microbiol Rev, 2004 Apr, 17(2), 268 - 80
Determination of fungicidal activities against yeasts and molds: lessons learned from bactericidal testing and the need for standardization; Pfaller MA et al.; In certain unique clinical settings, the ability of the antimicrobial agent administered to kill the pathogen outright may be quite important . These situations invariably involve infection of a site not easily accessed by host defenses and/or of a structure with essential anatomic or physiologic function such as the heart (endocarditis), central nervous system (meningitis), or bone (osteomyelitis) . Likewise, infections in immunosuppressed hosts, especially those who are neutropenic, are often thought to require microbicidal therapy . Proof of the cidal nature of an antimicrobial agent in vitro is tedious, complex, and fraught with error . Although several methods for assessing in vitro bactericidal activity have been standardized (NCCLS M26-A and M21-A), the clinical relevance of these determinations is questionable and the tests are performed infrequently in most laboratories . Most of the clinical data supporting the need for microbicidal therapy and testing have focused on bacterial infections . However, given the fact that most serious fungal infections occur in profoundly immunosuppressed individuals, it is generally assumed that a cidal regimen would be preferable in that setting as well . In view of this clinical concern and the perceived need to assess the fungicidal activity of a variety of agents, we considered that it would be useful to review what is known about the issues and problems in assessing bactericidal activity and the clinical utility of such measurements . Following this review, we discuss the issue of how one defines fungicidal activity in vitro and in vivo and how feasible it might be to determine the fungicidal activity of organism-drug combinations for purposes of both drug development and clinical care . Proposed methods for fungal time-kill determinations and minimal fungicidal concentration determinations are also discussed.

Biochem J, 2004 Jul 1, 381(Pt 1), 79 - 86
A new class (penaeidin class 4) of antimicrobial peptides from the Atlantic white shrimp (Litopenaeus setiferus) exhibits target specificity and an independent proline-rich-domain function; Cuthbertson BJ et al.; A highly pure, chemically defined representative of a new class of antimicrobial peptide from the Atlantic white shrimp (Litopenaeus setiferus), penaeidin class 4 {Pen4-1 (penaeidin class 4 isoform 1)}, was produced synthetically . Chemical synthesis was achieved by native ligation from two separate domains yielding a bioactive peptide that reflected the characteristics of native penaeidin . Synthetic Pen4-1 proved to be an effective antimicrobial peptide, particularly against the broad-spectrum pathogen Fusarium oxysporum, exhibiting a complex effect on reproductive growth at inhibitory concentrations resulting in the suppression of spore formation . Pen4-1 exhibits unique features {not previously observed for penaeidins from the Pacific white shrimp (L . vannamei)}, including target-species specificity against Gram-positive bacteria, indicating a potential partitioning of antimicrobial function among this family of peptides . The proline-rich domain of penaeidin class 4 alone was an active antimicrobial peptide, having the same target range as the full-length Pen4-1 . These findings indicate that the proline-rich domain of penaeidin is sufficient to confer target specificity and that divergence in this domain between classes can result in a gain in antimicrobial function as observed for the proline-rich domain of Pen4-1.

J Formos Med Assoc, 2004 Feb, 103(2), 96 - 103
Antimicrobial usage in ambulatory patients with respiratory infections in Taiwan, 2001; Ho M et al.; BACKGROUND AND PURPOSE: Excess use of antimicrobials by ambulatory patients is a determinant of antimicrobial resistance . This study investigated the types of illnesses for which antimicrobials were prescribed and the amounts prescribed with special emphasis on respiratory infections for the year in which the Bureau of National Health Insurance (BNHI) enforced a policy to restrict antimicrobials for upper respiratory infections . The number of ambulatory patients seen and the types of ambulatory facilities in Taiwan were also described . METHODS: Raw data were obtained from the BNHI database on every 500 th visit in 2001 . Medical diagnoses were categorized according to the ICD-9-CM system . Antimicrobial consumption was expressed in defined daily doses per 1000 population per day (DDD/1000/day) . RESULTS: Among the population of 22.3 million in Taiwan, there were 285.8 million ambulatory patient visits (12.8 per person), including 108.9 million visits (4.9 per person) for respiratory infections, of which 62.7 million (2.8 per person) were for upper respiratory infections (URI) . Antimicrobial consumption was 19.83 DDD/1000/day {standard error (SE), 0.00055}, of which 9.97 DDD/1000/day (SE, 0.00047) were for respiratory infections and 4.03 DDD/1000/day (0.00055) were for URI . 23.6% of visits for URI entailed a prescription for antimicrobials . About two-thirds (66.5%) of ambulatory patients were seen in clinics, mostly private ones, and 67.6% of all antimicrobials were received there . Aminopenicillins and cephalosporins constituted 35.2% and 19.5%, respectively, of antimicrobials prescribed . CONCLUSIONS: Despite the new BNHI rule restricting antimicrobial usage for URI, Taiwan still has an excessive number of ambulatory patient visits, especially for respiratory infections and URI . The majority of antimicrobials used were for URI . They were mostly prescribed in private clinics rather than hospital outpatient departments.

Nat Rev Microbiol, 2004 Mar, 2(3), 251 - 8
Opinion - anti-infectives: Confronting bacterial resistance in healthcare settings: a crucial role for microbiologists; McGowan JE et al.; Bacteria that are resistant to antimicrobial agents, which were previously isolated primarily in acute-care hospitals, now cause infection in a wide range of other healthcare settings . Improved detection of new resistant strains - especially by using practical and affordable screening methods and by evaluating mechanisms of resistance - is a priority for tackling this problem effectively . Standardized, effective surveillance systems for evaluating the emergence and prevalence of resistant strains are necessary to assess the success of intervention strategies.

J Korean Med Sci, 2004 Apr, 19(2), 218 - 22
Molecular analysis of X-linked chronic granulomatous disease in five unrelated Korean patients; Oh HB et al.; Chronic granulomatous disease (CGD) is a fatal genetic disorder in which phagocytes fail to produce antimicrobial superoxide because of NADPH oxidase deficiency . Molecular defects in CYBB gene causing X-linked CGD are responsible for about 70% of all cases . This study was done to confirm genetic defects of CYBB gene in five Korean patients who were highly suggestive of having CGD by clinical history . We performed initial screening for five unrelated Korean patients using single strand conformation polymorphism (SSCP) and then selective sequencing for the regions involving the abnormal bands . Activated NBT tests revealed that all patients were X-linked . SSCP analysis for CYBB gene showed abnormal bands in all patients . The molecular defects of five patients were as follows: c.1663insT, c.1111-1G>T, c.39_40insG, c.927delC and c.434T>C mutation . This result will help the families with prenatal diagnosis or genetic counseling.

J Magn Reson, 2004 May, 168(1), 153 - 63
Orientation of the antimicrobial peptide PGLa in lipid membranes determined from 19F-NMR dipolar couplings of 4-CF3-phenylglycine labels; Glaser RW et al.; A highly sensitive solid state (19)F-NMR strategy is described to determine the orientation and dynamics of membrane-associated peptides from specific fluorine labels . Several analogues of the antimicrobial peptide PGLa were synthesized with the non-natural amino acid 4-trifluoromethyl-phenylglycine (CF(3)-Phg) at different positions throughout the alpha-helical peptide chain . A simple 1-pulse (19)F experiment allows the simultaneous measurement of both the anisotropic chemical shift and the homonuclear dipolar coupling within the rotating CF(3)-group in a macroscopically oriented membrane sample . The value and sign of the dipolar splitting determines the tilt of the CF(3)-rotational axis, which is rigidly attached to the peptide backbone, with respect to the external magnetic field direction . Using four CF(3)-labeled peptide analogues (with L-CF(3)-Phg at Ile9, Ala10, Ile13, and Ala14) we confirmed that PGLa is aligned at the surface of lipid membranes with its helix axis perpendicular to the bilayer normal at a peptide:lipid ratio of 1:200 . We also determined the azimuthal rotation angle of the helix, which agrees well with the orientation expected from its amphiphilic character . Peptide analogues with a D-CF(3)-Phg label resulting from racemization of the amino acid during synthesis were separately collected by HPLC . Their spectra provide additional information about the PGLa structure and orientation but allow only to discriminate qualitatively between multiple solutions . The structural and functional characterization of the individual CF(3)-labeled peptides by circular dichroism and antimicrobial assays showed only small effects for our four substitutions on the hydrophobic face of the helix, but a significant disturbance was observed in a fifth analogue where Ala8 on the hydrophilic face had been replaced . Even though the hydrophobic CF(3)-Phg side chain cannot be utilized in all positions, it allows highly sensitive NMR measurements over a wide range of experimental conditions and dynamic regimes of the peptide.

Biochem Biophys Res Commun, 2004 May 7, 317(3), 882 - 6
Antimitochondrial activity displayed by the antimicrobial peptide microcin J25; Niklison Chirou MV et al.; In this report we studied the effect of the antimicrobial peptide, microcin J25, on the rat heart mitochondria . This peptide induced an important inhibition of the ATP synthesis with the concomitant enhancement of the ATP degradation . These effects were the result of two processes: on one hand, microcin J25 was able to insert into the membrane and hence alter its permeability with the consequent dissipation of the proton motive force . On the other, microcin J25 inhibited the enzymatic activity of the cytochrome c reductase (complex III) of the respiratory chain . The relevance of this study to the potential use of microcin J25 as an anti-tumoral agent is discussed.

Phytochemistry, 2004 Apr, 65(7), 881 - 4
Chemical composition and antimicrobial activity of the essential oil of Scutellaria barbata; Yu J et al.; The essential oil of Scutellaria barbata was obtained by hydrodistillation with a 0.3% (v/w) yield and analysed by GC and GC-MS . The main compounds in the oil were hexahydrofarnesylacetone (11.0%), 3,7,11,15-tetramethyl-2-hexadecen-1-ol (7.8%), menthol (7.7%) and 1-octen-3-ol (7.1%) . The antimicrobial activity of the oil was evaluated against 17 microorganisms using disc diffusion and broth microdilution methods . The gram-positive bacteria, including methicillin-resistant Staphlococcus aureus, were more sensitive to the oil than gram-negative bacteria and yeasts.

Int J Antimicrob Agents, 2004 Apr, 23(4), 405 - 7
In vitro antimicrobial susceptibility of Brucella species; Baykam N et al.; MIC50 and MIC90 values of doxycycline, rifampicin, ciprofloxacin, trimethoprim-sulphamethoxazole and ceftriaxone for 42 blood isolates of Brucella species were determined using the Etest . Thirty-seven isolates were identified as B . melitensis and five as B . abortus . Doxycycline had the lowest and rifampicin the highest MIC50 values . Four strains were non-susceptible to rifampicin, and one strain was resistant to trimethoprim-sulphamethoxazole . There is no significantly important resistance problem for antibiotics targeted against Brucella species in Turkey . However, since rifampicin is commonly used for prevalent diseases such as tuberculosis, the regional susceptibility pattern of rifampicin should be assessed periodically.

Int J Antimicrob Agents, 2004 Apr, 23(4), 382 - 9
Antiviral activity of antimicrobial cationic peptides against Junin virus and herpes simplex virus; Albiol Matanic VC et al.; The in vitro antiviral activity of antimicrobial cationic peptides: cecropin A, melittin, magainin I and II and indolicidin against the arenavirus Junin virus (JV), and herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) was evaluated . Cecropin A effectively inhibited JV multiplication and failed to affect HSV replication whereas melittin impeded the multiplication of JV and HSV, but was highly toxic for the host cell . Magainins I and II exhibited inhibitory action toward HSV-1 and HSV-2 but were inactive against JV . Only indolicidin showed a direct inactivation effect on cell-free virus stocks . Besides its inhibitory effect on JV replication cecropin A also was active against the arenaviruses Tacaribe and Pichinde, mainly affecting late events of arenavirus multiplication cycle by preventing viral morphogenesis and egress from infected cells.

Int J Antimicrob Agents, 2004 Apr, 23(4), 325 - 31
Do cultures contribute to optimisation of antibiotic therapy in the intensive care unit?
Schurink CA, Hoitsma M, Rozenberg-Arska M, Joore JC, Hoepelman IM, Bonten MJ.
Obtaining diagnostic microbiological cultures before initiating empirical antimicrobial therapy is part of the diagnostic work-up of intensive care patients with a clinical suspicion of infection . However, it is unknown to what extent these cultures provide a microbiological cause of infection and to what extent antimicrobial therapy is influenced . During a 6-month period, all episodes of suspected clinical infection were analysed and categorised as non-microbiologically proven infection (non-MPI) or MPI . Effects of culture results on antibiotic therapy were analysed for episodes of respiratory tract infection . Invasive diagnostic techniques were not routinely used for diagnosis of respiratory tract infections . Among 212 patients admitted, 147 episodes of clinical suspicion of infection were recorded (104 for respiratory tract infection) and 1147 microbiological cultures were obtained (0.64 culture per patient day) . Antibiotics were administered on 1111 (62%) of 1803 patients days . Of the respiratory tract infections, 571 cultures resulted in 49 (47%) MPI . Cover with empirical antibiotics was inappropriate in 7 of 104 cases (8%) of respiratory infections . In 12 cases (11.5%) empirical therapy could have been changed based on culture results . Negative cultures were never followed by cessation of therapy, but the duration of treatment was significantly shorter for non-MPI . Forty-seven percent of respiratory tract infections were microbiologically confirmed and, based on culture results, empirical antimicrobial therapy could have been influenced in 11.5% of cases of respiratory tract infections . These findings provide aspects to evaluate and improve the diagnostic work-up of infections in the ICU.

Bioorg Med Chem Lett, 2004 May 3, 14(9), 2067 - 72
DNA binding ligands with in vivo efficacy in murine models of bacterial infection: optimization of internal aromatic amino acids; Burli RW et al.; DNA binding ligands with potent antimicrobial activity against Gram-positive bacteria were further optimized by variation of the internal aromatic amino acids . This modification led to compounds with improved in vivo efficacy in lethal murine models of peritonitis (methicillin-resistant S . aureus, MRSA) and lung infection (S . pneumoniae).

Bioorg Med Chem Lett, 2004 May 3, 14(9), 2061 - 5
Antibacterial activity of glycine betaine analogues: involvement of osmoporters; Cosquer A et al.; Glycine betaine (GB) analogues were obtained using solid phase organic synthesis and assayed for their toxic activity against 15 Gram positive and Gram negative bacteria . Four benzyl derivatives of GB were selected to determine their effect on bacterial growth . Bacteriostatic and lethal effects were observed for compound 1 and compound 2, respectively . The importation of the two GB analogues into bacterial cells appeared strictly dependent on the presence of the powerful betaine membrane osmoporters; their capacity to be amassed intracellularly at molar levels from extremely dilute solutions might constitute a basis to design a new class of antimicrobial agents.

Bioorg Med Chem, 2004 May 1, 12(9), 2483 - 8
Synthesis and evaluation of some new spiro indoline-based heterocycles as potentially active antimicrobial agents; Abdel-Rahman AH et al.; Several new spiro indoline-based heterocycles were synthesized by prior preparation of the 4-(2'-oxo-indol-3'-ylidene)-oxazol-5-one derivatives and subsequent reaction of the produced indol-3-ylidene based heterocycles with activated nitrile reagents . The obtained products were allowed to react with hydrazine hydrate in alcoholic basic to give the target compounds . Structure of these products was confirmed on the bases of elemental as well as spectral data . Representative compounds of the hitherto synthesized products were tested and evaluated as antimicrobial agents.

Bioorg Med Chem, 2004 May 1, 12(9), 2151 - 61
Synthesis and preliminary evaluation of some pyrazine containing thiazolines and thiazolidinones as antimicrobial agents; Bonde CG et al.; A series of N'-{3,4-disubstituted-1,3-thiazol-2(3H)-ylidene}-2-(pyrazin-2-yloxy)acetohydrazide 11-66 and N'-{(2Z)-3-(4-bromophenyl)-4-oxo-1,3-thiazolidin-2-ylidene}-2-(pyrazin-2-yloxy)acetohydrazide 68-74 were synthesized using appropriate synthetic route . The entire test compounds 11-66 and 68-74 were assayed in vitro for antibacterial activity against two different strains of Gram-negative (E . coli and S . typhi), Gram-positive (S . aureus and B . subtilis) bacteria and the antimycobacterial activity was evaluated against H(37)Rv strain of Mycobacterium tuberculosis . The minimum inhibitory concentration (MIC) was determined for test compounds and for reference standards . The test compounds showed significant antibacterial and antimycobacterial activity against the microbial strains used, when tested in vitro . In general, pyrazine ring and substituted thiazoline ring are essential for antimicrobial activity . Among the compounds tested, compounds 11, 12 and 40 were found to be most potent . The toxicity of most potent compounds 11, 12 and 40 were determined using hemolytic assay and minimal hemolytic concentration (MHCs) were determined . The test compounds were found to be nontoxic up to a dose level of 250 microg/mL.

Mol Cancer Ther, 2004 Apr, 3(4), 403 - 7
N'-(phenyl-pyridin-2-yl-methylene)-hydrazine carbodithioic acid methyl ester enhances radiation-induced cell death by targeting Bcl-2 against human lung carcinoma cells; Park JK et al.; To develop a new radiosensitizer, we screened a chemical library and selected one chemical reagent, N'-(phenyl-pyridin-2-yl-methylene)-hydrazine carbodithioic acid methyl ester (PHCM), which was already known to have antifungal and antimicrobial properties . PHCM enhanced radiation-induced cell death and its mean calculated dose enhancement ratio was 1.17 . PHCM was found to induce the phosphorylation of p38 mitogen-activated protein kinase, and combined treatment with PHCM and radiation down-regulated Bcl-2 . In a xenograft assay, the combined PHCM and radiation group showed 39.3 days of growth delay versus the control in terms of tumor growth . The enhancement factor of this combined treatment was determined to be 4.02.

J Appl Microbiol, 2004, 96(5), 973 - 81
Selective isolation of bioactive soil actinomycetes belonging to the Streptomyces violaceusniger phenotypic cluster; Hayakawa M et al.; AIMS: To devise and evaluate a strategy for isolating members of the Streptomyces violaceusniger phenotypic cluster, which are known to be a promising source of bioactive metabolites . METHODS AND RESULTS: The treatment of four soil samples with 1.5% phenol (30 degrees C, 30 min) prior to inoculation on humic acid-vitamin (HV) agar eliminated most of the streptomycetes and other bacterial populations . The surviving streptomycetes on the HV isolation plates were subcultured, and species-group identification was made according to the probabilistic identification system of Williams et al . (1989) . Of the 133 streptomycetes subcultured, 102 (77%), were assigned to the S . violaceusniger cluster . A test with an overlay technique revealed that all of these S . violaceusniger-cluster isolates had broad antimicrobial spectra, as they inhibited the growth of all test Gram-positive bacteria, yeasts and filamentous fungi . Antitumour activity against colon carcinoma cells was found among 68 or 67%, of these S . violaceusniger-cluster isolates, following growth in submerged culture . CONCLUSIONS: Chemical pretreatment of soil samples with phenol reduces the growth of ubiquitous Streptomyces species, thereby facilitating the recovery of less-abundant S . violaceusniger-cluster strains that are characterized by high antimicrobial and antitumour activities . SIGNIFICANCE AND IMPACT OF THE STUDY: The development and application of new methodologies with which to selectively isolate rare, bioactive streptomycete groups is important for discovering novel secondary metabolites with bioactive properties.

J Oral Pathol Med, 2004 May, 33(5), 278 - 85
Expression of beta-defensins in gingival health and in periodontal disease; Bissell J et al.; BACKGROUND: Human beta-defensins (HBDs) are epithelial-derived antimicrobial peptides . The expression of three HBDs (HBD-1, HBD-2, and HBD-3) has been reported in oral mucosa, gingiva, and salivary glands . However, their role in protection against oral infections is not well understood . This study examined the expression of HBD-1, HBD-2, and HBD-3 mRNAs in gingival health and periodontal disease . METHODS: Gingival tissue discarded from periodontal procedures was obtained from 20 periodontally healthy and 29 periodontally diseased sites . Total RNA was isolated, and expression of beta-defensins was analyzed by both 35-cycle and semiquantitative (25-cycle) reverse transcription-polymerase chain reaction (RT-PCR) . The level of expression was assigned ordinal scores of no expression, low expression, or high expression . mRNA expression was compared between healthy and diseased groups using exact tests of homogeneity and Cochran-Mantel-Haenszel tests; associations among the variables were assessed using exact tests and Kendall's tau-b statistic . RESULTS: All 49 samples demonstrated basal mRNA expression of HBD-1, HBD-2, and HBD-3 . Significantly higher levels of HBD-3 (P = 0.012) expression were found in the healthy tissues as compared to the diseased ones . There was also a suggestion of higher expression of HBD-2 in the healthy tissues (P = 0.12) . Levels of HBD-1, HBD-2, and HBD-3 mRNA expression were correlated with one another (P < 0.001) . CONCLUSIONS: High levels of HBD-3 mRNA expression in healthy tissues suggest a potentially important protective role for defensins in the host immune response to infection by periodontal pathogens.

J Chemother, 2004 Feb, 16(1), 45 - 50
Incidence of antibiotic resistance in coliforms from drinking water and their identification using the Biolog and the API identification systems; Tokajian S et al.; Antibiotic-resistant bacteria were common in samples collected from an intermittent water distribution system in Lebanon . Multiply-resistant isolates were also present and most commonly to amoxycillin, cephalexin and sulfamethoxazole/trimethoprim . The aminoglycosides (amikacin, gentamicin and kanamycin) were the most effective, with almost all tested strains showing susceptibility to these antimicrobial agents . Both the Biolog GN MicroPlates and the API 20E strips can be used for the identification of coliform bacteria isolated from potable water, but the outcome of the identification should be viewed with caution . 51% of isolates were assigned similar identities by both the Biolog MicroPlates and the API 20E strips . The similarity at the species level was lower (33%) compared to that at the genus level (67%) . The identification of Escherichia coli strains, which represented 30% of all tested organisms, showed 95% similarity in the assigned genus and species using both identification schemes.

Med Trop (Mars), 2003, 63(6), 611 - 3
{Leptospirosis in Espiritu Santo, Vanuatu, 8 case reports}; Moranne O et al.; Our review of the literature on leptospirosis in Vanatu turned up only one previous report describing 3 cases at the Central Port Vila Hospital in 1992 . The purpose of this report is to describe 8 cases of leptospirosis in patients admitted to the North District Hospital on Espiritu Santo Island in 1997 . There were 6 men and 2 women with a mean age of 45 +/- 16 years . At the onset of the disease patients presented fever, myalgia, and diarrhea . After an average of four days initial symptoms were followed by visceral involvement with severe jaundice in all cases . Kidney failure occurred in 6 cases and neurological manifestations in 5 . Subconjunctival hemorrhage was observed in 2 cases . Laboratory studies demonstrated hyperleukocytosis in 6 cases and liver enzyme abnormalities in 6 cases . Three patients presented Weil syndrome . Microscopic agglutination testing performed more than a week after the onset of disease was positive at 1/800 in 6 cases and at 1/200 with typical clinical abnormalities and positive serum PCR in 2 cases . All patients responded favorably to antimicrobial therapy using penicillin IV and symptomatic treatment . The estimated incidence of leptospirosis in the North District of the Island of Espiritu Santo, in 1997 was 40/100,000 person-year but this was probably an underestimation because of unawareness of the disease, poor access to medical care, and underdiagnosis.

Cornea, 2004 Mar, 23(2), 158 - 64
Impact of prior therapy on the recovery and frequency of corneal pathogens; Marangon FB et al.; OBJECTIVE: To document the impact of prior antibiotic therapy on the recovery of corneal pathogens . METHODS: Medical records and laboratory reports of 334 consecutive microbial keratitis patients examined from January to December 2000 were reviewed . Comparisons of pathogens, culture positive rate, recovery time, antibiotic sensitivity profile, delay in presentation, and final visual acuity were analyzed for patients treated before presentation and those who were not . The chi square test was used to determine statistical significance . RESULTS: Of the 334 patients, 56% were exposed to at least one course of topical antimicrobials before culture . Patients on therapy were only slightly more likely to be culture negative (P = 0.317) but significantly more likely to have a delay in pathogen recovery (P = 0.002) . Patients given prior antibiotics took significantly longer to heal (P = 0.003) . Gram-negative organisms (47.5%) were the most frequent pathogens isolated from all culture-positive patients, followed by gram positives (28.7%), fungi (15.8%), and parasites (2%) . An increase and significant difference in the frequency of fungi (P = 0.000) and acanthamoeba was reserved for the pretreated group . Gram negative organisms were more often isolated from patients who had not been pretreated (P = 0.002) . Pretreated patients were more like to have a pathogen resistant to 1 or more of the commonly prescribed ocular antibiotics (P = 0.02) . CONCLUSIONS: There is a delay in starting microbiologic-guided antibiotic treatment in patients who have received empiric therapy . Nonbacterial corneal pathogens may be associated more frequently with patients on prior therapy.

J Biol Chem, 2004 Jun 18, 279(25), 25955 - 8 Epub 2004 Apr 09.
Antimicrobial and pore-forming peptides of free-living and potentially highly pathogenic Naegleria fowleri are released from the same precursor molecule; Herbst R et al.; The pore-forming polypeptides of Naegleria fowleri, naegleriapores A and B, are processed from separate multipeptide precursor structures . According to their transcripts, each precursor molecule appears to contain additional naegleriapore-like polypeptides, all of which share a structural motif of six invariant cysteine residues within their amino acid sequence . To identify the putative pronaegleriapore-derived peptides at the protein level, amoebic extracts were screened for small cysteine-rich polypeptides by fluorescently labeling their cysteine residues . Three novel naegleriapore isoforms derived from the precursor molecule of naegleriapore B were identified . Two of the isoforms were purified to homogeneity and tested for their biological activity . The pore-forming activity of the novel peptides was remarkably lower than that of the originally isolated naegleriapores, but both peptides killed bacteria by permeabilizing their cytoplasmic membranes . Collectively, these results indicate that naegleriapore isoforms with antibacterial and pore-forming activity are proteolytically released from the same precursor protein, presumably to generate a phylogenetically ancient complementary antimicrobial arsenal.

Pharmazie, 2004 Mar, 59(3), 226 - 30
Comparative study of the essential oils and extracts of Achillea fragrantissima (Forssk.) Sch . Bip . and Achillea santolina L . (Asteraceae) from Egypt; el-Shazly AM et al.; Essential oils obtained by steam distillation from the aerial parts of Achillea fragrantissima (Forssk.) Sch . Bip . and the flower, leaf and stem of A . santolina L . as well as their lipophilic constituents obtained by solvent extraction were analysed using GLC and GLC-mass spectrometry . Nineteen constituents in the essential oil of A . fragrantissima were identified, in addition to 41 compounds from its n-hexane-ether extract . The hydrodistilled oil and the solvent extract contain santolina alcohol, artemisia alcohol, artemisia ketone, cis-thujone and trans-thujone as major constituents . In A . santolina altogether 54 volatile components were detected . The major components were 1,8-cineole, fragranol, fragranyl acetate and terpin-4-ol . Furthermore, the essential oils and the n-hexane-ether extracts of the two plants were screened for their antimicrobial activity.

Cutis, 2004 Mar, 73(3), 183 - 7
Facial hygiene and comprehensive management of rosacea; Draelos ZD; The skin of patients with rosacea is exquisitely sensitive to various dietary, environmental, and topical factors that initiate the facial erythema characteristic of this sensitive skin condition . This sensitivity is probably due to epidermal barrier dysfunction . Overall management of rosacea involves the avoidance of dietary and environmental triggers, concurrent with the use of prescription therapies . The appropriate selection of over-the-counter and prescription skin care products is equally important . This article reviews the use of therapeutic skin cleansers, including the newest category of prescription antimicrobial cleansers, which can enhance the overall management of this inflammatory dermatologic disorder.

Pharmacoepidemiol Drug Saf, 1998 Aug, 7 Suppl 1, S23 - 36
Allergy to antibacterials: the problem with beta-lactams and sulfonamides; Cerny A et al.; This paper reviews the incidence, clinical manifestations, differential diagnosis, risk factors and pathogenesis of allergic reactions of two important classes of antimicrobials: beta-lactams and sulfonamides . The diagnostic work-up of a patient with a history of an allergic reaction will be discussed as well as the possibility of safe administration of the drug in the face of an allergy using desensitization . Emerging concepts of beta-lactam side-chain allergy, the role of cellular immune mechanisms and the clinical importance of cross-reactivity of allergic reactions to different classes of beta-lactams will be emphasized .

Pharmacoepidemiol Drug Saf, 1997 Jan, 6(1), 49 - 56
Problems with drugs in Croatia; Vrhovac B; Croatia has 4.8 million inhabitants, 11,800 physicians, 2000 pharmacists, two now shareholding, pharmaceutical companies (about 6500 employees, total sales of about 350 million US dollars) . There are a number of problems due to the war (GNP fell from 3800 to about 1500 US dollars), occupation of 25% of its territory, 0.5 million refugees and lack of resources (139 US dollars/capita for health, about 40 US dollars i.e . 30%!! for drugs)--about three times less than before the aggression . The drug situation is controlled with the help of: (1) donations (approximate value of 600 million US dollars since 1991 from Europe and US), (2) (essential) drug formularies--250 for outpatients, and 580 generic names for various levels of hospital use, (3) special efforts to purchase drugs of good quality at a reasonable price (a kind of tender), (4) control of prescribing (prescriptions, specialists referral) especially by GPs . A new Medicines Act is in preparation and about 1000 generic names are on the market . DRUG EDUCATION: Pharmaca: the Croatian journal of pharmacotherapy has been published since 1962, there are several Drug bulletins (one published since 1975); special chapters on clinical pharmacology in textbooks, translation of three editions of Laurence's textbook with special commentary and adaptation to local needs; ADR spontaneous and intensive monitoring (WHO programme) with a personal feedback to the reporters and regular articles on drug use in a number of periodicals . Data on drug consumption indicates that there is room for improvement of prescribing . There is an enthusiasm for 'vasoactive drugs'--after dipirydamole came oxpentifylline and antimicrobials are always overprescribed . All these problems will hopefully decrease when the war finally stops and when industry (especially tourism) starts being fruitful again . In any case the importance of teaching of pharmacotherapy at the under- and postgraduate level should be recognized .

Pharmacoepidemiol Drug Saf, 1997 Mar, 6(2), 93 - 100
Temporal trends in drug use in one UK region, revealed by chemical group matching; Rafferty T et al.; (1) The pharmaceutical pricing data for Northern Ireland were amended to include defined daily dosages (DDD) for all single chemical entities . Eight therapeutic groups were studied: antiasthmatics, antidepressants, antimicrobials, benzodiazepines, hormone replacement therapy (HRT), hypoglycaemics, lipid-lowering agents and ulcer-healing drugs . Each group was then subdivided into its main chemical groups . The regional use of each chemical group was defined as the combined DDDs of its individual chemical entities per quarter year, from January 1989 until December 1994 . (2) During this period, drug use increased in all eight therapeutic groups and in most of their constituent chemical groups . Increased use of newer drugs did not cause the expected decrease in use of established drugs . Use of all broad-spectrum antimicrobials increased by 314% . Use of sedative benzodiazepines decreased slowly and steadily (16%) throughout the study period but use of all hypnotics increased inexplicably by 21% in 1992 reaching a plateau in 1993 and 1994 . SSRI antidepressant use increased sharply (5333%) following their introduction in 1989, accompanied by a 24% increase in use of tricyclic antidepressants . There was a 23,626% increase in the use of proton pump inhibitors and a smaller but steady increase of 38% in use of histamine H(2) antagonists; it is unlikely that much of the prescribing of anti-ulcer and antimicrobials was accurately targeted and rationally defensible . (3) More positively, use of beta(2)-agonist inhalers increased by 45% despite a 254% increase in the use of inhaled steroids . Use of HRT increased by 389% though evidence of under-use is given . There was a steady increase in the use of both insulins (28%) and oral hypoglycaemics (34%) . The use of 'statins' (690%) and fibrates (123%) increased . (4) The possible interpretations and implications of these patterns of drug use is discussed, together with their potential as proxies for morbidity incidence in the community .

Int J Pharm, 2004 Apr 15, 274(1-2), 167 - 83
Formulation and preliminary in vivo dog studies of a novel drug delivery system for the treatment of periodontitis; Kelly HM et al.; A novel drug delivery system for the treatment of periodontitis was developed using two components . The first was tetracycline base loaded into the microtubular excipient halloysite, which was coated with chitosan to further retard drug release . Encapsulation efficiencies of 32.5% were achieved with the loading procedure, with tetracycline base showing in vitro release for up to 50 days in simulated gingival crevicular fluid . The second component developed was a vehicle for the drug loaded coated halloysite, which was primarily based on the thermoresponsive polymer, poloxamer 407 . A concentration of 20% was chosen with the thermoresponsivity of the system modified using PEG 20,000 so that the mobile product at room temperature would gel by temperature rise following syringing into a periodontal pocket . Retention of the overall system in the pocket was further improved by the addition of octyl cyanoacrylate (OCA) . The thermoresponsivity of the poloxamer 407 system proved to be sensitive to the presence of added excipients with the levels of PEG 20,000 and OCA requiring modification in the presence of the halloysite component . A final formulation was developed which consisted of 200 mg of halloysite double loaded with tetracycline base and coated with chitosan, suspended in 1 ml of poloxamer 407 20% (w/w), PEG 20,000 0.5% (w/w), OCA 1.0% (w/w), water to 100%, adjusted to pH 4 . The syringeability of this formulation at various temperatures was evaluated to ensure ease of delivery to the periodontal pocket . A stability study was performed to examine the change in thermoresponsivity over time, with the final formulation found to be stable for at least 9 months when stored at room temperature (approximately 20 degrees C) . This formulation offered ease of delivery to the periodontal pocket and sustained release of the antibiotic for up to 6 weeks . The formulation had preliminary in vivo testing performed in dogs to determine levels of drug release, antimicrobial activity and retentive ability of the product . A wound pocket creation model was developed for the purposes of the trial . The product was easy to deliver to the pockets with application times of less than 1 min . Results showed the product was retained in the pocket for up to 6 weeks with effective tetracycline levels released locally over this time period, which achieved good antibacterial activity.

Drug Resist Updat, 2004 Feb, 7(1), 41 - 51
Opportunistic amoebae: challenges in prophylaxis and treatment; Schuster FL et al.; This review focuses on free-living amoebae, widely distributed in soil and water, causing opportunistic and non-opportunistic infections in humans: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea . Diseases include primary amoebic meningoencephalitis (N . fowleri), granulomatous amoebic encephalitis, cutaneous and nasopharyngeal infections (Acanthamoeba spp., Balamuthia mandrillaris, S . diploidea), and amoebic keratitis (Acanthamoeba spp) . Acanthamoeba, Balamuthia, and Naegleria have been repeatedly isolated; S . diploidea has been reported only once, from a brain infection . Antimicrobial therapy for these infections is generally empirical and patient recovery often problematic . N . fowleri is highly sensitive to the antifungal agent amphotericin B, but delay in diagnosis and the fulminant nature of the disease result in few survivors . Encephalitis and other infections caused by Acanthamoeba and Balamuthia have been treated, more or less successfully, with antimicrobial combinations including sterol-targeting azoles (clotrimazole, miconazole, ketoconazole, fluconazole, itraconazole), pentamidine isethionate, 5-fluorocytosine, and sulfadiazine . The use of drug combinations addresses resistance patterns that may exist or develop during treatment, ensuring that at least one of the drugs may be effective against the amoebae . Favorable drug interactions (additive or synergistic) are another potential benefit . In vitro drug testing of clinical isolates points up strain and species differences in sensitivity, so that no single drug can be assumed effective against all amoebae . Another complication is risk of activation of dormant cysts that form in situ in Acanthamoeba and Balamuthia infections, and which can lead to patient relapse following apparently effective treatment . This is particularly true in Acanthamoeba keratitis, a non-opportunistic infection of the cornea, which responds well to treatment with chlorhexidine gluconate and polyhexamethylene biguanide, in combination with propamidine isothionate (Brolene), hexamidine (Desomodine), or neomycin . Acanthamoeba spp . may also be carriers of endosymbiotic bacteria (Legionella and Legionella-like pathogens) and have been implicated in outbreaks of pneumonias in debilitated hosts . As with other infectious diseases, recovery is dependent not only on antimicrobial therapy, but also on patient's immune status, infective dose and virulence of the ameba strain, and on how early the disease is diagnosed and drug therapy initiated.

Crit Care Med, 2004 Apr, 32(4), 938 - 45
Causes and predictors of nonresponse to treatment of intensive care unit-acquired pneumonia; Ioanas M et al.; OBJECTIVE: To prospectively evaluate the predictive factors for the nonresponse to empirical antibiotic treatment and mortality in patients with intensive care unit-acquired pneumonia . DESIGN: A 1-yr prospective cohort of patients with suspicion of intensive care unit-acquired pneumonia . SETTING: Five medical and surgical intensive care units of Hospital Clinic in Barcelona . PATIENTS: A total of 71 patients with intensive care unit-acquired pneumonia were studied . The definition of nonresponse included at least one of the following: failure to improve the Pao2/Fio2 ratio or need of intubation because of pneumonia, persistence of fever or hypothermia and purulent respiratory secretions, worsening of pulmonary infiltrates, or occurrence of septic shock or multiple organ dysfunction not present at onset of pneumonia . INTERVENTIONS: Clinical assessment, including severity scores, blood and quantitative cultures of respiratory secretions, and cytokine measurements in serum and bronchoalveolar lavage at onset of pneumonia and 72 hrs after antimicrobial treatment . MEASUREMENTS AND RESULTS: A total of 44 patients (62%) fulfilled criteria of nonresponse, and at least one cause of nonresponse could be determined in 28 cases (64%): inappropriate treatment in ten (23%), superinfection in six (14%), concomitant foci of infection in 12 (27%), and noninfectious causes in seven cases (16%) . The remaining 16 patients with no definite cause of nonresponse presented with septic shock, multiple organ dysfunction, or acute respiratory distress syndrome . Increased levels of interleukin-6 at onset of pneumonia (odds ratio, 9.7; p =.014) was an independent predictor of nonresponse to treatment . Likewise, increased level of interleukin-6 at follow-up (odds ratio, 27; p =.001) was the only independent predictor for hospital mortality . CONCLUSION: Increased systemic inflammatory response was the main predictor of nonresponse to treatment and mortality.

Curr Opin Pulm Med, 2004 May, 10(3), 204 - 10
Alternative and/or integrative therapies for pneumonia under development; Cazzola M et al.; PURPOSE OF REVIEW: Increasing antimicrobial resistance among common respiratory bacteria has created challenges in selecting appropriate therapy for pneumonia . Fortunately, the analysis of genome sequences has allowed us to find novel, nontraditional targets that are involved in disease pathogenesis or in adaptation and growth in infection sites . The advantage of the nonclassical targets is that targeting these sites could ablate infection without inducing resistance . Interfering with bacterial adhesion, inhibiting, neutralizing and clearing endotoxin, and administering cytokines as immunoadjuvants are the most promising alternative or integrative treatments for pneumonia that are under development . RECENT FINDINGS: Interference with bacterial adhesion is possible using inhibitors of sortase or inactivators of the srtA gene against gram-positive bacteria, inhibitors of the periplasmic chaperone or those of usher function against gram-negative bacteria, novel polysaccharides that are present on echinoderm surfaces, antiadhesin vaccines, or the passive administration of antiadhesin antibodies . Inhibition, neutralization, and clearance of endotoxin possibly interferes in the lipid A biosynthetic pathway or using lipid A analogues with reduced or lack of ability to activate the major endotoxin receptors or proteins such as recombinant Limulus antilipopolysaccharide factor, bactericidal/permeability increasing protein, or lipopolysaccharide binding protein . Tumor necrosis factor 70-80, an adenoviral vector that encodes murine tumor necrosis factor alpha, and recombinant interferon gamma seem to be the most promising cytokines for use as immunoadjuvants for the treatment of pneumonia . SUMMARY: Ideally, potential treatment of life-threatening bacterial pneumonia will combine immunoadjuvant and conventional antibiotic therapy . Compounds capable of stimulating early host defense and microbial clearance, but not the later phases of inflammatory tissue injury associated with sepsis, may be advantageous.

Curr Opin Pulm Med, 2004 May, 10(3), 189 - 96
Newer antibiotics for the treatment of respiratory tract infections; Blasi F et al.; PURPOSE OF REVIEW: In this review, we highlight some of the developments achieved over the past 2 years in the field of novel antimicrobial compounds . RECENT FINDINGS: Modification of existing compound classes to create more powerful compounds capable of overcoming pathogen resistance and the introduction of completely new classes of antibiotics and inhibitors of new bacterial targets or inhibitors of genes relating to virulence or pathogenesis are the strategies more commonly employed in pharmacologic research . Ketolides, oxazolidinones, streptogramins, glycylcyclines, and peptide deformylase inhibitors are among the most promising classes of antibiotics . Recently, several lines of research have documented that it is effective to target the infection process rather than killing bacteria . This is important because it is likely that such a therapeutic strategy could ablate infection without inducing resistance . SUMMARY: Emergence of resistance to the antibiotics currently employed in clinical practice is a continual stimulus for further research aimed at identifying novel antimicrobial compounds . These drugs will perhaps effectively fight against bacteria that now are scarcely controlled by the traditional antimicrobial agents . Health care personnel must appreciate that only judicious use of antimicrobial drugs will prevent the further uncontrolled spread of bacterial resistance . Implementation of reference guidelines would probably be an effective way to limit antibiotic misuse.

J Clin Microbiol, 2004 Apr, 42(4), 1466 - 70
Use of the BD PHOENIX Automated Microbiology System for direct identification and susceptibility testing of gram-negative rods from positive blood cultures in a three-phase trial; Funke G et al.; The present study describes the use of the automated BACTEC 9240 blood culture system, the Serum Separator Tube (SST), and the BD PHOENIX Automated Microbiology System in combination for the direct identification and antimicrobial susceptibility testing (AST) of gram-negative rods (GNRs) from positive blood cultures (BCs) without subculture . The study was conducted in three phases: (i) the recovery yield of Escherichia coli ATCC 25922 was determined with the SST between 0 and 8 h after spiked BC bottles turned positive; (ii) the identifications and susceptibility testing results obtained with the PHOENIX system for nine American Type Culture Collection strains of GNRs processed by the SST procedure and for colonies from agar medium were compared; and (iii) the procedure with the BACTEC system, SSTs, and the PHOENIX system was applied to positive cultures of blood from 309 patients during a 3-month period . The SST procedure with E . coli yielded sufficient numbers of cells to perform direct inoculation at any time between 0 and 8 h after a BC bottle turned positive . By using the identities obtained from pure cultures with the PHOENIX system and other biochemical identification systems as reference methods, the agreement between the reference methods and the PHOENIX system tested directly by using cultures of blood from patients was 92.9% . The 7.1% discrepant results were due to 6.5% incorrect identifications with the PHOENIX system with BC samples and 0.6% incorrect identifications with the PHOENIX system with samples from agar cultures . By AST the overall categorical accuracy was 99.0%, with 0.1% very major errors, 0.1% major errors, and 0.8% minor errors . In conclusion, use of the combination of the BACTEC system, SSTs, and the PHOENIX system has the potential to allow the agar isolation step to be skipped and the procedures for rapid direct identification and susceptibility testing of GNRs from positive BCs to be improved both in hospital-based and in central non-hospital-based laboratories.

Proc Natl Acad Sci U S A, 2004 Mar 30, 101(13), 4431 - 4 Epub 2004 Mar 12.
Understanding nature's design for a nanosyringe; Lopez CF et al.; Synthetic and natural peptide assemblies can possess transport or conductance activity across biomembranes through the formation of nanopores . The fundamental mechanisms of membrane insertion necessary for antimicrobial or synthetic pore formation are poorly understood . We observe a lipid-assisted mechanism for passive insertion into a model membrane from molecular dynamics simulations . The assembly used in the study, a generic nanotube functionalized with hydrophilic termini, is assisted in crossing the membrane core by transleaflet lipid flips . Lipid tails occlude a purely hydrophobic nanotube . The observed insertion mechanism requirements for hydrophobic-hydrophilic matching have implications for the design of synthetic channels and antibiotics.

J Basic Microbiol, 2004, 44(2), 157 - 60
Antimicrobial evaluation of fungal extracts produced by endophytic strains of Phomopsis sp; Corrado M et al.; Crude extract of cultures of 13 fungal strains identified as Phomopsis sp . and isolated as endophytes from the leaves of Aspidosperma tomentosum and twigs of Spondias mombin were examined for their antibacterial and antifungal activities . The screening was conducted using the bioautographic TLC agar-overlay technique against bacteria (E . coli, P . aeruginosa, S . aureus), yeast (C . albicans, S . cerevisiae), and readily adapted for use with filamentous fungi (A . niger, F . oxysporum) . Three of the 13 extracts effectively inhibited the growth of all test-organisms, indicating that they may represent a potential for pharmaceutical and/or agricultural applications and are worthy of further study .

Postepy Hig Med Dosw (Online).;58:65-73.
{Regulation of body iron homeostasis by hepcidin}; Lipinski P et al.; Hepcidin is a circulating antimicrobial peptide mainly synthesized in the liver, which has been recently proposed as a factor regulating the uptake of dietary iron and its release by reticuloendothelial macrophages . Hepcidin is a potent mediator of anemia of inflammation . Disrupted hepcidin expression is thought to mediate the pathological effects of mutations in the HFE gene in hereditary hemochromatosis . Discovery of the critical role of hepcidin in iron homeostasis could help in the design of new therapies for some iron metabolism disorders in humans . The aim of this review is to summarize current knowledge about the function and regulation of hepcidin in iron metabolism.

Am J Physiol Gastrointest Liver Physiol, 2004 May, 286(5), G698 - 701
Inflammation and cancer III . Somatostatin and the innate immune system; Zavros Y et al.; In the stomach, somatostatin is secreted from D cells and is a potent inhibitor of gastrin-induced acid secretion . During bacterial infection, somatostatin expression and release are suppressed . As a result, gastric infection often induces hypergastrinemia that, in turn, stimulates gastric acid secretion, the stomach's most important antimicrobial agent . There are an abundance of data showing that inflammatory cytokines regulate somatostatin in immune and neural cells . However, it was not until recently that the immunoregulation of gastric somatostatin was studied in vivo . This theme article discusses the role of somatostatin as an immunoregulatory peptide during gastritis.

Mol Diagn, 2003, 7(3-4), 209 - 11
Cerebral Whipple's disease diagnosed using PCR: the first case reported from Greece; Papadopoulou M et al.; BACKGROUND: Whipple's disease (WD) is a rare multisystemic bacterial infection, with variable clinical manifestations occasionally involving the central nervous system . As the cultivation of the etiologic agent, Tropheryma whippelii, is difficult, a laboratory diagnosis is usually based on histological methods . In the last few years, molecular detection of the bacterial 16SrRNA genes by PCR, with 2 primer sets, has greatly contributed to the ability of clinicians to diagnose this disease . We present a cerebral case of WD in a 48-year-old male, successfully diagnosed using PCR with T . whippelii in the blood and feces . As far as we know this is the first case reported from Greece . METHODS: For the diagnosis of WD, histological examination of duodenum biopsy for diastase-resistant, non-acid fast, periodic acid Schiff (PAS)-positive inclusions in macrophages, and molecular detection of the 16SrRNA genes of T . whippelii by PCR in cerebrospinal fluid, blood, and feces, were performed . RESULTS: The histological detection was negative . PCR results were positive in the blood and feces of the patient and negative in the cerebrospinal fluid . Seven months after the onset of antimicrobial therapy, PCR was negative in all three clinical specimens . CONCLUSIONS: The application of PCR proved to be an invaluable tool for the recognition, differential diagnosis and early initiation of antimicrobial therapy for the patient diagnosed with WD, a disease which is generally fatal if it remains untreated.

J Clin Invest, 2004 Mar, 113(6), 796 - 8
Emerging infectious diseases; Racaniello VR; Human population growth, technological advances, and changing social behaviors lead to the selection of new microbial pathogens . Antimicrobial drugs, vaccines, diagnostics, and treatments for emerging infectious diseases must be developed . The selective forces that drive the emergence of new infectious diseases, and the implications for our survival, are just beginning to be understood.

J Immunol, 2004 Apr 15, 172(8), 4987 - 94
A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release; Elssner A et al.; The release of IL-1 beta is a tightly controlled process that requires induced synthesis of the precursor pro-IL-1 beta and a second stimulus that initiates cleavage and secretion of mature IL-1 beta . Although ATP as a second stimulus potently promotes IL-1 beta maturation and release via P2X(7) receptor activation, millimolar ATP concentrations are needed . The human cathelicidin-derived peptide LL37 is a potent antimicrobial peptide produced predominantly by neutrophils and epithelial cells . In this study, we report that LL37 stimulation of LPS-primed monocytes leads to maturation and release of IL-1 beta via the P2X(7) receptor . LL37 induces a transient release of ATP, membrane permeability, caspase-1 activation, and IL-1 beta release without cell cytotoxicity . IL-1 beta release and cell permeability are suppressed by pretreatment with the P2X(7) inhibitors oxidized ATP, KN04, and KN62 . In the presence of apyrase, which hydrolyzes ATP to AMP, the effect of LL37 was not altered, indicating that LL37 rather than autocrine ATP is responsible for the activation of the P2X(7) receptor . We conclude that endogenous LL37 may promote IL-1 beta processing and release via direct activation of P2X(7) receptors.

Appl Environ Microbiol, 2004 Apr, 70(4), 2545 - 50
Development and evaluation of a reflective solar disinfection pouch for treatment of drinking water; Walker DC et al.; A second-generation solar disinfection (SODIS) system (pouch) was constructed from food-grade, commercially available packaging materials selected to fully transmit and amplify the antimicrobial properties of sunlight . Depending upon the season, water source, and challenge organism, culturable bacteria were reduced between 3.5 and 5.5 log cycles . The system was also capable of reducing the background presumptive coliform population in nonsterile river water below the level of detection . Similar experiments conducted with a model virus, the F-specific RNA bacteriophage MS2, indicated that the pouch was slightly less efficient, reducing viable plaques by 3.5 log units in comparison to a 5.0 log reduction of enterotoxigenic Escherichia coli O18:H11 within the same time period . These results suggest that water of poor microbiological quality can be improved by using a freely available resource (sunlight) and a specifically designed plastic pouch constructed of food-grade packaging materials.

Pathol Biol (Paris), 2004 Mar, 52(2), 104 - 14
{Strategies for bacterial virulence genes identification}; Foulongne V et al.; One of the recent preoccupations of medical microbiology has been to characterise the mechanisms of virulence of bacterial pathogens at the molecular level . One hundred years after Koch, Stanley Falkow proposed a new, molecular version of Koch's postulates to define avirulence gene: (a) the gene confers a certain phenotype to the studied bacteria, (b) inactivation of the gene abolishes the phenotype, (c)reintroduction of the gene restores the wild type to the mutant . Although this strategy, based upon mutagenesis and the use of experimental models, allows the identification of many genes, it is not comprehensive . Other methods can be used to complete the identification of virulence factors such as differential expression, either at the level of transcription (transcriptome) or at the level of protein expression (proteome) . All these techniques are now supported by the data from complete genome sequencing projects . The pool of information obtained from these approaches allows the definition of the 'virulome', which is the assembly of factors a pathogen requires for virulence . Understanding the virulome will open the way to the development of new strategies for vaccination or the development of new generation of antimicrobials.

Medicina (Kaunas), 2004, 40(3), 220 - 4
{Common perilla (Perilla frutescens (L.) Britton.) as a perspective immunomodulator}; Ragazinskiene O et al.; Common perilla (Perilla frutescens (L.) Britton) is a new perspective annual medicinal dead-nettle family (Lamiaceae Lindl.) plant in Lithuania . Its medicinal raw material and preparations produced of it are characterised by the variety of pharmacological effects: desensitizing, antimicrobial, anti tumorous, and antioxidative . This species was introduced from the East Asia and cultivated in many European, Asian, and North American countries . The common perilla has been cultivated in Lithuania as a decorative plant in parks and squares since 1990 . This plant has been introduced in the collection and exposition of medicinal plants in Kaunas Botanical Garden of Vytautas Magnus University since 1998 with the purpose to analyze biological and pharmacological properties of plants and to assess the quality and quantity of the raw herb . It would be reasonable to carry out experimental research on biological qualities and raw material of the common perilla in Lithuania in accordance with the contemporary technologies and requirements of the European Union standards.

J Vasc Interv Radiol, 2004 Apr, 15(4), 317 - 25
Sepsis in the interventional radiology patient; Smith TP et al.; Interventional radiologists often treat patients who are at risk of becoming acutely septic while in the radiology department . Identifying those most at risk and initiating treatment plans before the acute situation are fundamental to this difficult group of patients . Treatment plans for life-threatening infection are based on controlling the source of infection and administering appropriate systemic antimicrobial therapy as well as volume and cardiopulmonary support . The purpose of this review is to provide a framework for the diagnosis and treatment of sepsis in the interventional radiology patient.

J Am Med Inform Assoc, 2004 Jul-Aug, 11(4), 281 - 4 Epub 2004 Apr 02.
Information resources used in antimicrobial prescribing; Sellman JS et al.; To describe resources clinicians use when they prescribe antimicrobials, the authors surveyed prescribers by telephone within hours (median 2.9) after they ordered one or more antimicrobials for a patient . Among 157 prescribers, 87 (55%) used one or more external resources to aid in decisions about their order . The other 70 (45%) used only their own knowledge and experience . Fifty-nine (38%) consulted another person . Fifty-four (34%) used a print, computer, or Internet resource . In multivariate analysis, use of an external resource was associated with the clinician being on the medical service (odds ratio {OR} 2.99, 95% confidence interval {CI} 1.41-6.3) or being an intern (OR 13.65, 95% CI 1.44-128) . Eighty percent of providers said information about antimicrobial prescribing at the point of electronic order entry would be helpful . It was concluded that decision support at the point of electronic order entry is likely to be used and might improve antimicrobial prescribing.

J Am Med Inform Assoc, 2004 Jul-Aug, 11(4), 285 - 93 Epub 2004 Apr 02.
Structured representation of the pharmacodynamics section of the summary of product characteristics for antibiotics: application for automated extraction and visualization of their antimicrobial activity spectra; Duclos C et al.; OBJECTIVE: The aim of this study was to construct automatically a knowledge base concerning the pharmacodynamic properties of antibiotics and a visualization tool . DESIGN: The authors studied the various guidelines used to write the pharmacodynamics section of the Summary of Product Characteristics (SPC) for antibiotics and constructed a conceptual model of the information . Particular words, syntagms, and punctuation elements were marked in the SPC texts, and automatic extraction was then used to build a knowledge base . This base was used to create dynamic HTML tables displaying the activity spectra of the antibiotics . MEASUREMENTS: The authors analyzed the performances of automatic extraction (recall and precision) . RESULTS: The conceptual pharmacodynamics model dealt with antibiotics, pathogens, susceptibility tests, and the prevalence of resistance . Automatic extraction had a recall rate of 97.9% and a precision of 96.2% . The tool displaying antibiotic spectra and resistance prevalences used color codes to identify differences in susceptibility . CONCLUSION: This tool can provide an overview of the prevalence of resistance as expressed in SPC in primary care settings . Its potential impact should be evaluated.

Otolaryngol Clin North Am, 2004 Apr, 37(2), 365 - 79
The office management of recalcitrant rhinosinusitis; Zacharek MA et al.; The patient referred to the otolaryngologist for the treatment of CRS has received many therapies for the condition . Newer therapies available focus on the anti-inflammatory therapies and local application of antimicrobial and antifungal agents to the sinus cavities . Much clinical work remains to be done to prove the efficacy of currently available treatments . The recent advances in the understanding of allergic and immune mechanisms may allow eventual intervention at the level of cytokines and other immunomodulators of inflammation . The complex cascade of interleukins and proinflammatory agents in CRS patients may some day allow "silver bullet" therapies in the properly selected patient . Until then, a systematic approach to the evaluation of these patients and management with the currently available treatment modalities may help relieve the symptoms in patients with CRS.

Otolaryngol Clin North Am, 2004 Apr, 37(2), 253 - 66, v-vi
Microbiology and antimicrobial management of sinusitis; Brook I; The growing resistance to antimicrobial agents of all respiratory tract bacterial pathogens has made the management of sinusitis more difficult . The upper respiratory tract including the nasopharynx serves as the reservoir for pathogenic bacteria that can cause respiratory infections including sinusitis . During a viral respiratory infection, potential pathogens can relocate from the nasopharynx into the sinus cavity, causing sinusitis . Establishment of the correct microbiology of all forms of sinusitis is of primary importance, because it can serve as a guide for choosing the adequate antimicrobial therapy . This article summarizes the current information regarding the microbiology of all forms of sinusitis and approaches to antimicrobial therapy.

FEMS Microbiol Lett, 2004 Apr 15, 233(2), 193 - 9
Interactions of lactoferricin-derived peptides with LPS and antimicrobial activity; Farnaud S et al.; Synthetic peptides derived from human and bovine lactoferricin, as well as tritrpticin sequences, were assayed for antimicrobial activity against wild-type Escherichia coli and LPS mutant strains . Antimicrobial activity was only obtained with peptides derived from the bovine lactoferricin sequence and peptides corresponding to chimeras of human and bovine sequences . None of the peptides corresponding to different regions of native human lactoferricin showed any antimicrobial activity . The results underline the importance of the content of tryptophan and arginine residues, and the relative location of these residues for antimicrobial activity . Results obtained for the same assays performed with LPS mutants suggest that lipid A is not the main binding site for lactoferricin which interacts first with the negative charges present in the inner core . Computer modelling of the most active peptides led to a model in which positively charged residues of the cationic peptide interact with negative charges carried by the LPS to disorganise the structure of the outer membrane and facilitate the approach of tryptophan residues to the lipid A in order to promote hydrophobic interactions.

Peptides, 2004 Feb, 25(2), 143 - 50
Identification and functional characterization of novel scorpion venom peptides with no disulfide bridge from Buthus martensii Karsch; Zeng XC et al.; The scorpion venom peptides with no disulfide bridge are rarely identified and poorly characterized so far . Here, we report the identification and characterization of four novel disulfide-bridge-free venom peptides (BmKa1, BmKa2, BmKb1 and BmKn2) from Buthus martensii Kasch . BmKa1 and BmKa2 are very acidic and hydrophilic, showing no any similarity to other proteins, whereas BmKb1 and BmKn2 both are basic, alpha-helical peptide with an amidated C-terminus, showing a little homology with other peptides . Functional tests with synthetic peptide showed that BmKn2 has strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, whereas BmKb1 has weak activity in inhibiting the growth of these bacteria.

Vet Clin North Am Equine Pract, 2004 Apr, 20(1), 167 - 97
Postoperative management of the large colon volvulus patient; Southwood LL; Horses with large colon volvulus (LCV) often require intensive postoperative medical management . Although early referral and surgical intervention are critical for minimal postoperative complications and a successful outcome, this is often not possible for many reasons . Endotoxemia, extensive mucosal damage with subsequent severe hypoproteinemia, and focal ischemic necrosis are the major causes of postoperative morbidity and mortality.Although fluid therapy, flunixin meglumine, and antimicrobials are still the mainstay of perioperative management, synthetic colloids are being used to maintain plasma oncotic pressure, hyperimmune antiendotoxic plasma and polymixin B are being used for management of endotoxemia, and lidocaine and constant rate infusion of butorphanol can be used for postoperative analgesia . The use of heparin, dimethyl sulfoxide, and corticosteroids for management of LCV are still controversial . Future studies are required to investigate nutritional improvement and methods to manage cases after surgery to prevent recurrence.

Crit Care Nurs Clin North Am, 2004 Mar, 16(1), 1 - 11
Topical therapies and antimicrobials in the management of burn wounds; Honari S; With new technologies and techniques, the practice of treating burn patients has become increasingly specialized . A thorough understanding of the properties of topical wound product choices and nursing management of the dressing therapy is essential.

Clin Liver Dis, 2004 Feb, 8(1), 213 - 28, viii-ix
Cholestasis in HIV-infected patients; Te HS; Cholestasis is frequently observed in the HIV-infected population and can be caused by drugs, such as highly active antiretroviral therapy (HAART) and antimicrobial agents, and by opportunistic infections of the liver . Less common causes such as HIV-related malignancies or biliary tract disease are also encountered . Most disorders respond to medical management, but patient outcome was often dictated by the stage of the HIV infection and concomitant illnesses in the pre-HAART era . Prompt recognition and specific treatment may improve the outcome for these patients in the HAART era.

Hindustan Antibiot Bull, 2002 Feb-Nov, 44(1-4), 49 - 52
Sensitivity of ornithophillic fungi to some drugs; Patel A et al.; The occurrence of ornithophillic fungi and related dermatophytes was evaluated from the poultry farm soil samples . Two test species of Microsporum were tested by 'Spore germination' and 'Disc diffusion method' against the two well known antifungal antibiotics i.e . griseofulvin and mycostatin (polyene antibiotic) . The data showed cent percent inhibition of fungal spore germination and increased zone of inhibition at higher doses . The antimicrobial drugs including acetyl salicylic acid, benzoic acid and boric acid were also assessed at different doses against the test organisms . Acetyl salicylic acid and boric acid were found to be toxic at higher doses, while these pathogens seems to be somewhat resistant for benzoic acid . It is suggested that the effective doses of these drugs should also be tried for allergic effects on birds and other animals before commercial use.

Hindustan Antibiot Bull, 2002 Feb-Nov, 44(1-4), 25 - 33
Survey of antimicrobial streptomycetes from soils of West Bengal: characterization and identification of potent broad spectrum antibiotic producing Streptomyces albidoflavus 321.2; Roy RN et al.; Survey of 611 streptomycetes isolates from 330 soil samples from various parts of West Bengal were done for their antimicrobial activity against Gram positive, Gram negative bacteria, unicellular and filamentous fungi . The strain 321.2 showed inhibition against all the test organisms used and found as potent . The morphological, cultural, physiological and biochemical characters were studied, compared with known species and identified as Streptomyces albidoflavus . This strain produces an antibiotic.

Hindustan Antibiot Bull, 2002 Feb-Nov, 44(1-4), 17 - 24
Bioactive rare actinomycetes from indigenous natural substrates of Andhra Pradesh; Ellaiah P et al.; This investigation reports the occurrence of bioactive rare actinomycetes from different indigenous natural substrates of Andhra Pradesh . During the course of our investigation on 20 terrestrial soil samples, 5 marine samples and 3 fresh water samples, a total of 92 rare actinomycetes belonging to Micromonospora, Nocardia, Actinomadura and Thermoactinomyces genera were isolated . The antimicrobial and enzymatic activities were studied for all the isolates . The antibacterial and antifungal activities were studied preliminarily by cross-streak method followed by submerged fermentation studies employing standard cup-plate method for the assay . It was found that 34 isolates (36.95%) showed excellent antibacterial activity and 29 isolates (31.52%) showed good antifungal activity . Proteolytic and amylolytic activities were also studied . It was observed that 79 isolates (85.86%) showed proteolytic activity and 75 isolates (81.52%) showed amylolytic activity.

Hindustan Antibiot Bull, 2002 Feb-Nov, 44(1-4), 8 - 16
Bioactive actinomycetes from Krishna River sediments of Andhra Pradesh; Ellaiah P et al.; Sediment samples from Krishna River at Nagayalanka of Andhra Pradesh, India were investigated as a source of actinomycetes to screen for the production of novel bioactive compounds . During our investigation on fresh water actinomycetes from 5 different river sediment samples, a total of 80 actinomycetes were isolated . Out of these 80 isolates, 30 isolates which showed distinct macromorphological characteristics were selected . The antimicrobial and enzymatic activities were studied for all the 30 isolates . The preliminary study for antimicrobial activity by cross streak method indicated that 16 isolates (53.3%) have excellent antagonistic properties . All these 16 isolates were subjected to detailed submerged fermentation studies . It was observed that 12 isolates (40.0%) exhibited antibacterial activity, 9 isolates (30.0%) showed antifungal activity while 5 isolates (16.6%) showed both antibacterial and antifungal activities . All the 30 isolates were also subjected for the determination of enzymatic activities 25 isolates (83.3%) exhibited amylolytic activity while 27 isolates (90.0%) showed proteolytic activity . Among these isolates, six promising isolates were selected for detailed morphological, cultural, physiological and biochemical studies . It was established that these isolates belong to the Streptomyces genus by virtue of their cell wall composition pattern and were identified as strains of different Streptomyces species like S . rochei, S . alanosinicus, S . erumpens, S . griseoplanus, S . gancidicus and S . nigrogriseolus.

Epidemiol Infect, 2004 Apr, 132(2), 167 - 75
Systemic pneumococcal disease in Norway 1995-2001: capsular serotypes and antimicrobial resistance; Pedersen MK et al.; A total of 4624 pneumococcal isolates from episodes of systemic pneumococcal disease were received at the Norwegian Institute of Public Health during the period 1995-2001 . All isolates were serotyped and tested for susceptibility to benzylpenicillin, lincomycin, erythromycin, tetracycline and trimethroprim sulphamethoxazole . The proportion of strains resistant to these antimicrobial agents remained stable at a low level, ranging from 0.1% for benzylpenicillin to 2.5% for erythromycin . The distribution of serotypes was also stable over the 7 years: serotypes 1, 4, 9, 14, 7, 6 and 23 were the most frequent, representing 70.5% of isolates . Overall, 95.8% of the isolates were of serotypes/groups included in the current 23-valent polysaccharide vaccine, 52.2% were of serotypes/groups included in the 7-valent conjugated vaccine and 85.5% were of serotypes/groups included in the 11-valent conjugated vaccine.

Leuk Lymphoma, 2004 Jan, 45(1), 143 - 5
Fatal anerobic bacteremia after hematopoietic stem cell transplant; Slavin MA et al.; We describe 3 cases of fatal but clinically unsuspected anerobic bacteremia amongst hematopoietic stem cell transplant (HSCT) recipients treated empirically for fever and neutropenia with third or fourth generation cephalosporins . All patients had diarrhea but none had classical findings of neutropenic enterocolitis . HSCT recipients with fever, neutropenia and gastrointestinal tract symptoms such as abdominal pain or diarrhea or with septic shock despite broad spectrum antibiotics should receive an antimicrobial agent with anerobic activity.

BMC Biol . 2004 Apr 1;2(1):4.
Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin; Harms JM et al.; BACKGROUND: The bacterial ribosome is a primary target of several classes of antibiotics . Investigation of the structure of the ribosomal subunits in complex with different antibiotics can reveal the mode of inhibition of ribosomal protein synthesis . Analysis of the interactions between antibiotics and the ribosome permits investigation of the specific effect of modifications leading to antimicrobial resistances.Streptogramins are unique among the ribosome-targeting antibiotics because they consist of two components, streptogramins A and B, which act synergistically . Each compound alone exhibits a weak bacteriostatic activity, whereas the combination can act bactericidal . The streptogramins A display a prolonged activity that even persists after removal of the drug . However, the mode of activity of the streptogramins has not yet been fully elucidated, despite a plethora of biochemical and structural data . RESULTS: The investigation of the crystal structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with the clinically relevant streptogramins quinupristin and dalfopristin reveals their unique inhibitory mechanism . Quinupristin, a streptogramin B compound, binds in the ribosomal exit tunnel in a similar manner and position as the macrolides, suggesting a similar inhibitory mechanism, namely blockage of the ribosomal tunnel . Dalfopristin, the corresponding streptogramin A compound, binds close to quinupristin directly within the peptidyl transferase centre affecting both A- and P-site occupation by tRNA molecules . CONCLUSIONS: The crystal structure indicates that the synergistic effect derives from direct interaction between both compounds and shared contacts with a single nucleotide, A2062 . Upon binding of the streptogramins, the peptidyl transferase centre undergoes a significant conformational transition, which leads to a stable, non-productive orientation of the universally conserved U2585 . Mutations of this rRNA base are known to yield dominant lethal phenotypes . It seems, therefore, plausible to conclude that the conformational change within the peptidyl transferase centre is mainly responsible for the bactericidal activity of the streptogramins and the post-antibiotic inhibition of protein synthesis.

Clin Microbiol Infect, 2004 Apr, 10(4), 349 - 83
European recommendations for antimicrobial resistance surveillance; Cornaglia G et al.; The problem of antimicrobial resistance surveillance in Europe has been debated extensively in many excellent documents issued by national committees that often assume the value of national guidelines . However, a comprehensive document addressing the whole matter from a European perspective, as well as reviewing its present status and drafting future perspectives, has been lacking . The present recommendations have been produced by the ESCMID Study Group for Antimicrobial Resistance Surveillance (ESGARS) through a consensus process involving all members of the Study Group . The recommendations focus on the detection of bacterial resistance and its reporting to clinicians, public health officers and a wider-and ever-increasing-audience . The leading concept is that the basis for resistance monitoring is microbiological diagnostics . The prerequisites for resistance monitoring are findings of adequate quality and quantity, which have been recorded properly and evaluated correctly . Different types of surveillance studies should fulfil different requirements with regard to data collection and reporting, the expected use of data, and the prerequisites for networking such activities . To generate relevant indicators, bacterial resistance data should be reported using adequate denominators and stratification . Reporting of antimicrobial resistance data is necessary for selection of empirical therapy at the local level, for assessing the scale of the resistance problem at the local, national or international levels, for monitoring changes in resistance rates, and for detecting the emergence and spread of new resistances types . Any type of surveillance study should conclude, where appropriate, with a proposal for intervention based on the data obtained.

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