Antimicrobials

Peptides, 2003 Apr, 24(4), 523 - 30
Antimicrobial peptides in the first line defence of human colon mucosa; Tollin M et al.; Antimicrobial peptides and proteins are effector molecules in the protection of epithelial surfaces . We have evaluated the presence of antimicrobial peptides/proteins that can participate in human colonic defence against microbes . A peptide/protein extract of normal human colon mucosa was found to be active against Gram-positive bacteria, Gram-negative bacteria, and fungi . Four polypeptides with antimicrobial activity were isolated from this material and they were identified by N-terminal amino acid sequence analysis as ubiquicidin, histone H2B, eosinophil cationic protein, and phospholipase A(2) (PLA(2)) . Using immunodetection and mass spectrometry, LL-37, HNP1-3, and HBD-1 were also identified . Combined, these results indicate that the colon mucosa is protected by a complex mixture of polypeptides, able to kill invading microbes and working in synergy as a barrier against bacterial invasion.

Int Immunopharmacol, 2003 Aug, 3(8), 1159 - 67
Combinatorial immunotherapies for infectious diseases; Hengel H et al.; Combating pathogenic organisms by combinatorial approaches involving appropriate immune response molecules and antimicrobial drugs represents a progessively more apparent and successful therapeutic paradigm for the treatment of acute and chronic persistent infectious diseases . This review explores areas of current innovation and provides an update of the present state of knowledge concerning combination of chemotherapy with several immune-based interventions in infections . In the future, a better understanding of microbial immune modulation and evasion may continue to open new avenues of inquiry and carefully targeted application of adjunctive immunotherapies.

J Infect, 2003 Aug, 47(2), 110 - 6
Q fever: epidemiology, clinical features and prognosis . A study from 1983 to 1999 in the South of Spain; Alarcon A et al.; OBJECTIVES: Clinical polymorphism is a main feature of Q fever and, depending upon the geographic location, differences in its clinical picture have been described . The objective of this study was to determine the epidemiology, clinical features and prognosis of acute Q fever in our area . METHODS: From 1985 to 1999, consecutive cases of Q fever, presented as febrile syndrome and attended in a tertiary teaching hospital in Sevilla, Spain, were included and followed prospectively . RESULTS: Two hundred and thirty-one cases of acute Q fever were included . A non-focalized febrile syndrome lasting from 7 to 28 days (fever of intermediate duration) was the most frequent presentation (n=208, 90%) . One hundred and forty-eight patients had hepatitis . Overall, 53% of the cases were urban and contact with animals was referred in 39% of the patients . No relationship between clinical presentation and possible route of infection was observed . Prognosis was excellent (100% cured), although in 18 patients fever was prolonged more than 28 days and three patients developed life-threatening organ affection . Antimicrobial treatment was more effective if it was administered in the first two weeks (median defervescence of fever: 3 days versus 5.5 days, p<0.01) . CONCLUSIONS: Acute Q fever is a common cause of fever of intermediate duration, even in urban areas . Elevation of hepatic enzymes was the most frequent laboratory finding . Severe organ affection is uncommon and the overall prognosis of the disease is excellent . Early treatment seems to shorten the duration of the disease.

Vet Microbiol, 2003 Aug 29, 95(1-2), 75 - 89
Interleukin 6, serum amyloid A and haptoglobin as markers of treatment efficacy in pigs experimentally infected with Actinobacillus pleuropneumoniae; Hulten C et al.; The possibility to use acute phase proteins to monitor the elimination of a bacterial infection in pigs would facilitate an objective assessment of treatment with various antimicrobial substances . To examine this possibility, the acute phase response (IL-6, serum amyloid A (SAA), and haptoglobin) elicited by Actinobacillus pleuropneumoniae and its reduction on treatment with various antibiotics was studied in serum from specific pathogen free (SPF) pigs . Pigs were infected intranasally with A . pleuropneumoniae serotype 2, and either left as non-treated control pigs or treated with different antibiotics intramuscularly at onset of respiratory disease (20h post-infection) . Pigs responded to the infection with prominent increases in activity and concentrations of IL-6, SAA, and haptoglobin . These responses were to a certain extent overlapping and covered the time span from a few hours after infection until development of detectable levels of specific antibodies (7-10 days post-infection in untreated pigs) . The haptoglobin response lasted until the end of the study on day 17 and thereby partly coincided with the antibody response . Treatment with antimicrobials that effectively reduced establishment of the infection with A . pleuropneumoniae also reduced the duration of all three acute phase responses, and reduced the concentration of serum haptoglobin . In contrast, less efficacious treatments did not reduce these acute phase responses . Thus, acute phase reactants can be applied to monitor therapeutic effects of antimicrobial drugs in the pig and measurements of IL-6, SAA and haptoglobin could add valuable information about the stage of infection during a disease outbreak.

Biochem Biophys Res Commun, 2003 Jul 25, 307(2), 369 - 74
Yeast sphingolipid bypass mutants as indicators of antifungal agents selectively targeting sphingolipid synthesis; Nagiec MM et al.; Standard methods for evaluating the target specificity of antimicrobial agents often involve the use of microorganisms with altered expression of selected targets and thus either more resistant or more susceptible to target specific inhibitors . In this study we present an alternative approach that utilizes physiological bypass mutants . The Saccharomyces cerevisiae sphingolipid bypass mutant strain AGD is able to grow without making sphingolipids and importantly, tolerates loss-of-function mutations in the otherwise essential genes for both serine palmitoyltransferase (SPT) and inositol phosphorylceramide (IPC) synthase . We found that strain AGD was >1000-fold more resistant than the wild-type strain to selective inhibitors of SPT and IPC synthase . In contrast, strain AGD, which due to abnormal composition of the plasma membrane is sensitive to a variety of environmental stresses, was more susceptible than the wild-type to amphotericin B, voriconazole, and to cycloheximide . We show that in a simple growth assay the AGD strain is an appropriate and useful indicator for inhibitors of IPC synthase, a selective antifungal target.

Biochemistry, 2003 Jul 22, 42(28), 8434 - 44
Recognition and resistance in TEM beta-lactamase; Wang X et al.; Developing antimicrobials that are less likely to engender resistance has become an important design criterion as more and more drugs fall victim to resistance mutations . One hypothesis is that the more closely an inhibitor resembles a substrate, the more difficult it will be to develop resistant mutations that can at once disfavor the inhibitor and still recognize the substrate . To investigate this hypothesis, 10 transition-state analogues, of greater or lesser similarity to substrates, were tested for inhibition of TEM-1 beta-lactamase, the most widespread resistance enzyme to penicillin antibiotics . The inhibitors were also tested against four characteristic mutant enzymes: TEM-30, TEM-32, TEM-52, and TEM-64 . The inhibitor most similar to the substrate, compound 10, was the most potent inhibitor of the WT enzyme, with a K(i) value of 64 nM . Conversely, compound 10 was the most susceptible to the TEM-30 (R244S) mutant, for which inhibition dropped by over 100-fold . The other inhibitors were relatively impervious to the TEM-30 mutant enzyme . To understand recognition and resistance to these transition-state analogues, the structures of four of these inhibitors in complex with TEM-1 were determined by X-ray crystallography . These structures suggest a structural basis for distinguishing inhibitors that mimic the acylation transition state and those that mimic the deacylation transition state; they also suggest how TEM-30 reduces the affinity of compound 10 . In cell culture, this inhibitor reversed the resistance of bacteria to ampicillin, reducing minimum inhibitory concentrations of this penicillin by between 4- and 64-fold, depending on the strain of bacteria . Notwithstanding this activity, the resistance of TEM-30, which is already extant in the clinic, suggests that there can be resistance liabilities with substrate-based design.

J Cosmet Sci, 2003 May-Jun, 54(3), 251 - 61
N,N',N"-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane (Deofix) - a high-affinity, high-specificity chelator for first transition series metal cations with significant deodorant, antimicrobial, and antioxidant activity; Laden K et al.; Deofix, N,N',N"-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane, is a high-affinity, high-specificity chelator for first transition series cations such as iron, zinc, manganese, and copper . A 1% solution in 50% ethanol was found to be significantly better at reducing underarm malodor than a solution of 0.3% Triclosan in 50% ethanol . Compared to a 50% alcohol control, Deofix was found to produce a significant reduction in malodor for at least 48 hours . Deofix appears to work by reducing the concentration of first transition series metal ions below the levels needed for microbial cell reproduction and by inhibiting oxidative processes by interfering with catalytic formation of free radicals . Deofix has very low levels of toxicity when measured via a number of screening techniques.

J Biol Chem, 2003 Sep 19, 278(38), 36250 - 6 Epub 2003 Jul 11.
Macrophage-independent fungicidal action of the pulmonary collectins; McCormack FX et al.; Histoplasma capsulatum (Hc) is a facultative intracellular fungal pathogen that causes acute and chronic pneumonia . In this study, we investigated the role of the pulmonary collectins, surfactant proteins (SP) A and D, in the clearance of Hc yeast from the lung . Exposure of yeast to either collectin induced a dose-dependent decrease in {3H}leucine incorporation by several strains of Hc . This decrement was attributed to killing of the collectin-exposed yeast since it failed to grow on agar medium . Exposure to SP-A or -D resulted in increased yeast permeability based on a leak of protein from the organism and enhanced access of an impermeant substrate to intracellular alkaline phosphatase . Inbred and outbred SP-A null (-/-) mice were modestly more susceptible to pulmonary infection with Hc than strain and age-matched SP-A (+/+) control mice . The increase in susceptibility was associated with a decrement in the number of CD8+ cells in the lungs of SP-A-/- mice . Neither SP-A nor SP-D inhibited the growth of macrophage-internalized Hc . We conclude that the SP-A and SP-D are antimicrobial proteins that directly inhibit the growth of Hc by increasing permeability of the organism and that Hc gains asylum from collectin-mediated killing by rapid entry into pulmonary macrophages.

J Biomol Screen, 2003 Jun, 8(3), 340 - 6
Amplified detection of transcriptional and translational inhibitors in bioluminescent Escherichia coli K-12; Galluzzi L et al.; The excessive prescription of antimicrobial agents and their use as animal growth promoters lead to the spread of resistance among pathogenic bacteria . Consequently, unnecessary use should be minimized, and new chemicals with novel mechanisms of action are needed . The authors have developed a fast method to measure the activity of antibiotics by means of a genetically engineered strain of Escherichia coli K-12 . The system is based on the full-length bacterial luciferase operon coupled to the tetracycline-inducible tetA promoter in the reporter plasmid pTetLux1 . Sublethal doses of tetracycline are used to start the luciferase synthesis in cultures that were previously incubated with the antibiotic under investigation . After a variable time frame-from 1 to 4 h, depending on the antimicrobial mode of action-the level of light emission from treated cultures is compared to the level obtained in control cultures . The gap in bioluminescence outlines the antibiotic interference in bacterial metabolism . Throughout this study, freeze-dried sensor cells were used to avoid repeated cultures from day to day . The authors show the results of 10 model antibiotics, representing different molecular structures and mechanisms of action . The results show that no actively dividing cells are needed for sensitive responses, especially when transcriptional and translational inhibitors, directly interfering with the luciferase production, are tested . The assay can be easily automated for high-throughput screening purposes of pharmaceutical industry.

Pharmazie, 2003 Jun, 58(6), 372 - 7
Synthesis and antimicrobial testing of some new S-substituted-thiopyridines, thienopyridines, pyridothienopyrimidines and pyridothienotriazines; Abdel-Rahman AE et al.; The reaction of 5-acetyl-4-aryl-3-cyano-6-methylpyridine-2(1H)-thiones (1a, b) with 4-methylphenacyl bromide, chloro-N-arylacetamides or chloroacetonitrile gave the corresponding S-substituted thiopyridines 2a-c, 4a-f and 6a-c, respectively . The latter compounds underwent intramolecular Thorpe-Ziegler cyclization to give 2-substituted 5-acetyl-3-amino-4-aryl-6-methylthieno{2,3-b}pyridines 3a-c, 5a-f and 7a-c . Compounds 5a-f and 7b, c are key intermediates in the synthesis of the target compounds . Some compounds showed remarkable antimicrobial activity.

Plant Mol Biol, 2003 May, 52(2), 433 - 46
A maize defense-inducible gene is a major facilitator superfamily member related to bacterial multidrug resistance efflux antiporters; Simmons CR et al.; A defense-inducible maize gene was discovered through global mRNA profiling analysis . Its mRNA expression is induced by pathogens and defense-related conditions in various tissues involving both resistant and susceptible interactions . These include Cochliobolus heterostrophus and Cochliobolus carbonum infection, ultraviolet light treatment, the Les9 disease lesion mimic background, and plant tissues engineered to express flavonoids or the avirulence gene avrRxv . The gene was named Zm-mfs1 after it was found to encode a protein related to the major facilitator superfamily (MFS) of intregral membrane permeases . It is most closely related to the bacterial multidrug efflux protein family, typified by the Escherichia coli TetA, which are proton motive force antiporters that export antimicrobial drugs and other compounds, but which can be also involved in potassium export/proton import or potassium re-uptake . Other related plant gene sequences in maize, rice, and Arabidopsis were identified, three of which are introduced here . Among this new plant MFS subfamily, the characteristic MFS motif in cytoplasmic TM2-TM3 loop, and the antiporter family motif in transmembrane domain TM5 are both conserved, however the TM7 and the cytoplasmic TM8-TM9 loop are divergent from those of the bacterial multidrug transporters . We hypothesize that Zm-Mfs1 is a prototype of a new class of plant defense-related proteins that could be involved in either of three nonexclusive roles: (1) export of antimicrobial compounds produced by plant pathogens; (2) export of plant-generated antimicrobial compounds; and (3) potassium export and/or re-uptake, as can occur in plant defense reactions.

Microbiology, 2003 Jul, 149(Pt 7), 1893 - 900
EST analysis of genes expressed by the zygomycete pathogen Conidiobolus coronatus during growth on insect cuticle; Freimoser FM et al.; Conidiobolus coronatus (Zygomycota) is a facultative saprobe that is a pathogen of many insect species . Almost 2000 expressed sequence tag (EST) cDNA clones were sequenced to analyse gene expression during growth on insect cuticle . Sixty percent of the ESTs that could be clustered into functional groups (E<or=10(-5)) had their best BLAST hits among fungal sequences . These included chitinases and multiple subtilisins, trypsin, metalloprotease and aspartyl protease activities with the potential to degrade host tissues and disable anti-microbial peptides . Otherwise, compared to the ascomycete entomopathogen Metarhizium anisopliae, Con . coronatus produced many fewer types of hydrolases (e.g . no phospholipases), antimicrobial agents, toxic secondary metabolites and no ESTs with putative roles in the generation of antibiotics . Instead, Con . coronatus produced a much higher proportion of ESTs encoding ribosomal proteins and enzymes of intermediate metabolism that facilitate its rapid growth . These results are consistent with Con . coronatus having adapted a modification of the saprophytic ruderal-selected strategy, using rapid growth to overwhelm the host and exploit the cadaver before competitors overrun it . This strategy does not preclude specialization to pathogenicity, as Con . coronatus produces the greatest complexity of proteases on insect cuticle, indicating an ability to respond to conditions in the cuticle.

Microbiology, 2003 Jul, 149(Pt 7), 1719 - 27
Rapid identification of Gram-positive anaerobic coccal species originally classified in the genus Peptostreptococcus by multiplex PCR assays using genus- and species-specific primers; Song Y et al.; Here, a rapid and reliable two-step multiplex PCR assay for identifying 14 Gram-positive anaerobic cocci (GPAC) species originally classified in the genus Peptostreptococcus (Anaerococcus hydrogenalis, Anaerococcus lactolyticus, Anaerococcus octavius, Anaerococcus prevotii, Anaerococcus tetradius, Anaerococcus vaginalis, Finegoldia magna, Micromonas micros, Peptostreptococcus anaerobius, Peptoniphilus asaccharolyticus, Peptoniphilus harei, Peptoniphilus indolicus, Peptoniphilus ivorii and Peptoniphilus lacrimalis) is reported . Fourteen type strains representing 14 GPAC species were first identified to the genus level by multiplex PCR (multiplex PCR-G) . Since three of these genera (Finegoldia, Micromonas and Peptostreptococcus) contain only a single species, F . magna, M . micros and P . anaerobius, respectively, these organisms were identified to the species level directly by using the multiplex PCR-G . Then six species of the genus Anaerococcus (A . hydrogenalis, A . lactolyticus, A . octavius, A . prevotii, A . vaginalis and A . tetradius) were further identified to the species level using multiplex PCR assays (multiplex PCR-Ia and multiplex PCR-Ib) . Similarly, five species of the genus Peptoniphilus (Pn . asaccharolyticus, Pn . harei, Pn . indolicus, Pn . ivorii and Pn . lacrimalis) were identified to the species level using multiplex PCR-IIa and multiplex PCR-IIb . The established two-step multiplex PCR identification scheme was applied to the identification of 190 clinical isolates of GPAC species that had been identified previously to the species level by 16S rRNA sequencing and phenotypic tests . The identification obtained from multiplex PCR assays showed 100 % agreement with 16S rDNA sequencing identification, but only 65 % (123/190) agreement with the identification obtained by phenotypic tests . The multiplex PCR scheme established in this study is a simple, rapid and reliable method for the identification of GPAC species . It will permit a more accurate assessment of the role of various GPAC species in infection and of the degree of antimicrobial resistance in each of the group members.

Blood, 2003 Nov 1, 102(9), 3396 - 403 Epub 2003 Jul 10.
Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells; Yang D et al.; Recent publications have highlighted the chemotactic activities of antimicrobial proteins derived from the granules of neutrophils and basophils . Eosinophil granules also contain antimicrobial proteins . One of them is eosinophil-derived neurotoxin (EDN), a protein belonging to the ribonuclease A (RNase A) superfamily, which has recently been found to have antiviral activity in vitro . We found that EDN was selectively chemotactic for dendritic cells (DCs) . The DC chemotactic activity of EDN was inhibited by either pretreatment of DCs with pertussis toxin or by simultaneous addition of placental RNase inhibitor to inhibit the activity of EDN . EDN was not chemotactic for leukocytes other than DCs . Mouse eosinophil-associated RNase 2 (mEAR2), one of a cluster of divergent orthologs of human EDN, was also chemotactic for human as well as mouse DCs . Sequence and mutational analysis demonstrated the importance of the N-terminal region of mEAR2 in mediating its chemotactic effect on DCs . EDN also induced the activation of p42/44 mitogen-activated protein kinase (MAPK) in DCs . Furthermore, injection of mEAR2 into the air pouches of mice resulted in the recruitment of DCs into the air pouches . Thus, EDN and its mouse ortholog, mEAR2, are eosinophil granule-derived antimicrobial RNases that function as chemoattractants for DCs in vitro and in vivo.

Ann Transplant, 2002, 7(4), 42 - 5
Interaction of E . coli with dendritic cells--a model for studies of graft infections; Stanislawska J et al.; The rejection process of skin allografts is mediated by dendritic cells (DC) and lymphocytes . The recipient DCs are engaged not only into an allogenic but also antibacterial reaction to the penetrating bacteria . The capacity of these cells to sample sites of pathogen entry, respond to microbial signals and activate naive T cells suggests a critical role for DC in initiating antimicrobial immunity . In our study, we investigated the ability of the green fluorescent protein (Gfp) labelled E . coli to infect DC . We studied kinetics of in vitro and in vivo adherence and incorporation of E . coli by rat spleen and bone marrow (BM) DC . Bacterial adherence to the cell surface was observed after 2 h incubation of DC with bacteria . A 24-hour culture of DC from both sources was followed by bacterial adherence to all cells and engulfment by at least 50% of cells . There was an increased expression of the phenotypic markers on the DC cultured with E.coli . The Gfp-labelled E.coli should be useful for studies of the activation of dendritic cells . The method will allow to study the process of simultaneous activation of DC by allo- and bacterial antigens.

Biochim Biophys Acta, 2003 Jul 14, 1638(2), 157 - 63
Limited proteolysis of surfactant protein D causes a loss of its calcium-dependent lectin functions; Griese M et al.; Surfactant protein D (SP-D) is a multimeric collagenous lectin that mediates the clearance of pathogens and modulates immune cell functions via its C-terminal carbohydrate recognition domain (CRD) . We hypothesized that extracellular proteolysis of SP-D may result in a loss of its functional properties . Multimeric SP-D was partially digested by human leukocyte elastase (HLE) dose- and time-dependently . Physiologic concentrations of calcium slowed, but did not protect from degradation . In solution, both native and degraded SP-D had an apparent molecular weight of 650 to >1000 kDa . Under reducing conditions, the degraded SP-D monomers run at 10 kDa less than native SP-D . Amino acid sequencing located all major cleavage sites into the CRD . Functional studies showed that degraded SP-D had lost its calcium-dependent lectin properties, i.e . neither bound to mannose nor agglutinated bacteria . These studies demonstrate that elastase results in the limited proteolysis of SP-D with loss of its CRD-dependent activities and suggest that proteases at concentrations observed in various lung diseases may impair the antimicrobial and immunomodulatory roles of SP-D.

Hematology, 2002 Oct, 7(5), 281 - 9
Oral mucositis: time for more studies; Alvarado Y et al.; Oral Mucositis (OM) is a frequent cause of severe morbidity in patients receiving chemotherapy and/or radiotherapy . The pathophysiology of OM involves direct cytotoxic effects, local inflammatory responses, and alterations in oral microflora . There are currently no approved agents for the prevention or treatment of OM . In this review we briefly describe current knowledge of the pathophysiology, clinical presentation, and management of OM . We then discuss investigational agents being studied in OM with a particular focus on local antimicrobial agents, hemopoietic growth factors, and cytokines . Measures to reduce the incidence of OM and/or alleviate its clinical sequelae should be incorporated into all chemotherapy or radiotherapy studies.

Zhonghua Liu Xing Bing Xue Za Zhi, 2003 Jun, 24(6), 447 - 8
{In-vitro activity of rabeprazole, lansoprazole, and esomeprazole against Helicobacter pylori}; He LH et al.; OBJECTIVE: To investigate the antimicrobial activity of Pariet, Tekpron, Nexium, respectively, against Helicobacter pylori (H . pylori) in vitro . METHODS: Antimicrobial effects of these medicines were evaluated through detection of MICs for 3 H . pylori strains isolated from different countries . RESULTS: The MIC(99) contents were 2.25 mg/L, 42.5 mg/L and 360 mg/L, respectively, for the three medicines . The strains under testing exhibited the same susceptibility to each medicine . Nexium did not inhibit the bacteria under the concentration of 3.6 - 36 mg/L with more and bigger H . pylori colonies seen when compared with controls . CONCLUSIONS: The growth inhibitory activity appeared to be different among the three PPI medicines under investigation, with Rabeprazole the most potential agent of the three . Data suggested that the action of growth inhibition in vitro was resting on the characteristic of the given PPI as well as the supplements of the medicine.

Clin Microbiol Infect, 2003 May, 9(5), 380 - 7
A series of infections due to Capnocytophaga spp in immunosuppressed and immunocompetent patients; Bonatti H et al.; OBJECTIVE: To investigate the epidemiology, microbiology and outcome of infections caused by Capnocytophaga spp . at a single center . METHODS: We report on ten documented infectious episodes caused by Capnocytophaga observed between 1994 and 1999 at the Innsbruck University Hospital . RESULTS: In seven of ten patients, Capnocytophaga septicemia was diagnosed during periods of neutropenia . In contrast, the remaining three patients had normal white blood cell counts when acquiring Capnocytophaga septicemia (one) and pleural empyema (two) . Blood cultures containing long, slender, Gram-negative rods, which grew slowly under anaerobic conditions and lacked susceptibility to metronidazole, were subcultivated in a CO2-enriched atmosphere (5%) . Subcultivation yielded Capnocytophaga in all ten cases within 2-12 days . The patients were then placed on appropriate antibiotic therapy, with or without additional surgical intervention, and the organism was eradicated . CONCLUSION: Identification of Capnocytophaga facilitates appropriate, and in most cases effective, antimicrobial therapy.

Clin Microbiol Infect, 2003 Jun, 9(6), 531 - 7
Changing epidemiology and predictors of mortality in patients with spontaneous bacterial peritonitis at a liver transplant unit; Singh N et al.; OBJECTIVES: To determine whether antimicrobial resistance in pathogens and outcome in patients with spontaneous bacterial peritonitis (SBP) has evolved over time . METHODS: Sixty-one consecutive episodes of SBP were studied in patients with end-stage liver disease undergoing evaluation for liver transplantation between 1991 and 2001 . Patients were dichotomized into a cohort between 1991 and 1995 (the earlier cohort) and 1996-2001 (the later cohort) . RESULTS: Overall, 19% of all bacteria were multiply-antibiotic resistant . The frequency of multiple-antibiotic resistance in bacteria increased from 8.3% to 38.5% in the earlier as compared to the later cohort (P = 0.07) . Overall, mortality at 30 days in the study patients was 26% and had remained unchanged between the two cohorts . The mortality rate was significantly higher in patients with multiply-antibiotic-resistant bacteria than in those with other bacteria (P = 0.045) . However, the Child-Pugh score (P = 0.003), and renal failure (P = 0.04) were the only independently significant predictors of mortality in patients with SBP . CONCLUSIONS: Mortality in patients with end-stage liver disease who developed SBP has remained unchanged over the last decade . Although multiple-antibiotic resistance in bacteria causing SBP has increased over time, the severity of hepatic and renal dysfunction were the predominant determinants of outcome in these patients.

Clin Microbiol Infect, 2003 Jun, 9(6), 467 - 74
Multicenter evaluation of the reproducibility of the proposed antifungal susceptibility testing method for fermentative yeasts of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST); Cuenca-Estrella M et al.; OBJECTIVE: To evaluate the intra- and inter-laboratory reproducibility of a new standard for susceptibility testing of fermentative yeasts . This standard is based on the M27-A procedure of the National Committee for Clinical Laboratory Standards (NCCLS), but incorporates several modifications, including spectrophotometric growth-dependent endpoint reading . METHODS: Nine laboratories participated in the study . Common material lots were used to test six Candida species (one each of C . albicans, C . tropicalis, C . parapsilosis, C . glabrata, C . krusei, and C . lusitaniae), and two quality control strains (C . krusei ATCC6258 and C . parapsilosis ATCC22019) . Triplicate testing on three separate days was performed in microtiter format with RPMI-2% glucose, pH 7.0 . Flucytosine, fluconazole and itraconazole were tested . In total, 3888 MIC values were included in the analyses . Reproducibility was calculated by means of agreement (percentage of MICs within one two-fold dilution of the mode) and intraclass correlation coefficient (ICC, maximum value of 1) . RESULTS: The average intra-laboratory agreements were 99% and 96% after 24 h and 48 h of incubation, respectively, with ICCs of 0.98 and 0.97 (P < 0.05) . Two strains exhibiting a trailing effect showed intra-laboratory agreement of 92% and ICCs of < 0.91 at 48 h . The inter-laboratory agreement was 94% and 88% after 24 h and 48 h, respectively, with ICCs of 0.93 and 0.91 (P < 0.05) . Lower values of agreement and ICCs were obtained for strains exhibiting trailing after 48 h of incubation . Itraconazole yielded the lowest values of reproducibility . CONCLUSION: The new procedure of EUCAST for antifungal susceptibility testing is a reproducible method within and between laboratories and offers several advantages over the NCCLS approved method.

J Agric Food Chem, 2003 Jul 16, 51(15), 4225 - 32
Rapid confirmatory assay for determining 12 sulfonamide antimicrobials in milk and eggs by matrix solid-phase dispersion and liquid chromatography-mass spectrometry; Bogialli S et al.; A rapid confirmatory method for determining 12 sulfonamide (SAs) antibacterials in whole milk and eggs is presented . This method is based on the matrix solid-phase dispersion technique with hot water as extractant followed by liquid chromatography (LC)-mass spectrometry (MS) . The LC-MS instrument was equipped with an electrospray ion source and a single quadrupole . After 4 mL of a milk sample containing the analytes had been deposited on sand (crystobalite), this material was packed into an extraction cell . SAs were extracted by flowing 4 mL of water through the cell heated at 75 degrees C . With some modifications, this procedure was applied also to eggs . After pH adjustment and filtration, 0.5 mL of the final extracts was then injected into the LC column . MS data acquisition was performed in the positive-ion mode and by monitoring at least three ions for each target compound . The in-source collision-induced dissociation process produced confirmatory ions . At the 50 ng/g level, recovery of the analytes in milk and eggs was 77-92% with relative standard deviations ranging between 1 and 11% . Estimated limits of quantification (S/N = 10) were 1-3 ng/g of SAs in milk and 2-6 ng/g in eggs . With both matrices, attempts to reduce the analysis time by using a short chromatographic run time caused severe ion signal suppression for the early-eluted SAs . This effect was traced to competition effects by polar endogenous coextractives, maybe proteinaceous species, which are eluted in the first part of the chromatographic run . This unwelcome effect was almost completely removed by simply adopting more selective chromatographic conditions.

Acta Pol Pharm, 2003 Jan-Feb, 60(1), 97 - 100
Chemoprevention of cancerogenesis--the role of sulforaphane; Solowiej E et al.; Isothiocyanates are a group of naturally occurring compounds with interesting medical properties, such as antimicrobial, antioxidant and antitumor activities . In our work we were trying to present the tumoricidal activity of new synthesized derivatives of one isothiocyanate: 1-isothio-cyanato-(4R)-(methylsulfinyl) butane {sulforaphane} . Many chemical substances derived from plants, undoubtedly have protective properties . The effectiveness of sulforaphane is based on induction of hepatic detoxifying enzymes.

Acta Pol Pharm, 2003 Jan-Feb, 60(1), 31 - 9
Technology of eye drops containing aloe (Aloe arborescens Mill.--Liliaceae) and eye drops containing both aloe and neomycin sulphate; Kodym A et al.; Eye drops made of aloe are a sterile, aqueous extract of fresh leaves of Aloe arborescens Mill., containing necessary additives and neomycin sulphate . The aim of the studies was to establish the technology of eye drops containing biologically active aloe substances and those containing both chemical constituents of aloe and neomycin sulphate . Within the studies, the formulary content and the way of preparing eye drops were determined, criteria were defined and methods of qualitative assessment of drops were proposed . On the basis of the proposed analytical methods, the physicochemical and microbiological stability of the eye drops stored at a temperature of 20-25 degrees C was studied . As the criteria of qualitative assessment of the eye drops, the following analyses were considered: sterility, appearance of the eye drops (clarity), pH, osmotic pressure, density, viscosity, TLC analysis, content of aloenin and aloin, studies of anti-microbial activity of neomycin in the drops, and preservative efficiency of thiomersal in the eye drops . The studies showed that the additives such as: sodium chloride, benzalkonium chloride, chlorhexidine diacetate and digluconate, phenylmercuric borate and Nipagins M and P could not be used to prepare the eye drops because they were involved in pharmaceutical interactions with chemical constituents of aloe in the eye drops . The eye drops containing: aqueous extract of fresh leaves of aloe, boric acid, thiomersal, sodium pyrosulphite, disodium EDTA, beta-phenylethyl alcohol and neomycin sulphate, both freshly prepared and after two years of storage, met the requirements of the Polish Pharmacopoeia (PPh V) mentioned in the monograph Guttae ophthalmicae . They were sterile, clear, their osmotic pressure approximated the osmotic pressure of lacrimal fluid and they were characterized by appropriate pH . Aloenin in the drops was much more stable than aloin . Neomycin after two years of storage retained almost 98% of its starting antimicrobial activity which allows the conclusion that the biologically active aloe substances did not decrease the stability of neomycin in the drops . The preservation assay showed that thiomersal, both in the freshly prepared drops and after two years of storage, maintained antimicrobial activity, which was in accordance with PPh V.

Orv Hetil, 2003 Jun 1, 144(22), 1077 - 83
{Eradication of Helicobacter pylori infection in Hungary (1993-2002): a meta-analysis}; Buzas GM; INTRODUCTION: Meta-analysis is a useful tool in obtaining sound data in evidence-based medicine . The guidelines of eradication have been proposed in the I . Maastricht consensus (1996), which was modified in 2000 . AIM OF STUDY: The scope of present paper is the meta-analysis of eradication studies performed in Hungary between 1993-2002 . METHODS: Articles/abstracts dealing with eradication, published in peer-reviewed Hungarian and international journals, meetings of the Hungarian Society of Gastroenterology and its Endoscopic Section and international congresses were identified from major databases and by manual search . The data were classified into groups based on eradication schedules, type of antibiotic used, and provenience of the study . The pooled eradication rates were calculated and compared with the international data . RESULTS: The pooled eradication rate of proton pump inhibitor-based triple therapies was 82.9% (confidence interval: 72.1-93.7%); omeprazole, pantoprazole and lansoprazole-based therapies given b.i.d . were equally efficient . H2-blockers based triple combinations lasting 10-14 days obtained a pooled eradication rate of 86.3% (confidence interval: 72.2-99.8%), insignificantly higher (p = 0.07) than the rate obtained with proton pump inhibitors . Classical triple therapy's (bismuth + 2 antimicrobials) pooled eradication rate is significantly lower as that of proton pump inhibitor (p = 0.01) or H2 blocker-based combinations (p = 0.008) . Clarithromycin, nitroimidazoles, amoxicillin and doxycyclin-based therapies obtained pooled eradication rates of 79.4%, 74.7%, 79.3% and 73.0%, respectively . The results obtained in randomized controlled trials and university centers were better than those achieved in county and urban hospitals . CONCLUSIONS: The results are in part contrasting with the recommendations of European and national consensus . Proton pump inhibitor-based triple regimens are proposed as first-line treatment, which is in agreement with our results, but H2-blockers based regimens seem to be of same efficacy in open studies, although these represent a lower level of evidence . Classical triple therapies, also recommended, did not reach acceptable rates of eradication . Antibiotic-based analysis did not reflect the local resistance profile . A multicenter, randomized Hungarian study is warranted to assess the real efficacy of the eradication schedules.

J Immunol, 2003 Jul 15, 171(2), 964 - 70
Early self-regulatory mechanisms control the magnitude of CD8+ T cell responses against liver stages of murine malaria; Hafalla JC et al.; Following immunization with Plasmodium yoelii sporozoites, the CD8(+) T cell population specific for the SYVPSAEQI epitope expressed in sporozoite and liver stages of this malaria parasite revealed the existence of a short term Ag presentation process that translated into a single clonal burst . Further expansion of this CD8(+) T cell population in conditions of sustained Ag exposure and additional supply of naive cells was inhibited by regulatory mechanisms that were developed as early as 24-48 h after priming . Studies using mouse models for Plasmodium or influenza virus infections revealed that this mechanism is Ag specific and is mediated by activated CD8(+) T cells that inhibit the priming of naive cells . This interference of the priming of naive cells appeared to result from limited access to Ag-presenting dendritic cells, which become disabled or are eliminated after contact with activated cells . Thus, concomitantly with the development of their effector antimicrobial capacity, CD8(+) T cells also acquire a self-regulatory role that is likely to represent one of the earliest mechanisms induced in the course of an immune response and that limits the magnitude of the early expansion of CD8(+) T lymphocytes reactive to microorganisms.

J Immunol, 2003 Jul 15, 171(2), 931 - 7
Inactivation of human beta-defensins 2 and 3 by elastolytic cathepsins; Taggart CC et al.; beta-Defensins are antimicrobial peptides that contribute to the innate immune responses of eukaryotes . At least three defensins, human beta-defensins 1, 2, and 3 (HBD-1, -2, and -3), are produced by epithelial cells lining the respiratory tract and are active toward Gram-positive (HBD-3) and Gram-negative (HBD-1, -2, and -3) bacteria . It has been postulated that the antimicrobial activity of defensins is compromised by changes in airway surface liquid composition in lungs of patients with cystic fibrosis (CF), therefore contributing to the bacterial colonization of the lung by Pseudomonas and other bacteria in CF . In this report we demonstrate that HBD-2 and HBD-3 are susceptible to degradation and inactivation by the cysteine proteases cathepsins B, L, and S . In addition, we show that all three cathepsins are present and active in CF bronchoalveolar lavage . Incubation of HBD-2 and -3 with CF bronchoalveolar lavage leads to their degradation, which can be completely (HBD-2) or partially (HBD-3) inhibited by a cathepsin inhibitor . These results suggest that beta-defensins are susceptible to degradation and inactivation by host proteases, which may be important in the regulation of beta-defensin activity . In chronic lung diseases associated with infection, overexpression of cathepsins may lead to increased degradation of HBD-2 and -3, thereby favoring bacterial infection and colonization.

Can J Gastroenterol, 2003 Jun, 17 Suppl B, 41B - 45B
Eradication therapy should be different for dyspeptic patients than for ulcer patients; de Boer WA; Physicians should try to achieve an optimal cure rate with their initial Helicobacter pylori eradication therapy . Most physicians use the same treatment in all their patients . H pylori infection in patients with peptic ulcer disease (PUD) is more likely to be cured than that in patients with functional dyspepsia (FD) . Differences in cure rates of 5% to 15% are usually reported, which is considered to be clinically relevant . A plausible biological explanation for this finding suggests that different strains (virulent {cagA+, vacA type s1} compared with nonvirulent strains {cagA-, vacA type s2}) in PUD and FD induce different changes in the gastric mucosa, and this facilitates or impairs antimicrobial efficacy . Physicians should be aware that most published treatment studies have included only PUD patients . This means that in clinical practice cure rates obtained in patients with FD or perhaps uninvestigated dyspepsia are usually lower than those reported in the literature . This has implications for the choice of treatment . Physicians should consider prolonging the duration of initial Helicobacter eradication therapy from seven to 10 to 14 days in patients without ulcers.

Can J Gastroenterol, 2003 Jun, 17 Suppl B, 30B - 32B
Are there geographical and regional differences in Helicobacter pylori eradication?
Vakil N.
An important area of controversy in Helicobacter pylori eradication is the apparent difference in eradication rates seen in different countries and populations . A recent meta-analysis showed that several factors may affect the outcome of therapy . Individuals residing in northeast Asia had higher eradication rates than those residing in Europe or other areas of Asia . Triple and quadruple drug therapies had significantly higher eradication rates than did dual drug therapies . Treatment regimens that lasted longer than 14 days were better than those that lasted less than seven days, but there was no significant advantage for 10 day therapy over seven day therapy . A number of factors may play a role in determining the regional and geographical differences in H pylori eradication therapy . Included in these factors are genetic differences in the metabolism of the proton pump inhibitor, which can alter the availability of antimicrobials in the stomach . Regional differences in antimicrobial resistance also affect the outcome of therapy . Some studies suggest that the degree of gastritis and the nature of the underlying disease may affect the outcome of therapy, but the data are controversial . Understanding the regional and geographical differences in H pylori eradication can help physicians select the optimal treatment regimen in different regions.

Drugs Today (Barc), 2000 Dec, 36(12), 829 - 34
Slowly resolving and nonresolving pneumonias; Cunha BA; Nonresolving or slowly resolving pulmonary infiltrates are a clinical diagnostic challenge for physicians . It is important to differentiate slowly resolving from nonresolving pneumonias because the causes of each of these two clinical entities are different . In general, slowly resolving pneumonias are due to antimicrobial or host defense factors . Nonresolving pneumonias are usually noninfectious and usually require invasive diagnostic techniques to confirm the diagnosis . The most common clinical error made in approaching patients with nonresolving or slowly resolving pulmonary infiltrates is to treat the patient with different antibiotics over an extended period of time . Non-resolving or slowly resolving pneumonia should prompt the clinician to intensify diagnostic efforts to arrive at an etiologic diagnosis . The response should not be extended to polypharmacy since antibiotic-related causes of failure in treating problems resulting in slowly resolving pneumonia are one of the least common reasons for this clinical presentation.

Drugs Today (Barc), 2000 Nov, 36(11), 785 - 91
Pneumonia in the elderly; Cunha BA; Pneumonia is a frequent cause of mortality and morbidity in the elderly . This article discusses pneumonia in the elderly based on causative organisms and sites where the pneumonia was acquired . Community-acquired pneumonia, nursing home-acquired pneumonia and nosocomial pneumonia in the elderly are reviewed from a diagnostic and therapeutic perspective . Optimal antimicrobial therapy is based on knowledge of the pulmonary pathogens associated with community-acquired, nursing home-acquired and nosocomial pneumonias . Antibiotic dosing should take into account the functional action of the liver and kidneys in individuals of advanced age.

Nature, 2003 Jul 17, 424(6946), 277 - 83 Epub 2003 Jun 29.
Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans; Murphy CT et al.; Ageing is a fundamental, unsolved mystery in biology . DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling . Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing . Here we find that many of these genes influence the ageing process . The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue . Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.

Urol Int, 2003, 71(1), 124 - 6
Amoxicillin-induced nephritis and tubulitis in a child; Ferrara P et al.; The occurrence of interstitial nephritis in patients receiving antimicrobial therapy has frequently been reported in adults while it has rarely been described in children . We report the case of a patient treated with amoxicillin who presented hallucinations and serosanguineous blisters during treatment and developed renal failure a few days after discontinuation of the drug . On renal biopsy an interstitial nephritis with tubulitis was identified .

Rev Chir Orthop Reparatrice Appar Mot, 2003 Jun, 89(4), 287 - 96
{Use of combined gallium-technetium scintigraphy to determine the interval before second-stage prosthetic reimplantation in hip arthroplasty infection: a consecutive series of 30 cases}; Piriou P et al.; PURPOSE OF THE STUDY: We report a series of 30 consecutive patients with chronically infected total hip replacement in a prospective treatment protocol that included two-stage revision surgery and scintigraphic monitoring . The serial bone scans were used to evaluate the course of infection, but not for diagnosis . Negative scintigraphic results were required before the second-stage prosthesis reinsertion after laboratory, clinical, and radiographic normalization were achieved . MATERIAL AND METHODS: Between 1987 and 1997, we prospectively followed thirty patients, who had a chronically infected hip arthroplasty treated by the conventional two-stage revision procedure using scintigraphic verification . For the present series, negative bone scan results were achieved in the resected hip before reinsertion of the prosthesis in all patients except one . The labels used were in every case gallium-67 and technetium-99m MDP with early and late (after 30 hours) scans . A scintigraphic result was considered positive if more gallium than technetium was fixed at a site . Our conventional medical and surgical protocol consisted of an initial complete excision of all foreign bodies with systematic parenteral administration of two antibiotics after having searched for the causative organism . A spacer was never used . Tibial pin traction was always applied during the duration of drainage of the wound . The antimicrobial regimen was administered to all of these patients for 3 months . The prosthesis was reinserted when C-reactive protein (CRP) levels returned to normal and negative scintigraphic results were obtained after a period with no antibiotic therapy . Reimplantation of the prosthesis was always performed with preventive antibiotic therapy selected according to the susceptibility of the initial organisms and begun after collecting new intraoperative bacteriological culture specimens . This antibiotic therapy was pursued only for the duration of the postoperative drainage . RESULTS: This follow-up based on combined technetium-gallium bone scans demonstrated two major advantages . First, no recurrence of infection was observed except in the single patient for whom the protocol was not observed . The second advantage was to permit nonarbitrary determination of the moment of reimplantation of the prosthesis, as there is no clear consensus regarding the interval before reinsertion in the literature . The patients underwent the second-stage of hip reconstruction after a mean interval of 9 months . The mean delay before negative scintigraphic results was 7 months . DISCUSSION: This method, which determines the optimum delay before reimplantation reducing the risk of reinfection to a minimum, gave promising results in this prospective study of 30 patients.

J Clin Microbiol, 2003 Jul, 41(7), 3175 - 80
Environmental isolation of Balamuthia mandrillaris associated with a case of amebic encephalitis; Schuster FL et al.; This report describes the first isolation of the ameba Balamuthia mandrillaris from an environmental soil sample associated with a fatal case of amebic encephalitis in a northern California child . Isolation of the ameba into culture from autopsied brain tissue confirmed the presence of Balamuthia: In trying to locate a possible source of infection, soil and water samples from the child's home and play areas were examined for the presence of Balamuthia: The environmental samples (plated onto nonnutrient agar with Escherichia coli as a food source) contained, in addition to the ameba, a variety of soil organisms, including other amebas, ciliates, fungi, and nematodes, as contaminants . Presumptive Balamuthia amebas were recognized only after cultures had been kept for several weeks, after they had burrowed into the agar . These were transferred through a succession of nonnutrient agar plates to eliminate fungal and other contaminants . In subsequent transfers, axenic Naegleria amebas and, later, tissue cultures (monkey kidney cells) served as the food source . Finally, the amebas were transferred to cell-free axenic medium . In vitro, the Balamuthia isolate is a slow-growing organism with a generation time of approximately 30 h and produces populations of approximately 2 x 10(5) amebas per ml . It was confirmed as Balamuthia by indirect immunofluorescence staining with rabbit anti-Balamuthia serum and human anti-Balamuthia antibody-containing serum from the amebic encephalitis patient . The environmental isolate is similar in its antimicrobial sensitivities and identical in its 16S ribosomal DNA sequences to the Balamuthia isolate from the deceased patient.

J Clin Microbiol, 2003 Jul, 41(7), 3142 - 6
Evaluation of the NCCLS extended-spectrum beta-lactamase confirmation methods for Escherichia coli with isolates collected during Project ICARE; Tenover FC et al.; To determine whether confirmatory tests for extended-spectrum beta-lactamase (ESBL) production in Escherichia coli are necessary, we selected 131 E . coli isolates that met the National Committee for Clinical Laboratory Standards (NCCLS) screening criteria for potential ESBL production from the Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology) strain collection . For all 131 isolates, the broth microdilution (BMD) MIC of at least one extended-spectrum cephalosporin was >/=2 micro g/ml . For 21 of 131 (16%) isolates, the ESBL confirmatory test was positive; i.e., the BMD MICs of ceftazidime or cefotaxime decreased by >/=3 doubling dilutions in the presence of clavulanic acid (CA) or the disk diffusion zone diameters increased by >/=5 mm around ceftazidime or cefotaxime disks in the presence of CA . All 21 isolates were shown by PCR to contain at least one of the genes bla(TEM), bla(SHV), and bla(OXA), and in isoelectric focusing (IEF) tests, all isolates demonstrated at least one beta-lactamase band consistent with a TEM, SHV, or OXA enzyme . Of the 21 isolates, 3 showed a CA effect for cefotaxime by BMD but not by disk diffusion testing . A total of 59 (45%) of the 131 isolates demonstrated decreased susceptibility to cefpodoxime alone (MIC = 2 to 4 micro g/ml), and none had a positive ESBL confirmatory test result . These were classified as false positives according to ESBL screen test results . For the remaining 51 (39%) isolates, the cefpodoxime MICs ranged from 16 to >128 micro g/ml and the MICs for the other extended-spectrum cephalosporins were highly variable . All 51 isolates gave negative ESBL confirmatory test results . Most showed IEF profiles consistent with production of both a TEM and an AmpC beta-lactamase, and representative isolates of several phenotypic groups showed changes in porin profiles; these 51 isolates were considered true negatives . In all, only 16% of 131 E . coli isolates identified as potential ESBL producers by the current NCCLS screening criteria were confirmed as ESBL producers . Thus, changing the interpretation of extended-spectrum cephalosporins and aztreonam results from the susceptible to the resistant category without confirming the presence of an ESBL phenotype would lead to a large percentage of false resistance results and is not recommended . However, by increasing the cefpodoxime MIC screening breakpoint to >/=8 micro g/ml, 45% of the false-positive results could be eliminated . NCCLS has incorporated this change in the cefpodoxime screening breakpoint in its recent documents.

J Biol Chem, 2003 Sep 19, 278(38), 36859 - 67 Epub 2003 Jul 03.
Solution structure of the recombinant penaeidin-3, a shrimp antimicrobial peptide; Yang Y et al.; Penaeidins are a family of antimicrobial peptides of 47-63 residues isolated from several species of shrimp . These peptides display a proline-rich domain (N-terminal part) and a cysteine-rich domain (C-terminal part) stabilized by three conserved disulfide bonds whose arrangement has not yet been characterized . The recombinant penaeidin-3a of Litopenaeus vannamei (63 residues) and its {T8A}-Pen-3a analogue were produced in Saccharomyces cerevisiae and showed similar antimicrobial activity . The solution structure of the {T8A}-Pen-3a analogue was determined by using two-dimensional 1H NMR and simulated annealing calculations . The proline-rich domain, spanning residues 1-28 was found to be unconstrained . In contrast, the cysteine-rich domain, spanning residues 29-58, displays a well defined structure, which consists of an amphipathic helix (41-50) linked to the upstream and the downstream coils by two disulfide bonds (Cys32-Cys47 and Cys48-Cys55) . These two coils are in turn linked together by the third disulfide bond (Cys36-Cys54) . Such a disulfide bond packing, which is in agreement with the analysis of trypsin digests by ESI-MS, contributes to the highly hydrophobic core . Side chains of Arg45 and Arg50, which belong to the helix, and side chains of Arg37 and Arg53, which belong to the upstream and the downstream coils, are located in two opposite parts of this globular and compact structure . The environment of these positively charged residues, either by hydrophobic clusters at the surface of the cysteine-rich domain or by sequential hydrophobic residues in the unconstrained proline-rich domain, gives rise to the amphipathic character required for antimicrobial peptides . We hypothesize that the antimicrobial activity of penaeidins can be explained by a cooperative effect between the proline-rich and cysteine-rich features simultaneously present in their sequences.

Int J Antimicrob Agents, 2003 Jul, 22(1), 77 - 80
Production and resolution of cantharidin-induced inflammatory blisters; Maglio D et al.; While inflammatory blisters have long been utilized as a means of evaluating antimicrobial disposition to aid in the development of new treatments for skin and skin structure infections, sparse data are available regarding the healing of the blisters once the experiment has been completed . We report the blister induction technique and resolution time in ten volunteers enrolled in a pharmacokinetic study using the cantharidin-induced inflammatory blister technique.

Int J Antimicrob Agents, 2003 Jul, 22(1), 1 - 6
Empirical treatment of acute cystitis in women; Nicolle LE; Empirical antimicrobial treatment for acute cystitis in women requires continuing reassessment as the antimicrobial susceptibility of community isolates of Escherichia coli evolves . Current recommendations for 3 days trimethoprim or trimethoprim/sulphamethoxazole are compromised by increasing resistance of community E . coli to these agents . Fluoroquinolones are an alternate 3-day therapy, but increasing resistance is being reported from some countries, and widespread community use may promote resistance, limiting effectiveness of these agents for more serious infections . Alternate regimens supported by recent clinical trials suggest pivmecillinam given twice daily for 7 days is as effective as 3 days of quinolone therapy, while microbiological cure is 80% with 3 days therapy twice daily, and 90% with 3 days therapy thrice daily . Nitrofurantoin given for 7 days has a cure rate of 80-85% . Fosfomycin trometamol as a single dose has cure rates of 75-85% . All these agents are effective, but a compromise in efficacy or duration of therapy compared with current 3-day regimens may have to be considered.

Aging Clin Exp Res, 2003 Feb, 15(1), 12 - 8
Risks for frequent antimicrobial-treated infections in postmenopausal women; Boudreau DM et al.; BACKGROUND AND AIMS: Infections are a major cause of morbidity and mortality in older adults . Little is known about factors that alter the susceptibility to infection in the older population . This study in postmenopausal women examines health-related conditions and behavioral factors that may increase the risk of frequent infections, defined as having, on average, one or more infections per year . METHODS: A prospective cohort study with 5 years of follow-up was conducted in 1320 women aged 55 to 80 years . The subjects were Group Health Cooperative of Puget Sound (GHC) enrollees screened for a large fracture prevention trial who also participated in a survey of dietary and supplemental vitamin use . The main outcome, total number of infection events per subject, was derived from a new method of identifying outpatient infections based on the antimicrobial prescription fills recorded in GHC automated pharmacy records . RESULTS: Prevalent lung disease (OR = 6.1, 95% CI 2.8-13.4), receiving a prescription for vitamin C (OR = 2.1, 95% CI 1.4-3.4), and the second and third tertiles of the Chronic Disease Score (OR = 1.7, 95% CI 1.1-2.7 and OR = 2.4, 95% CI 1.5-3.9, respectively) were associated with 5 or more antimicrobial-treated infections during follow-up . A body mass index (BMI) of less than 22 kg/m2 (OR = 0.6, 95% CI 0.3-1.0) was suggestive of an association . CONCLUSIONS: The study provides new information on risk factors for outpatient infections and raises new questions regarding the susceptibility to frequent infections in older women . In addition, the automated pharmacy record method used in this study offers a low-cost alternative for use in future epidemiologic research.

Semin Respir Infect, 2003 Jun, 18(2), 122 - 8
When can empiric therapy for intensive care unit-acquired pneumonia be withheld or withdrawn?
Koeman M, Bonten MJ.
Diagnosing ventilator-associated pneumonia (VAP) is difficult, creating important clinical dilemmas for intensive care physicians . Adequate empiric antimicrobial therapy is crucial because VAP is associated with increased morbidity and mortality, especially when initial treatment is inappropriate . Because VAP is the most frequent occurring nosocomial infection, it is, to a large extent, responsible for the high antibiotic consumption in ICUs, which is an important cause for selection and induction of antibiotic resistance . In addition, antibiotics may have adverse effects and their costs should be considered . Therefore, a balance should be found between the obvious necessary therapeutic benefits and the negative effects (selection of resistant pathogens, costs, and adverse effects) of antibiotics in the treatment of VAP . Although guidelines for initial antimicrobial therapy have been established, no such recommendations exist for withholding or withdrawing antimicrobial treatment, and little is known about the optimal duration of therapy.

Semin Respir Infect, 2003 Jun, 18(2), 112 - 21
Effectiveness of programs to decrease antimicrobial resistance in the intensive care unit; Hall CS et al.; Resistance of microbes to antibiotics is an increasing problem in intensive care units (ICUs) with a prevalence of 86% in some isolates . Resistance results in increased morbidity, mortality, and increased costs . Risk factors associated with the development of resistance and strategies to combat resistance are discussed . Risk factors include increased antibiotic use, host factors including severity of illness and length of stay, and lack of adherence to infection control practices . Multiple strategies to decrease resistance have been studied . Changing antimicrobial practices via guideline development, antibiotic restriction, use of information systems technology, crop rotation, narrowing spectrum of empiric antibiotics, multidisciplinary approaches, and selective decontamination have had variable results . Prevention of horizontal transmission via handwashing, glove and gown use, alternatives to soap, and improving the workload and facilities for health care workers is discussed . Primary prevention via decreased length of stay, selective digestive decontamination, vaccine development, and decreased use of invasive devices also plays a role.

Proc Natl Acad Sci U S A, 2003 Jul 22, 100(15), 8880 - 5 Epub 2003 Jul 02.
Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3; Wu Z et al.; Human defensins form a family of small, cationic, and Cys-rich antimicrobial proteins that play important roles in innate immunity against invading microbes . They also function as effective immune modulators in adaptive immunity by selectively chemoattracting T lymphocytes and immature dendritic cells . On the basis of sequence homology and the connectivity of six conserved Cys residues, human defensins are classified into alpha and beta families . Structures of several beta-defensins have recently been characterized, confirming the disulfide connectivity conserved within the family, i.e., Cys1-Cys5, Cys2-Cys4, and Cys3-Cys6 . We found that human beta-defensin 3 (hBD3), a recently described member of the growing beta family, did not fold preferentially into a native conformation in vitro under various oxidative conditions . Using the orthogonal protection of Cys1-Cys5 and of Cys1-Cys6, we chemically synthesized six topological analogs of hBD3 with predefined disulfide connectivities, including the (presumably) native beta pairing . Unexpectedly, all differently folded hBD3 species exhibited similar antimicrobial activity against Escherichia coli, whereas a wide range of chemotactic activities was observed with these analogs for monocytes and cells transfected by the chemokine receptor CCR6 . Furthermore, whereas substitution of all Cys residues by alpha-aminobutyric acid completely abolished the chemotactic activity of hBD3, the bactericidal activity remained unaffected in the absence of any disulfide bridge . Our findings demonstrate that disulfide bonding in hBD3, although required for binding and activation of receptors for chemotaxis, is fully dispensable for its antimicrobial function, thus shedding light on the mechanisms of action for human beta-defensins and the design of novel peptide antibiotics.

Appl Environ Microbiol, 2003 Jul, 69(7), 4190 - 1
A selective medium for quantitative reisolation of Trichoderma harzianum from Agaricus bisporus compost; Williams J et al.; We adapted a selective medium, previously developed for reisolation of Trichoderma spp . from soil, for quantitative determination of growth of T . harzianum from commercial Agaricus bisporus composts . This medium enables comparisons of aggressive (sensu inhibition of A . bisporus yield) with nonaggressive T . harzianum groups . The resulting medium contains the antimicrobials chloramphenicol, streptomycin, quintozene, and propamocarb and was highly selective, allowing the recovery of T . harzianum, as viable conidia and hyphal fragments, in compact colonies with the absence of visible microbial contaminants.

Int J Infect Dis, 2003 Mar, 7 Suppl 1, S5 - 12
Why do we need to eradicate pathogens in respiratory tract infections?
Garau J.
Evidence from studies in otitis media, acute bacterial sinusitis and acute exacerbations of chronic bronchitis indicate that clinical efficacy is dependent on bacterial eradication . Failure to eradicate bacterial pathogens increases the potential for clinical failure, incurring further costs, and may also select and maintain bacteria that are resistant to a wide range of antimicrobials . Bacteriologically confirmed clinical failures have been reported in pneumococcal pneumonia with both macrolides and older fluoroquinolones (ciprofloxacin, ofloxacin, and levofloxacin) . These failures were due to the involvement of resistant pathogens (macrolides) or suboptimal pharmacokinetics/pharmacodynamics (PK/PD) (quinolones) . However, persistent positive blood cultures have not been reported during therapy with adequate doses of benzylpenicillins or aminopenicillins . Treatment failure, driven by the failure to eradicate pathogens, leads to both economic and environmental costs, hospitalization being the major cost driver . Failure to achieve bacterial eradication may also lead to the development and spread of resistance . Different types of antimicrobials appear to be driving resistance to different extents, and this may be due to suboptimal PK/PD . In conclusion, factors to consider when prescribing include an accurate diagnosis, knowledge of local epidemiology, the role of PK/PD principles in antimicrobial choice, clinical outcomes in relation to bacteriologic efficacy, and resistance and its bacteriologic and clinical impact . The vicious cycle of infection, inappropriate therapy, bacteriologic failure, selection/spread of resistance and further infection needs to be broken by the use of appropriate treatments to achieve bacterial eradication.

Int J Infect Dis, 2003 Mar, 7 Suppl 1, S1 - 4
Introduction: the goals of antimicrobial therapy; Song JH; Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demonstrating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy . However, large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and, generally, studies are powered to show only clinical equivalence . In addition, diagnosis is often based on clinical symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant pathogens are often excluded . Clinical efficacy can be achieved in some bacterial infections in which antimicrobials are suboptimal or even not prescribed . However, bacterial eradication maximizes clinical efficacy and may also reduce the development and spread of resistant organisms . The goal of antimicrobial therapy is, therefore, to eradicate bacteria at the site of infection . Bacterial eradication is not usually assessed as a primary endpoint within the limits of currently recommended clinical trial design . However, pharmacokinetic (PK) (serum concentration profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy . PK/PD predictions should be confirmed during all phases of antimicrobial development and throughout clinical use in response to changing patterns of resistance . A clear rationale for dose recommendations can be determined preclinically based on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials . The duration of treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well tolerated . Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for bacteriologic eradication . Recommendations for appropriate antimicrobial therapy should be based on PK/PD parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant pathogens.

Pediatrics, 2003 Jul, 112(1 Pt 2), 253 - 8
Antibiotic resistance: what is the impact of agricultural uses of antibiotics on children's health?
Shea KM.
Antimicrobial resistance has reached crisis stage in human medicine . The rapid acceleration of multidrug-resistant bacteria in the past 2 decades has overtaken new drug development, and patients and clinicians are faced with the prospect of untreatable infections . Although much of the problem stems from overuse and misuse of antimicrobial agents in human medicine, large-scale use of antimicrobials in agriculture also contributes to the crisis . Agricultural uses of antibiotics produce environmental exposures in a variety of reservoirs, which select for resistant microbes and microbial genes . This article presents the major lines of evidence documenting the risks to human health of some of the agricultural uses of antimicrobials . A brief review of the microbiologic antecedents of resistance is followed by a discussion of agricultural uses of antimicrobials and a targeted review of the literature, which provides the background knowledge and evidence necessary for pediatricians and other clinicians to be informed and to advocate for judicious use of antimicrobials in all sectors.

Pediatrics, 2003 Jul, 112(1 Pt 1), 143 - 9
Diagnosis and treatment of acute otitis media: an assessment; Garbutt J et al.; OBJECTIVE: To assess compliance with the Centers for Disease Control and Prevention (CDC) evidence-based guidelines for the judicious use of antimicrobials in children with acute otitis media (AOM) . METHODS: Compliance with CDC's recommended diagnostic criteria and antimicrobial treatments for management of AOM was assessed by chart review and self-report for 29 community pediatricians in St . Louis, Missouri . For each physician, a simple random sample of AOM visits was selected and reviewed by trained reviewers . In addition, each physician completed a questionnaire . RESULTS: Compliance with recommended diagnostic criteria was 38% (95% confidence interval: 34%-42%; n = 573) by chart audit and 41% (95% confidence interval: 24%-61%; n = 29) by self-report . Antimicrobial selection assessed by chart audit was consistent with CDC guidelines in 68% (95% confidence interval: 64%-72%) of visits for a new infection, 63% (95% confidence interval: 47%-78%) of visits for treatment failure, and 50% (95% confidence interval: 33%-67%) for recurrent disease . Self-reported compliance with treatment guidelines for new infection was 100% (95% confidence interval: 88%-100%) and 83% (95% confidence interval: 64%-94%) for treatment failure . Noncompliance was most frequently attributable to overuse of broad-spectrum antimicrobials . Most patients treated with amoxicillin received a 10-day course (98%) . Subtherapeutic dosing occurred in 26% of patients treated with amoxicillin . CONCLUSIONS: Overdiagnosis of AOM is common . Efforts to improve the judicious use of antimicrobials for AOM should focus on improving diagnostic accuracy, limiting the use of broad-spectrum antimicrobials to cases where they offer clinical benefit, and ensuring that amoxicillin dosing regimens are optimal.

J Antimicrob Chemother, 2003 Aug, 52(2), 224 - 8 Epub 2003 Jul 01.
Antibiotic susceptibilities of Gram-positive anaerobic cocci: results of a sentinel study in England and Wales; Brazier JS et al.; OBJECTIVE: A sentinel study was carried out to determine the antimicrobial susceptibilities of Gram-positive anaerobic cocci (GPAC) freshly isolated from clinical material in diagnostic laboratories in England and Wales . METHODS: A total of 113 GPAC isolates consisting predominantly of current or former members of the genus Peptostreptococcus was obtained from 17 sentinel laboratories in England and one in Wales . Minimum inhibitory concentrations (MICs) of 10 antimicrobial agents were determined by the Etest method . The agents tested were: penicillin, tetracycline, erythromycin, cefoxitin, clindamycin, chloramphenicol, imipenem, co-amoxiclav, piperacillin/tazobactam and metronidazole . MIC50 and MIC90 values for each drug-species combination were calculated whenever suitable numbers of each species were obtained . RESULTS: Excellent spectra of activity (0% resistance) against GPAC were seen for metronidazole, piperacillin/tazobactam, cefoxitin, imipenem and chloramphenicol . Low degrees of resistance to co-amoxiclav (3.5%), clindamycin (7.1%), penicillin (7.1%) and significant degrees of resistance to tetracycline (41.6%) and erythromycin (27.4%) were detected . Some examples of putative macrolide-lincosamide linked resistance were noted in seven (6.2%) isolates of GPAC . CONCLUSION: This study is one of the largest susceptibility studies specifically on GPAC carried out to date and the resulting data may be of value to those involved in the empirical treatment of infections involving Gram-positive anaerobic cocci.

Fitoterapia, 2003 Jul, 74(5), 476 - 8
Antimicrobial activity of Amomum cannicarpum; Mathew J et al.; The petroleum ether and methanol extracts of rhizomes of Amomum cannicarpum exhibited moderate inhibiting activity against both Gram-positive and Gram-negative bacteria . None of the extractives was active against the tested moulds.

Lancet Infect Dis, 2003 Jul, 3(7), 405 - 12
Antimicrobial therapy to prevent or treat oral mucositis; Donnelly JP et al.; Oral mucositis represents a significant source of morbidity after chemotherapy and radiation therapy . Since infection may have an important role in the pathophysiology of oral mucositis, several antimicrobial agents have been investigated for their efficacy in preventing and treating this disease . We sought to establish the weight of evidence for antimicrobial treatment and identified 31 prospectively designed clinical trials of which 13 reported some benefit and 15 did not . No clear pattern was identified regarding patient type, cancer treatment, or type of antimicrobial agent used, and inconsistent assessment of oral mucositis made comparison of outcomes difficult . Newer drugs, such as the topical antimicrobial peptide iseganan HCl initially showed promise in reducing mucositis and the related oral pain but the results of a phase 3 trial were disappointing and the line of enquiry was abandoned altogether . Hence, there is a need to better understand the role of the microflora in the cause of oral mucositis if an antimicrobial agent for prevention and treatment of this disease is to be developed.

Genomics, 2003 Aug, 82(2), 172 - 84
Expansion of the BPI family by duplication on human chromosome 20: characterization of the RY gene cluster in 20q11.21 encoding olfactory transporters/antimicrobial-like peptides; Andrault JB et al.; Antimicrobial peptides provide a defense system against microorganisms . One class of these molecules binds lipophilic substrates and is therefore directed against gram-negative bacteria . This family includes proteins related to bactericidal/permeability-increasing protein (BPI) . We characterized an approximately 100-kb cluster of three human genes named RYSR, RYA3, and RY2G5 that are related to the BPI family . The RY cluster maps to 20q11.21, >5 Mb upstream of the BPI cluster . The RY and BPI genes have similar exon structures, indicating that they were derived by duplication from a common ancestor . We identified mouse BPI-related and RY orthologues in syntenic regions, indicating that the gene family expanded before mouse and human diverged . Expression analyses show that RYs are strongly expressed in the olfactory epithelium, suggesting that they also could act as odorant transporters or detoxification agents in the olfactory system . Together, these data show how mammals diversified their antimicrobial defenses/olfactory pathways through a duplication-driven adaptive selection process.

Med Microbiol Immunol (Berl), 2004 Feb, 193(1), 1 - 17 Epub 2003 Jun 27.
The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases; Holscher C; Appropriate induction of a Th1 immune response is required for effective antimicrobial immunity . However, dysregulated Th1 immune responses after infection may also lead to immunopathology . Thus, cell-mediated immune responses have to be tightly regulated . Upon infection, the production of interleukin (IL)-12, a heterodimeric cytokine composed of a p35 and a p40 subunit, is the dominant factor in Th1 cell development . The recent discovery of novel dimeric cytokines closely related to IL-12 add now to our understanding of cellular immunity and the fine tuning of T cell responses . At the onset of infection, IL-27, a heterodimer composed of the IL-12p40-related protein EBI-3 (Epstein-Barr virus-induced gene 3) and the IL-12p35-related protein p28 induces the expression of a functional IL-12 receptor in naive CD4+ T cells, making these cells sensitive to IL-12-mediated Th cell development . Later during infection, IL-23, a heterodimer composed of the IL-12p40 subunit and the IL-12p35-related molecule p19, preferentially acts on Th1 effector/memory CD4+ T cells . The IL-12p40 subunit can also form a homodimer, IL-12p80, which act as an IL-12 and IL-23 antagonist by competing at their receptors . This review focuses on these IL-12-related cytokines contributing to fine tuning of T cell responses after infection with intracellular pathogens.

Anal Sci, 2003 Jun, 19(6), 969 - 70
Crystal structure of 3,3-dichloro-N-p-methoxyphenyl-4-(2-phenylstryl)-2-azetidinone; Kabak M et al.; 3,3-Dichloro-N-p-methoxyphenyl-4-(2-phenylstryl)-2-azetidinone (C22H15Cl2NO2) was studied by X-Ray analysis, which indicated a monoclinic space group, P2(1)/c, with a = 9.619(5), b = 13.879(4), c = 14.161(5)A, beta = 100.16(3)degrees, V = 1860.8(13)A3, Z = 4, Dc = 1.414 g cm(-3), micro(Mo Kalpha) = 0.366 mm(-1) and F000 = 816 . The structure was solved by direct methods and refined to R = 0.041 for 4026 reflections {I > 2sigma(I) . The beta-lactam ring (2-azetidinone) has antimicrobial affects . The substituents of the methoxyphenyl and phenyl substituents do not change the activity property of the beta-lactam ring, and the activity properties depend on the planarity of the beta-lactam ring.

Rev Argent Microbiol, 2003 Jan-Mar, 35(1), 29 - 40
{Consensus on antimicrobial sensitivity tests in gram-positive cocci . Subcommittee on Antimicrobials, SADEBAC (Argentinian Society of Clinical Bacteriology), Argentinian Association of Microbiology}; Famiglietti A et al.; Antimicrobial susceptibility testing is mainly performed in Argentina by disk diffusion method, following National Committee for Clinical Laboratory Standards (NCCLS) recommendations . We worked out new recommendations for the reporting and interpretation of this test when dealing with gram-positive cocci, in accordance to local trends and epidemiology . General considerations for performing the diffusion assay, quality control, and an update on susceptibility testing for gram-positive cocci are reported in this first document . The present update should be considered as a group of recommendations summarized by Argentinean experts and as the result of a consensus meeting coordinated by the Subcomision de Antimicrobianos of the Sociedad Argentina de Bacteriologia Clinica (Asociacion Argentina de Microbiologia) . Experts in antimicrobial agents were convened in order to prepare this final document . These recommendations take into account local needs, affordability and availability to be used in current practice, tending to contribute to the correct antimicrobial treatment election, according to the particular microorganism and the infection sites.

J Formos Med Assoc, 2003 Apr, 102(4), 270 - 2
Peritonitis caused by Chryseobacterium meningosepticum in a patient undergoing continuous ambulatory peritoneal dialysis; Wu VC et al.; Chryseobacterium meningosepticum is rarely encountered as a pathogen causing peritonitis in adults . A 54-year-old woman who underwent continuous ambulatory peritoneal dialysis for 8 years developed peritonitis due to C . meningosepticum . Although she received intravenous antibiotics with good in vitro activity against the organism, the fever and signs of peritonitis persisted . The Tenckhoff catheter was finally removed on the 25th day of hospitalization and the fever subsided . Four isolates of C . meningosepticum recovered from 4 ascites samples drawn on the third, 13th, 18th, and 23rd hospitalization days had identical antibiograms and random amplified DNA polymorphism patterns generated by an arbitrarily primed polymerase chain reaction . Early removal of Tenckhoff catheter and appropriate antimicrobial therapy are crucial to the successful treatment of peritonitis due to C . meningosepticum.

Acta Biochim Pol, 2003, 50(2), 461 - 9
Novel properties of antimicrobial peptides; Kamysz W et al.; Endogenous peptide antibiotics are known as evolutionarily old components of innate immunity . Due to interaction with cell membrane these peptides cause permeabilization of the membrane and lysis of invading microbes . However, some studies proved that antimicrobial peptides are universal multifunctional molecules and their functions extend far beyond simple antibiotics . In this review we present an overview of the general mechanism of action of antimicrobial peptides and discuss some of their additional properties, like antitumour activity, mitogenic activity, role in signal transduction pathways and adaptive immune response.

Actas Urol Esp, 2003 Apr, 27(4), 305 - 7
{Meningitis caused by multiresistant E . coli after an echo-directed transrectal biopsy}; Rodriguez-Patron Rodriguez R et al.; Transrectal prostate biopsy is the most accurate method for prostate cancer diagnosis . Although an antimicrobial prophylaxis is employed in most cases, infectious complications are among the most severe . We present a case of E . coli multirresistant meningitis after transrectal prostate biopsy despite quinolone prophylaxis.

Clin Infect Dis, 2003 Jul 1, 37(1), 65 - 72 Epub 2003 Jun 24.
Do antimicrobial-impregnated central venous catheters prevent catheter-related bloodstream infection?
McConnell SA, Gubbins PO, Anaissie EJ.
Controversy surrounds the role of central venous catheters (CVCs) impregnated with antimicrobial agents in the prevention of catheter-related bloodstream infection (CRBSI) . We reviewed the current literature to evaluate the efficacy of antimicrobial-impregnated CVCs for preventing CRBSI . Eleven randomized studies published in article form were identified that included a control group that received nonimpregnated CVCs . We evaluated study methodologies, inclusion of key patient characteristics, use of clinically relevant end points, and molecular-relatedness studies . Review of these 11 trials revealed several methodological flaws, including inconsistent definitions of CRBSI, failure to account for confounding variables, suboptimal statistical and epidemiological methods, and rare use of clinically relevant end points . This review also failed to demonstrate any significant clinical benefit associated with the use of antimicrobial-impregnated CVCs for the purpose of reducing CRBSI or improving patient outcomes . More rigorous studies are required to support or refute the hypothesis that antimicrobial-impregnated CVCs reduce the rate of or prevent CRBSI.

Clin Infect Dis, 2003 Jul 1, 37(1), 59 - 64 Epub 2003 Jun 23.
Antibiotic combinations with redundant antimicrobial spectra: clinical epidemiology and pilot intervention of computer-assisted surveillance; Glowacki RC et al.; Redundant antibiotic combinations are a potentially remediable source of antibiotic overuse . At a public teaching hospital, we determined the incidence, cost, and indications for such combinations and measured the effects of a pharmacist-based intervention . Of 1189 inpatients receiving >or=2 antibiotics, computer-assisted screening identified 192 patients (16.1%) receiving potentially redundant combinations . Chart reviews showed that 137 episodes (71%) were inappropriate . Physician overprescribing errors were found in 77 episodes (56%); most involved redundant coverage for gram-positive or anaerobic organisms . In 76 episodes (55%), lapses in the medication ordering and distribution system led to the persistence in the pharmacy records of regimens no longer active according to the patient charts . The incidence of redundant antibiotic combinations was significantly higher in the intensive care unit and surgery services, compared with medical services . Interventions to discontinue redundant agents were successful in 134 (98%) of the 137 episodes . Potential drug cost savings and reduction in redundant antibiotic combination days were 10,800 dollars and 584 days, respectively; pharmacist time for patient review and intervention cost 2880 dollars . Use of redundant antibiotic combinations was common, and a pharmacist-based intervention was feasible, with a potential annualized cost savings of 48,000 dollars.

Blood, 2003 Oct 1, 102(7), 2660 - 9 Epub 2003 Jun 26.
Toll-like receptors stimulate human neutrophil function; Hayashi F et al.; The first immune cell to arrive at the site of infection is the neutrophil . Upon arrival, neutrophils quickly initiate microbicidal functions, including the production of antimicrobial products and proinflammatory cytokines that serve to contain infection . This allows the acquired immune system enough time to generate sterilizing immunity and memory . Neutrophils detect the presence of a pathogen through germ line-encoded receptors that recognize microbe-associated molecular patterns . In vertebrates, the best characterized of these receptors are Toll-like receptors (TLRs) . We have determined the expression and function of TLRs in freshly isolated human neutrophils . Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10-all the TLRs except TLR3 . Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increased TLR2 and TLR9 expression levels . The agonists of all TLRs expressed in neutrophils triggered or primed cytokine release, superoxide generation, and L-selectin shedding, while inhibiting chemotaxis to interleukin-8 (IL-8) and increasing phagocytosis of opsonized latex beads . The response to the TLR9 agonist nonmethylated CpG-motif-containing DNA (CpG DNA) required GM-CSF pretreatment, which also enhanced the response to the other TLR agonists . Finally, using quantitative polymerase chain reaction (QPCR), we demonstrate a chemokine expression profile that suggests that TLR-stimulated neutrophils recruit innate, but not acquired, immune cells to sites of infection.

J Clin Virol, 2003 Jul, 27(2), 146 - 51
Varicella zoster and Borrelia burgdorferi are the main agents associated with facial paresis, especially in children; Jaamaa S et al.; BACKGROUND: The etiology of facial paresis (FP) often remains unresolved . Yet, a microbial association is frequently suspected . OBJECTIVE: To evaluate the infectious etiology of FP by using sensitive tests . STUDY DESIGN: We studied the serum and cerebrospinal fluid of 42 patients diagnosed with idiopathic peripheral facial paresis using sensitive serological methods and nucleic acid detection and for reference, 42 patients with other neurological disorders (OND) matched for age, sex, season and geographical area . RESULTS: Varicella zoster virus and Borrelia burgdorferi accounted for 56% of all associated agents in children with FP compared with 11% of OND (P=0.01) . In adults, the respective numbers were 29 and 13% . Other treatable etiological agents, Chlamydia pneumoniae and Mycoplasma pneumoniae, accounted for 11% in children and 8% in adults and with the same prevalence between patients with FP and OND . CONCLUSIONS: Microbes, with specific therapy available accounted for 52% of all associated agents in the patients with FP when compared with 26% in controls with OND (P=0.04) . Based on this, we conclude that the patients with FP may benefit from antimicrobial therapy.

Exp Hematol, 2003 Jun, 31(6), 535 - 44
Unrelated umbilical cord blood transplants in adults: Early recovery of neutrophils by supportive co-transplantation of a low number of highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor; Fernandez MN et al.; OBJECTIVE, METHODS, AND RESULTS: To reduce the period of posttransplant neutropenia and related early morbidity and mortality of cord blood (CB) transplants, we assessed the feasibility of co-infusion of a low number of highly purified peripheral blood CD34+ cells from a related haploidentical donor with a CB graft . Between March 1999 and May 2002, 11 patients with high-risk hematologic malignancies were transplanted using this strategy . The seven patients who received a haploidentical peripheral blood graft and a CB graft from a sibling (6) or the father (1) had prompt recovery (9-17 days, median 10) of the absolute neutrophil count (ANC) to greater than 0.5 x 10(9)/L . Analysis of DNA polymorphisms showed initial predominance of the haploidentical genotype both in granulocytes and in mononuclear cells, and subsequent progressive replacement by cells of CB genotype until final complete CB chimerism was achieved by patients who survived for sufficient periods of time . The four patients who received maternal haploidentical cells had no significant contribution of these to blood leukocytes, although complete CB chimerism was achieved by three of them and two reached engraftment of the CB on days +20 and +36 . Morbidity due to early bacterial or fungal infections was remarkably low in patients with prompt ANC recovery . CONCLUSION: Our data show that co-infusion of a CB unit and a low number of haploidentical CD34+ cells may result in a shortened period of posttransplant neutropenia . This is likely the result of prompt and transient engraftment of the haploidentical hematopoietic stem cells that may provide the patient antimicrobial protection until the later engraftment of the CB hematopoietic stem cells.

Scand J Immunol, 2003 Jul, 58(1), 67 - 75
Interaction between Borrelia burgdorferi and immature human dendritic cells; Suhonen J et al.; Antigen uptake and the following maturation of dendritic cells (DCs) are pivotal to the initiation of specific antimicrobial immune responses . DCs also play an important role in the recruitment and activation of the cells of the innate immune system . We have examined the interactions of DCs with Borrelia burgdorferi to find explanations for the difficulties the human immune system has in dealing with the bacterium . Phagocytosis of B . burgdorferi by immature DCs and the effect of the bacterium on the maturation and interleukin-8 (IL-8) secretion of DCs were studied . Borreliae were phagocytized and processed into fragments by DCs; narrow tube-like pseudopods and broad pseudopods were used for the engulfment . The immature DC population gained a heterogeneous appearance within 2 h of incubation with the borreliae . A 24 h coculture with borreliae induced maturation and IL-8 secretion in the DCs in a manner comparable with the effect of lipopolysaccharides . All strains studied, including a mutant strain lacking outer surface proteins A and B, were capable of inducing these responses . Thus, our results did not show any clear inadequacy concerning the way DCs are dealing with B . burgdorferi . However, further studies on the subject are required.

Am J Vet Res, 2003 Jun, 64(6), 694 - 9
Pharmacokinetics of imipenem in dogs; Barker CW et al.; OBJECTIVE: To determine the plasma pharmacokinetics of imipenem (5 mg/kg) after single-dose IV, IM, and SC administrations in dogs and assess the ability of plasma samples to inhibit the growth of Escherichia coli in vitro . ANIMALS: 6 adult dogs . PROCEDURE: A 3-way crossover design was used . Plasma concentrations of imipenem were measured after IV, IM, and SC administration by use of high-performance liquid chromatography . An agar well antimicrobial assay was performed with 3 E coli isolates that included a reference strain and 2 multidrug-resistant clinical isolates . RESULTS: Plasma concentrations of imipenem remained above the reported minimum inhibitory concentration for E coli (0.06 to 0.25 microg/mL) for a minimum of 4 hours after IV, IM, and SC injections . Harmonic mean and pseudo-standard deviation half-life of imipenem was 0.80 +/- 0.23, 0.92 +/- 0.33, and 1.54 +/- 1.02 hours after IV, IM, and SC administration, respectively . Maximum plasma concentrations (Cmax) of imipenem after IM and SC administration were 13.2 +/- 4.06 and 8.8 +/- 1.7 mg/L, respectively . Time elapsed from drug administration until Cmax was 0.50 +/- 0.16 hours after IM and 0.83 +/- 0.13 hours after SC injection . Growth of all 3 E coli isolates was inhibited in the agar well antimicrobial assay for 2 hours after imipenem administration by all routes . CONCLUSIONS AND CLINICAL RELEVANCE: Imipenem is rapidly and completely absorbed from intramuscular and subcutaneous tissues and effectively inhibits in vitro growth of certain multidrug-resistant clinical isolates of E coli.

Eur J Clin Microbiol Infect Dis, 2003 Jul, 22(7), 427 - 30 Epub 2003 Jun 24.
Mycobacterium elephantis: not an exceptional finding in clinical specimens; Tortoli E et al.; Following the recent report of new 16S rDNA sequences of Mycobacterium elephantis, three clinical strains suspected to belong to such species were investigated using biochemical and cultural tests, high performance liquid chromatography of cell wall mycolic acids and genetic sequencing . Antimicrobial susceptibility was also determined . The findings confirmed recent data concerning human isolates of this new mycobacterium and identified a new 16S rDNA sequevar for this species.

Surg Neurol, 2003 Jun, 59(6), 509 - 11
Delirium in the elderly resulting from azithromycin therapy; Cone LA et al.; BACKGROUND: Azithromycin, a semi-synthetic azalide antibiotic, is a macrolide that thus far has not shared the neuropsychiatric side effects of other macrolides such as erythromycin and clarithromycin . METHODS: We now report significant delirium associated with conventional dosing of azithromycin in two geriatric patients who were being treated for lower respiratory tract infection . RESULTS: The onset of delirium was apparent within 72 hours of initiating azithromycin therapy and lasted 48 to 72 hours after discontinuing treatment with the drug . CONCLUSIONS: In contrast to the adverse central nervous system symptoms associated with clarithromycin, those induced by azithromycin seem to take longer to resolve, perhaps based upon the longer elimination half-life of the latter antimicrobial, particularly in geriatric women.

Microvasc Res, 2003 Jul, 66(1), 38 - 48
CAP37, a neutrophil-derived inflammatory mediator, augments leukocyte adhesion to endothelial monolayers; Lee TD et al.; Cationic antimicrobial protein of molecular weight 37 kDa (CAP37) is a multifunctional inflammatory mediator that was originally isolated from human neutrophils and described to possess bactericidal and monocyte-activating functions . More recently its expression in endothelial and epithelial cells in response to inflammatory mediators and its ability to activate endothelial cells and alter permeability has been demonstrated . We hypothesize that CAP37 facilitates the process of transendothelial migration not only because of its potential to act as a chemoattractant but also through its ability to promote leukocyte adhesion to the endothelium by modulating adhesion molecule expression on the endothelium . Here we describe its ability to mediate neutrophil and monocyte adherence to endothelial monolayers in vitro . Using reverse transcriptase-polymerase chain reaction and flow cytometry, we demonstrate its ability to upregulate the adhesion molecules, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in human umbilical vein and lung microvessel endothelial cells . The identity and kinetics of upregulation of the specific adhesion molecule was dependent on the endothelial cell type, suggesting that adhesion molecules on endothelial cells from different vascular beds are differentially regulated by CAP37 . The cell-specific kinetics of adhesion molecule upregulation by CAP37 may influence selective leukocyte migration in certain inflammatory situations.

J Infect Dis, 2003 Jul 1, 188(1), 146 - 52 Epub 2003 Jun 16.
Killing of African trypanosomes by antimicrobial peptides; McGwire BS et al.; Antimicrobial peptides are components of the innate immune systems of a wide variety of eukaryotic organisms and are being developed as antibiotics in the fight against bacterial and fungal infections . We explored the potential activities of antimicrobial peptides against the African trypanosome Trypanosoma brucei, a vector-borne protozoan parasite that is responsible for significant morbidity and mortality in both humans and animals . Three classes of mammalian antimicrobial peptides were tested: alpha-defensins, beta-defensins, and cathelicidins . Although members of all 3 classes of antimicrobial peptides showed activity, those derived from the cathelicidin class were most effective, killing both insect and bloodstream forms of the parasite . The mechanism of action of the cathelicidins against T . brucei involves disruption of surface membrane integrity . Administration of cathelicidin antimicrobial peptides to mice with late-stage T . brucei infection acutely decreased parasitemia and prolonged survival . These results highlight the potential use of antimicrobial peptides for the treatment of African trypanosomiasis.

Med Electron Microsc, 2003 Jun, 36(2), 94 - 7
Localization of human beta-defensin 3 mRNA in normal oral epithelium, leukoplakia, and lichen planus: an in situ hybridization study; Nishimura M et al.; Human beta-defensin 3 (hBD-3), an antimicrobial peptide, is produced by various epithelial and some nonepithelial tissues . hBD-3 mRNA is widely expressed in oral tissues, including oral epithelium and the salivary glands . Although the localization of hBD-1 and hBD-2 has been well demonstrated in tissue sections, the localization pattern of hBD-3 has not yet been shown . In the present study, we investigated the expression pattern of hBD-3 mRNA by in situ hybridization using specific RNA probes; the signal for hBD-3 was detected in upper spinous and granular layers in normal oral epithelium . In cases of leukoplakia, a strong signal of hBD-3 mRNA was observed in the granular layer . In lichen planus, the signal was strongly detected in the spinous and suprabasal layers . The signals were stronger than those of either normal oral epithelium or leukoplakia . The results indicate that the localization pattern of hBD-3 is very similar to that of hBD-2 . hBD-2 and hBD-3 may function together or compensate each other for expressional loss.

ORL J Otorhinolaryngol Relat Spec, 2003 Mar-Apr, 65(2), 117 - 20
Microbiology and management of deep facial infections and Lemierre syndrome; Brook I; This review describes the microbiology, diagnosis and management of deep facial infections and Lemierre syndrome . The origins of most of these infections are odontogenic infections that spread to fascial spaces of the lower head and upper neck . Other sources include pharyngotonsillar, nasal, otologic, salivary gland and dermatologic infections, hematogenic spread, cervical adenitis and trauma . These space infections can be divided into those around the face (masticatory, buccal, canine and parotid), the suprahyoid area (submandibular, sublingual and lateral pharyngeal) and the infrahyoid region or lateral neck (retropharyngeal and pretracheal spaces) . The organisms accounting for these infections are aerobic and anaerobic that arise from the oropharyngeal flora . Complications of these infections can be life threatening and can result from hematogenic or direct spread . Complications that arise following local extension include suppurative jugular thrombophlebitis, cavernous sinus thrombosis, carotid erosion, maxillary sinusitis and osteomyelitis of the jaws . Management includes surgical drainage and antimicrobial therapy .

FASEB J, 2003 Aug, 17(11), 1502 - 4 Epub 2003 Jun 03.
Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense; Geiszt M et al.; Lactoperoxidase (LPO) is an enzyme with antimicrobial properties present in saliva, milk, tears, and airway secretions . Although the formation of microbicidal oxidants by LPO has been recognized for some time, the source of hydrogen peroxide (H2O2) for LPO-catalyzed reactions remains unknown . Reactive oxygen species produced by the phagocyte NADPH oxidase (phox) play a critical role in host defense against pathogens; however, analogous oxidant-generating systems in other tissues have not been associated with antimicrobial activity . Several homologues of gp91phox, the catalytic core of this enzyme, were described recently; dual oxidase (Duox)1/thyroid oxidase 1 and Duox2/thyroid oxidase 2 were identified in the thyroid gland and characterized as H2O2 donors for thyroxin biosynthesis . We examined Duox1 and Duox2 expression in secretory glands and on mucosal surfaces and give evidence for their presence and activity in salivary glands, rectum, trachea, and bronchium . Epithelial cells in salivary excretory ducts and rectal glands express Duox2, whereas tracheal and bronchial epithelial cells express Duox1 . Furthermore, we detected Duox1-dependent H2O2 release by cultured human bronchial epithelial cells . Our observations suggest that Duox1 and Duox2 are novel H2O2 sources that can support LPO-mediated antimicrobial defense mechanisms on mucosal surfaces.

Int Endod J, 2003 Jul, 36(7), 453 - 63
Microbial causes of endodontic flare-ups; Siqueira JF Jr; LITERATURE REVIEW: Inter-appointment flare-up is characterized by the development of pain, swelling or both, following endodontic intervention . The causative factors of flare-ups encompass mechanical, chemical and/or microbial injury to the pulp or periradicular tissues . Of these factors, microorganisms are arguably the major causative agents of flare-ups . Even though the host is usually unable to eliminate the root canal infection, mobilization and further concentration of defence components at the periradicular tissues impede spreading of infection, and a balance between microbial aggression and host defences is commonly achieved . There are some situations during endodontic therapy in which such a balance may be disrupted in favour of microbial aggression, and an acute periradicular inflammation can ensue . Situations include apical extrusion of infected debris, changes in the root canal microbiota and/or in environmental conditions caused by incomplete chemo-mechanical preparation, secondary intraradicular infections and perhaps the increase in the oxidation-reduction potential within the root canal favouring the overgrowth of the facultative bacteria . Based on these situations, preventive measures against infective flare-ups are proposed, including selection of instrumentation techniques that extrude lesser amounts of debris apically; completion of the chemo-mechanical procedures in a single visit; use of an antimicrobial intracanal medicament between appointments in the treatment of infected cases; not leaving teeth open for drainage and maintenance of the aseptic chain throughout endodontic treatment . Knowledge about the microbial causes of flare-ups and adoption of appropriate preventive measures can significantly reduce the incidence of this highly distressing and undesirable clinical phenomenon.

J Pept Res, 2003 Aug, 62(2), 53 - 62
From pro defensins to defensins: synthesis and characterization of human neutrophil pro alpha-defensin-1 and its mature domain; Wu Z et al.; Human neutrophil alpha-defensins (HNPs) are small, cationic, Cys-rich antimicrobial proteins that play important roles in innate immunity against infectious microbes such as bacteria, fungi and enveloped viruses . Synthesized as inactive precursors in vivo (pre-proHNPs), HNPs are activated through proteolytic removal of the inhibitory pro-peptide required for subcellular sorting and correct folding . We seek to understand the molecular basis for the recognition between the 45-residue pro-peptide and the C-terminal functional domain . Here we described, total chemical synthesis of the 75-residue human neutrophil pro alpha-defensin-1 (proHNP1) via native chemical ligation . After oxidative folding, proHNP1 is cleaved by cyanogen bromide at the Met45-Ala46 peptide bond to release the mature form . The native disulfide connectivity in HNP1, i.e . Cys1-Cys6, Cys2-Cys4 and Cys3-Cys5, is verified by mass mapping of peptide fragments generated by proteolytic digestion and Edman degradation . Fluorescence spectroscopy studies and antimicrobial activity assays further support that synthetic proHNP1 and HNP1 are correctly folded . While largely unstructured in aqueous solution, the pro-peptide binds to HNP1 intermolecularly with an apparent Kd value of 6.2 microM at pH 7.4, confirming the mode of intramolecular inactivation of human alpha-defensin precursors.

Eur J Biochem, 2003 Jul, 270(13), 2805 - 13
Key role of the loop connecting the two beta strands of mussel defensin in its antimicrobial activity; Romestand B et al.; To elucidate the structural features of the mussel defensin MGD1 required for antimicrobial activity, we synthesized a series of peptides corresponding to the main known secondary structures of the molecule and evaluated their activity towards Gram-positive and Gram-negative bacteria, and filamentous fungi . We found that the nonapeptide corresponding to residues 25-33 of MGD1 (CGGWHRLRC) exhibited bacteriostatic activity once it was cyclized by a non-naturally occurring disulfide bridge . Longer peptides corresponding to the amino acid sequences of the alpha-helical part or to the beta-strands of MGD1 had no detectable activity . The bacteriostatic activity of the sequence 25-33 was strictly dependent on the bridging of Cys25 and Cys33 and was proportional to the theoretical isoelectric point of the peptide, as deduced from the variation of activity in a set of peptide analogues of the 25-33 sequence with different numbers of cationic charges . By using confocal fluorescence microscopy, we found that the cyclic peptides bound to Gram-positive bacteria without apparent lysis . However, by using a fluorescent dye, we observed that dead bacteria had been permeated by the cyclic peptide 25-33 . Sequence comparisons in the family of arthopod defensins indicate that MGD1 belongs to a subfamily of the insect defensins, characterized by the constant occurrence of both positively charged and hydrophobic amino acids in the loop . Modelling studies showed that in the MGD1 structure, positively charged and hydrophobic residues are organized in two layered clusters, which might have a functional significance in the docking of MGD1 to the bacterial membrane.

Aliment Pharmacol Ther, 2003 Jun 15, 17(12), 1545 - 51
Is antimicrobial susceptibility testing necessary before second-line treatment for Helicobacter pylori infection?
Miwa H, Nagahara A, Kurosawa A, Ohkusa T, Ohkura R, Hojo M, Enomoto N, Sato N.
BACKGROUND: An antimicrobial susceptibility test for Helicobacter pylori before second-line treatment is often performed, although whether the test is truly necessary remains unknown . PATIENTS AND METHODS: Eighty-two patients with H . pylori infection for whom first-line treatment with a 1-week proton pump inhibitor/amoxicillin-clarithromycin (AC) regimen had failed were randomly assigned to two groups: those having or not having the susceptibility test before re-treatment . The cure rates for these two groups were compared . RESULTS: Five of the 82 patients were excluded from the analysis . For 38 patients in the susceptibility-test group, we used what we considered the best regimen based on susceptibility testing: 10 patients {no resistance to clarithromycin (CAM)} received the lansoprazole-amoxicillin-clarithromycin regimen, 22 patients {19 CAM resistant, metronidazole (MNZ) susceptible; three failure of culture} were given the lansoprazole-amoxicillin-metronidazole (LAM) regimen, and six patients (both MNZ and CAM resistant) received dual therapy with omeprazole (OPZ) and amoxicillin (AMOX) in which the OPZ dose was determined by the CYP2C19 gene polymorphism . For 39 patients in the group with no susceptibility testing, LAM regimens were prescribed . The intention-to-treat (ITT)-based cure rates in the groups with and without susceptibility testing were 81.6% (95% confidence interval; 66-92%) and 92.4% (79-98%), respectively, and there was no significant difference between these two groups . CONCLUSION: Susceptibility testing is not necessarily required before second-line therapy if the first-line treatment has been performed using proton pump inhibitor/AC regimens.

Nat Prod Res, 2003 Aug, 17(4), 253 - 7
Synthesis and biological activity of bactobolin glucosides; Adachi H et al.; Bactobolin glucosides, 5-O-(alpha-D-glucopyranosyl)-, 5-O-(beta-D-glucopyranosyl)- and 6-O-(beta-D-glucopyranosyl)-bactobolin were prepared by glycosidation of bactobolin (1) with the glucopyranosyl trichloroacetoimidate . These compounds were evaluated antimicrobial activity and cytotoxicity.

Curr Opin Infect Dis, 2002 Dec, 15(6), 565 - 8
Cost effective approaches to antimicrobial use in oncology patients; Goff DA; PURPOSE OF REVIEW: In the current era of cost containment, the management of the oncology patient who presents with neutropenia and fever remains a challenge . This article will review which measures of cost are helpful in determining cost effective antibiotic use in patients with febrile neutropenia . RECENT FINDINGS: The majority of direct medical costs associated with treating febrile neutropenic patients are room and board costs . The most recent cost analysis reports a mean cost/day of US$1598 . SUMMARY: Over the past two decades, infection-related mortality rates have decreased from 50% to rates as low as 10% . In contrast to the numerous studies comparing clinical outcomes of patients receiving different antimicrobial regimens for febrile neutropenia, the recent literature revealed limited studies that evaluate economic data . Typically, new antibiotic regimens show equal efficacy to the standard regimens but are often more expensive . If efficacy rates and safety are the same for an antibiotic, the cost is often used to select the product.

Curr Opin Infect Dis, 2003 Jun, 16(3), 199 - 204
Toll-like receptors and T-helper-1/T-helper-2 responses; Dabbagh K et al.; PURPOSE OF REVIEW: Toll-like receptors (TLRs) are a family of pattern recognition receptors that are activated by specific components of microbes and certain host molecules . They constitute the first line of defense against many pathogens and play a crucial role in the function of the innate immune system . Recently, TLRs were observed to influence the development of adaptive immune responses, presumably by activating antigen-presenting cells . This has important implications for our understanding of how the host tailors its immune response as a function of specific pathogen recognition . The present review discusses the recent studies that demonstrate the role of TLRs in the regulation of adaptive T-helper-1 (Th1) and Th2 responses, and the mechanisms by which the effects are carried out . RECENT FINDINGS: Most studies have focused on the role of TLRs and components of their signaling pathways in the control of Th1-type immune responses, and on the implications for their use as antimicrobial agents, such as adjuvants in vaccines, or to treat or prevent the Th2-type dominated immune responses seen in allergies . TLR-deficient mice have been described and used to come to these conclusions . Although controversial, there is also evidence that TLRs may be important for Th2-type responses, possibly by augmenting the overall maturity of dendritic cells . SUMMARY: A greater understanding of the processes by which TLRs regulate adaptive immunity may yield not only improved ways to treat infectious diseases but also new approaches to the treatment and prevention of allergic and certain autoimmune disorders.

Antimicrob Agents Chemother, 2003 Jul, 47(7), 2354 - 7
In vitro antimicrobial susceptibility of Brachyspira pilosicoli isolates from humans; Brooke CJ et al.; The in vitro antimicrobial susceptibility of the anaerobic intestinal spirochete Brachyspira pilosicoli was investigated by an agar dilution method . Human (n = 123) and porcine (n = 16) isolates were susceptible to metronidazole, ceftriaxone, meropenem, tetracycline, moxifloxacin, and chloramphenicol; erythromycin and ciprofloxacin were not active . Resistance to amoxicillin and clindamycin varied . Amoxicillin susceptibility was restored by clavulanic acid.

Antimicrob Agents Chemother, 2003 Jul, 47(7), 2323 - 6
Decolorization of malachite green and crystal violet by waterborne pathogenic mycobacteria; Jones JJ et al.; Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium scrofulaceum, Mycobacterium marinum, and Mycobacterium chelonae tolerate high concentrations of the dyes malachite green and crystal violet . Cells of strains of those species decolorized (reduced) both malachite green and crystal violet . Because decolorized malachite green lacked antimicrobial activity, the resistance of these mycobacteria could be due, in part, to their ability to decolorize the dyes . Small amounts of malachite green and its reduced, decolorized product were detected in the lipid fraction of M . avium strain A5 cells grown in the presence of malachite green, suggesting that a minor component of resistance could be due to sequestering the dyes in the extensive mycobacterial cell surface lipid . The membrane fraction of M . avium strain A5 had at least a fivefold-higher specific decolorization rate than did the crude extract, suggesting that the decolorization activity is membrane associated . The malachite green-decolorizing activity of the membrane fraction of M . avium strain A5 was abolished by either boiling or proteinase exposure, suggesting that the decolorizing activity was due to a protein . Decolorization activity of membrane fractions was stimulated by ferrous ion and inhibited by dinitrophenol and metyrapone.

Antimicrob Agents Chemother, 2003 Jul, 47(7), 2249 - 55
Gastric transitional zones, areas where Helicobacter treatment fails: results of a treatment trial using the Sydney strain mouse model; van Zanten SJ et al.; Current combination therapies cure Helicobacter pylori infection in 75 to 85% of cases . However, many treatment failures are not explained by antibiotic resistance . Our goal was to explore treatment failures under in vivo conditions by using the H . pylori Sydney strain (SS1) mouse model . Mice infected with H . pylori (SS1) were treated with monotherapies or combination therapies used in human trials . Bacterial levels and distribution of organisms within the stomach were assessed 24 h after treatment to determine clearance and location of treatment failures and 29 days after treatment to determine cure rates . Except for treatment with metronidazole, mono- and dual therapies did not cure infection but resulted in decreases in bacterial levels and differences in distribution within the stomach . In cases of treatment failure when clarithromycin was used, omeprazole and dual therapy with omeprazole and amoxicillin resulted in organisms being cleared from the antrum, but organisms remained in the antrum-body transitional zone . The triple therapies of OMC and bismuth subcitrate, metronidazole, and tetracycline were successful in eradicating infection . Except for metronidazole monotherapy and triple therapy with OAC, there was good correlation between the Sydney strain mouse model and humans with respect to the success of antimicrobial therapy . The antrum-body transitional zone was identified as a sanctuary site in treatment failure . This could result from antimicrobial agents not functioning effectively at this site or bacteria in this location expressing products that protect them against antimicrobial agents . This is the first demonstration of a possible sanctuary site as a reason for failure of therapy.

Microb Drug Resist, 2003 Summer, 9(2), 201 - 9
Beta-lactamase characterization in Escherichia coli isolates with diminished susceptibility or resistance to extended-spectrum cephalosporins recovered from sick animals in Spain; Brinas L et al.; A total of 1439 Escherichia coli isolates from sick animals were received from the Spanish Network of Veterinary Antimicrobial Resistance Surveillance (VAV) from 1997 to 2001 . Antimicrobial susceptibility tests were performed and diminished susceptibility to cefotaxime and ceftazidime was identified in 2.5% and 2.8% of the isolates, respectively . Beta-lactamase characterization was carried out in the group of 20 E . coli isolates with both characteristics . The MIC ranges of different beta-lactams showed by these 20 isolates were as follows (in microg/ml): ampicillin (64-->256), amoxicillin-clavulanic acid (4-64), ticarcillin (8-->128), cefazolin (32-->256), cefoxitin (4-->128), cefotaxime (1-64), ceftazidime (2-->64), ceftriaxone (0.5-64), imipenem (< or = 0.06-0.25), and aztreonam (2-->32) . TEM, SHV, CMY, and FOX beta-lactamase genes were analyzed by PCR and sequencing . The beta-lactamase genes detected were the following ones (number of isolates): bla(TEM-1b) (3), bla(TEM-1a) (1), bla(TEM-30f) (2), bla(TEM-1b) + bla(CMY-2) (2), and bla(SHV-12) (1) . Sequences of the promoter and/or attenuator region of the chromosomal ampC gene were studied in all the 20 isolates . Mutations at position -42 or -32 were detected in 16 isolates and these mutations were associated with the presence of a TEM type beta-lactamase in 6 isolates . Besides, a high variety of plasmidic beta-lactamases was detected including TEM-30 and CMY-2 . To our knowledge, this is the first time that TEM-30 beta-lactamase has been detected in E . coli isolates of animal origin.

Drug News Perspect, 2001 Apr, 14(3), 167 - 74
The battle against microbes and their growing resistance; Hunter PA; Scientists involved in the battle against microbes--and the worrying increase in their immunity to antimicrobial agents--gathered at the Royal College of Physicians, London, U.K., to discuss the current situation and the scope of drug discovery research efforts . In addition to analyzing the clinical implications of rising immunity to antibacterial agents, sessions covered the problem of growing resistance to antiviral, antifungal and antimalarial agents . (c) 2001 Prous Science . All rights reserved.

Dev Comp Immunol, 2003 Oct, 27(9), 781 - 91
Acanthoscurrin: a novel glycine-rich antimicrobial peptide constitutively expressed in the hemocytes of the spider Acanthoscurria gomesiana; Lorenzini DM et al.; We report the isolation of a novel antimicrobial peptide, acanthoscurrin, from the hemocytes of unchallenged tarantula spider Acanthoscurria gomesiana . A combination of Edman degradation, mass spectrometry and cDNA cloning revealed the presence of two isoforms of acanthoscurrin, differing by two glycine residues . Both displayed cationic properties and a high percentage of glycine residues . However, acanthoscurrins have no structural similarities with already known glycine-rich antimicrobial peptides from animals and plants . As deduced from cDNA cloning and mass spectrometry, the amino acid sequence of acanthoscurrin begins with a putative signal peptide of 23 amino acids followed by the mature peptide, which is post-translationally modified by a C-terminal amidation . Acanthoscurrins are constitutively expressed in hemocytes and released to plasma following an immune challenge.

Maturitas, 2003 Jul 25, 45(3), 225 - 9
Effect of hormone replacement therapy on lacrimal fluid peroxidase activity in woman; Marcozzi G et al.; OBJECTIVE: Lacrimal fluid peroxidase (POD) is an antioxidant and antimicrobial enzyme involved in the protection of the ocular surface . Our recent findings showed the existence of significant cyclic variations in POD activity that were positively correlated with those of 17beta-estradiol plasma levels throughout the menstrual cycle of fertile women . During the menopause, women lacrimal fluid POD activity significantly (P<0.05) decreased according to the natural oestrogen reduction . Since a possible influence of oestrogen on human POD activity was suggested, aim of the present investigation is to evaluate whether hormone replacement therapy (HRT) might influence this enzyme activity . METHODS: Lacrimal fluid POD activities of 10 healthy postmenopausal women (mean age: 52.0) and eight healthy postmenopausal women (mean age: 53.0) treated by oral or transdermal routes containing oestrogen or oestrogen plus progestin were determined . Enzyme activity of each tear sample (5 microl) was spectrophotometrically determined by the 5,5'-dithiobis, 2-nitrobenzoic acid thiocyanate (NBS-SCN) assay; total protein content of tears was determined too . 17beta-Estradiol plasma levels were assayed by ELISA test . RESULTS: HRT significantly (P<0.05) increased tear POD low postmenopausal levels . The significant (P<0.05) rise of 17beta-estradiol plasma levels of treated women was not strictly correlated to the enzyme activity increase in tears . CONCLUSIONS: The suggested estrogen regulation of lacrimal fluid POD activity could be one possible cause for the female gender predilection in some ocular diseases . HRT is able to increase tear POD activity levels of postmenopausal women, probably contributing to the effective relieve of ocular surface complications occurring during menopause.

Thromb Res, 2003 Mar 15, 109(5-6), 259 - 63
Clinical and laboratory effects of recombinant human activated protein C in the treatment of a patient with sepsis-induced multiple organ failure; Brueckmann M et al.; OBJECTIVES: To evaluate clinical and laboratory effects of the administration of recombinant human activated protein C (rhAPC) in the treatment of a 25-year-old patient with septic shock and multiple organ failure secondary to perinephritic abscesses . INTERVENTIONS: Intravenous administration of rhAPC-or drotrecogin alfa (activated)-(24 mcg/kg/h) for a total of 80 h as an adjunct to antimicrobial therapy, mechanical ventilation, hemodynamic support, hemodiafiltration and surgical intervention . MEASUREMENTS AND MAIN RESULTS: The administration of rhAPC was associated with a rapid recovery of the patient's clinical condition reflected by decreasing Sepsis-related Organ Failure Assessment (SOFA) scores . Laboratory parameters monitoring inflammation and coagulopathy improved during the treatment . No drug-related adverse events were noted . CONCLUSIONS: RhAPC has been observed to have anticoagulant, anti-inflammatory and profibrinolytic properties in vitro and in vivo . This report describes the effects of rhAPC administration on standard laboratory parameters indicating that no single laboratory parameter exists that is capable of monitoring the effects of rhAPC on the coagulation cascade and the clinical course of sepsis . This description of a patient suffering from sepsis-induced multiple organ failure may illustrate a possible beneficial effect of rhAPC on the course of coagulopathy and systemic inflammatory response and provides evidence for rhAPC complementing standard intensive care therapy in severe sepsis.

Int J Biochem Cell Biol, 2003 Oct, 35(10), 1407 - 12
Tuberculosis: amplification-based clinical diagnostic techniques; Huggett JF et al.; Tuberculosis (TB) is one of the major infectious causes of morbidity and mortality worldwide . TB is difficult to control due to the time taken for the microbiological diagnosis; typically culture on solid media takes 6-8 weeks . There are number of rapid molecular methods that have been developed to diagnose new cases of tuberculosis, detect drug resistance and identify the type of mycobacteria . These assays are based on recognition of mycobacterial DNA sequences and the subsequent amplification of nucleic acid sequences to facilitate detection . This review will describe some of the molecular assays that are in use for TB diagnosis and the considerations in designing and performing such assays . Early diagnosis of tuberculosis is critical for the successful management of patients allowing informed use of chemotherapy ensuring that the right patients are treated with the right antimicrobials.

J Anim Sci, 2003 Jun, 81(6), 1456 - 63
Effects of antimicrobials and weaning on porcine serum insulin-like growth factor binding protein levels; Hathaway MR et al.; The effects of subtherapeutic antimicrobial supplementation and weaning on serum levels of IGF-I and insulin-like growth factor binding proteins (IGFBP)-2, -3 and -4 were determined in crossbred weanling pigs . At weaning, pigs were allotted to a diet containing 21.8% crude protein and 1.15% lysine with or without Aureozol (110 mg/kg of Aureomycin chlortetracycline, 110 mg/kg of sulfathiazole, and 55 mg/kg of penicillin) for 4 wk . Insulin-like growth factor-binding proteins and IGF-I analyses were performed on blood samples that were drawn weekly . Weaning decreased serum IGFBP-3 levels in both control and Aureozol-treated groups on d 6 and d 14 (P < 0.05) relative to preweaning levels . The IGFBP-3 values returned to preweaning levels by d 21 . Although the circulating levels of both the 43-kDa and the 39-kDa glycosylation variants of IGFBP-3 were affected by weaning, the level of the 39-kDa IGFBP-3 was affected relatively more than that of the 43-kDa IGFBP-3 (P < 0.05) . Compared with circulating IGFBP-3 levels in control pigs, Aureozol-treated pigs had higher circulating IGFBP-3 levels on d 21 (43%, P < 0.05) and d 27 (46%, P < 0.05) . In direct contrast to the effect of weaning on serum IGFBP-3 level, serum IGFBP-2 levels increased on d 6 and d 14 after weaning (P < 0.05) and decreased to preweaning levels by d 21 . The IGFBP-2 levels continued to decline and were less than preweaning levels by d 27 (P < 0.05) . Aureozol treatment had no effect on serum IGFBP-2 levels at any time . Serum levels of nonglycosylated IGFBP-4 were not affected by either weaning or Aureozol supplementation . Weaning decreased circulating IGF-I concentration on d 6 in both control and Aureozol-treated pigs (76 and 73%, respectively, P < 0.05) and on d 14 (62%, P < 0.05) and d 21 (32%, P < 0.05) in control pigs . Aureozol-supplemented pigs had higher serum IGF-I concentrations than control pigs on d 14 (82%, P < 0.05), d 21 (55%, P < 0.05), and d 27 (36%, P < 0.05) . The Aureozol-fed pigs had a 14.2% increase in BW gain (P < 0.05) and a 59.6% increase in ADG (P < 0.05) compared with pigs fed the control diet . Both Aureozol-supplementation and weaning cause changes in serum IGFBP levels and IGF-I concentrations that might be involved in regulating rate and efficiency of growth.

Am J Respir Cell Mol Biol, 2003 Dec, 29(6), 757 - 70 Epub 2003 Jun 19.
Interactions of surfactant protein D with fatty acids; DeSilva NS et al.; Surfactant Protein D (SP-D) plays important roles in antimicrobial host defense, inflammatory and immune regulation, and pulmonary surfactant homeostasis . The best-characterized endogenous ligand is phosphatidylinositol; however, this lipid interaction at least in part involves the carbohydrate moiety . In this study we observed that SP-D binds specifically to saturated, unsaturated, and hydroxylated fatty acids (FA) . Binding of biotinylated-SP-D to FAs or biotinylated FA to SP-D was dose-dependent, saturable, and specifically competed by the corresponding unlabeled probe . Specific binding to FA chains was also demonstrated by solution phase competition for FA binding to acrylodan-labeled FA binding protein (ADIFAB), and by overlay of thin layer chromatograms with SP-D . Maximal binding to FA was dependent on calcium, and binding was localized to the neck and carbohydrate recognition domains (CRD) using recombinant trimeric neck+CRDs . Saccharide ligands showed complex, dose-dependent effects on FA binding, and FAs showed dose- and physical state-dependent effects on the binding of SP-D to mannan . In addition, CD spectroscopy suggested alterations in SP-D structure associated with binding to monomeric FA . Together, the findings indicate specific binding of FA to one or more sites in the CRD . We speculate that the binding of SP-D to the fatty acyl chains of surfactant lipids, microbial ligands, or other complex lipids contributes to the diverse biological functions of SP-D in vivo.

Zhonghua Liu Xing Bing Xue Za Zhi, 2003 Mar, 24(3), 216 - 9
{Impact clinically related factors on the outcomes of ventilator-associated pneumonia}; Zhou P et al.; OBJECTIVE: To define the influence clinically related factors in the prognosis of ventilated pneumonia (VAP) . METHODS: A prospective clinical study involving 120 patients with VAP was carried ont . Etiologic diagnosis was established under quantitative culture of endotracheal aspiration, a protected specimen brush and bronchoalveolar lavage . Prognostic using a statistical software package (SPSS) factors were examined for univariate and multivariate analyses . RESULTS: Case fatality directly related to the infection was 14 percent . From univariate analysis, variables that significantly associated with attributable mortality were age older than 45 years, use of corticosteroids, presence of shock, in-hospital days of VAP over as follows 9, antecedent chronic obstructive pulmonary disease, and a prior antibiotic use . Through step-forward logistic regression analysis, only prior antibiotic use (P < 0.000 1, OR = 9.2) was defined as a significant factor influencing the risk of death from VAP . The same result was obtained when severity was included in the model . However, prior antibiotic use entirely dropped out as a significant risk factor when the etiologic agent was included in the regression equation . CONCLUSIONS: Distribution of microorganisms that responsible for VAP shown different in patients who had received prior antimicrobial therapy, and this factor caused higher mortality rate . We suggested a restrictive antibiotic use strategy among mechanically ventilated patients to reduce the risk of death from VAP.

Vet Immunol Immunopathol, 2003 Jun 20, 93(3-4), 177 - 84
In silico identification of components of the Toll-like receptor (TLR) signaling pathway in clustered chicken expressed sequence tags (ESTs); Lynn DJ et al.; We have described a bioinformatic approach that involves the clustering of expressed sequence tags (ESTs) to reveal homologs of the Toll-like receptor (TLR) pathway in the chicken . Homology searching of proteins, predicted to be encoded by these EST clusters, resulted in the in silico identification of full-length sequences for Toll-interacting protein (Tollip), IL-1 receptor-associated kinase 4 (IRAK-4), myeloid differentiation factor 88 adapter-like (Mal), TGF beta-activated kinase 1 binding protein 1 (TAB1) . We also determined partial sequence information for myeloid differentiation factor 88 (MyD88), two novel TLRs, TNF receptor-associated factor 6 (TRAF6), TGF beta-activated kinase 1 (TAK1), TAB2, inhibitor of nuclear factor kappa B kinase alpha (IKK alpha) and IKK beta . This bioinformatics study has confirmed the evolutionary conservation of the TLR pathway in chicken and demonstrated its essential homology to the TLR pathway in mammals . We have identified in silico the full-length sequence for liver-expressed antimicrobial peptide 2 (LEAP-2) . This is the first time a non-mammalian LEAP-2 has been described.

Br J Clin Pharmacol, 2003 Jun, 55(6), 620 - 4
Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis; Tomaselli F et al.; OBJECTIVES: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect . Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available . The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma . PATIENTS AND METHODS: The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema . The condition was treated by decortication after lateral thoracotomy . Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values . Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v . administration of a single dose of 4 g piperacillin and 500 mg tazobactam . RESULTS: The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively . The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1 . There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043) . The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h . The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed . CONCLUSION: This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia . The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.

Respir Med, 2003 Jun, 97(6), 709 - 17
Pulmonary nocardiosis re-visited: experience of 35 patients at diagnosis; Hui CH et al.; Pulmonary infection by Nocardia is an uncommon opportunistic infection in humans . Thirty-five patients with pulmonary nocardiosis were identified in two tertiary referral hospitals . A retrospective review of the patient characteristics, clinical and laboratory features including antimicrobial susceptibility at diagnosis was carried out . Radiological features derived from chest radiographs and CT scans were also documented . In our population, the predominant risk factors were immuno-compromised state, corticosteroid therapy, and underlying pulmonary pathology . The presenting features were similar to those previously described but disseminated infection was not common . The radiological changes were diverse and non-specific . Nocardia asteroides was the commonest species . Most Nocardia isolates were susceptible to imipenem, ceftriaxone, amikacin, and cotrimoxazole . Co-existing microbial agents are common and reflect the underlying complex disorders.

Drug News Perspect, 2001 Jun, 14(5), 309 - 17
Coping with the rising tide of resistance to antimicrobial agents; Hunter PA; The 11th European Congress of Clinical Microbiology and Infectious Diseases was held in Istanbul, Turkey, from April 2nd to April 4th, 2001 . The meeting was attended by approximately 4,500 people . Sessions were well attended and included a number of workshops, keynote lectures, symposia, free papers and posters . As at many chemotherapy meetings in recent years, a major topic was the continuing growth of resistance among all microbes to antimicrobial agents, and this is the topic highlighted in this report . (c) 2001 Prous Science . All rights reserved.

Mol Cancer Ther, 2003 Jun, 2(6), 517 - 26
Characterization of the cytotoxic activities of novel analogues of the antitumor agent, lavendamycin; Fang Y et al.; Lavendamycin is a bacterially derived quinolinedione that displays significant antimicrobial and antitumor activities . However, preclinical development of lavendamycin as an anticancer agent was halted due to the poor aqueous solubility and relatively nonspecific cytotoxic activity of this compound . In this report, we have examined the cytotoxic activities of a series of novel lavendamycin analogues . The cytotoxic activities of these compounds were evaluated in clonogenic survival assays with A549 lung carcinoma cells . Compounds bearing an amide or amine substituent at the R(3) position were the most potent inhibitors of colony formation . MB-97, the most active member of this subgroup, decreased clonogenic outgrowth by 70% at a concentration of 10 n . Treatment of A549 cells with MB-97 led to an increase in p53 protein expression and phosphorylation and a concomitant increase in the expression of the p53 target gene, p21 . Exposure of p53-positive cells to MB-97 triggered cell cycle arrest in G(1) and G(2) phases but induced a selective G(2)-phase arrest in p53-negative cells . MB-97 treatment also induced a higher level of apoptosis in p53-null cells relative to their p53-positive counterparts . Finally, MB-97 showed significant cytotoxic activity in the National Cancer Institute's panel of 60 cancer cell lines and antitumor activity in vivo in hollow fiber tumorigenesis assays.

Urologiia, 2003 Mar-Apr, (2), 26 - 8
{Anti-inflammatory, antimicrobial and antidesquamative effect of "Uro-Biofon" in treating sexually transmitted urogenital infections}; Atiushev GP et al.; The antiinflammatory reaction in patients with sexually transmitted urogenital infections (STUI) was assessed by the leucocyte count, causative agents, amount of lecitin particles and pH in prostatic secretion . Great amount of desquamated epithelial cells indicated natural death of epitheliocytes and tissue necrosis . These processes were traced in the course of different treatments . Standard therapy in combination with the antimicrobial drug (AMD) and URO-Biophon radiation (UBR) produced the highest effect in patients with chronic urethroprostatitis . This promoted reduction in the number of leukocytes, removal of epithelial cells, elimination of the microflora and an increase in the number of lecitin particles . Among patients with chronic urethritis effective levelling of the leukocytic reaction was observed in patients on the standard therapy or with UBR alone, or AMD alone . By the intensity of epithelial desquamation the result was highest in the control group . The highest microbiological disinfection effect was achieved in using combination of the above methods.

Int J Food Microbiol, 2003 Aug 15, 85(1-2), 197 - 202
Isolation of antimicrobial-resistant Escherichia coli from retail meats purchased in Greater Washington, DC, USA; Schroeder CM et al.; Four hundred and seventy-two generic Escherichia coli isolates were recovered from ground and whole retail beef, chicken, pork, and turkey obtained from Greater Washington, DC, USA during the years 1998 to 2000 . Many of the isolates displayed resistance to tetracycline (59%), sulfamethoxazole (45%), streptomycin (44%), cephalothin (38%) and ampicillin (35%) . Resistance was also observed, but to a lesser extent, to gentamicin (12%), nalidixic acid (8%), chloramphenicol (6%), ceftiofur (4%) and ceftriaxone (1%) . Sixteen percent of the isolates displayed resistance to one antimicrobial, followed by 23% to two, 23% to three, 12% to four, 7% to five, 3% to six, 2% to seven and 2% to eight . Three E . coli isolates were shown to possess Shiga toxin genes (stx2) via PCR; all were O non-typeable and were recovered from ground beef samples purchased on the same day at the same supermarket . One of the Shiga toxin-producing E . coli (STEC) isolates was susceptible to each of the antimicrobials tested, whereas one displayed resistance to cephalothin and sulfamethoxazole, and one displayed resistance to ampicillin, cephalothin, gentamicin, streptomycin, sulfamethoxazole and tetracycline . Findings from this study indicate that retail raw meats may often be contaminated with antimicrobial-resistant E . coli.

Phytochemistry, 2003 Jul, 63(5), 569 - 75
Antimicrobial action of palmarosa oil (Cymbopogon martinii) on Saccharomyces cerevisiae; Prashar A et al.; The essential oil extracted from palmarosa (Cymbopogon martinii) has proven anti-microbial properties against cells of Saccharomyces cerevisiae . Low concentrations of the oil (0.1%) inhibited the growth of S . cerevisiae cells completely . The composition of the sample of palmarosa oil was determined as 65% geraniol and 20% geranyl acetate as confirmed by GC-FTIR . The effect of palmarosa oil in causing K(+) leakage from yeast cells was attributed mainly to geraniol . Some leakage of magnesium ions was also observed . Blocking potassium membrane channels with caesium ions before addition of palmarosa oil did not change the extent of K(+) ion leakage, which was equal to the total sequestered K(+) in the cells . Palmarosa oil led to changes in the composition of the yeast cell membrane, with more saturated and less unsaturated fatty acids in the membrane after exposure of S . cerevisiae cells to the oil . Some of the palmarosa oil was lost by volatilization during incubation of the oil with the yeast cells . The actual concentration of the oil components affecting the yeast cells could not therefore be accurately determined.

J Am Med Inform Assoc, 2003 Sep-Oct, 10(5), 454 - 62 Epub 2003 Jun 04.
Development of a clinical data warehouse for hospital infection control; Wisniewski MF et al.; Existing data stored in a hospital's transactional servers have enormous potential to improve performance measurement and health care quality . Accessing, organizing, and using these data to support research and quality improvement projects are evolving challenges for hospital systems . The authors report development of a clinical data warehouse that they created by importing data from the information systems of three affiliated public hospitals . They describe their methodology; difficulties encountered; responses from administrators, computer specialists, and clinicians; and the steps taken to capture and store patient-level data . The authors provide examples of their use of the clinical data warehouse to monitor antimicrobial resistance, to measure antimicrobial use, to detect hospital-acquired bloodstream infections, to measure the cost of infections, and to detect antimicrobial prescribing errors . In addition, they estimate the amount of time and money saved and the increased precision achieved through the practical application of the data warehouse.

Commun Dis Intell, 2003, 27 Suppl, S111 - 6
Towards a national surveillance program for antimicrobial resistance in animals and animal-derived food; Webber J; One of the major recommendations of the JETACAR report was that a comprehensive national surveillance system be established to measure antimicrobial resistance to cover medical, food-producing and veterinary areas . While there are a number of existing passive surveillance programs on a national, regional and state basis in the medical field, there are few analogous programs in the veterinary area, and none with a particular emphasis on the food chain . The Commonwealth Interdepartmental JETACAR Implementation Group is working with stakeholders to develop this aspect of the national surveillance program based on the Guidelines published by the world organisation for animal health, the Office International des Epizooties.

Commun Dis Intell, 2003, 27 Suppl, S67 - 9
TSN Database Australia, a new tool to monitor antimicrobial resistance in Australia; Turnidge J et al.; An electronic network of Australian microbiology laboratories was established to monitor the emergence and occurrence of antimicrobial resistance among clinically relevant bacteria . It is believed that the data network collected approximately 42 per cent of all antibacterial susceptibility test results generated by Australian laboratories . The network comprised 94 hospitals and 9 private commercial laboratories . Selected data elements were extracted and electronically transmitted to a central location . Upon receipt, all data were first normalised and thereafter examined for errors . Duplicate results for the same patient were identified to prevent skewing of the data toward resistance . All data passing quality assessment was staged for release of a new database release that occurred monthly . Unusual test results were first validated prior to their inclusion into the database . Using an Internet-based query tool, individual institutions could query their own data, but could only query aggregated data for other regional or national analyses . Individual patient results could be examined nor could the results of any individual institution other than their own . As of March 2002, TSN Database Australia contained 14,648,752 test results, from 2,000,394 strains (453 different taxa) and 1,213,605 patients . Since the same database concept has been established in 10 other countries (United States of America, Europe, and Canada), observations made in Australia may be compared to those observed elsewhere in the world . This article will describe TSN in greater detail, describe the query tool and some of the analyses that are possible.

Commun Dis Intell, 2003, 27 Suppl, S42 - 6
Consumer activities on antimicrobial resistance in Australia; Donovan J; Australian Pharmaceutical Advisory Council; The focus of this article is the role of consumer education campaigns in Australia and overseas as an important step in helping people develop a more considered use of antibiotics . Evidence of the success of campaigns in Australia, New Zealand and the United Kingdom is presented . On the basis of this evidence, the paper argues that education campaigns are central to reducing inappropriate antibiotic use and lowering the chances of antibiotic resistance building up in the populations of developed countries.

Commun Dis Intell, 2003, 27 Suppl, S19 - 27
State-wide surveillance of in-hospital antimicrobial utilisation in South Australia; Dollman CM et al.; In late 2001, a group of South Australian metropolitan public and private hospitals commenced voluntary contribution of data on in-hospital utilisation of antimicrobials to the Communicable Disease Control Branch of the Department of Human Services . Where possible, hospitals contributed data on all antimicrobials dispensed for use within the institution each month . These data were stratified into antimicrobials issued to intensive care units and antimicrobials issued to all other areas within the hospital . In the first instance, only data relating to four antimicrobial classes have been analysed . These classes are third or fourth generation cephalosporins, carbapenems, glycopeptides and fluoroquinolones . Utilisation of these four classes was presented as a monthly utilisation rate i.e., total defined daily doses for each antimicrobial class per month per 1,000 occupied bed days . These utilisation rates were calculated for each individual hospital and for the combined group of contributing hospitals (state-wide rate) . Although limited data are currently available, results to date demonstrate a much higher antimicrobial usage rate in intensive care units than other in-patient areas for the classes currently analysed . Considerable variation in the usage of various antimicrobials has been noted for individual hospitals, and analysis of trends over a longer time period, in conjunction with resistance surveillance data, will be required.

Commun Dis Intell, 2003, 27 Suppl, S13 - 8
Active promotion of antibiotic guidelines: an intensive program; Tiley SM et al.; John Hunter Hospital, a 600 bed tertiary referral centre, has an antimicrobial working party comprising representatives from pharmacy, microbiology and infectious diseases areas, which is responsible for the development, implementation and evaluation of guidelines for the appropriate use of antimicrobials . Activities include the development and promotion of a restricted antimicrobial policy, and specific guidelines for the management of pneumonia, and surgical prophylaxis and wound infection . These guidelines are available on the hospital intranet, in hard copies in all wards, and on laminated cards (10 x 6.5 cm) attached to the hospital identification tag . Active promotion of the guidelines is undertaken at orientation and via a 2 week intensive period four times per year (corresponding with the registrar rotation), weekly meetings and follow up of non-compliance courses directly with the attending medical officer . Education and feedback to specific groups is provided as required . Other projects include a campaign to encourage oral antibiotics where indicated . Regular drug utilisation evaluations are undertaken to measure outcomes, along with other indicators of antibiotic use such as the prevalence of antimicrobial resistance . Appropriate prescribing of third generation cephalosporins has increased from 21 per cent to 52 per cent (p = 0.008) of courses between December 1999 and June 2001.

Commun Dis Intell, 2003, 27 Suppl, S9 - 12
Improving antibiotic use: 25 years of antibiotic guidelines and related initiatives; Harvey K et al.; In the late 1970s concern in Melbourne teaching hospitals over the increasing incidence of antibiotic-resistant microorganisms and inappropriate antibiotic prescribing, led to the establishment of a working party to produce guidelines on appropriate antimicrobial therapy . Therapeutic Guidelines: Antibiotic is now produced, marketed and sold by Therapeutic Guidelines Limited, an independent, not-for-profit enterprise that distils best-practice prescribing guidelines for Australian health professionals . Therapeutic Guidelines now cover all major therapeutic areas . Mere distribution of the guidelines had little impact on prescribing habits . However, targeted education campaigns have helped to improve antibiotic prescribing . The Antibiotic title remains the flagship of Therapeutic Guidelines Limited with sales, surveys and endorsements over 11 editions attesting to its wide acceptance and use . Therapeutic Guidelines: Antibiotic is one of many initiatives that have contributed to improving antibiotic use and it serves as a valuable foundation on which to build other strategies . There is demand for a consumer friendly version of the guidelines . In addition, the increasing use of computerised prescribing programs has highlighted the need for electronic guidelines to be closely integrated with decision support software.

Commun Dis Intell, 2003, 27 Suppl, S6 - 8
Regulation of veterinary antibiotics in Australia; Dyke TM; The Australian Pesticides and Veterinary Medicines Authority (APVMA)* registers veterinary antibiotic products before they can be supplied, distributed or sold in Australia . Extensive scientific assessment on all new veterinary antibiotic products is undertaken for the APVMA by experts in other government agencies including the Therapeutic Goods Administration (toxicology), the National Occupational Health and Safety Commission (occupational health and safety), Environment Australia (environmental hazards) and state departments of agriculture or primary industry (efficacy and safety) as well as APVMA assessments on food residues, trade and manufacturing . The National Health and Medical Research Council Expert Advisory Group on Antimicrobial Resistance provides advice to the APVMA on the potential transfer of antibiotic resistance from the use of antibiotics in animals to humans, and the impact transfer may have on public health . Food Standards Australia New Zealand (previously Australia New Zealand Food Authority) set maximum residue levels for human foods . The APVMA monitors registered product use through compliance activities and an adverse experience reporting program, and reviews registered products as necessary . The import, manufacture, supply and use of veterinary antibiotics are regulated by Commonwealth and State governments in Australia.

J Biomater Sci Polym Ed, 2003, 14(5), 423 - 38
Chitosan: potential use as a bioactive coating for orthopaedic and craniofacial/dental implants; Bumgardner JD et al.; Chitosan is a biopolymer that exhibits osteoconductive, enhanced wound healing and antimicrobial properties which make it attractive for use as a bioactive coating to improve osseointegration of orthopaedic and craniofacial implant devices . Coatings made from 91.2% de-acetylated chitosan were chemically bonded to titanium coupons via silane-glutaraldehyde molecules . The bond strength of the coatings was evaluated in mechanical tensile tests, and their dissolution and cytocompatibility were evaluated in vitro using cell-culture medium and UMR 106 osteoblastic cells, respectively . The results showed that the chitosan coatings were chemically bonded to the titanium substrate and that the bond strengths (1.5-1.8 MPa) were not affected by gas sterilization . However, the chitosan bond strengths were less than those reported for calcium-phosphate coatings . The gas-sterilized coatings exhibited little dissolution over 8 weeks in cell-culture solution, and the attachment and growth of the UMR 106 osteoblast cells was greater on the chitosan-coated samples than on the uncoated titanium . These results indicated that chitosan has the potential to be used as a biocompatible, bioactive coating for orthopaedic and craniofacial implant devices.

J Antimicrob Chemother, 2003 Jul, 52(1), 11 - 7 Epub 2003 Jun 12.
The mutant selection window and antimicrobial resistance; Drlica K; The mutant selection window is an antimicrobial concentration range extending from the minimal concentration required to block the growth of wild-type bacteria up to that required to inhibit the growth of the least susceptible, single-step mutant . The upper boundary is also called the mutant prevention concentration (MPC) . Placing antimicrobial concentrations inside the window is expected to enrich resistant mutant subpopulations selectively, whereas placing concentrations above the window is expected to restrict selective enrichment . Since window dimensions are characteristic of each pathogen-antimicrobial combination, they can be linked with antimicrobial pharmacokinetics to rank compounds and dosing regimens in terms of their propensity to enrich mutant fractions of bacterial populations . For situations in which antimicrobial concentrations cannot be kept above the window, restricting the enrichment of mutants requires combination therapy.

Cochrane Database Syst Rev . 2003;(2):CD003295.
Prophylactic antibiotics for preventing early central venous catheter Gram positive infections in oncology patients; van de Wetering MD et al.; BACKGROUND: Long-term tunnelled central venous catheters (TCVC) are increasingly used in oncology patients . Despite guidelines on insertion, maintenance and use, infections remain an important complication . Most infections are caused by Gram-positive bacteria . Therefore antimicrobial prevention strategies aimed at these micro-organisms could potentially decrease the majority of the TCVC infections . OBJECTIVES: To determine the efficacy of administering antibiotics prior to insertion of a TCVC with or without vancomycin/heparin flush technique in the first 45 days after insertion of the catheter to prevent Gram-positive catheter-related infections in oncology patients . SEARCH STRATEGY: We searched MEDLINE, EMBASE,and CENTRAL up to July 2001 . Reference lists from relevant articles were scanned and conference proceedings were hand searched . The authors of eligible studies were contacted to obtain additional information . SELECTION CRITERIA: We selected randomized controlled trials giving prophylactic antibiotics prior to insertion of the TCVC, and trials using the combination of an antibiotic and heparin to flush the TCVC in oncology patients . DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the studies for inclusion, extracted the data and assessed the quality . MAIN RESULTS: We included eight trials totalling 527 patients . Four reported on vancomycin/teicoplanin prior to insertion of the TCVC, and four reported on antibiotic flushing combined with heparin . The overall effect of an antibiotic prior to catheter insertion decreases the number of Gram-positive TCVC infections (odds ratio {OR} = 0.55, 95% confidence interval {CI} 0.29 to1.04) . Given an expected infection rate of TCVC during the first 45 days of up to 30% this OR implies that the number needed to treat (NNT) will be 10 (95% CI 4 to13), this means vancomycin needs to be given to 10 patients to prevent one TCVC infection . Flushing the TCVC with antibiotics and heparin proved to be beneficial (OR = 0.35, 95% CI 0.16 -to 0.77) . For intraluminal colonization the baseline infection-rate is 15% which leads to a NNT of 13 (95% CI 5 to 23) . REVIEWER'S CONCLUSIONS: Both interventions lead to a positive overall effect but should be considered with care due to the small number of studies . Depending on the baseline TCVC infection rate it is justified to administer antibiotics prior to the TCVC insertion or to flush the catheter with a combination of an antibiotic and heparin, if the catheter-related infection rate is high.

Cochrane Database Syst Rev . 2003;(2):CD001439.
Antibiotics versus placebo for prevention of postoperative infection after appendicectomy; Andersen BR et al.; BACKGROUND: Appendicitis is the most common cause of acute abdominal pain requiring surgical intervention . The cause of appendicitis is unclear and the mechanism of pathogenesis continues to be debated . Despite improved asepsis and surgical techniques, postoperative complications, such as wound infection and intraabdominal abscess, still account for a significant morbidity . Several studies implicate that postoperative infections are reduced by administration of antimicrobial regimes . OBJECTIVES: The objective of this review is to evaluate the use of antibiotics with placebo or no treatment in patients undergoing appendectomy . Will these patients benefit from antimicrobial prophylaxis? The outcomes are described according to the nature of the appendix, as either simple appendicitis (including the non-infectious stage) and complicated appendicitis . This review do not attempt to compare the effect of different regimens . That clinical question is addressed in another review undertaken by Bleuer 1999 . SEARCH STRATEGY: We searched The Cochrane Controlled Trials Register (Cochrane Library 2002 issue 4); Pubmed, Embase and the Cochrane Colorectal Cancer Group Specialised Register (Up to October 2002) . In addition we manually searched the reference lists of the primary identified trials . SELECTION CRITERIA: We evaluated Randomised Controlled Trials (RCTs) and Controlled Clinical Trials (CCTs) in which any antibiotic regime were compared to placebo in patients suspected of having appendicitis, and undergoing appendectomy . Both studies on children and adults were reviewed . The outcome measures of the studies were: Wound infection, intra abdominal abscess, length of stay in hospital, and mortality . DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed, recorded and cross-checked by two reviewers . MAIN RESULTS: Forty-five studies including 9576 patients were included in this review . The overall result is that the use of antibiotics is superior to placebo for preventing wound infection and intraabdominal abscess, with no apparent difference in the nature of the removed appendix . Studies exclusively on children and studies examining topical application reported results in favour to the above although the results were not significant . REVIEWER'S CONCLUSIONS: Antibiotic prophylaxis is effective in the prevention of postoperative complications in appendectomised patients, whether the administration is given pre-, peri- or post-operatively, and could be considered for routine in emergency appendectomies.

Vector Borne Zoonotic Dis, 2002 Winter, 2(4), 241 - 7
Nervous system Lyme disease; Halperin JJ; Nervous system involvement in Lyme borreliosis is a much-feared, often-misunderstood disorder . Both the peripheral and central nervous systems may be involved, typically in a multifocal, patchy fashion, perhaps suggesting a vasocentric mechanism . Clinical manifestations vary widely, depending on the site and severity of involvement . Although neurologic manifestations observed in Europe differ somewhat from those reported in the United States, there are also striking similarities, permitting some generalization of information obtained in each population . In general, diagnosis of neurologic disease requires objective evidence of nervous system damage, and must be differentiated from both psychiatric disorders and metabolic encephalopathies, both of which typically occur in the absence of significant neurologic damage or infection . Laboratory confirmation of nervous system involvement by Borrelia burgdorferi has limitations . However, neurophysiologic testing of the peripheral nervous system, imaging of the neuraxis, and examination of the cerebrospinal fluid can all be informative . In contrast, to date functional brain imaging has been of limited specificity . Treatment with one of several straightforward antimicrobial regimens, typically 2-4 weeks in duration, generally results in microbiologic cure . Although some symptoms may persist after this, the data do not suggest that these are responsive to further antimicrobial therapy.

Vector Borne Zoonotic Dis, 2002 Winter, 2(4), 233 - 9
Diagnosis of human granulocytic ehrlichiosis: state of the art; Aguero-Rosenfeld ME; Human granulocytic ehrlichiosis is an emerging zoonosis caused by Anaplasma phagocytophilum and transmitted through the bite of infected Ixodes scapularis . It is prevalent in the Midwest and Northeast United States and also in Europe, and it presents as a nonspecific febrile illness a few days after a tick bite usually between late spring and fall . Most cases present in adult patients with a mild form of the disease, although it can be severe with multiorgan failure, particularly in the elderly and in the immunocompromised . Routine laboratory abnormalities include leukopenia with a left shift, lymphopenia, and thrombocytopenia . These abnormalities are more frequently present during the first week of illness and then tend to normalize; therefore their absence should not exclude the diagnosis . Specific tests to confirm the diagnosis during the acute phase include microscopic detection of morulae in granulocytes, culture of A . phagocytophilum, and polymerase chain reaction . Of these methods, culture appears to have the greatest sensitivity during the acute phase prior to antimicrobial treatment . Serology has an important role in the confirmation of the diagnosis when used in paired specimens and when high cutoff titers by indirect fluorescence antibody assay (> or = 640) are used to diagnose a recent infection.

Ann Trop Med Parasitol, 2003 Apr, 97(3), 281 - 7
Inhibition of the transcription of the Escherichia coli O157:H7 genes coding for shiga-like toxins and intimin, and its potential use in the treatment of human infection with the bacterium; Matar GM et al.; Reverse-transcription PCR (RT-PCR) was used to assess the effects, in vitro, of rifampicin on the transcription of the eaeA, stx1 and stx2 genes (coding for intimin and shiga-like toxins I and II, respectively) of seven strains of Escherichia coli O157:H7 associated with human infection . Each strain was found to possess all three genes and, in the absence of rifampicin, all seven strains transcribed eaeA and stx2 (three strains did not transcribe their stx1 genes) . Transcription of all three genes was inhibited (as witnessed by a negative result in the RT-PCR), however, when the strains were incubated, at 37 degrees C, with rifampicin at 4 microg/ml (found to be the minimum concentration of this antimicrobial agent that inhibited the multiplication of E . coli O157:H7) . The results of an assay based on reversed passive latex agglutination (RPLA) revealed that exposure of the bacteria to 4 microg rifampicin/ml led to a 12-fold decrease in the release of shiga-like toxin I and a 16-fold decrease in the release of shiga-like toxin II . As rifampicin is capable of inhibiting the in-vitro transcription of the genes encoding the shiga-like toxins and intimin attachment protein of E . coli O157:H7, it may be useful in the treatment of human infections with strains of this bacterium . Studies are now underway to assess the in-vitro and in-vivo effects of rifampicin, at both transcription-inhibitory and bactericidal concentrations, on E . coli O157:H7 . The effects of other agents on the inhibition of the expression or activity of the shiga-like toxins and intimin attachment protein will also be determined.

Ann Trop Paediatr, 2003 Jun, 23(2), 145 - 8
A child with neurobrucellosis; Hesseling AC et al.; An 11-year-old boy presented with chronic meningitis followed by acute flaccid paralysis . The aetiology remained uncertain until the brucellar serology test became positive and there was a good response to specific antimicrobial therapy . Nerve conduction studies confirmed a proximal radiculopathy . Awareness of the condition and performance of the appropriate tests will differentiate neurobrucellosis from other chronic central nervous system infections.

Planta Med, 2003 May, 69(5), 468 - 70
Antimicrobial diterpenes from the seeds of Cephalotaxus harringtonia var . drupacea; Politi M et al.; Six diterpenes, including two new natural products, were isolated from the seeds of Cephalotaxus harringtonia . The new metabolites were characterised as 8 beta-hydroxy-9(11),13-abietadien-12-one and 5,6-didehydroferruginol, while the known compounds were identified as ferruginol, sugiol, 6,12-dihydroxyabieta-5,8,11,13-tetraen-7-one, and abieta-8,11,13-trien-7 beta-ol . These compounds were studied in vitro for their antimicrobial activity against clinically isolated bacteria and Candida strains . Ferruginol and 6,12-dihydroxyabieta-5,8,11,13-tetraen-7-one showed antimicrobial activity against Gram-positive bacteria . None of the six diterpenes was active against the Gram-negative organisms and yeasts tested.

Res Vet Sci, 2003 Aug, 75(1), 3 - 7
In vitro susceptibilities of field isolates of Mycoplasma agalactiae to oxytetracycline, tylosin, enrofloxacin, spiramycin and lincomycin-spectinomycin; Loria GR et al.; The minimum inhibitory concentrations (MICs) of tetracycline, enrofloxacin, tylosin, spiramycin and a lincomycin:spectinomycin 1:2 combination, against 24 Sicilian isolates of Mycoplasma agalactiae, the causative organism of contagious agalactia were determined in vitro by a broth dilution method . Enrofloxacin was the most effective antimicrobial in vitro with a range of MIC values from 0.125 to 0.500 microg/ml and an MIC(50) of 0.203 and MIC(90) of 0.365 microg/ml . Using the MIC(50) and MIC(90) values the remaining four antimicrobials are ranked in order of in vitro effectiveness as follows: tylosin (MIC(50)0.292; MIC(90)0.525 microg/ml) was slightly more effective than tetracycline (MIC(50)0.296; MIC(90)0.533 microg/ml), followed by lincomycin:spectinomycin (MIC(50)0.521; MIC(90)0.938 microg/ml) and spiramycin (MIC(50)1.583; MIC(90)2.850 microg/ml) . MIC values above 1.000 microg/ml were obtained using tetracycline, tylosin and spiramycin for some M . agalactiae isolates.

Folia Microbiol (Praha), 2003, 48(2), 123 - 37
Mammalian antibiotic peptides; Sima P et al.; The increasing development of bacterial resistance to traditional antibiotics has reached alarming levels, thus creating a strong need to develop new antimicrobial agents . These new antibiotics should possess novel mechanisms of action and different cellular targets compared with existing antimicrobials . Recent discoveries and isolations of so-called animal antibiotics, mostly small cationic peptides, which represent a potent branch of natural immunity, offered the possibility to acquire new and effective antibiotics of this provenance . To this date, more than 500 antibiotic peptides have been distinguished and defined . Their antimicrobial properties present new opportunities for their use as antibiotics or for construction of their more effective derivatives, but much research is still required to pave the way to their practical use . This is a survey of substances forming an armamentarium of natural immunity of mammals.

Pediatr Infect Dis J, 2003 Jun, 22(6), 494 - 9
Factors associated with hand hygiene practices in two neonatal intensive care units; Cohen B et al.; OBJECTIVE: To determine whether hand hygiene practices differ between levels of contact with neonates; to characterize the hand hygiene practices of different types of personnel; and to compare hand hygiene practices in neonatal intensive care units (NICUs) using different products . METHODS: Research assistants observed staff hand hygiene practices during 38 sessions in two NICUs . Patient touches were categorized as touching within the neonates' environment but only outside the Isolette (Level 1), touching within the Isolette but not the neonate directly (Level 2) or directly touching the neonate (Level 3) . Hand hygiene practices for each touch were categorized into five groups: cleaned hands and new gloves; uncleaned hands and new gloves; used gloves; clean hands and no gloves; uncleaned hands and no gloves . RESULTS: Research assistants observed 1472 touches . On average each neonate or his or her immediate environment was touched 78 times per shift . Nurses (P = 0.001), attending physicians (P = 0.02) and physicians-in-training (P = 0.03) were more likely to use appropriate practices during Level 3 touches, but only 22.8% of all touches were with cleaned and/or newly gloved hands . The mean number of direct touches by staff members with cleaned hands was greater in the NICU using an alcohol-based hand rub than in the NICU using antimicrobial soap (P < 0.01) . CONCLUSIONS: Hand hygiene was suboptimal in this high risk setting; administrative action and improved products may be needed to assure acceptable practice . In this study use of an alcohol-based product was associated with significantly improved hand hygiene and should be encouraged, as recommended in the new CDC hand hygiene guideline.

J Chromatogr B Analyt Technol Biomed Life Sci, 2003 Jul 5, 791(1-2), 345 - 56
Human hemoglobin-derived peptides exhibit antimicrobial activity: a class of host defense peptides; Liepke C et al.; Hemoglobin is a known source of biologically active peptides with various functions . In the present study, we report for the first time the existence of natural processed hemoglobin fragments exhibiting antimicrobial activity in humans . Two antimicrobial hemoglobin-derived peptides were purified from a human placental peptide library by consecutive chromatographic steps tracking the maximum growth inhibitory activity against Escherichia coli BL21 . These peptides, consisting of 17 and 36 amino acid residues, were identified as being C-terminal fragments of gamma-hemoglobin and beta-hemoglobin, respectively . The antimicrobial beta-hemoglobin fragment was also purified from lysed erythrocytes, demonstrating that proteolytic degradation of hemoglobin into small bioactive peptides already starts inside erythrocytes . The identified peptides inhibit the growth of Gram-positive and Gram-negative bacteria and yeasts in micromolar concentrations . Moreover, by LPS-binding, the beta-hemoglobin fragment reduces biological activity of endotoxins . In contrast, even at high concentrations, the identified antimicrobial hemoglobin peptides do not exhibit toxic activity on human primary blood cells . We conclude that antimicrobial hemoglobin-derived peptides could be important effectors of the innate immune response killing microbial invaders.

Arch Bronconeumol, 2003 Jun, 39(6), 261 - 5
{Efficacy of an antibacterial filter for preventing contamination of respiratory function diagnostic equipment}; Macian V et al.; OBJECTIVES: Devices to assess lung function are a potential source of nosocomial infection . Our aims in this study were: 1) to determine the efficacy of an antimicrobial filter to prevent contamination of a multifunctional device; 2) to assess the ability of the filter to prevent cross contamination of individuals being tested; and 3) to evaluate the efficacy of the recommendations of the Spanish Society of Respiratory Diseases and Thoracic Surgery for disinfecting lung function equipment . DESIGN: In this prospective, randomized study in two phases we used filters in phase 1 but not in phase 2 . A pharyngeal swab culture was started within 7 days of a patient's lung function test . Swab samples for culturing were taken from three different places in the equipment at the beginning and end of each working day . PATIENTS: Sixty-five patients (31 in phase 1 and 34 in phase 2) were studied . Thirty-two (49.2%) were men and the mean age was 49.4 15.7 years.Results: Significantly less equipment contamination was found in phase 1 (4.2%) than in phase 2 (21%) . We detected no cases of cross contamination using the criteria in this study . No cultures from any of the samples taken before exploration were positive . CONCLUSIONS: a) The antimicrobial filter used is effective for preventing the contamination of lung function testing equipment, b) throughout both phases of the study, we observed no cross contamination of patients tested, such that we cannot conclude that the antimicrobial filter is effective for preventing possible nosocomial infections, c) the recommendations of SEPAR for disinfecting lung function equipment are effective.

Curr Top Microbiol Immunol, 2003, 276, 199 - 214
Dendritic cell vaccination and viral infection--animal models; Ludewig B; Dendritic cells (DCs) play a pivotal role in the initiation and maintenance of immune responses against viruses and other microbial pathogens . Adoptively transferred, in vitro manipulated DCs presenting antigen derived from different viruses have been shown to elicit cytotoxic T cell (CTL) and T helper (Th) cell responses and to induce protective antiviral immunity . Furthermore, DC-based adoptive immunotherapies have the potential to specifically (re)activate antiviral immunity in chronic viral diseases such as HIV or hepatitis virus infections . Cellular dendritic cell vaccines, however, are not suitable for large-scale prophylactic immunization . Strategies for vaccine development should therefore aim at the specific delivery of microbial antigens to DCs in situ . Furthermore, appropriate mobilization and activation of DCs by the vaccine is important for the generation of optimal antimicrobial immune responses . Here, we discuss recent data on induction of antiviral immunity with various DC-vaccination approaches and outline future directions for the development of specific antigen targeting to DCs.

J Chemother, 2003 Apr, 15(2), 152 - 6
Antibiotic lock-technique for the treatment of catheter-related bloodstream infections; Viale P et al.; The management of central venous catheter-related bloodstream infections (CRBSI), though still debated, requires the removal of the line in most cases: we investigated the efficacy of an alternative approach, based on higher concentrations of antibiotics locked within the catheter lumen, in an open, pilot study aimed at preserving the line in place and at eradicating the infection . Thirty consecutive patients carrying a central line over 10 days and who fulfilled criteria for ascertained diagnosis of bacterial CRBSI, had the catheter "locked" with antimicrobials therein; all patients also received systemic antibiotic therapy within the first 48 hours . Subsequently, 15 patients underwent locks alone, and 15 locks plus systemic therapy . Twenty-eight out of 30 (93.3%) patients retained the catheter in place, appearing to be cleared of infection and no treatment-related untoward events were observed . Locks should be considered as effective as line removal in the management of bacterial CRBSI in unselected patients, and could thus provide advantages in terms of resource sparing and lowered antibiotic pressure in the hospital setting.

J Chemother, 2003 Apr, 15(2), 129 - 33
Antiendotoxin activity of antimicrobial peptides and glycopeptides; Giacometti A et al.; An animal study was performed to investigate the efficacy of two glycopeptides and two cationic peptides in the prevention of lethality in a septic shock rat model . Adult Wistar rats were given an intraperitoneal injection of 2x10(10) CFU of Escherichia coli ATCC 25922, with the exception of an uninfected control group (C0) . Animals were randomized to receive, immediately after bacterial challenge, intraperitoneally isotonic sodium chloride solution (control group C1), 3 mg/Kg teicoplanin (group 1), 7 mg/Kg vancomycin (group 2), 1 mg/Kg colistin (group 3), 1 mg/Kg buforin II (group 4), or 60 mg/Kg piperacillin (group C(PIP)) . In addition, four groups (1a, 2a, 3a, and 4a) received the above mentioned drugs in combination with piperacillin . All compounds and combinations significantly reduced the lethality and the number of E . coli in abdominal fluid compared with C1 group, with the exception of the glycopeptides . Colistin and buforin II combined with piperacillin significantly decreased the lethality compared with piperacillin alone . Finally, colistin, buforin II, and teicoplanin significantly reduced plasma endotoxin concentration in comparison with piperacillin and saline treatment . Antimicrobial peptides and teicoplanin act as antiendotoxin agents and enhance the efficacy of piperacillin.

Chest, 2003 Jun, 123(6), 2034 - 42
Hospital-acquired pneumonia: risk factors for antimicrobial-resistant causative pathogens in critically ill patients; Leroy O et al.; STUDY OBJECTIVES: To determine factors associated with antimicrobial-resistant hospital-acquired pneumonia (AR-HAP), to build an algorithm evaluating the risk for such a pneumonia, and to test this algorithm . DESIGN: Combined observational and validation cohorts over two periods: January 1994 to December 1999, and January 2000 to March 2001 . SETTING: One ICU from a university-affiliated urban teaching hospital . PATIENTS: One hundred twenty-four patients in the observational cohort and 26 patients in the validation cohort exhibiting bacteriologically documented hospital-acquired pneumonia (HAP) . INTERVENTIONS: Prospective data collection and multivariate analysis using the chi(2) automatic interaction and detection technique . RESULTS: In the observational cohort, 39 antimicrobial-resistant bacteria were incriminated in 37 patients (30%) . Multivariate analysis identified four independent variables allowing a binary stratification of risk . According to the presence or absence of prior antimicrobial treatment, neurologic disturbances on ICU admission, aspiration on ICU admission, and time elapsed between ICU admission and the onset of pneumonia, we were able to identify and separate patients at high, low, or even no risk for acquiring AR-HAP . In the validation cohort, nine antimicrobial-resistant bacteria were incriminated in nine patients (34.6%) . In this cohort, the algorithm performed well allowing the identification of null risk categories: the absence of prior antimicrobial treatment, the presence of prior antimicrobial treatment with neurologic disturbances on ICU admission and an early-onset pneumonia, and the presence of prior antimicrobial treatment without neurologic disturbances but with aspiration on ICU admission were always associated with antimicrobial-susceptible HAP . CONCLUSION: We developed and tested a binary algorithm allowing the identification of patients at low risk for acquiring AR-HAP . An antibiotic strategy including an initial antimicrobial treatment guided by such an algorithm, followed, if possible, by a de-escalation when antimicrobial data are available, could increase the administration of adequate initial antimicrobial treatment and help prevent the emergence of antibiotic resistance in the ICU.

J Clin Periodontol, 2003 Jun, 30(6), 532 - 41
Acquisition and loss of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Prevotella intermedia over a 5-year period: effect of a triclosan/copolymer dentifrice; Cullinan MP et al.; OBJECTIVES: The present study describes the natural history of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Prevotella intermedia over a 5-year period and the effect of a triclosan/copolymer dentifrice on these organisms in a normal adult population . MATERIAL AND METHODS: Subgingival plaque samples were collected from 504 adult volunteers . Probing pocket depths (PPD) and relative attachment levels were measured using an automated probe . Participants were matched for disease status (CPI), plaque index, age and gender, and allocated to receive either a triclosan/copolymer or placebo dentifrice . Re-examination and subgingival plaque sampling was repeated after 1, 2, 3, 4 and 5 years . P . gingivalis, A . actinomycetemcomitans and P . intermedia were detected and quantitated using an enzyme linked immunosorbent assay . Logistic regression and generalised linear modelling were used to analyse the data . RESULTS: This 5-year longitudinal study showed considerable volatility in acquisition and loss (below the level of detection) of all three organisms in this population . Relatively few subjects had these organisms on multiple occasions . While P . gingivalis was related to loss of attachment and to PPD >/=3.5 mm, there was no relationship between A . actinomycetemcomitans or P . intermedia and disease progression over the 5 years of the study . Smokers with P . gingivalis had more PPD >/=3.5 mm than smokers without this organism . There was no significant effect of the triclosan dentifrice on P . gingivalis or A . actinomycetemcomitans . Subjects using triclosan were more likely to have P . intermedia than those not using the dentifrice; however this did not translate into these subjects having higher levels of P . intermedia and its presence was uniform showing no signs of increasing over the course of the study . CONCLUSION: The present 5-year longitudinal study has shown the transient nature of colonisation with P . gingivalis, A . actinomycetemcomitans and P . intermedia in a normal adult population . The use of a triclosan-containing dentifrice did not lead to an overgrowth of these organisms . The clinical effect of the dentifrice would appear to be independent of its antimicrobial properties.

Mol Plant Microbe Interact, 2003 Jun, 16(6), 536 - 44
Characterization of a Ralstonia solanacearum operon required for polygalacturonate degradation and uptake of galacturonic acid; Gonzalez ET et al.; The bacterial wilt pathogen Ralstonia solanacearum produces three extracellular polygalacturonases (PGs): PehA, PehB, and PehC . All three PGs hydrolyze pectin's polygalacturonic acid backbone, but each releases different reaction products . PehA and PehB contribute significantly to pathogen virulence, probably by facilitating root invasion and colonization . To determine the collective contribution of PGs to virulence and saprophytic survival, we cloned, characterized, and mutated the R . solanacearum pehC gene, which encodes a distinctive monogalacturonate-releasing exo-PG . The virulence of a pehC mutant on tomato was indistinguishable from that of its wild-type parent; thus, this exo-PG alone does not contribute significantly to wilt pathogenesis . Unexpectedly, a completely PG-deficient triple pehA/B/C mutant was slightly more virulent than a pehA/B mutant . PehC may degrade galacturonide elicitors of host defense, thereby protecting the pathogen from plant antimicrobial responses . A galacturonate transporter gene, exuT, is immediately downstream of pehC and the two genes are co-transcribed . It has been hypothesized that galacturonic acid released by PGs from plant cell walls nourishes bacteria during pathogenesis . To separate the pectolytic and nutrient-generating roles of the PGs, we made an exuT mutant, which still produces all three isozymes of PG but cannot uptake PG degradation products . This exuT mutant had wild-type virulence on tomato, demonstrating that metabolism of galacturonic acid does not contribute significantly to bacterial success inside the plant.

Mol Plant Microbe Interact, 2003 Jun, 16(6), 525 - 35
Phylogeny of HCN synthase-encoding hcnBC genes in biocontrol fluorescent pseudomonads and its relationship with host plant species and HCN synthesis ability; Ramette A et al.; Hydrogen cyanide (HCN) is a broad-spectrum antimicrobial compound involved in biological control of root diseases by many plant-associated fluorescent pseudomonads . The HCN synthase is encoded by three biosynthetic genes (hcnA, hcnB, and hcnC), but little is known about the diversity of these genes in fluorescent Pseudomonas spp . and in other bacteria . Here, the partial hcnBC sequence was determined for a worldwide collection of biocontrol fluorescent Pseudomonas spp . Phylogenies based on hcnBC and deduced protein sequences revealed four main bacterial groups, but topological incongruences were found between hcnBC and rrs-based phylogenies, suggesting past lateral transfer of hcnBC among saprophytic root-colonizing pseudomonads . Three of the four groups included isolates from different countries and host plants . Yet, these groups corresponded to distinct, ecologically-adapted populations of HCN-producing biocontrol fluorescent pseudomonads, as indicated by high hcnBC distinctness ratio values and the differences in production levels of HCN in vitro found between groups . This is in accordance with previous results on catabolic properties and biocontrol abilities of these strains . HCN synthase gene diversity may thus reflect the adaptive radiation of HCN+ biocontrol fluorescent pseudomonads . Positive correlations were found between HCN production in vitro and plant protection in the cucumber/Pythium ultimum and tomato/Fusarium oxysporum f . sp . radicis-lycopersici pathosystems.

Nihon Kokyuki Gakkai Zasshi, 2003 Apr, 41(4), 261 - 7
{The efficacy of switch therapy in community-acquired pneumonia in Japan}; Uchiyama N et al.; To evaluate the efficacy of Switch therapy for community-acquired pneumonia, we conducted a prospective randomized controlled study in thirty-two hospitalized patients . These cases corresponded to Fine's risk classes II to IV . Using a table of random numbers, sixteen patients were assigned to a Switch therapy group, and the other sixteen, to a clinical pathway group . Both groups initially received intravenous antimicrobials . Within the Switch therapy group, when all the patients were afebrile for more than sixteen hours, their intravenous antimicrobials were switched to oral, and the patients were discharged on the following day . For all patients in the clinical pathway group, the critical pathway was defined as an eight-day planned hospitalization, with a time-task matrix formatted for disease treatment, laboratory testing, physical examination, oxygen saturation monitoring, ambulation, diet, patient education and clinical outcome . Switch therapy reduced the period of intravenous antimicrobial administration from 7.6 days to 4.0 days (p < 0.0001) . The period required to switch to oral antimicrobials decreased from 8.3 days to 4.8 days (p < 0.0001); hospital stay length, from 9.8 days to 6.5 days (p = 0.0001); and medical resource utilization, from 330, 373 to 227,768 Japanese yen (p = 0.0002) . No patient from either group required readmission . In conclusion, Switch therapy was more efficient than management with a clinical pathway for mild to moderate community-acquired pneumonia in hospitalized patients.

Ann N Y Acad Sci, 2003 May, 992, 168 - 78
Antimicrobial chromogranins and proenkephalin-A-derived peptides: Antibacterial and antifungal activities of chromogranins and proenkephalin-A-derived peptides; Metz-Boutigue MH et al.; The secretory granules from adrenal medullary chromaffin cells contain a complex mixture of low-molecular mass constituents such as catecholamines, ascorbate, nucleotides, calcium, peptides, and several high-molecular mass water-soluble proteins including chromogranins and proenkephalin-A . These proteins are sequestered into secretory granules in which processing yields a large variety of peptides . These fragments are released into the extracellular space upon cell stimulation and are recovered in blood, lymph, cerebrospinal fluid, and synovial fluid . Some of them have biological activity on cells in an autocrine, paracrine, or endocrine fashion . In addition, we have shown that peptides with antimicrobial activity are present with the secretory chromaffin granules and demonstrated that they are released from stimulated chromaffin cells . We have shown that posttranslational modifications modulate the antimicrobial activities . For some peptides, using confocal laser microscopy, we have examined the interaction of the rhodaminated peptides with biological membranes . In addition, we have shown that chromofungin, the antifungal peptide corresponding to chromogranin A(47-66), can bind calmodulin in the presence of calcium and induce inhibition of calcineurin, a calmodulin-dependent enzyme . Because these antibacterial peptides are colocalized with catecholamines, they may be activated during stress, playing a role as a first protective barrier against bacterial infection, and thus act as factors of the innate immunity shortly after infection and before the induction and mobilization of an adaptative immune system.

J Infect Dis, 2003 Jun 15, 187 Suppl 2, S327 - 34
Drosophila melanogaster antimicrobial defense; Hetru C et al.; The Drosophila melanogaster host defense is complex but remarkably efficient . It is a multifaceted response to a variety of fungal, bacterial, and parasitic invaders . Current knowledge is discussed on recognition of infectious microorganisms and on the activation of intracellular signaling cascades that concur with the expression of numerous immune-responsive genes, among which, to date, the most prominent appear to encode potent antimicrobial peptides.

J Infect Dis, 2003 Jun 15, 187 Suppl 2, S321 - 6
From phenomenon to phenotype and from phenotype to gene: forward genetics and the problem of sepsis; Beutler B et al.; Genetic tools (especially classical tools) have enlightened our understanding of biology as no other approach could . Mendel, Morgan, Bridges, and their heirs began with phenotypic traits and ended with genes . At first, the chemical identity of genes was not known, and even after years of methodologic refinement, more years of effort were needed to find the gene and the mutational difference that caused a particular phenotype . Chemistry has now outraced phenotypic analysis; all the genes are suddenly known, but most of their functions are not . The greatest challenge confronting all fields in biology is to establish correspondence between genes and discrete biologic functions . Sepsis is a devastating problem that has eluded a solution, despite the introduction of highly effective antimicrobial agents . Sepsis is an orchestrated process, understood in broad outline, but not in all details . Which genes are involved in the pathogenesis of sepsis? As in the golden age of genetics, the answer requires the solution of phenotypic puzzles, which, in turn, requires the creation of phenotypes.

Drug News Perspect, 2003 Mar, 16(2), 87 - 92
Piscidins: a novel family of peptide antibiotics from fish; Noga EJ et al.; The global emergence of many new infectious diseases, as well as concerns about the antibiotic resistance of an increasing number of microbial pathogens, necessitates that new approaches be sought in combating these serious infections . Peptide antibiotics, host-produced antimicrobial defenses that have been isolated from all types of organisms, from plants to mammals, possess a number of characteristics that make them attractive drug candidates . An example of the diversity and potential for new discoveries in this area is a novel family of peptide antibiotics named "piscidins," which have been recently isolated from fish . Piscidins have potent, broad-spectrum in vitro activity against many pathogens, including multidrug-resistant bacteria . Interestingly, piscidins reside in mast cells, a highly common tissue granulocyte of uncertain function that is ubiquitous in all vertebrate classes . The discovery of peptide antibiotics in mast cells may be a previously unappreciated, yet crucial, function for this highly common yet enigmatic immune cell . (c) 2003 Prous Science . All rights reserved.

J Clin Microbiol, 2003 Jun, 41(6), 2596 - 604
Antimicrobial susceptibility testing of porcine Brachyspira (Serpulina) species isolates; Karlsson M et al.; No standardized method for susceptibility testing of Brachyspira spp . is currently available . A broth dilution procedure was evaluated and used to test the activities of six antimicrobial agents for 108 isolates of Swedish porcine Brachyspira spp . representing biochemical groups I, II, and III . Group I corresponds to Brachyspira hyodysenteriae, group II corresponds to B . intermedia, and group III corresponds to B . murdochii and B . innocens . A panel was designed with the antimicrobial agents dried in tissue culture trays with wells that allowed a liquid volume of 0.5 ml in each and agitation of the broth when incubated on a shaker . The MICs were determined by using brain heart infusion broth with 10% fetal calf serum . For 10 isolates, the results obtained in broth were compared to the MICs obtained on two different types of agar . Different inoculum densities and incubation times were also compared . The concentrations at which 90% of the B . hyodysenteriae isolates (n = 72) were inhibited in the broth dilution test by tiamulin (0.25 micro g/ml), tylosin (>256 micro g/ml), erythromycin (>256 micro g/ml), clindamycin (>4 micro g/ml), virginiamycin (4 micro g/ml), and carbadox (0.06 micro g/ml) were determined . The MICs tended to be lower in broth than on agar . Differences in inoculum densities and incubation times had little influence on the MICs . The evaluated broth dilution test was simple to perform, the end points were easily read, and the results were reproducible and reliable . No isolates with decreased susceptibility to tiamulin were found among the Swedish isolates tested.

J Clin Microbiol, 2003 Jun, 41(6), 2560 - 8
Nocardia veterana as a pathogen in North American patients; Conville PS et al.; The molecular methodologies used in our laboratories have allowed us to define a group of Nocardia isolates from clinical samples which resemble the type strain of Nocardia veterana . Three patient isolates and the type strain of N . veterana gave identical and distinctive restriction fragment length polymorphisms (RFLPs) for an amplified portion of the 16S rRNA gene . These three isolates and the N . veterana type strain also gave identical RFLPs for an amplified portion of the 65-kDa heat shock protein gene, but this pattern was identical to that obtained for the Nocardia nova type strain . Sequence analysis of both a 1,359-bp region of the 16S rRNA gene and a 441-bp region of the heat shock protein gene of the patient isolates showed 100% identities with the same regions of the N . veterana type strain . DNA-DNA hybridization of the DNA of one of the patient isolates with the DNA of the N . veterana type strain showed a relative binding ratio of 82%, with 0% divergence, confirming that the isolate was N . veterana . Biochemical and susceptibility testing showed no significant differences among the patient isolates and the N . veterana type strain . Significantly, the results of antimicrobial susceptibility testing obtained for our isolates were similar to those obtained for N . nova, indicating that susceptibility testing alone cannot discriminate between these species . We present two case studies which show that N . veterana is a causative agent of pulmonary disease in immunocompromised patients residing in North America . We also describe difficulties encountered in using 16S rRNA gene sequences alone for discrimination of N . veterana from the related species Nocardia africana and N . nova because of the very high degree of 16S rRNA gene similarity among them.

Int J Antimicrob Agents, 2003 Jun, 21(6), 574 - 7
Inhibitory and bactericidal activities of gemifloxacin and other antimicrobials against Mycoplasma pneumoniae; Waites KB et al.; The MIC of gemifloxacin was compared with that of sparfloxacin, levofloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, doxycycline, erythromycin, azithromycin and clarithromycin using 97 clinical isolates of Mycoplasma pneumoniae . MBCs of fluoroquinolones were determined for a subgroup of 12 isolates . Macrolides were the most potent agents with MIC(90)s for all drugs <or=0.001 mg/l . The doxycycline MIC(90) was 0.5 mg/l . Gemifloxacin MICs ranged from <or=0.001 to 0.25 mg/l . The gemifloxacin MIC(90) (0.125 mg/l) was equivalent to moxifloxacin and gatifloxacin, was 2-fold lower than sparfloxacin, 8-fold lower than levofloxacin and 32-fold lower than ciprofloxacin . MBCs for gemifloxacin were predominantly within 2-4 times the corresponding MIC values, indicating a bactericidal effect.

Structure (Camb), 2003 Jun, 11(6), 607 - 8
Complementing thymidylate synthase; Montfort WR; The structure of thymidylate synthase complementing protein with substrates dUMP and FAD, presented in this issue of Structure, sheds light on a fascinating new catalytic mechanism, suggests a strategy for the design of new antimicrobial compounds, and highlights the promise of proteomics in medicine.

Mol Microbiol, 2003 Jun, 48(6), 1609 - 19
Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with Rob regulatory protein; Rosenberg EY et al.; AcrAB of Escherichia coli, an archetype among bacterial multidrug efflux pumps, exports an extremely wide range of substrates including solvents, dyes, detergents and antimicrobial agents . Its expression is regulated by three XylS/AraC family regulators, MarA, SoxS and Rob . Although MarA and SoxS regulation works by the alteration of their own expression levels, it was not known how Rob, which is constitutively expressed, exerts its regulatory action . We show here that the induction of the AcrAB efflux pump by decanoate and the more lipophilic unconjugated bile salts is mediated by Rob, and that the low-molecular-weight inducers specifically bind to the C-terminal, non-DNA-binding domain of Rob . Induction of Rob is not needed for induction of AcrAB, and we suggest that the inducers act by producing conformational alterations in pre-existing Rob, as was suggested recently (Rosner, Dangi, Gronenborn and Martin, J Bacteriol 184: 1407-1416, 2002) . Decanoate and unconjugated bile salts, which are present in the normal habitat of E . coli, were further shown to make the bacteria more resistant to lipophilic antibiotics, at least in part because of the induction of the AcrAB efflux pump . Thus, it is likely that E . coli is protecting itself by the Rob-mediated upregulation of AcrAB against the harmful effects of bile salts and fatty acids in the intestinal tract.

Compend Contin Educ Dent, 2002 May, 23(5 Suppl), 15 - 21
Minocycline microspheres: a complementary medical-mechanical model for the treatment of chronic periodontitis; Paquette DW; Locally delivered antimicrobials represent an expanding class of therapeutics that may complement conventional mechanical treatments for chronic periodontitis . Currently available locally delivered antimicrobials include a tetracycline fiber, chlorhexidine chip, doxycycline gel, and newly approved minocycline microspheres . This last therapeutic is formulated to contain 3 mg polyglycolide-co-dl lactide (PGLA) copolymer and 1 mg of minocycline per unit (pocket) dose . As the polymer microspheres resorb, minocycline is released locally within the periodontal pocket at effective concentrations for at least 14 days . Recently, three phase 3 human clinical trials were conducted to assess the efficacy and safety of minocycline microspheres in patients with moderate-to-advanced chronic periodontitis . Data from an open-label trial involving 173 subjects indicated that minocycline microspheres plus scaling and root planing (SRP) at baseline produced significant improvements in pocket depth (PD) (> or = 1.5 mm) at 1 and 3 months . Retreatment with minocycline microspheres at 3 and 6 months maintained these improvements for 12 months . Two concurrent, blinded studies cumulatively recruited 748 periodontitis subjects who were randomized to SRP plus minocycline microspheres, SRP plus vehicle (placebo), or SRP alone at baseline . Minocycline microspheres or the vehicle were readministered per the randomization at 3 and 6 months . Patients receiving minocycline microspheres plus SRP exhibited significantly greater PD reduction at 1, 3, 6, and 9 months compared to patients receiving SRP plus vehicle or SRP alone . Overall, mean PD reduction with adjunctive minocycline-microsphere treatment increased when patients with more advanced periodontitis (mean PD > or = 6 mm or 7 mm) were considered . Similarly, significant improvements in clinical attachment level and percent bleeding on probing were observed among advanced periodontitis patients treated with SRP plus minocycline microspheres relative to controls . Patients treated with minocycline microspheres plus SRP were 50% more likely to shift to an overall mean PD < 5 mm or to a more maintainable case definition . No increased incidence of adverse events or tetracycline resistance were observed with minocycline-microsphere treatment . The data from these clinical trials indicate that minocycline microspheres plus SRP are safe in patients and more effective than SRP alone in reducting the signs of chronic periodontitis.

Am J Health Syst Pharm, 2003 May 15, 60(10 Suppl 1), S16 - 9
Antimicrobial formularies: can they minimize antimicrobial resistance?
Polk RE.
The relationship between antimicrobial drug use and resistance rates and the implications for antimicrobial formularies are described . Efforts to restrict antimicrobial drug use to reduce resistance in certain microorganisms have been accompanied by increases in resistance in other microorganisms . Random cycling of a variety of antimicrobial agents to treat infections caused by the same microorganism in different patients within a health care institution has been advocated as a means to reduce antimicrobial resistance . Analysis of actual antimicrobial drug use and resistance data from a network of 40 hospitals revealed wide variability in antimicrobial use . The specific type and volume of antimicrobial agents used appear to play key roles in determining resistance rates . It may be feasible to optimize diversity in antimicrobial drug use and minimize resistance by making judicious changes to the antimicrobial formulary.

Am J Health Syst Pharm, 2003 May 15, 60(10 Suppl 1), S12 - 5
Formulary decision-making about cephalosporins with similar therapeutic uses; Mabe DM; The various costs and intangible factors that enter into formulary decisions in an era of increasingly frequent drug product shortages that can adversely affect patient care and increase treatment costs are described . Pharmacy administration at Carolinas HealthCare System analyzed the costs associated with making a formulary switch from the third-generation cephalosporin ceftriaxone to cefotaxime, which recently became available in generic form and has a similar spectrum of antimicrobial activity and therapeutic uses . Hard dollar costs for purchasing drugs and the supplies needed to administer them; soft dollar costs for staff time spent acquiring, preparing, and administering doses; and intangible factors were considered . A reliable supply of drug product from the manufacturer was an important intangible factor because of frequent drug shortages in the past few years and the adverse effect on patient care and the increased soft dollar costs associated with these shortages . Administrators at Carolinas HealthCare System decided not to make the proposed formulary change after weighing the many factors and costs.

Assist Inferm Ric, 2003 Jan-Mar, 22(1), 13 - 8
{Variability of intestinal preparation in patients undergoing stomach, intestine, uterus surgery at 4 hospitals}; Palese A et al.; The standard preoperative care of the surgical wards of 4 hospitals for patients undergoing abdominal (stomach and colon) and gynaecological (uterum) surgery has been described . Date collection included the comparative assessment of standard protocols and intervention, with nurses in charge of the preoperative care . Patients undergoing colon surgery may be prescribed an ash-free diet for 7-10 days or may eat normal meals till two days before the surgery . The same variability exists for the antimicrobial prophylaxis and its route of administration . Patients are not allowed to drink from the midnight before the surgery . Enemas administered the afternoon before the surgery may contain castor oil . A systematic review of preoperative care is warranted and guidelines for an evidence based practice should be provided in order to reduce the variability and improve the effectiveness of preoperative care.

Appl Environ Microbiol, 2003 Jun, 69(6), 3406 - 11
Increasing the oxidative stress response allows Escherichia coli to overcome inhibitory effects of condensed tannins; Smith AH et al.; Tannins are plant-derived polyphenols with antimicrobial effects . The mechanism of tannin toxicity towards Escherichia coli was determined by using an extract from Acacia mearnsii (Black wattle) as a source of condensed tannins (proanthocyanidins) . E . coli growth was inhibited by tannins only when tannins were exposed to oxygen . Tannins auto-oxidize, and substantial hydrogen peroxide was generated when they were added to aerobic media . The addition of exogenous catalase permitted growth in tannin medium . E . coli mutants that lacked HPI, the major catalase, were especially sensitive to tannins, while oxyR mutants that constitutively overexpress antioxidant enzymes were resistant . A tannin-resistant mutant was isolated in which a promoter-region point mutation increased the level of HPI by 10-fold . Our results indicate that wattle condensed tannins are toxic to E . coli in aerobic medium primarily because they generate H(2)O(2) . The oxidative stress response helps E . coli strains to overcome their inhibitory effect.

Appl Environ Microbiol, 2003 Jun, 69(6), 3165 - 9
Identification of intermediate and branch metabolites resulting from biotransformation of 2-benzoxazolinone by Fusarium verticillioides; Glenn AE et al.; Detoxification of the maize (Zea mays) antimicrobial compound 2-benzoxazolinone by the fungal endophyte Fusarium verticillioides involves two genetic loci, FDB1 and FDB2, and results in the formation of N-(2-hydroxyphenyl)malonamic acid . Intermediate and branch metabolites were previously suggested to be part of the biotransformation pathway . Evidence is presented here in support of 2-aminophenol as the intermediate metabolite and 2-acetamidophenol as the branch metabolite, which was previously designated as BOA-X . Overall, 2-benzoxazolinone metabolism involves hydrolysis (FDB1) to produce 2-aminophenol, which is then modified (FDB2) by addition of a malonyl group to produce N-(2-hydroxyphenyl)malonamic acid . If the modification is prevented due to genetic mutation (fbd2), then 2-acetamidophenol may accumulate as a result of addition of an acetyl group to 2-aminophenol . This study resolves the overall chemistry of the 2-benzoxazolinone detoxification pathway, and we hypothesize that biotransformation of the related antimicrobial 6-methoxy-2-benzoxazolinone to produce N-(2-hydroxy-4-methoxyphenyl)malonamic acid also occurs via the same enzymatic modifications . Detoxification of these antimicrobials by F . verticillioides apparently is not a major virulence factor but may enhance the ecological fitness of the fungus during colonization of maize stubble and field debris.

Appl Environ Microbiol, 2003 Jun, 69(6), 3077 - 84
Mycotoxigenic Fusarium and deoxynivalenol production repress chitinase gene expression in the biocontrol agent Trichoderma atroviride P1; Lutz MP et al.; Mycotoxin contamination associated with head blight of wheat and other grains caused by Fusarium culmorum and F . graminearum is a chronic threat to crop, human, and animal health throughout the world . One of the most important toxins in terms of human exposure is deoxynivalenol (DON) (formerly called vomitoxin), an inhibitor of protein synthesis with a broad spectrum of toxigenicity against animals . Certain Fusarium toxins have additional antimicrobial activity, and the phytotoxin fusaric acid has recently been shown to modulate fungus-bacterium interactions that affect plant health (Duffy and Defago, Phytopathology 87:1250-1257, 1997) . The potential impact of DON on Fusarium competition with other microorganisms has not been described previously . Any competitive advantage conferred by DON would complicate efforts to control Fusarium during its saprophytic growth on crop residues that are left after harvest and constitute the primary inoculum reservoir for outbreaks in subsequent plantings . We examined the effect of the DON mycotoxin on ecological interactions between pathogenic Fusarium and Trichoderma atroviride strain P1, a competitor fungus with biocontrol activity against a wide range of plant diseases . Expression of the Trichoderma chitinase genes, ech42 and nag1, which contribute to biocontrol activity, was monitored in vitro and on crop residues of two maize cultivars by using goxA reporter gene fusions . We found that DON-producing F . culmorum and F . graminearum strains repressed expression of nag1-gox . DON-negative wild-type Fusarium strains and a DON-negative mutant with an insertional disruption in the tricothecene biosynthetic gene, tri5, had no effect on antagonist gene expression . The role of DON as the principal repressor above other pathogen factors was confirmed . Exposure of Trichoderma to synthetic DON or to a non-DON-producing Fusarium mutant resulted in the same level of nag1-gox repression as the level observed with DON-producing FUSARIUM: DON repression was specific for nag1-gox and had no effect, either positive or negative, on expression of another key chitinase gene, ech42 . This is the first demonstration that a target pathogen down-regulates genes in a fungal biocontrol agent, and our results provide evidence that mycotoxins have a novel ecological function as factors in Fusarium competitiveness.

J Ethnopharmacol, 2003 Jul, 87(1), 99 - 101
Antimicrobial and antiproliferative activity of Peucedanum nebrodense (Guss.) Strohl; Schillaci D et al.; Acetone extract of Peucedanum nebrodense (Guss.) Strohl., a rare endemic species from the Madonie mountains (Sicily), was tested in vitro for its antimicrobial activity against bacterial reference strains and antiproliferative activity against K562 (human chronic myelogenous leukemia), HL-60 (human leukemia) and L1210 (murine leukemia) cell lines . The acetone extract showed antiproliferative IC50 values in the range of 14-0.27 microg/ml.

J Ethnopharmacol, 2003 Jul, 87(1), 89 - 92
The in vitro effects of Hypericum species on human leukocyte myeloperoxidase activity; Pabuccuoglu A et al.; Myeloperoxidase (MPO) is a major component of the antimicrobial system of polymorphonuclear neutrophils . The heme enzyme MPO catalyzes the conversion of hydrogen peroxide and chloride to hypochlorous acid . Hypochlorous acid is the major strong oxidant produced by neutrophils and may contribute to inflammatory tissue damage . It was reported that certain antiinflammatory drugs are capable of inhibiting MPO activity and this inhibition may account for their antiinflammatory effect . Hypericum L . is a genus of about 400 species, widespread throughout the world . Some species of genus exhibit a significant antiinflammatory activity beside their several pharmacological properties such as antidepressant, diuretic, antihelmintic, and antibacterial . In this study, we investigated the in vitro effects of three Hypericum species, which exhibit antiinflammatory activity, on human polymorphonuclear leukocyte MPO activity . We found that each extract of Hypericum species reduced the peroxidative and chlorinating activity of human leukocyte MPO in concentration-dependent manner . The antiinflammatory activity of these species may be related with inhibition of MPO activity.

Biochim Biophys Acta, 2003 Jun 10, 1612(2), 164 - 71
Molecular basis for membrane selectivity of NK-2, a potent peptide antibiotic derived from NK-lysin; Schroder-Borm H et al.; Increasing resistance of pathogenic bacteria against antibiotics is a severe problem in health care . Natural antimicrobial peptides and derivatives thereof have emerged as promising candidates for "new antibiotics" . In contrast to classical antibiotics, these peptides act by direct physical destabilization of the target cell membrane . Nevertheless, they exhibit a high specificity for bacteria over mammalian cells . However, the precise mechanism of action and the molecular basis for membrane selectivity are still a matter of debate . We have designed a new peptide antibiotic (NK-2) with enhanced antimicrobial activity based on an effector protein of mammalian immune cells (NK-lysin) . Here we describe the interaction of this alpha-helical synthetic peptide with membrane mimetic systems, designed to mimic the lipid compositions of mammalian and bacterial cytoplasmic membranes . Utilizing fluorescence and biosensor assays, we could show that on one hand, NK-2 strongly interacts with negatively charged membranes; on the other hand, NK-2 is able to discriminate, without the necessity of negative charges, between the zwitterionic phospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC), the major constituents of the outer leaflet of the cytoplasmic membranes of bacteria and mammalian cells, respectively.

Best Pract Res Clin Rheumatol, 2003 Apr, 17(2), 319 - 43
Arthritis associated with tuberculosis; Malaviya AN et al.; There has been a resurgence in tuberculosis (TB) worldwide . Approximately 2 billion people have latent infection, 8 million would develop active TB annually, and 2-3 million would die due to TB . With this resurgence, cases with extrapulmonary TB have also shown an increase . Approximately 10-11% of extrapulmonary TB involves joints and bones, which is approximately 1-3% of all TB cases . The global prevalence of latent joint and bone TB is approximately 19-38 million.TB arthritis most commonly manifests as a monoarthritis of weight-bearing joints in the hip or the knee . Oligo- or polyarticular presentation is not rare and may cause diagnostic confusion with inflammatory arthritis . Owing to the low incidence in developed countries, the diagnosis of joint and bone TB is often delayed . A high degree of sensitivity to this diagnosis would prevent delays, permitting prompt institution of anti-TB therapy and preventing irreversible joint damage . Despite advances, confirmation of diagnosis still relies on lengthy microbiological techniques or invasive biopsy . Due to the frequency of isoniazid resistance, initial treatment at present typically includes a combination of four drugs: isoniazid, rifampicin, pyrazinamide and streptomycin or ethambutol . Antimicrobial therapy should be of at least 9 months duration, longer in children and immunocompromised hosts . Surgical procedures should be restricted to joints with severe cartilage destruction, large abscesses, joint deformity, multiple drug resistance or atypical mycobacteria.

J Clin Periodontol, 2002, 29 Suppl 3, 136 - 59; discussion 160-2
A systematic review on the effect of systemic antimicrobials as an adjunct to scaling and root planing in periodontitis patients; Herrera D et al.; BACKGROUND: Scaling and root planing (SRP) are the bases of non-surgical therapy in the treatment of periodontitis . However, results from this therapy are often unpredictable and dependable from many different factors . OBJECTIVES: The aim of this systematic review was to evaluate the effectiveness of the adjunctive use of systemic antimicrobials with scaling and root planing (SRP) vs . SRP alone in the treatment of chronic (CP) or aggressive periodontitis (AgP) . SEARCH STRATEGY: Use of computerized databases, namely MEDLINE, the Cochrane Oral Health Group Specialty Trials Register and EMBASE; reference lists from relevant articles were hand-searched; and a hand-search of selected journals until April 2001 . SELECTION CRITERIA: Studies were selected if they were designed as controlled clinical trials in which systemically healthy patients with either AgP or CP were treated with SRP plus systemic antimicrobials in comparison with SRP alone or with placebo, for a minimum of 6 months . Main outcome measures were clinical attachment level (CAL) change and probing pocket depth (PPD) change . DATA COLLECTION AND ANALYSIS: Two reviewers extracted independently information regarding quality and study characteristics, in duplicate . Kappa scores determined their agreement . Main results were collected and grouped by drug, disease and PPD category . For the quantitative data synthesis, the data was pooled (when mean differences and standard errors were available), and either a Fixed Effects or Random Effects meta-analysis was used for the analysis . RESULTS: After an initial selection, 158 papers were identified by the manual and electronic searches; 25 papers were eligible for inclusion . Their quality assessment showed that randomization and allocation concealment methods were seldom reported and blindness was usually not defined clearly . In general, selected studies showed high variability and lack of relevant information for an adequate assessment . Overall, SRP plus systemic antimicrobial groups demonstrated better results in CAL and PPD change than SRP alone or with placebo groups . Only limited meta-analyses could be performed, due to the difficulties in pooling the studies and the lack of appropriate data . This analysis showed a statistically significant additional benefit for spiramycin (PPD change) and amoxicillin/metronidazole (CAL change) in deep pockets . CONCLUSION: Systemic antimicrobials in conjunction with SRP, can offer an additional benefit over SRP alone in the treatment of periodontitis, in terms of CAL and PPD change, and reduced risk of additional CAL loss . However, differences in study methodology and lack of data precluded an adequate and complete pooling of data for a more comprehensive analyses . It was difficult to establish definitive conclusions, although patients with deep pockets, progressive or 'active' disease, or specific microbiological profile, can benefit more from this adjunctive therapy.

Aliment Pharmacol Ther, 2003 Jun 1, 17(11), 1333 - 43
Review article: the treatment of refractory Helicobacter pylori infection; Megraud F et al.; The occurrence of refractory Helicobacter pylori infection is increasing . When the bacteria are not eradicated it means that the antibiotics have not reached the gastric mucosa at a sufficient concentration and over a sufficient time lapse to kill them . The main reasons for this are poor patient compliance, resistant bacteria, low gastric pH and a high bacterial load . Therefore, when administering a new treatment, it is important to choose antibiotics which do not face resistance problems and which increase the dosage of antisecretory drugs and the duration of treatment and, if possible, to add a topical agent such as bismuth salt . The recommended empirical strategy is to prescribe quadruple therapy or, alternatively, 2-week triple therapy including amoxicillin-metronidazole, tetracycline-metronidazole or amoxicillin-rifabutin . However, when H . pylori is susceptible, clarithromycin can still be used . In the case of a high level of metronidazole resistance, furazolidone can be employed . In each case, it is important to ensure good patient compliance, and counselling is helpful in this regard . However, the best approach remains the prevention of refractory H . pylori infection and, for this purpose, antimicrobial susceptibility testing before first-line therapy is important and should be encouraged.

Cell Mol Life Sci, 2003 Apr, 60(4), 711 - 20
Cathelicidins--a family of multifunctional antimicrobial peptides; Bals R et al.; One component of host defence at mucosal surfaces are epithelial-derived antimicrobial peptides . Cathelicidins are one family of antimicrobial peptides characterized by conserved pro-peptide sequences that have been identified in several mammalian species . LL-37/hCAP-18 is the only cathelicidin found in humans and is expressed in inflammatory and epithelial cells . Besides their direct antimicrobial function, cathelicidins have multiple roles as mediators of inflammation influencing diverse processes such as cell proliferation and migration, immune modulation, wound healing, angiogenesis and the release of cytokines and histamine . Finally, cathelicidin antimicrobial peptides qualify as prototypes of innovative drugs that may be used to treat infection and/or modulate the immune response . This review provides an overview of antimicrobial peptides of the cathelicidin family, the structures of their genes and peptides and their biological functions.

Infect Control Hosp Epidemiol, 2003 May, 24(5), 347 - 50
A prospective observational study of the effect of penicillin skin testing on antibiotic use in the intensive care unit; Arroliga ME et al.; BACKGROUND: Patients with penicillin allergy admitted to the intensive care unit (ICU) frequently receive non-beta-lactam antimicrobials for the treatment of infection . The use of these antimicrobials, more commonly vancomycin and fluoroquinolones, is associated with the emergence of multidrug-resistant infections . The penicillin skin test (PST) can help detect patients at risk of developing an immediate allergic reaction to penicillin and those patients with a negative PST may be able to use a penicillin antibiotic safely . METHODS: We determined the incidence of true penicillin allergy, the percentage of patients changed to a beta-lactam antimicrobial when the test was negative, the safety of the test, and the safety of administration of beta-lactam antimicrobials in patients with a negative test . Skin testing was performed using standard methodology . RESULTS: One hundred patients admitted to 4 ICUs were prospectively studied; 58 of them were male . The mean age was 63 years . Ninety-six patients had the PST: one was positive (1.04%), 10 (10.4%) were nondiagnostic, and 85 (88.5%) were negative . Of the 38 patients who received antimicrobials for therapeutic reasons, 31(81.5%) had the antibiotic changed to a beta-lactam antimicrobial after a negative reading versus 7 patients of the 57 (12%) who had received a prophylactic antimicrobial (P < .001) . No adverse effects were reported after the PST or after antimicrobial administration . CONCLUSIONS: The PST is a safe, reliable, and effective strategy to reduce the use of non-beta-lactam antimicrobials in patients who are labeled as penicillin allergic and admitted to the ICU.

Antonie Van Leeuwenhoek, 2003, 83(2), 175 - 81
Assessment of antimicrobial activity of hydrophilic betaines in osmotically stressed bacteria; Peddie BA et al.; A series of hydrophilic aromatic and semi-aromatic betaines related to trigonelline was synthesized and tested for antimicrobial activity . 4-Methylthiazolium betaine was the only one that showed significant antibacterial activity towards Escherichia coli under hyperosmotic conditions . None of the tested betaines showed any evidence of osmoprotection or urea protection.

Vet Surg, 2003 May-Jun, 32(3), 251 - 61
Elution of metronidazole and gentamicin from polymethylmethacrylate beads; Ramos JR et al.; OBJECTIVE: To characterize the elution and bioactivity of metronidazole and gentamicin sulfate polymerized, individually and in combination, with polymethylmethacrylate (PMMA) . STUDY DESIGN: In vitro experimental study . METHODS: PMMA beads containing metronidazole (3 concentrations), gentamicin sulfate, or metronidazole and gentamicin sulfate were immersed in 5 mL of phosphate-buffered saline in triplicate . Eluent was replaced at specified time intervals for 1 or 21 days, and antibiotic concentrations were measured by high-performance liquid chromatography . Changes in antibiotic bioactivity attributable to polymerization or copolymerization of the antibiotics with PMMA, ethylene oxide sterilization, and storage of AIPMMA beads containing metronidazole were evaluated . RESULTS: Antibiotic elution patterns were similar for all groups . Day 1 elution for groups containing metronidazole or gentamicin individually represented a mean 63%-66% and 79%, respectively, of the 21-day total . Approximately 50% of the day 1 elution occurred during the first hour . The elution of metronidazole was dose dependent . The elution of metronidazole (day 3-21) and gentamicin (all days) was significantly greater when metronidazole and gentamicin were combined (P <.05) . The addition of metronidazole delayed polymerization of PMMA . Neither polymerization nor copolymerization of metronidazole and gentamicin with PMMA, gas sterilization, or 2-month storage of beads containing metronidazole significantly affected antimicrobial bioactivity . CONCLUSIONS: Metronidazole elution from PMMA was dose dependent . Copolymerization of metronidazole and gentamicin sulfate in PMMA resulted in increased rates of elution . Intraoperative preparation of metronidazole-impregnated PMMA beads is not practical, but sterilization and storage for 2 months should not affect efficacy . CLINICAL RELEVANCE: The local delivery of biologically active metronidazole and gentamicin by elution from PMMA is feasible .

Expert Opin Ther Targets, 2003 Jun, 7(3), 329 - 41
Minidefensins and other antimicrobial peptides: candidate anti-HIV microbicides; Cole AM; Antimicrobial peptides have long been presumed to act as effector molecules of innate immunity . However, direct evidence that antimicrobial peptides have central roles in host defence has only recently become available . An overview of the types and characteristics of endogenous human antimicrobial peptides and proteins is presented, with particular emphasis on peptides that are active against HIV . These antiviral peptides are discussed in the context of utilising natural peptides for the design of effective topical microbicides for the treatment of sexually transmitted infections (STIs) . Several antimicrobial peptides, termed minidefensins, are potently active against HIV, and bear structural similarity to their larger defensin cousins . Strategies to develop potent peptide antibiotics based on defensin and minidefensin templates are promising in the development of antiviral therapeutics and preventatives.

J Clin Invest, 2003 Jun, 111(11), 1665 - 72
An angiogenic role for the human peptide antibiotic LL-37/hCAP-18; Koczulla R et al.; Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation . The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid . Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor-like 1 expressed on endothelial cells . Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia . The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells . Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo . Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.

J Clin Invest, 2003 Jun, 111(11), 1643 - 5
What is the real role of antimicrobial polypeptides that can mediate several other inflammatory responses?
Elsbach P.
Antimicrobial peptides are effector molecules of innate immunity with microbicidal and pro- or anti-inflammatory activities . Their role is now widening following evidence that one such multifunctional peptide, LL-37, induces angiogenesis, a process essential for host defense, wound healing, and tissue repair.

Toxicon, 2003 Jun, 41(7), 899 - 907
Contribution of crotoxin for the inhibitory effect of Crotalus durissus terrificus snake venom on macrophage function; Sampaio SC et al.; Previous work of our group demonstrated that Crotalus durissus terrificus venom has a dual effect on macrophage function: it inhibits spreading and phagocytosis and stimulates hydrogen peroxide and nitric oxide production, antimicrobial activity and glucose and glutamine metabolism of these cells . Crotalid venom also induces analgesia and this effect is mediated by opioid receptors . The involvement of opioidergic mechanism and the determination of the active component responsible for the inhibitory effect of crotalid venom on macrophage function were investigated . The venom reduced the spreading and phagocytic activities of peritoneal macrophages . This effect was observed in vitro, 2 h after incubation of resident peritoneal macrophages with the venom, and in vivo, 2 h after subcutaneous injection of the venom . The inhibition of phagocytosis was not modified by naloxone, an antagonist of opioid receptors . Venom neutralization with crotalid antivenom abolished the inhibitory effect of the venom, indicating that venom toxins are involved in this effect . Crotoxin, the main toxin of crotalid venom, s.c . injected to rats or added to the medium of peritoneal cell incubation, inhibited macrophage function in a similar manner to that observed for crude venom . The present results suggest that crotoxin causes a direct inhibition of macrophage spreading and phagocytic activities and may contribute to the inhibitory effect of crotalid venom on macrophage function.

Fitoterapia, 2003 Jun, 74(4), 397 - 400
Antimicrobial activity of extracts of Clematis vitalba towards pathogenic yeast and yeast-like microorganisms; Buzzini P et al.; A broad activity against pathogenic yeast and yeast-like microorganisms was shown in crude extracts of young shoots of Clematis vitalba . MICs ranging from 1.4 to 12.3 microg/ml were observed . After fractionating with petroleum ether, ethyl acetate and methanol, antimycotic activity has been observed only in methanol fractions.

Pediatr Crit Care Med, 2002 Apr, 3(2), 190 - 193
Systemic inflammatory response syndrome associated with Sweet's syndrome; Otheo E et al.; PURPOSE: To describe the first pediatric report of systemic inflammatory response syndrome, shock, and multiple organ dysfunction syndrome associated with Sweet's syndrome . DESIGN: Case report . SETTING: Pediatric intensive care unit . PATIENTS: A patient with Sweet's syndrome and multiple organ dysfunction syndrome . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: We report the case of a 7-yr-old female child with an acute nonlymphoblastic leukemia in complete remission after an autologous bone marrow transplantation, with a clinical picture of skin lesions and fever that met the criteria of Sweet's syndrome and developing systemic inflammatory response syndrome, septic shock, and multiple organ dysfunction syndrome . Her clinical condition worsened despite broad-spectrum antimicrobial therapy and standard measures of cardiovascular support . An infectious site could not be identified, and all culture results were negative . Her condition improved dramatically once steroid therapy was administered, and she made a full recovery . CONCLUSION: Although it is a rare condition, the diagnosis of Sweet's syndrome must be considered in a patient with the typical skin lesions and systemic inflammatory response syndrome . The correct diagnosis is of great clinical importance, because therapy with systemic steroids results in a fast and remarkable improvement.

J Dairy Sci, 2003 May, 86(5), 1578 - 89
Effect of temperature of CO2 injection on the pH and freezing point of milks and creams; Ma Y et al.; The objectives of this study were to measure the impact of CO2 injection temperature (0 degree C and 40 degrees C) on the pH and freezing point (FP) of (a) milks with different fat contents (i.e., 0, 15, 30%) and (b) creams with 15% fat but different fat characteristics . Skim milk and unhomogenized creams containing 15 and 30% fat were prepared from the same batch of whole milk and were carbonated at 0 and 40 degrees C in a continuous flow CO2 injection unit (230 ml/min) . At 0 degree C, milk fat was mostly solid; at 40 degrees C, milk fat was liquid . At the same total CO2 concentration with CO2 injection at 0 degree C, milk with a higher fat content had a lower pH and FP, while with CO2 injection at 40 degrees C, milks with 0%, 15%, and 30% fat had the same pH . This indicated that less CO2 was dissolved in the fat portion of the milk when the CO2 was injected at 0 degree C than when it was injected at 40 degrees C . Three creams, 15% unhomogenized cream, 15% butter oil emulsion in skim milk, and 15% vegetable oil emulsion in skim milk were also carbonated and analyzed as described above . Vegetable oil was liquid at both 0 and 40 degrees C . At a CO2 injection temperature of 0 degree C, the 15% vegetable oil emulsion had a slightly higher pH than the 15% butter oil emulsion and the 15% unhomogenized cream, indicating that the liquid vegetable oil dissolved more CO2 than the mostly solid milk fat and butter oil . No difference in the pH or FP of the 15% unhomogenized cream and 15% butter oil emulsion was observed when CO2 was injected at 0 degree C, suggesting that homogenization or physical dispersion of milk fat globules did not influence the amount of CO2 dissolved in milk fat at a CO2 injection temperature of 0 degree C . At a CO2 injection temperature of 40 degrees C and at the same total CO2 concentration, the 15% unhomogenized cream, 15% vegetable oil emulsion, and 15% butter oil emulsion had similar pH . At the same total concentration of CO2 in cream, injection of CO2 at low temperature (i.e., < 4 degrees C) may produce a better antimicrobial effect during refrigerated shelf life due to the higher concentration of CO2 in the skim portion of the cream.

Asian J Androl, 2003 Jun, 5(2), 131 - 5
Sperm immobilization activity of Allium sativum L . and other plant extracts; Chakrabarti K et al.; AIM: To identify possible spermicidal agents through screening a number of edible medicinal plants with antimicrobial activity . METHODS: Initial screening was made on the basis of ram cauda epididymal sperm immobilization immediately after addition of extracts . The most potent extract was selected and was evaluated on both ram and human spermatozoa . To unravel its mode of action several sperm functional tests were carried out, namely viability of cells, hypo-osmotic swelling test for membrane integrity and assays of membrane-bound enzyme 5'-nucleotidase and acrosomal marker enzyme acrosin . RESULTS: The crude aqueous extract of the bulb of Allium sativum L . showed the most promising results by instant immobilization of the ram epididymal sperm at 0.25 g/mL and human ejaculated sperm at 0.5 g/mL . Sperm immobilizing effects were irreversible and the factor of the extract responsible for immobilization was thermostable up to 90 deg . On boiling at 100 deg for 10 minutes, this activity was markedly reduced . Moreover, this extract was able to cause aggregation of ram sperms into small clusters after 30 minutes of incubation at 37 deg . However this property was not found in human spermatozoa . More than 50 % reduction in sperm viability and hypo-osmotic swelling occurred in treated sperm as compared with the controls, indicating the possibility of plasma membrane disintegration which was further supported by the significant reduction in the activity of membrane bound 5'-nucleotidase and acrosomal acrosin . CONCLUSION: The crude aqueous extract of A . sativum bulb possesses spermicidal activity in vitro.

Nat Rev Genet, 2003 Jun, 4(6), 442 - 56
Genetic strategies for antibacterial drug discovery; Miesel L et al.; The availability of genome sequences is revolutionizing the field of microbiology . Genetic methods are being modified to facilitate rapid analysis at a genome-wide level and are blossoming for human pathogens that were previously considered intractable . This revolution coincided with a growing concern about the emergence of microbial drug resistance, compelling the pharmaceutical industry to search for new antimicrobial agents . The availability of the new technologies, combined with many genetic strategies, has changed the way that researchers approach antibacterial drug discovery.

Mil Med, 2003 May, 168(5), 355 - 9
Infections of febrile neutropenic patients in malignant hematological diseases; Rokusz L et al.; We observed 71 febrile, neutropenic episodes in 25 oncohematological patients after chemotherapy during a 3-years period from 1995 to 1997 . Three patients died because of infections (pneumonia with septic shock, gram-negative bacteremia and sepsis, pseudomembranous colitis and diffuse peritonitis) at the period of prolonged, deep neutropenia (absolute neutrophil count < 100/mm3) . During the 71 febrile, neutropenic episodes, we observed 24 bacteremia (33.8%) and 1 fungemia (1.4%) . There were 35 cases of microbiologically documented and 12 cases of clinically documented infections . In 24 patients, the origin of fever was unknown . We analyzed the characteristics of infections, microbes and their susceptibility conditions, and the efficacy of empiric antimicrobial therapy.

J Chem Ecol, 2003 Apr, 29(4), 881 - 98
Novel detection of formylated phloroglucinol compounds (FPCs) in the wound wood of Eucalyptus globulus and E . nitens; Eyles A et al.; This study characterized the chemical responses of Eucalyptus globulus and Eucalyptus nitens to artificial inoculation with a basidiomycete decay fungus . Nine-year-old trees responded to mechanical wounding or inoculation with the decay fungus by producing new wound wood characterized by the presence of dark extractives 17 months after wounding . Analysis of crude wound wood extracts by HPLC coupled to negative ion electrospray mass spectrometry revealed the presence of a complex mixture of many unidentified formylated phlorglucinol compounds (FPCs), in addition to a diverse range of other polyphenolic compounds (hydrolyzable tannins, proanthocyanidins, flavanone glycoside, stilbene glycosides) . Prior to this study, FPCs have only been reported from leaves and buds of Eucalyptus spp . Unequivocal evidence for the presence of macrocarpal A and B, and sideroxylonal A and B in the crude extracts was obtained, as well as evidence for a wide range of as yet unreported FPCs . Subsequent preliminary in vitro fungal and bacterial bioassays did not support an antimicrobial role for FPCs in host-pathogen interactions in eucalypts.

Environ Sci Technol, 2003 May 1, 37(9), 1713 - 9
Effects of three pharmaceutical and personal care products on natural freshwater algal assemblages; Wilson BA et al.; Treated wastewaters in the United States contain detectable quantities of surfactants, antibiotics, and other types of antimicrobial chemicals contained in pharmaceutical and personal-care products (PPCPs) that are released into stream ecosystems . The degradation characteristics of many of these chemicals are not yet known, nor are the chemical properties of their byproducts . They also are not currently mandated for removal under the U.S . Clean Water Act . Three representative PPCPs were individually tested in this study using a series of laboratory dilution bioassays: Ciprofloxacin (an antibiotic), Triclosan (an antimicrobial agent), and Tergitol NP 10 (a surfactant), to determine their effects on natural algal communities sampled both upstream and downstream of the Olathe, KS wastewater treatment plant (WWTP) . There were no significant treatment effects on algal community growth rates during the exponential phase of growth, but significant differences were observed in the final biomass yields (p < 0.001) . All three compounds caused marked shifts in the community structure of suspended and attached algae at both the upstream and downstream sites (p < 0.05) . Increasing the concentrations of all three compounds over a 3 orders of magnitude range also caused a consistent decline in final algal genus richness in the bioassays . Our results suggest that these three PPCPs may potentially influence both the structure and the function of algal communities in stream ecosystems receiving WWTP effluents . These changes could result in shifts in both the nutrient processing capacity and the natural food web structure of these streams.

Nat Immunol, 2003 Jun, 4(6), 517 - 23
Understanding the function of CD1-restricted T cells; Vincent MS et al.; CD1 molecules bind foreign lipid antigens as they survey the endosomal compartments of infected antigen-presenting cells . Unlike T cells that recognize CD1-restricted foreign lipids, CD1-restricted T cells that are self-antigen-reactive function as 'auto-effectors' that are rapidly stimulated to carry out helper and effector functions upon interaction with CD1-expressing antigen-presenting cells . The functional distinctions between subsets of CD1-restricted T cells, and the pathways by which these cells both influence the inflammatory and tolerogenic effects of dendritic cells and activate natural killer cells and other lymphocytes, provide insight into how CD1-restricted T cells regulate antimicrobial responses, antitumor immunity and the balance between tolerance and autoimmunity.

Crit Care Med, 2003 May, 31(5), 1347 - 52
Bioavailability of gatifloxacin by gastric tube administration with and without concomitant enteral feeding in critically ill patients; Kanji S et al.; OBJECTIVE: Sequential intravenous-to-oral antimicrobial therapy with highly bioavailable antiinfective agents such as the fluoroquinolones may improve patient safety and decrease cost of infection management . However, physiologic changes associated with critical illness may alter drug absorption, distribution, and clearance, and concomitant enteral feeding may decrease fluoroquinolone bioavailability . We evaluated the effect of critical illness and concomitant gastric tube feeding on gatifloxacin bioavailability . DESIGN: Prospective, randomized, single-dose, two-way crossover, pharmacokinetic study.SETTINGA tertiary, level-one, trauma center . PATIENTS: Sixteen critically ill patients (baseline Acute Physiology and Chronic Health Evaluation II score >or=16) tolerating enteral nutrition administered by gastric tube (NG) for >or=12 hrs were randomized to receive gatifloxacin concurrently with continuous tube feeding or with interrupted tube feeds . Patients with renal insufficiency or those receiving concomitant fluoroquinolone therapy or postpyloric feeding were excluded . Patients received gatifloxacin 400 mg either by the intravenous or NG route followed by the alternative dosage form after a 72-hr washout period . MEASUREMENTS AND MAIN RESULTS: Serial serum gatifloxacin concentrations (from 5 mins to 24 hrs) were analyzed using a validated high-performance liquid chromatography method . Bioavailability was determined as the ratio of NG/intravenous area under the concentration-time curve (AUC infinity ) measured by the trapezoidal method . Although there was no difference in the bioavailability between NG (AUC infinity : 38.0 {range 20.1 to 48.5} microg x h/mL) and intravenous (AUC infinity : 39.5 {range 24.1 to 63.1} microg x h/mL, p =.60) gatifloxacin (bioavailability: 98.5% {range 61.1% to 119.7%}), a wide variability was observed in three of eight patients (>30% reduction in bioavailability) . Concomitant gastric tube feeding did not affect gatifloxacin bioavailability (interrupted tube feeds: 98.5% {range 61.1% to 119.7%}; continuous tube feeding: 109.0% {range 86.2% to 142.1%}; p =.42) . Neither a period nor differential carryover effect was observed . CONCLUSIONS: Although concomitant tube feeding did not affect gatifloxacin bioavailability, critical illness resulted in significant variability that may complicate the role of gatifloxacin in sequential intravenous-to-oral therapy . More research is needed to identify those patients in whom gatifloxacin bioavailability is reduced and for whom an empirical increase in gatifloxacin dose should be considered.

Biophys J, 2003 Jun, 84(6), 3751 - 8
Evidence for membrane thinning effect as the mechanism for peptide-induced pore formation; Chen FY et al.; Antimicrobial peptides have two binding states in a lipid bilayer, a surface state S and a pore-forming state I . The transition from the S state to the I state has a sigmoidal peptide-concentration dependence indicating cooperativity in the peptide-membrane interactions . In a previous paper, we reported the transition of alamethicin measured in three bilayer conditions . The data were explained by a free energy that took into account the membrane thinning effect induced by the peptides . In this paper, the full implications of the free energy were tested by including another type of peptide, melittin, that forms toroidal pores, instead of barrel-stave pores as in the case of alamethicin . The S-to-I transitions were measured by oriented circular dichroism . The membrane thinning effect was measured by x-ray diffraction . All data were in good agreement with the theory, indicating that the membrane thinning effect is a plausible mechanism for the peptide-induced pore formations.

J Insect Physiol, 1999 Jul, 45(7), 667 - 675
In vitro superoxide activity in the haemolymph of the West Indian leaf cockroach, Blaberus discoidalis; Whitten MM et al.; The respiratory burst is an NADPH oxidase-driven reduction of molecular oxygen to superoxide, which can occur in phagocytic cells as part of an antimicrobial defence, and is well documented among the vertebrates . This paper describes a process resembling the respiratory burst, which occurs in the haemolymph and haemocytes of the cockroach, Blaberus discoidalis . The in vitro reduction of nitroblue tetrazolium by superoxide to formazan was measured spectrophotometrically in B . discoidalis haemolymph in response to various immune elicitors . Nitroblue tetrazolium reduction was partly impeded in the presence of superoxide dismutase, a specific antioxidant which converts superoxide to hydrogen peroxide, as well as by chemicals known to inhibit the respiratory burst in vertebrates (trifluoperazine, diphenylene iodonium, and N-ethylmaleimide) . This suggests the generation of superoxide anions by haemolymph as part of an immune response . Furthermore, formazan staining of elicitor-treated haemocytes was observed microscopically, with less intense staining in the presence of superoxide dismutase . Finally, respiratory burst inhibitors and superoxide dismutase enhanced the growth of E . coli incubated in whole haemolymph, implying a role for haemolymph-derived superoxide in antibacterial defence.

J Insect Physiol, 2000 Apr, 46(4), 429 - 437
The immune response of the desert locust Schistocerca gregaria during mycosis of the entomopathogenic fungus, Metarhizium anisopliae var acridum; Gillespie JP et al.; Topical application of Metarhizium anisopliae var acridum to the desert locust Schistocerca gregaria resulted in changes in the biochemistry and antimicrobial defenses of the haemolymph . M . anisopliae var acridum colonized the host haemolymph from day two post application . The haemocytes did not attach to, phagocytose or nodulate elements of the fungus . However, the presence of the fungus appeared to stimulate hemocyte aggregation over the first few days of mycosis though the number of aggregates declined subsequently . The total hemocyte count increased two days after application, indicating an overall stimulation of the immune system, but declined to a value below that for uninoculated controls by day four . The differential haemocyte count showed that the initial increase in total haemocyte count was primarily due to a larger number of coagulocytes . After day two consistent declines in cell number were observed for all haemocyte classes in mycosed insects . The activity of the enzyme, phenoloxidase, decreased during the course of infection . However, the converse was true for prophenoloxidase . Lysozyme levels were significantly smaller in infected than control locusts . There was a significant correlation between lysozyme and PO activities when data from mycosed and control insects were combined . The total protein content of the haemolymph decreased during the course of infection.

J Insect Physiol, 2002 Mar, 48(3), 269 - 278
Hemolymph proteins in ticks; Gudderra NP et al.; In comparison to insects and Crustacea, our knowledge of the predominant hemolymph proteins in ticks is minimal . The hemolymph protein most studied in ticks has been vitellogenin (Vg) . Vg is synthesized by the tick fat body after female adults obtain a blood meal, is released into the hemolymph and is absorbed by developing oocytes as vitellin (Vn) . Much of what we know about Vg is from studies of Vn . In general, the carbohydrate, lipid and amino acid composition is similar to insects except that in the tick, Vg contains heme, most likely from the digestion of host hemoglobin . In the American dog tick, Dermacentor variabilis, Vg is comprised of two native proteins and seven subunits on SDS-PAGE . Vg has been characterized in five tick species but the amino acid sequence is not yet available . Another predominant hemolymph protein, apparently a carrier protein (CP), has recently been studied in two tick species . This protein is found in the hemolymph of both male and females adults, in adult tissues outside of the hemolymph in some tick species, in coxal fluid of soft ticks and in whole body homogenates from eggs, larvae and nymphs . CP from the hard tick, D . variabilis, contains cholesterol, phospholipids, monoacylglycerides, triacylglycerides, free fatty acids, carbohydrate and heme . Under identical assay conditions, the analogous protein in the soft tick, Ornithodoros parkeri, did not contain heme . CP in the American dog tick consists of two subunits, one of which has 61% identity to the biliprotein, artemocyanin, from the fairy shrimp . CP is identical to a heme-lipoprotein (HeLp) from Boophilus microplus . The exact roles of CP and HeLp have not yet been fully determined, but they apparently are important in heme sequestration and as a storage depot for protein and lipid . Macroglobulin, lectin, antimicrobial, JH binding, JH esterase, and other tick hemolymph proteins are also discussed.

Curr Drug Targets Immune Endocr Metabol Disord, 2003 Jun, 3(2), 143 - 9
Drug-induced aseptic meningitis; Nettis E et al.; Aseptic meningitis is a rare but well-recognized complication of drug therapy . The clinical presentation of drug-induced aseptic meningitis (DIAM) is distinct . Symptoms typically include fever, neck stiffness, headache, confusion, nausea and vomiting . The major categories of causative agents are non-steroidal anti-inflammatory drugs, antimicrobials and also intravenous immunoglobulins, monoclonal antibodies and vaccines . These drugs most commonly implicated as causes of aseptic meningitis act more likely through an immunological mechanisms . However, the exact pathogenetic mechanism of DIAM is still unknown . The diagnosis of drug-induced aseptic meningitis is difficult and infectious etiologies must be excluded . In some cases the diagnosis has been confirmed by rechallenging the patient with the suspected agent . In this case, informed written consent is necessary and rechallenge must be medically supervised both to document the response and to offer medical care and advice, if required . The outcome of DIAM is generally good, usually without long term sequelae.

Curr Pharm Des, 2003, 9(16), 1345 - 55
Biogenic peptides and their potential use; Yamamoto N et al.; This paper reviews bioactive peptides, biogenic peptides, opioid peptides, immunostimulating peptides, mineral soluble peptides, antihypertensive peptides and antimicrobial peptides originating from food materials and enzymatic hydrolysis of proteins . Antihypertensive peptides are extensively reviewed and have been divided into angiotensin I-converting enzyme inhibitory peptides and others . These peptides are produced in the enzymatic hydrolysate of treated food materials such as milk, animal and fish meat, maize, wheat, soybeans and egg, and also from microbe-fermented products . Peptides with strong antihypertensive effects on spontaneously hypertensive rats are discussed and are divided into high and low angiotensin I-converting enzyme inhibitory activities . In addition, new topics from our studies on antihypertensive peptides are introduced . Efficacies of these peptides in clinical studies and differences with medicinal substances are summarized . Recent studies in this area shown the possibility of using biogenic peptides for improvements in treatment or prevention of hypertension.

Curr Pharm Des, 2003, 9(16), 1277 - 87
Lactoferricin derived from milk protein lactoferrin; Wakabayashi H et al.; Lactoferricin (LFcin) was initially identified as an antimicrobial peptide derived by pepsin digestion of lactoferrin (LF), a multifunctional innate-defense protein in milk . Various synthetic analogs of LFcin have also been reported . LFcin inhibits a diverse range of microorganisms such as gram-negative bacteria, gram-positive bacteria, yeast, filamentous fungi, and parasitic protozoa, including some antibiotic-resistant pathogens . LFcin kills target organisms by membrane perturbation and acts synergistically with some antimicrobial agents . LFcin exhibits numerous biological activities in common with those of LF . Whereas LFcin suppresses the activation of innate immunity by microbial components such as lipopolysaccharide (LPS) and CpG DNA, the peptide itself activates immunity . Administration of LFcin analogs has been shown to protect the host via direct antimicrobial activity and immunostimulatory effects in several infection models of mice . Here we present a comprehensive review of investigations of LFcin and related peptides.

Curr Pharm Des, 2003, 9(16), 1239 - 55
Biodefense properties of milk: the role of antimicrobial proteins and peptides; Clare DA et al.; Mammary fluids, colostrum and milk, deliver nature's first host defense systems upon birth, and these essential liquids are critical for survival of the neonate . The identification and characterization of anti-infectious proteins were among the early scientific discoveries and this group of proteins has long been recognized for promoting health benefits in both newborns and adults . Among the more widely studied are the immunoglobulins, lactoperoxidase, lysozyme, and lactoferrin . Recently, it was shown that alpha--lactalbumin may also function in a protective capacity dependent upon its folding state . Some of these, especially lactoferrin, also display an immunomodulatory role in which case a totally separate cascade of host defense responses is initiated . It was noted that the mechanism of action for this cluster of sentry proteins does vary; thus, this protective strategy provides for a broad range of responsive reactions to infection . Presently, there is a major focus on the discovery of novel peptides that can be generated from existing milk proteins via proteolytic reactions . To date, this substrate list includes alpha--lactalbumin, beta-lactoglobulin, all casein fractions, and lactoferrin . Again, the immunoregulatory effects prompted as a result of the appearance of these peptides are currently being defined . Herein, we review the principal biological properties associated with each of these contributing milk components with a special emphasis on the role of biodefensive milk peptides . We envision future contributions emerging from this research field as an opportunity to develop effective new therapies to be used in treating infectious diseases and promoting health benefits in vivo.

Curr Pharm Des, 2003, 9(16), 1225 - 38
Antimicrobial peptides from food proteins; Pellegrini A; Antimicrobial peptides are present in men, animals and plants and represent an important component of the innate immunity . Nevertheless they can also be generated through proteolytical digestion of food proteins . Thus, food proteins can be regarded not only for their nutritive value but also as a possible resource to increase the natural defence of the organism against invading pathogens . Consequently food proteins can be considered as component of nutritional immunity . Antimicrobial peptides generated from food proteins present the great advantage to be derived from harmless substances, therefore one can expect their safety for use in medicine and in food industry . Many biologically active peptides have been produced from food proteins, in particularly from milk proteins . The possibility that proteins can be tailored and their fragments modelled to achieve a particular function is recently giving rise to increased interest . This strategy has had particular success with food proteins like lactoferrin and lysozyme . Both bactericidal domains of these proteins have been extensively investigated . A number of short peptides with high bactericidal activity have been developed from the bactericidal domain of lysozyme through the strategy "tailoring and modelling" . Ovotransferrin, alpha--lactalbumin and beta-lactoglobulin are further examples of food proteins which are a source of antimicrobial peptides . The observation that antimicrobial peptides can be generated through proteolytical digestion of parent proteins, which usually have another physiological function in the organism, led us to consider these latter as multifunctional molecules . This raises the question, whether multifunctionality is an intrinsic property of many proteins or limited to a few.

Curr Pharm Des, 2003, 9(18), 1463 - 73
Minidefensins: antimicrobial peptides with activity against HIV-1; Cole AM et al.; Over 80 different alpha-defensin or beta-defensin peptides are expressed by the leukocytes and epithelial cells of birds and mammals . Although their broad spectrum antimicrobial properties makes them candidates for therapeutic development, technical limitations related to their size (typically 30-45 residues) and complex structure have impeded such development . The minidefensins covered in this review are antimicrobial peptides with 16-18 residues, approximately half the number found in alpha-defensins . The theta-defensins are evolutionarily related toalpha- and beta-defensins, but other minidefensins probably arose independently . Like alpha- or beta-defensins, minidefensin molecules have a net positive charge and a largely beta-sheet structure that is stabilized by intramolecular disulfide bonds . Whereas alpha-defensins are found only in mammals and theta-defensins only in nonhuman primates, the other minidefensins come from widely divergent species, including horseshoe crabs, spiders, and pigs . Several alpha-defensins and minidefensins are effective inhibitors of HIV-1 infection in vitro, and recent evidence implicates alpha-defensins in resistance to HIV-1 progression in vivo . This review compares defensins and minidefensins with respect to their activity against HIV-1 . It pays special attention to retrocyclins - the ancestral theta-defensins of humans, and their extant counterparts in rhesus monkeys . In addition to describing critical elements of their structure and unusual mode of formation, we will venture some predictions about using theta-defensins as antiviral agents.

Curr Drug Metab, 2003 Jun, 4(3), 241 - 8
Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes; Ow YY et al.; Gallic acid and its structurally related compounds are found widely distributed in fruits and plants . Gallic acid, and its catechin derivatives are also present as one of the main phenolic components of both black and green tea . Esters of gallic acid have a diverse range of industrial uses, as antioxidants in food, in cosmetics and in the pharmaceutical industry . In addition, gallic acid is employed as a source material for inks, paints and colour developers . Studies utilising these compounds have found them to possess many potential therapeutic properties including anti-cancer and antimicrobial properties . In this review, studies of the effects of gallic acid, its esters, and gallic acid catechin derivatives on Phase I and Phase II enzymes are examined . Many published reports of the effects of the in vitro effects of gallic acid and its derivatives on drug metabolising enzymes concern effects directly on substrate (generally drug or mutagen) metabolism or indirectly through observed effects in Ames tests . In the case of the Ames test an antimutagenic effect may be observed through inhibition of CYP activation of indirectly acting mutagens and/or by scavenging of metabolically generated mutagenic electrophiles . There has been considerable interest in the in vivo effects of the gallate esters because of their incorporation into foodstuffs as antioxidants and in the catechin gallates with their potential role as chemoprotective agents . Principally an induction of Phase II enzymes has been observed however more recent studies using HepG2 cells and primary cultures of human hepatocytes provide evidence for the overall complexity of actions of individual components versus complex mixtures, such as those in food . Further systematic studies of mechanisms of induction and inhibition of drug metabolising enzymes by this group of compounds are warranted in the light of their distribution and consequent ingestion, current uses and suggested therapeutic potential . However, it must be noted that numerous constituents of foodstuffs have been found to be potent modulators of xenobiotic metabolism and the net human health effects may depend on concentrations of individual components and individual genetic makeup.

Leuk Lymphoma, 2003 Apr, 44(4), 649 - 52
Vaccination against infections in chronic lymphocytic leukemia; Sinisalo M et al.; Chronic lymphocytic leukemia (CLL) is a well-defined mature B-cell neoplasm associated with increased susceptibility to infections . Two major options in prevention of infections in CLL, intravenous gammaglobulin treatment and antimicrobial chemoprophylaxis, have not resulted in satisfactory outcome . A third strategy, antimicrobial vaccination, is the topic of this minireview . We collected articles and their references concerning CLL vaccination from the Medline database starting from 1966 and thirteen relevant studies were found . Plain bacterial polysaccharide vaccines would seem to be ineffective in antibody formation in patients with CLL . However, protein and conjugate vaccines appear to be more immunogenic and their responses may be further enhanced with ranitidine adjuvant treatment . New well-designed investigations are needed to develop appropriate vaccination strategies and evaluate vaccination efficacy in infection morbidity and mortality in CLL.

An Med Interna, 2003 Apr, 20(4), 198 - 200
{Iliopsoas abscess and systemic lupus erythematosus}; Garcia Hernandez FJ et al.; Iliopsoas muscle abscess (IPA) is an uncommon condition, and it is usually associated with immunosuppression . Three out of a cohort of 552 patients diagnosed of systemic lupus erythematosus (SLE) developing an IPA, are reported herein . Patients showed fever and other symptoms related to SLE . They improved only partially under SLE therapy, and showed pain suggestive of IPA . It was confirmed by CT in all cases . S . aureus was isolated in one patient (primary IPA), and M . tuberculosis in the others . Specific antimicrobial therapy and surgical drainage were required . In summary, SLE might be considered as a risk condition for the development of IPA, due to the immunosuppression inherent in the disease and its treatment.

J Gastroenterol, 2003, 38(5), 436 - 41
Changing pattern of antimicrobial resistance of Helicobacter pylori in Korean patients with peptic ulcer diseases; Eun CS et al.; BACKGROUND: Antibiotic resistance of Helicobacter pylori is problematic because it reduces the efficacy of eradication therapy . It has been suggested that the incidence of resistance is rising . In Korea, information on the antimicrobial resistance of H . pylori is rare . The aim of this study was to assess the prevalence of H . pylori antibiotic resistance at a single center in Korea, and the changes in its antimicrobial resistance, and to detect the mutation foci of clarithromycin-resistant strains . METHODS: H . pylori isolates obtained from 224 patients with peptic ulcer disease in Korea between June 1996 and March 2000 were tested for antimicrobial resistance . The minimum inhibitory concentration (MIC) for metronidazole and clarithromycin was determined by the broth microdilution method . Isolates were considered resistant when the MIC was more than 8 microg/ml for metronidazole and more than 1 microg/ml for clarithromycin . To detect H . pylori 23S rRNA mutations, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed . Sequencing was performed on the two strands of the nonrestricted amplicons . RESULTS: Overall, resistance to metronidazole and clarithromycin was detected in 41.9% and 5.4% of patients, respectively . There was no significant difference in metronidazole and clarithromycin resistance according to age group and sex . Six strains were resistant to both metronidazole and clarithromycin . Six of nine clarithromycin-resistant isolates possessed the A2144G mutation in the gene encoding 23S rRNA . Sequencing of the three non-restricted clarithromycin-resistant strains revealed a T-to-C mutation at position 2182 . CONCLUSIONS: In Korea, there was no significant increase in the prevalence of metronidazole resistance, but clarithromycin-resistant H . pylori strains had increased relatively over the 5-year period . There was an increasing tendency for the emergence of strains with dual resistance to metronidazole and clarithromycin . Many of the clarithromycin-resistant strains possessed the A2144G mutation.

Anal Bioanal Chem, 2003 Jul, 376(5), 701 - 5 Epub 2003 May 24.
Determination of antifungal proteins in soil by liquid chromatography; Bolygo E et al.; A liquid chromatography method was developed for the determination of antifungal/antimicrobial proteins Rs-AFP1 and Dm-AMP1 in sandy loam soils . The extraction of these highly basic proteins was achieved by mechanical shaking with aqueous Tris buffer pH 9 containing guanidinium thiocyanate salt (4.1 M), EDTA and nonionic polyoxyethylene 20 cetyl ether, Brij-58 detergent . The extracts were cleaned up on Oasis HLB polymer solid-phase extraction cartridges and quantified by liquid chromatography fluorescence detection based on the fluorescence properties of the tryptophan content of these proteins . The detector response was linear for 0.3-10 microg mL(-1) . Procedural recoveries were tested in the range 10-100 mg kg(-1) . The limit of quantification was 10 mg kg(-1 )protein in the soil sample representing the lowest validated fortification level . The antifungal proteins were found to be stable in soil extract tested up to 9 days when stored at 4 degrees C.

Infez Med, 1998, 6(3), 129 - 138
{Surgical strategies in severe abdominal infections}; Marvaso A; Initial treatment of peritonitis is largely standardised (elimination source of infection, debridement and intraoperative lavage) but a major problem is the management policy of patients who are at high risk of further infective complications after the initial operation . Existing prognostic scores based on physiological variables, age and chronic disease (APACHE II), and scores that include intraoperative information about the infection (MPI) unfortunately do not seem to be useful in identifying these patients . Management of severe intra-abdominal infections is founded on three main principles: 1) supportive care of patient, 2 timely and appropriate antimicrobial therapy and 3) an operative treatment to aim at control the source of infection (evacuate pus, treat abdominal compartment syndrome) and prevent or treat persistant and recurrent infections . In the patients with severe intrabdominal infection there is a great variance in surgical strategies but four may be distingued: continous postoperative peritoneal lavage, relaparotomy on demand ("wait and see" policy), open drainage (laparostomy) and planned relaparotomy . The continous postoperative peritoneal lavage and relaparotomy on demand do not seem to prevent residual o recurrent intrabdominal infections and are associated with a high mortality . The planned relaparotomy seem to decrease the rate of residual peritoneal infection but has a high complication rate . It may be concluded that the ideal operative approach for patients with severe intra-abdominal infection has not been established yet . However, these techniques to be beneficial must be performed in well-selected patients and performed by a team of dedicated surgeons.

J Control Release, 2003 Jun 5, 90(1), 97 - 107
A general approach to describe the antimicrobial agent release from highly swellable films intended for food packaging applications; Buonocore GG et al.; A mathematical model able to describe the release kinetics of antimicrobial agents from crosslinked polyvinylalcohol (PVOH) into water is presented . The model was developed by taking into account the diffusion of water molecules into the polymeric film, the counter-diffusion of the incorporated antimicrobial agent from the film into water, and the polymeric matrix swelling kinetic . To validate the model the water sorption kinetics as well as the release kinetics of three antimicrobial agents (i.e., lysozyme, nisin and sodium benzoate, all approved to be used in contact with food) were determined at ambient temperature (25 degrees C) . The three investigated active agents were entrapped in four films of PVOH with a different degree of crosslink . The model was successfully used to fit all the above sets of data, corroborating the validity of the hypothesis made to derive it.

Eur J Med Chem, 2003 May, 38(5), 519 - 23
Preparation and antimicrobial behaviour of gemini fluorosurfactants; Massi L et al.; The introduction of perfluorinated chains in the molecular structure of quaternary ammonium gemini surfactants have led to particularly active antimicrobial agents evaluated in this work . Connectors and spacers were studied in relation with antimicrobial activity in order to determine which molecular parameters are "critical" for biological activity.

Biochemistry, 2003 Jun 3, 42(21), 6545 - 58
Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37; Henzler Wildman KA et al.; LL-37 is an amphipathic, alpha-helical, antimicrobial peptide . (15)N chemical shift and (15)N dipolar-shift spectroscopy of site-specifically labeled LL-37 in oriented lipid bilayers indicate that the amphipathic helix is oriented parallel to the surface of the bilayer . This surface orientation is maintained in both anionic and zwitterionic bilayers and at different temperatures and peptide concentrations, ruling out a barrel-stave mechanism for bilayer disruption by LL-37 . In contrast, electrostatic factors, the type of lipid, and the presence of cholesterol do affect the extent to which LL-37 perturbs the lipids in the bilayer as observed with (31)P NMR . The (31)P spectra also show that micelles or other small, rapidly tumbling membrane fragments are not formed in the presence of LL-37, excluding a detergent-like mechanism . LL-37 does increase the lamellar to inverted hexagonal phase transition temperature of both PE model lipid systems and Escherichia coli lipids, demonstrating that it induces positive curvature strain in these environments . These results support a toroidal pore mechanism of lipid bilayer disruption by LL-37.

Biopolymers, 2003, 71(2), 103 - 16
Successful identification of novel agents to control infectious diseases from screening mixture-based peptide combinatorial libraries in complex cell-based bioassays; Boggiano C et al.; Mixture-based peptide synthetic combinatorial libraries (SCLs) represent a valuable source for the development of novel agents to control infectious diseases . Indeed, a number of studies have now proven the ability of identifying active peptides from libraries composed of thousands to millions of peptides in cell-based biosystems of varying complexity . Furthermore, progressing knowledge on the importance of endogenous peptides in various immune responses lead to a regain in importance for peptides as potential therapeutic agents . This article is aimed at providing recent studies in our laboratory for the development of antimicrobial or antiviral peptides derived from mixture-based SCLs using cell-based assays, as well as a short review of the importance of such peptides in the control of infectious diseases . Furthermore, the use of positional scanning (PS) SCL-based biometrical analyses for the identification of native optimal epitopes specific to HIV-1 proteins is also presented .

Clin Infect Dis, 2003 Jun 1, 36(11), 1438 - 44 Epub 2003 May 20.
Routine cycling of antimicrobial agents as an infection-control measure; Fridkin SK; Antimicrobial cycling is the deliberate, scheduled removal and substitution of specific antimicrobials or classes of antimicrobials within an institutional environment (either hospital-wide or confined to specific units) to avoid or reverse the development of antimicrobial resistance . True antimicrobial cycling requires a return to the antimicrobial(s) that were first used . Testing of the hypothesis that cycling will result in a lower prevalence of resistance is ongoing, mostly occurs within intensive care units, and largely involves cycling regimens targeted for treatment of suspected gram-negative bacterial infections . Unfortunately, there has been insufficient study to determine whether any meaningful impact on resistance has occurred as a result of a cycling program . Mathematical models question the usefulness of cycling as an infection-control method . Published studies demonstrate that cycling may be one way to change prescribing practices by clinicians without sacrificing patient safety . However, optimizing antimicrobial use through traditional and novel methods (e.g., computer decision support) should not be abandoned.

Clin Infect Dis, 2003 Jun 1, 36(11), 1433 - 7 Epub 2003 May 16.
The impact of antimicrobial resistance on health and economic outcomes; Cosgrove SE et al.; Despite an increasing prevalence of antimicrobial-resistant pathogens, the health and economic impact of colonization and infection with these organisms has not been fully elucidated . We explore how antimicrobial resistance can affect patient outcomes by enhancing virulence, causing a delay in the administration of appropriate therapy, and limiting available therapy . Next, we examine the different perspectives held by hospitals, third-party payers, patients, and society on the impact of resistance . Finally, we review methodological issues in designing and assessing studies that address the clinical outcomes for patients infected or colonized with resistant pathogens, including adjustment for important confounding variables, control group selection, and the quantification of economic outcomes.

Minerva Anestesiol, 2003 Apr, 69(4), 302 - 7
{Infection prevention and control in intravascular devices}; Colombo D et al.; Intravascular devices (IVD) are indispensable in the care of the critical patient; even so, their use can be complicated by infection, which is generally associated with longer hospital stay and ensuing higher hospital costs . It is therefore imperative that guidelines are applied that constitute a basis of information upon which the individual facility can develop its own strategy . The strategy can be outlined under the following points: a) staff training, b) surveillance of IVD-associated infections, c) hand washing, d) barrier measures during catheter introduction and management, e) insertion site management and medication systems for the insertion site, f) choice and replacement of the IVD, g) replacement of intravenous administration devices and liquids, h) antimicrobial prophylaxis . In the management of central venous catheters (CVC), recommendations call for: 1) the use of a single lumen CVC, unless multiple accesses are needed; 2) the peripheral placement of CVCs, both in the use of tunneled catheters and/or implantable vascular devices in patients over 4 years of age in which long-term vascular access (> 30 days) is planned; 3) the use of completely implantable devices in pediatric patients less than 4 years of age requiring long-term vascular access; 4) the use of the subclavian artery as the site of CVC insertion unless clinically contraindicated (e.g . coagulopathy, anatomic alterations); 5) the application of barrier precautions during CVC introduction and in the management of the catheter and the insertion site.

Neth J Med, 2003 Mar, 61(3), 91 - 4
Severe diffuse interstitial pneumonia due to Mycoplasma pneumoniae in a patient with respiratory insufficiency; de Boer J et al.; We report a 25-year-old man presenting with high fever, dyspnoea and somnolence . The presence of severe diffuse interstitial pneumonia with extrapulmonary symptoms, such as myositis and subclinical haemolysis, strongly suggested an infection by Mycoplasma pneumoniae . This diagnosis was supported by high titres of cold agglutinins and a positive Coombs test, and directly confirmed by specific IgM serological tests . After initiation of the appropriate antimicrobial treatment mechanical ventilation could be avoided and the patient showed a slow but complete clinical recovery . This diagnosis should be considered in any febrile patient with hypoxaemia and diffuse interstitial pneumonia, and rapid initiation of appropriate antibiotic treatment seems to be crucial for a favourable outcome.

Wien Med Wochenschr, 2003, 153(7-8), 166 - 8
{New antimicrobial drugs: an update}; Burgmann H; Several procedures such as antimicrobial restriction, microbial monitoring, calculated antimicrobial treatment and the development of new antimicrobials are used to reduce the resistance . The following reviews deals with new substances such as carbapenems, quinolones, ketolides, oxazolidinones, glycylcyclines, echinocandines and azoles.

Zhonghua Er Bi Yan Hou Ke Za Zhi, 1999 Aug, 34(4), 221 - 3
{Protective effect of poly DL-aspartic acid on ototoxicity of gentamicin}; Guo Y et al.; OBJECTIVE: To observe the protective effect of poly DL-aspartic acid (PAA) on ototoxicity of gentamicin (GM) . METHODS: Fifty F-344 rats were divided into four groups, GM only PAA + GM, PAA only and saline control . ABR thresholds at different frequencies were measured at different times and hair cell losses were numerated . Two-dimensional diffusion assays in the culture medium were performed to evaluate the effect of PAA on the antimicrobial activity . RESULTS: Eighteen days after the treatment, ABR thresholds at 10 kHz and 8 kHz as well as hair cell losses in the GM-treated group showed significant differences as compared with other three groups (P < 0.01) . CONCLUSION: PAA had the protective effect against the cochlear ototoxicity of GM without decreasing its antimicrobial activity.

Drugs Today (Barc), 2001 Jun, 37(6), 377 - 383
Antimicrobial selection in the penicillin-allergic patient; Cunha BA; Patients frequently state that they have a penicillin allergy that often presents a therapeutic problem in treating a variety of infectious disorders . Penicillin and beta-lactam allergic reactions should be determined by a careful history . Many patients who say they have a penicillin allergy, in fact do not . If it is determined that the patient has a penicillin allergy, then the clinician should determine whether it is of an anaphylactic or nonanaphylactic variety . Most reactions to beta-lactams are of the nonanaphylactic variety and are usually manifested clinically as a mild maculopapular rash or drug fever . Uncommonly, penicillin allergies are clinically manifested as anaphylactic reactions, e.g., bronchospasm, laryngospasm, hypotension or hives . Patients' hypersensitivity reactions tend to be stereotyped on rechallenge, which make the reactions predictable . Patients who have a questionable penicillin allergy, or have had only fever or rash, may be safely given beta-lactam antibiotics without fear of anaphylaxis . Patients with a documented history of anaphylactic reactions should receive non-beta-lactam antibiotics . Although monobactams and carbapenems are structurally related to beta-lactams, they are unrelated in terms of allergic potential . There is no cross-reactivity between mono-bactams or carbapenems with beta-lactams, and these drugs may be used safely in patients with anaphylactic reactions to beta-lactams . Because so many antibiotics are available that are allergically unrelated to beta-lactams, beta-lactam desensitization procedures are rarely necessary . (c) 2001 Prous Science . All rights reserved.

Crit Rev Oral Biol Med, 2003, 14(2), 128 - 37
Yeasts in apical periodontitis; Waltimo TM et al.; Microbiological reports of apical periodontitis have revealed that yeasts can be isolated from approximately 5-20% of infected root canals . They occur either in pure cultures or together with bacteria . Almost all isolated yeasts belong to the genus Candida, and the predominant species is C . albicans . Pheno- and genotypic profiles of C . albicans isolates show heterogeneity comparable with those of isolates from other oral sites . C . albicans expresses several virulence factors that are capable of infecting the dentin-pulp complex, including dentinal tubules . This causes, consequentially, an inflammatory response around the root apex, which suggests a pathogenic role for this organism in apical periodontitis . Yeasts are particularly associated with persistent root canal infections that do not respond favorably to conservative root canal therapy . This may be due to the resistance of all oral Candida species against a commonly used topical medicament, calcium hydroxide . However, other antimicrobial agents may offer alternative therapeutic approaches and improve the treatment of these persistent cases of apical periodontitis.

J Inorg Biochem, 2003 Jun 1, 95(2-3), 208 - 20
Ligand-exchangeability of 2-coordinate phosphinegold(I) complexes with AuSP and AuNP cores showing selective antimicrobial activities against Gram-positive bacteria . Crystal structures of {Au(2-Hmpa)(PPh(3))} and {Au(6-Hmna)(PPh(3))} (2-H(2)mpa=2-mercaptopropionic acid, 6-H(2)mna=6-mercaptonicotinic acid); Nomiya K et al.; Selective and effective antimicrobial activities against Gram-positive bacteria (B . subtilis and/or S . aureus) were found in 2-coordinate gold(I)-PPh(3) complexes with AuSP and AuNP cores, i.e . {Au(L)(PPh(3))} (HL=2-H(2)mna {H(2)mna=mercaptonicotinic acid} 3, D-H(2)pen {H(2)pen=penicillamine} 4, D,L-H(2)pen 5, 4-H(2)mba {H(2)mba=mercaptobenzoic acid} 8, Hpz {Hpz=pyrazole} 9, Him {Him=imidazole} 10, 1,2,3-Htriz {Htriz=triazole} 11, 1,2,4-Htriz 12, Htetz {Htetz=tetrazole} 13), whereas no activity was observed in 2-coordinate AuSP core complexes {Au(2-Hmba)(PPh(3))} 6 and {Au(3-Hmba)(PPh(3))} 7 . The two novel AuSP core complexes, {Au(2-Hmpa)(PPh(3))} {H(2)mpa=mercaptopropionic acid} 1 and {Au(6-Hmna)(PPh(3))} 2, were prepared and characterized by elemental analysis, FT-IR, TG/DTA, and ((31)P, 1H and 13C) NMR spectroscopy . The crystal structures of 1 and 2 were determined as a supramolecular arrangement of the 2-coordinate AuSP core . Both 1 and 2 significantly showed antibacterial activities . As a model reaction of phosphinegold (I) complexes with the cysteine residue in the biological ligands, we examined if the ligand exchange reactions of the aromatic anions L(1)(-) in {Au(L(1))(PPh(3))} (HL(1)=6-H(2)mna 2, 2-H(2)mna 3, 2-H(2)mba 6, Hpz 9, Him 10, 1,2,3-Htriz 11, 1,2,4-Htriz 12) with aliphatic thiols HL(2) (HL(2)=2-H(2)mpa, D-H(2)pen) occurred under the mild conditions and, also, if the 'reverse' reactions, namely, the ligand exchange reactions of the thiolate anions in {Au(2-Hmpa)(PPh(3))} 1, {Au(D-Hpen)(PPh(3))} 4 and {Au(2-Hmba)(PPh(3))} 6 with the free ligands HL(1) took place under similar conditions . In this work, a relationship of the ligand-exchangeability among 2-coordinate gold(I) complexes (1-4, 6, 9-12) was revealed . Complex 6 was substitution-inert, whereas complexes 1-4 and 9-12 were substitution-labile . The ligand-exchangeability of Au-S and Au-N bonds in the 2-coordinate phosphinegold(I) complexes with AuSP and AuNP cores to form new AuSP cores, with retention of the Au-P bond, was closely related to the observed activities against Gram-positive bacteria, and the ease of the ligand-exchange reaction was strongly related to the intensity of the activities.

Am J Clin Dermatol, 2003, 4(6), 389 - 97
A guide to selection and appropriate use of macrolides in skin infections; Parsad D et al.; Dermatologists must be aware of the adverse effects of antimicrobial agents as well as various drug interactions that may influence the choice of drug as well as specific drug schedules . The development of modern antibacterials has improved the treatment of cutaneous bacterial infections . Macrolide antibacterials continue to be an important therapeutic class of drugs with established efficacy in a variety of skin infections . All macrolides inhibit protein synthesis by reversibly binding to the 23S ribosomal RNA in the 50S-subunit . Erythromycin, the prototype of macrolide antibacterials, was isolated from the metabolic products of a strain of Streptomyces erytherus in 1952 . Originally, erythromycin was introduced as an alternative to penicillin because of its activity against the Gram-positive organisms . Numerous studies have demonstrated the efficacy and safety of erythromycin for various infectious diseases . Unfortunately, erythromycin is associated with a number of drawbacks including a narrow spectrum of activity, unfavorable pharmacokinetic properties, poor gastrointestinal tolerability, and a significant number of drug-drug interactions . Newer macrolides have been developed to address these limitations . The pharmacokinetics of azithromycin and clarithromycin allow for shorter dosing schedules because of prolonged tissue levels . The efficacy of azithromycin for the treatment of skin and soft tissue infections in adults and children is well established . The unique pharmakinetics of azithromycin makes it a suitable agent for the treatment of acne . Clarithromycin represents a clear advance in the macrolide management of patients with leprosy and skin infections with atypical mycobacteria . Dirithromycin and roxithromycin display no clinical or bacteriological adcantage over erythromycin despite a superior pharmacokinetic profile . An area of concern is the increasing macrolide resistance that is being reported with some of the common pathogens which may limit the clinical usefulness of this class of antimicrobial agents in future.

Arch Pharm (Weinheim), 2003 Apr, 336(2), 111 - 8
Design and synthesis of some substituted 1H-pyrazolyl-oxazolidines or 1H-pyrazolyl-thiazolidines as anti-inflammatory-antimicrobial agents; Bekhit AA et al.; Four series of 1 H-pyrazole derivatives have been synthesized . The first series was synthesized starting with the reaction of 3-(5-bromo-2-thienyl)-1-phenyl-1 H-pyrazole-4-carboxaldehyde 1 with L-serine, L-cysteine, or L-penicillamine, followed by N-protection using (Boc)(2)O to provide compounds 2 . The latter compounds could be N-deprotected by 4N HCl/dioxane to afford the second series 3 or reacted with NH(4)OH in the presence of DCC/HOBt to give the corresponding amides 4 followed by N-deprotection giving rise to compounds 5 . The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities . In addition, the ulcerogenic and acute toxicity profiles were determined . Compound 5b (2RS, 4R)-2-{3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazol-4-yl}-5-methylthiazolidine-4-carboxamide, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.

Genes Immun, 2003 Jun, 4(4), 251 - 7
Evolution of the beta defensin 2 gene in primates; Boniotto M et al.; With the aim of further investigating the molecular evolution of beta defensin genes, after having analysed beta defensin 1 (DEFB1) in humans and several nonhuman primate species, we have studied the evolution of the beta defensin 2 gene (DEFB2), which codifies for a peptide with antimicrobial and chemoattractant activity, in humans and 16 primate species . We have found evidence of positive selection during the evolution of orthologous DEFB2 genes at two points on a phylogenetic tree relating these primates: during the divergence of the platyrrhines from the catarrhines and during the divergence of the Cercopithecidae from the Hylobatidae, Great Apes and humans . Furthermore, amino acid variations in Old World Monkeys seem to centre either on residues that are involved in oligomerisation in the human molecule, or that are conserved (40-80%) in beta-defensins in general . It is thus likely that these variations affect the biological function of the molecules and suggest that their synthesis and functional analysis might reveal interesting new information as to their role in innate immunity.

Infect Immun, 2003 Jun, 71(6), 3540 - 50
Drosophila melanogaster is a genetically tractable model host for Mycobacterium marinum; Dionne MS et al.; Mycobacterium marinum is a pathogenic mycobacterial species that is closely related to Mycobacterium tuberculosis and causes tuberculosis-like disease in fish and frogs . We infected the fruit fly Drosophila melanogaster with M . marinum . This bacterium caused a lethal infection in the fly, with a 50% lethal dose (LD(50)) of 5 CFU . Death was accompanied by widespread tissue damage . M . marinum initially proliferated inside the phagocytes of the fly; later in infection, bacteria were found both inside and outside host cells . Intracellular M . marinum blocked vacuolar acidification and failed to colocalize with dead Escherichia coli, similar to infections of mouse macrophages . M . marinum lacking the mag24 gene were less virulent, as determined both by LD(50) and by death kinetics . Finally, in contrast to all other bacteria examined, mycobacteria failed to elicit the production of antimicrobial peptides in DROSOPHILA: We believe that this system should be a useful genetically tractable model for mycobacterial infection.

Antimicrob Agents Chemother, 2003 Jun, 47(6), 1988 - 90
Eradication of resident bacteria of normal human skin by antimicrobial ointment; Hendley JO et al.; The application of a topical triple-antibiotic ointment (containing neomycin, polymyxin, and bacitracin) eradicated resident bacteria through 25 layers of the stratum corneum and prevented repopulation of bacteria overnight but not at 1 week . Through 15 layers, mupirocin had some effect, whereas a double-antibiotic ointment had none . The reservoir of resident bacteria in the sebaceous glands is not affected by a topical antibiotic.

Antimicrob Agents Chemother, 2003 Jun, 47(6), 1958 - 62
High prevalence of antimicrobial resistance in rapidly growing mycobacteria in Taiwan; Yang SC et al.; An increasing number of clinical isolations of rapidly growing mycobacteria (RGM) at the National Taiwan University Hospital were noted from 1992 to 2001 . Broth microdilution MICs of 15 antimicrobial agents were determined for 200 clinical isolates of RGM, including the Mycobacterium fortuitum group (69 isolates), M . chelonae (39 isolates), and M . abscessus (92 isolates) . Our results showed that the resistance rates of these isolates to the currently available agents were remarkably high . Amikacin was active against nearly all RGM isolates . Clarithromycin was usually active against M . abscessus (79% susceptibility) and the M . fortuitum group (65% susceptibility) . The majority of M . fortuitum group isolates were susceptible to ciprofloxacin (62%) and imipenem (61%) . The susceptibilities to other conventional anti-RGM agents of these isolates were poor but differed markedly by species . The newer fluoroquinolones (levofloxacin, moxifloxacin, and gatifloxacin) and meropenem showed better in vitro activities against the M . fortuitum group isolates than against the other two species of RGM . Linezolid had fairly good activity against these RGM isolates, particularly against M . chelonae isolates (82% susceptible) . Telithromycin had poor activity against these RGM isolates (the MICs at which 50% of the isolates tested are inhibited {MIC(50)s} were 32 to 64 microg/ml, and the MIC(90)s were >64 microg/ml).

Antimicrob Agents Chemother, 2003 Jun, 47(6), 1952 - 7
Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of norfloxacin in rats; Chenel M et al.; A previously developed pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of norfloxacin as a representative antibiotic with concentration-dependent antimicrobial activity . Rats received an intravenous infusion of norfloxacin at a rate of 5 mg kg of body weight(-1) min(-1) over 30 min . Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion . An important delay was observed between concentrations of norfloxacin in plasma and the EEG effect . Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site, as previously observed with imipenem . The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 120 and 240 min . Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied . In conclusion, the successful PK-PD modeling of the norfloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone (E . Fuseau and L . B . Sheiner, Clin . Pharmacol . Ther . 35:733-741, 1984).

Antimicrob Agents Chemother, 2003 Jun, 47(6), 1832 - 5
Antimicrobial resistance of invasive pneumococci in Finland in 1999-2000; Pihlajamaki M et al.; The resistance patterns and macrolide resistance mechanisms of 910 Finnish invasive pneumococci isolated during 1999 and 2000 were studied . Macrolide resistance was detected in 6.9% of isolates . Penicillin resistance was detected in 1.5% of isolates, and penicillin intermediate resistance was detected in 4.0% of isolates . Active macrolide efflux, mediated by the mef(A) gene, was the most common macrolide resistance mechanism . Four macrolide-resistant isolates had mutations in rRNA or ribosomal protein L22.

J Antibiot (Tokyo), 2003 Mar, 56(3), 253 - 8
Studies on novel bacterial translocase I inhibitors, A-500359s . II . Biological activities of A-500359 A, C, D and G; Muramatsu Y et al.; A-500359 A, C, D, G and capuramycin inhibited bacterial phospho-N-acetylmuramyl-pentapeptide-translocase (translocase I: EC 2.7.8.13) with IC50 values of 0.017, 0.12, 0.53, 0.14 and 0.018 microM, respectively . Consistently, A-500359 A, C and capuramycin inhibited in vitro peptidoglycan biosynthesis . A-500359 A exhibited reversible inhibition, which was mixed type and noncompetitive with respect to UDP-MurNAc-(N(epsilon)-Dns)pentapeptide (Ki=0.0079 microM) and undecaprenyl-phosphate, respectively . A-500359 A, C, D and G showed antimicrobial activity against Mycobacterium smegmatis . As a single intravenous injection of A-500359 A at a dose of 500 mg/kg showed no toxicity in mice, it was suggested that the capuramycin derivatives might become candidates as novel therapeutic agents for various diseases caused by Mycobacteria including tuberculosis.

J Immunol, 2003 Jun 1, 170(11), 5583 - 9
Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors; Sorensen OE et al.; In addition to acting as a physical barrier against microorganisms, the skin produces antimicrobial peptides and proteins . After wounding, growth factors are produced to stimulate the regeneration of tissue . The growth factor response ceases after regeneration of the tissue, when the physical barrier protecting against microbial infections is re-established . We found that the growth factors important in wound healing, insulin-like growth factor I and TGF-alpha, induce the expression of the antimicrobial peptides/polypeptides human cationic antimicrobial protein hCAP-18/LL-37, human beta-defensin 3, neutrophil gelatinase-associated lipocalin, and secretory leukocyte protease inhibitor in human keratinocytes . Both an individual and a synergistic effect of these growth factors were observed . These findings offer an explanation for the expression of these peptides/polypeptides in the skin disease psoriasis and in wound healing and define a host defense role for growth factors in wound healing.

J Biol Chem, 2003 Aug 1, 278(31), 28540 - 6 Epub 2003 May 20.
Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin: a novel mechanism of generating antimicrobial peptides in vagina; Sorensen OE et al.; The human cathelicidin, hCAP-18, is expressed both in neutrophils and in epithelial cells . hCAP-18 is processed to the antimicrobial peptide LL-37 by proteinase 3 in neutrophils . hCAP-18 is highly expressed in the epididymis with a subsequent high concentration in seminal plasma where the protein is present in its unprocessed and antimicrobially inactive form . We report here that hCAP-18 in seminal plasma is processed to generate a 38-amino acid antimicrobial peptide ALL-38 by the prostate-derived protease gastricsin when incubated at a pH corresponding to the vaginal pH . In accordance with this, seminal plasma derived hCAP-18 was found in its processed form in the vagina following sexual intercourse . The antimicrobial activity of ALL-38 against a variety of microorganisms tested is equal to that of LL-37 . This enzymatic activation of a proantimicrobial substance in seminal plasma following exposure to the vaginal milieu represents a novel mechanism to prevent infection following sexual intercourse.

Proc Natl Acad Sci U S A, 2003 Jun 10, 100(12), 6916 - 21 Epub 2003 May 19.
Seaweed resistance to microbial attack: a targeted chemical defense against marine fungi; Kubanek J et al.; Pathogenic microbes can devastate populations of marine plants and animals . Yet, many sessile organisms such as seaweeds and sponges suffer remarkably low levels of microbial infection, despite lacking cell-based immune systems . Antimicrobial defenses of marine organisms are largely uncharacterized, although from a small number of studies it appears that chemical defenses may improve host resistance . In this study, we asked whether the common seaweed Lobophora variegata is chemically defended against potentially deleterious microorganisms . Using bioassay-guided fractionation, we isolated and characterized a 22-membered cyclic lactone, lobophorolide (1), of presumed polyketide origin, with sub-microM activity against pathogenic and saprophytic marine fungi . Deterrent concentrations of 1 were found in 46 of 51 samples collected from 10 locations in the Bahamas over a 4-year period . Lobophorolide (1) is structurally unprecedented, yet parts of the molecule are related to tolytoxin, the scytophycins, and the swinholides, macrolides previously isolated from terrestrial cyanobacteria and from marine sponges and gastropods . Until now, compounds of this structural class have not been associated with marine macrophytes . Our findings suggest that seaweeds use targeted antimicrobial chemical defense strategies and that secondary metabolites important in the ecological interactions between marine macroorganisms and microorganisms could be a promising source of novel bioactive compounds.

Am J Vet Res, 2003 May, 64(5), 627 - 34
Activities of gastric, pancreatic, and intestinal brush-border membrane enzymes during postnatal development of dogs; Buddington RK et al.; OBJECTIVE: To measure activities of digestive enzymes during postnatal development in dogs . SAMPLE POPULATION: Gastrointestinal tract tissues obtained from 110 Beagles ranging from neonatal to adult dogs . PROCEDURE: Pepsin and lipase activities were measured in gastric contents, and amylase, lipase, trypsin, and chymotrypsin activities were measured in small intestinal contents and pancreatic tissue . Activities of lactase, sucrase, 4 peptidases, and enteropeptidase were assayed in samples of mucosa obtained from 3 regions of the small intestine . RESULTS: Gastric pH was low at all ages . Pepsin was not detected until day 21, and activity increased between day 63 and adulthood . Activities of amylase and lipase in contents of the small intestine and pancreatic tissue were lower during suckling than after weaning . Activities of trypsin and chymotrypsin did not vary among ages for luminal contents, whereas activities associated with pancreatic tissue decreased between birth and adulthood for trypsin but increased for chymotrypsin . Lactase and gamma-glutamyltranspeptidase activities were highest at birth, whereas the activities of sucrase and the 4 peptidases increased after birth . Enteropeptidase was detected only in the proximal region of the small intestine at all ages . CONCLUSIONS AND CLINICAL RELEVANCE: Secretions in the gastrointestinal tract proximal to the duodenum, enzymes in milk, and other digestive mechanisms compensate for low luminal activities of pancreatic enzymes during the perinatal period . Postnatal changes in digestive secretions influence nutrient availability, concentrations of signaling molecules, and activity of antimicrobial compounds that inhibit pathogens . Matching sources of nutrients to digestive abilities will improve the health of dogs during development.

J Neurol Neurosurg Psychiatry, 2003 Jun, 74(6), 728 - 33
Aetiological diagnosis of brain abscesses and spinal infections: application of broad range bacterial polymerase chain reaction analysis; Kupila L et al.; OBJECTIVE: To evaluate the usefulness of the broad range bacterial rDNA polymerase chain reaction (PCR) method combined with DNA sequencing in the aetiological diagnosis of intracranial or spinal infections in neurosurgical patients . METHODS: In addition to conventional methods, the broad range bacterial PCR approach was applied to examine pus or tissue specimens from cerebral or spinal lesions in patients treated in a neurosurgical unit for a clinical or neuroradiological suspicion of bacterial brain abscess or spondylitis . RESULTS: Among the 44 patients with intracranial or spinal lesions, the final diagnosis suggested bacterial disease in 25 patients, among whom the aetiological agent was identified in 17 . A causative bacterial species was identified only by the rDNA PCR method in six cases, by both the PCR methodology and bacterial culture in six cases, and by bacterial culture alone in five . All samples in which a bacterial aetiology was identified only by the PCR approach were taken during antimicrobial treatment, and in three patients the method yielded the diagnosis even after >/= 12 days of parenteral treatment . One case also identified by the PCR approach alone involved a brain abscess caused by Mycoplasma hominis, which is not readily cultured by routine methods . CONCLUSIONS: In patients with brain abscesses and spinal infections, the broad range bacterial rDNA PCR approach may be the only method to provide an aetiological diagnosis when the patient is receiving antimicrobial treatment, or when the causative agent is fastidious.

Reprod Domest Anim, 2003 Jun, 38(3), 187 - 92
The effects of the periodical use of in-feed chlortetracycline on the reproductive performance of gilts and sows of a commercial pig farm with a history of clinical and subclinical viral and bacterial infections; Alexopoulos C et al.; The objective of this study was to assess the effects of in-feed chlortetracycline (CTC) as a measure of preventing or minimizing infectious problems of reproductive failure in gilts and sows . In a farm of 400 Large White x Landrace gilts and sows with a clinical history of porcine respiratory and reproductive syndrome (PRRS) virus, the animals were treated with CTC . Treatment consisted of 10 g CTC sow/day for 15 days every 3 months . It improved the health status of sows by decreasing post-farrowing clinical mastitis and vaginal discharges, abortions, return-to-oestrus and irregular return-to-oestrus rates . These beneficial effects had a positive impact on the performance of the litter . More piglets were born live and weaned . These positive effects improved with repeated use of CTC . The serological evidence of PRRS virus, Leptospira spp . and Chlamydia spp . and the subsequent beneficial use of the antimicrobial agent indicate that reproductive failure, possibly resulting from the bacterial agents can be controlled with in-feed use of broad spectrum antimicrobials.

J Pept Res, 2003 Jun, 61(6), 298 - 306
Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach; de Visser PC et al.; As part of a program towards the development of novel antibiotics, a convenient method for solid-phase synthesis of the cyclic cationic peptide polymyxin B1 and analogues thereof is described . The methodology, based on cleavage-by-cyclization using Kenner's safety-catch linker, yields crude products with purities ranging from 37-67% . Antibacterial assays revealed that analogues 23-26, in which the (S)-6-methyloctanoic acid moiety is replaced with shorter acyl chains, exhibit distinct antimicrobial activity . The results suggest that the length of the acyl chain is rather critical for antimicrobial activity . On the other hand, substitution of the hydrophobic ring-segment D-Phe-6/Leu-7 in polymyxin B1 with dipeptide mimics (i.e . analogues 27-33) resulted in almost complete loss of antimicrobial activity.

J Periodontal Res, 2003 Jun, 38(3), 311 - 7
Povidone-iodine as a periodontal pocket disinfectant; Hoang T et al.; OBJECTIVES AND BACKGROUND: Povidone-iodine {polyvinylpyrrolidone-iodine complex (PVP-iodine)} might constitute a valuable adjunct to current periodontal therapy because of its broad-spectrum antimicrobial activity, low potential for developing resistance and adverse reactions, wide availability, ease of use, and low financial cost . This investigation employed a randomized, split-mouth study design to determine the microbiological and clinical effects of 10% PVP-iodine subgingival irrigation in periodontitis lesions showing radiographic evidence of subgingival calculus . METHODS: Sixteen adults having at least one periodontal pocket of 6 mm or more in each quadrant of the dentition and harboring one or more periodontopathic bacteria participated in the study . In each subject, a study site in each quadrant was randomly chosen to receive either subgingival irrigation with 10% PVP-iodine together with scaling and root planing, scaling and root planing alone, subgingival irrigation with 10% PVP-iodine, or subgingival irrigation with sterile saline . Prior to therapy and at 5 weeks post-treatment, microbiological culture was carried out without knowledge of the clinical status or the type of treatment rendered . A blinded clinical examiner determined presence of dental plaque, probing pocket depth, and gingival bleeding on probing . Microbiological and clinical data were analyzed using a repeated measures analysis of variance and Kruskal-Wallis rank test with the Tukey and Mann-Whitney post hoc tests . RESULTS: At 5 weeks post-treatment, subgingival irrigation with PVP-iodine together with scaling and root planing caused a 95% or greater reduction in total pathogen counts in 44% of pockets having >/= 6 mm depth whereas scaling and root planing alone, povidone-iodine irrigation alone and water irrigation alone caused 95% reduction of total pathogens only in 6-13% of similar study sites (P = 0.02) . Reduction in mean pocket depth was 1.8 mm for the PVP-iodine/scaling and root planing group, 1.6 mm for the scaling and root planing group, and 0.9 mm for the PVP-iodine and the saline monotherapy groups, with statistical significance reached for the scaling and root planing group vs . the PVP-iodine group (P = 0.04) and for the scaling and root planing group vs . the saline group (P = 0.02) . Reduction in visible dental plaque, which ranged from 38% to 62%, showed no significant differences among treatment groups . CONCLUSIONS: The addition of subgingival PVP-iodine irrigation to conventional mechanical therapy may be a cost-effective means of reducing total counts of periodontal pathogens and helping control periodontal disease . However, subgingival irrigation with PVP-iodine without concomitant mechanical debridement might not improve microbiological and clinical variables in comparison with saline irrigation, at least not in sites with radiographic evidence of subgingival calculus.

Helicobacter, 2003 Jun, 8(3), 207 - 15
Antimicrobial activity of essential oils against Helicobacter pylori; Ohno T et al.; BACKGROUND: Helicobacter pylori is an important pathogen responsible for gastroduodenal diseases in humans . Although the eradication of H . pylori using antibiotics often improves gastroduodenal diseases, resistance to the antibiotics is emerging . MATERIALS AND METHODS: The antimicrobial effect of essential oils and the development of resistance to the essential oils were evaluated in vitro and in vivo . RESULTS: Thirteen essential oils used in this study completely inhibited the growth of H . pylori in vitro at a concentration of 0.1% (v/v) . Cymbopogon citratus (lemongrass) and Lippia citriodora (lemon verbena) were bactericidal against H . pylori at 0.01% at pH 4.0 and 5.0 . Resistance to lemongrass did not develop even after 10 sequential passages, whereas resistance to clarithromycin developed under the same conditions . In in vivo studies, the density of H . pylori in the stomach of mice treated with lemongrass was significantly reduced compared with untreated mice . CONCLUSIONS: These results demonstrate that the essential oils are bactericidal against H . pylori without the development of acquired resistance, suggesting that essential oils may have potential as new and safe agents for inclusion in anti-H . pylori regimens.

Helicobacter, 2003 Jun, 8(3), 202 - 6
Mixed-infection of antibiotic susceptible and resistant Helicobacter pylori isolates in a single patient and underestimation of antimicrobial susceptibility testing; Kim JJ et al.; Antibiotic resistance among Helicobacter pylori has been increasing worldwide and has begun to affect the overall efficacy of current antibiotic regimens adversely . We examined 220 pairs of H . pylori isolates obtained from both the antrum and corpus of separate patients; 109 (50%) harbored antibiotic-resistant H . pylori: amoxicillin (0.5%), clarithromycin (5.9%), furazolidone (1.4%), metronidazole (45.5%), nitrofurantoin (1.4%), and tetracycline (6.8%) . Heteroresistance among the two biopsy sites from each patient was present in 41 of the 109 patients (38%) with antibiotic resistant H . pylori (e.g . 34% with resistant strains would be misclassified as susceptible if a biopsy of the antrum alone used for antimicrobial susceptibility testing) . DNA fingerprinting genotype analysis was carried out on the 41 pairs of isolates with heteroresistance . While different patients had different fingerprinting patterns, each pair of isolates showed identical or similar fingerprinting patterns . These results suggest that antibiotic-resistant H . pylori typically develop from pre-existing susceptible strain rather than coinfection with a different strain . The minor differences in genotype (degeneration of genotype) seen reflect one of the processes for development of genetic diversity in H . pylori . No biopsy single site can be considered representative for antimicrobial susceptibility testing.

Helicobacter, 2003 Jun, 8(3), 159 - 67
Helicobacter pylori infection and perforated peptic ulcer prevalence of the infection and role of antimicrobial treatment; Gisbert JP et al.; Although the role of Helicobacter pylori infection on noncomplicated peptic ulcer disease has been definitively established, the precise relationship between the organism and complicated ulcer has hardly been studied . The mean prevalence of H . pylori infection in patients with perforated peptic ulcer is of only about 65-70%, which contrasts with the almost 90-100% figure reported in noncomplicated ulcer disease . However, H . pylori infection rates in various studies range markedly from 0% to 100%, suggesting that differences in variables as number and type of diagnostic methods used to diagnose H . pylori infection, or frequency of nonsteroidal anti-inflammatory drug intake, may be responsible for the low prevalence reported in some studies . Recurrent ulcer disease after peptic ulcer perforation mainly occurs in patients with H . pylori infection, which suggests that the microorganism plays an important role in this complication . All patients with perforated peptic ulcer should be treated by simple closure of the perforation and with therapy aimed at healing of the ulcer and eradicating the H . pylori infection, as disappearance of the organism prevents, or at least decreases, ulcer recurrence and ulcer perforation in patients with H . pylori-associated perforated ulcers after simple closure . Therefore, H . pylori eradicating treatment should be started during the immediate postoperative period . The patients with intractable recurrent symptoms of peptic ulcer despite adequate medical treatment, but without H . pylori infection (e.g . a patient using nonsteroidal anti-inflammatory drugs), is probably the only remaining indication for elective definitive surgical treatment of peptic ulcer disease.

Artif Organs, 2003 May, 27(5), 486 - 91
In vitro effects of a chlorhexidine controlled delivery system; Franco CF et al.; The aim of this work was study the effect of the chlorhexidine : hydroxypropyl-beta-cyclodextrin (CLX : HP-beta-CD) inclusion compound (IC) on in vitro slabs of bovine dentine . The substantivity, antimicrobial activity, and morphological effect of this inclusion compound were evaluated . Cyclodextrin improves the physical-chemical and pharmacological properties of drugs . Fragments of bovine dentine were immersed into either IC serial solutions at 0.24%, 0.12%, 0.06%, 0.03%, 0.015%, and 0.008% or controls water and free chlorhexidine . The desorption kinetics showed that CLX : HP-beta-CD compound release CLX for 6 days in a rate flow near to zero-order profile in comparison to plain CLX . Antimicrobial activity tests showed that CLX : HP-beta-CD inhibited A . actinomycetemcomitans and S . mutans significantly . The morphological effect studied by scanning electron microscopy (SEM) showed that CLX : HP-beta-CD did not cause morphological changes to the slab's surface . It is concluded that the chlorhexidine : hydroxypropyl-beta-CD inclusion compound creates an effective controlled release system with biological activity and that it may act as a good prevention and control agent of caries and periodontal disease in vivo.

J Mammary Gland Biol Neoplasia, 2002 Jul, 7(3), 347 - 53
The mammary gland in mammalian evolution: a brief commentary on some of the concepts; Peaker M; Current thinking is highlighting the mammary glands and the process of lactation in the evolutionary success of mammals over and above the selective advantages provided by the nutritional and antimicrobial properties of milk . The extended period of contact between mothers and their young, necessitated by the regular and frequent transfer of milk, particularly characteristic of the primate strategy of reproduction and the primate mode of life, has been suggested to afford the offspring the opportunity for more learning and the eventual development of the levels of intelligence present in "higher" primates . Lactation offers the opportunity for maternal effects on development and the eventual phenotype of the offspring in addition to those that occur during pregnancy or from behavioral interactions . Lactation comes with high metabolic costs, which are manifested in parent-offspring conflict, and special physiological adaptations have evolved which match milk supply to demand by the young.

J Mammary Gland Biol Neoplasia, 2002 Jul, 7(3), 277 - 89
Evolution of the mammary gland defense system and the ontogeny of the immune system; Goldman AS; A decisive event in the evolution of mammals from synapsid reptiles was the modification of ventral thoracic-abdominal epidermal glands to form the mammary gland . The natural selection events that drove the process may have been the provision of certain immunological agents in dermal secretions of those nascent mammals . This is mirrored by similar innate immune factors in mammalian sebum and in protherian and eutherian milks . On the basis of studies of existing mammalian orders, it is evident that immune agents in milk such as immunoglobulins, iron-binding proteins, lysozyme, oligosaccharides, and leukocytes compensate for developmental delays in early postnatal production of antimicrobial factors . At least in human milk, anti-inflammatory and immunomodulating agents also evolved to provide different types of protection for the offspring . In addition, investigations reveal that the types or concentrations of immunological agents in milk vary depending upon the type of placenta, lactation pattern, and environment of the species.

Pulm Pharmacol Ther, 2003, 16(3), 131 - 45
Novelties in the field of antimicrobial compounds for the treatment of lower respiratory tract infections; Cazzola M et al.; Emergence of antimicrobial resistance is a growing problem and a public health threat . New drugs must be designed with emerging needs in mind: specific resistant and hard-to-treat organisms . But the difficulty to find real new drugs is a major problem . Only the oxazolidinones, the cationic peptides and the lipopeptide antibiotics can be truly regarded as structurally novel drugs, although the peptide deformylase inhibitors and, possibly, the pleuromutilins can be considered a potential advancement in the field . Obviously, these antibiotics must be reserved only to cases of documented ineffectiveness of the common antimicrobial agents.

Fertil Steril, 2003 Apr, 79(4), 856 - 63
Hormonal contraception can suppress natural antimicrobial gene transcription in human endometrium; Fleming DC et al.; OBJECTIVE: To determine the effect of hormonal contraception with a combined oral contraceptive pill and levonorgestrel intrauterine system on the expression of the natural antimicrobials secretory leukocyte protease inhibitor, beta-defensins 1 and 2, and granulysin in human endometrium . DESIGN: Observational study . SETTING: Day case ward in a department of obstetrics and gynecology . PATIENT(S): Fifty seven women undergoing gynecologic procedures for benign conditions; 24 received no contraception for more than 3 months, 20 received a combined oral contraceptive for more than 3 months, and 13 wore a levonorgestrel intrauterine system for more than 3 months . MAIN OUTCOME MEASURE(S): Endometrial samples were collected from all women . Messenger RNA was extracted and quantitative polymerase chain reaction was used to investigate expression of secretory leukocyte protease inhibitor, beta-defensin 1, beta-defensin 2, and granulysin . Immunohistochemistry for secretory leukocyte protease inhibitor was performed . RESULT(S): All antimicrobials varied cyclically . The level of secretory leukocyte protease inhibitor was maximal in the late secretory and menstrual phase, beta-defensin 1 in the mid secretory phase, granulysin in the late secretory phase, and beta-defensin 2 in the menstrual phase . Use of a combined oral contraceptive or levonorgestrel intrauterine system use decreased messenger RNA expression of beta-defensin 1 and 2 and granulysin but not secretory leukocyte protease inhibitor . CONCLUSION(S): Endogenous and exogenous sex-steroid hormones, in the form of a combined oral contraceptive or levonorgestrel intrauterine system, influence gene transcription of secretory leukocyte protease inhibitor, beta-defensin 1, beta-defensin 2, and granulysin in the endometrium.

Am J Health Syst Pharm, 2003 Apr 15, 60(8), 759 - 67
Effect of an educational program on the treatment of RSV lower-respiratory-tract infection; Purcell K et al.; The effectiveness and outcomes of an educational program to decrease ribavirin and antimicrobial prescribing rates and associated costs for patients with respiratory syncytial virus (RSV) lower-respiratory-tract infection are described . An educational program on the appropriate treatment for RSV infections was conducted for attending physicians and medical residents with multiple methods and forums during the 1994-95 RSV season . A retrospective chart review of 2396 patients admitted to a pediatric teaching hospital from July 1, 1991, through June 30, 1998, was conducted to measure the frequencies of ribavirin and antimicrobial prescribing in infants and young children hospitalized with RSV lower-respiratory-tract infection . The results before and after the educational program were compared . Ribavirin was prescribed for 37.9% of patients before the program, and only 9.0% received it afterward (p < 0.001) . Before the program, 24.8% of patients with no risk factors received ribavirin compared with 1.6% of patients after the program (p < 0.001) . However, more patients with three or more risk factors for morbidity and mortality received ribavirin before the program than afterward (97.8% versus 39.2%, respectively) . A broad-spectrum i.v . antimicrobial was prescribed for 85.6% of patients before the program while 60.6% received one afterward (p < 0.001) . The cost savings for ribavirin and antimicrobials during the three-year period after the program were $1,235,484 and $34,839, respectively . Hospital length of stay decreased from 5.6 to 5.1 days (p < 0.001) . No readmissions occurred during the study period . A multifaceted educational intervention program may have been somewhat effective in modifying physician's prescribing habits for the treatment of RSV lower-respiratory-tract infection.

Dtsch Med Wochenschr, 2003 May 16, 128(20), 1109 - 14
{Clinical presentation and management of the severe acute respiratory syndrome (SARS)}; Rickerts V et al.; BACKGROUND AND OBJECTIVE: In February 2003, a newly emerged infectious disease was described, the etiology of which was initially unknown . It is referred to under the term SARS . In the beginning, it spread in some regions South-East Asia . Import infections appeared in many other parts of the world . Based on the first cases in Germany, this report illustrates the clinical appearance, the diagnostic results and the management of this new disease . PATIENTS AND METHODS: We analysed the data of two patients with SARS and one suspected patient . The results of radiological, laboratory, microbiological and physical examinations were abstracted and compared with the data obtained in other regions . RESULTS: Two of the three patients under our care developed SARS disease . This is characterised by fever of sudden onset lasting for more than 5 days, rapidly changing consolidations in chest x-ray not affected by antimicrobial therapy, leuko-, lympho- as well as thrombopenia with a compromised pulmonary function later in the course . Close contacts with SARS patients does not regularly result in full development of the disease . Secretion of a coronavirus could be detected in respiratory samples during the febrile phase and in feces for a longer time . It is still an open question whether bedrest and antibiotic prophylaxis by themselves or an additional administration of ribavirin and corticosteroids can improve the outcome . CONCLUSION: SARS is a new and highly contagious lung disease . It is crucial to be able to recognize the clinical appearance and the diagnostic features of this disease at an early stage, in order to prevent a further dissemination of the disease.

Natl Toxicol Program Tech Rep Ser, 1985 Apr, 276, 1 - 170
NTP Toxicology and Carcinogenesis Studies of 8-Hydroxyquinoline (CAS No . 148-24-3) in F344/N Rats and B6C3F1 Mice (Feed Studies); National Toxicology Program ; Carcinogenesis studies of 8-hydroxyquinoline (99% pure), a metal chelator and antimicrobial agent, were conducted by administering the test chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at concentrations of 0, 1,500, or 3,000 ppm for 103 weeks . These concentrations were selected because the chemical at higher concentrations resulted in reduced feed consumption, decreases in mean body weights, and deaths in the 15-day and 13-week studies . The average daily doses were estimated to be 73 and 143 mg/kg for male rats, 89 and 166 mg/kg for female rats, 217 and 396 mg/kg for male mice, and 349 and 619 mg/kg for female mice . Survival of dosed male and female rats and mice in the 2-year studies was comparable to that of the corresponding controls . The high dose rats and mice of each sex exhibited slight decreases in mean body weights and decreased feed consumption . Compound-related gross or microscopic pathologic effects were not observed in either species in the 15-day or 13-week studies . In the 2-year studies, C-cell adenomas/carcinomas of the thyroid gland showed a positive trend (P=0.03) for male rats (control, 1/50; low dose, 1/49; high dose, 6/47) . The incidence of C-cell neoplasms in the high dose was not significantly increased compared with the controls, and the occurrence of C-cell hyperplasia was not elevated (4/50; 3/49; 1/47) . The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) in male rats with a positive trend, and the incidence in the high dose group was greater than that in the controls (0/50; 3/50; 4/50) . This marginal effect was not supported by an increase in epithelial hyperplasia (5/50; 5/50; 3/50) . These marginal increases in male rats were not regarded as being related to the administration of 8-hydroxyquinoline . In in vitro tests, 8-hydroxyquinoline did not induce either unscheduled DNA synthesis in rat hepatocytes or transformation of BALB/c-3T3 cells . An audit of the experimental data for these carcinogenesis studies on 8-hydroxyquinoline was conducted . No data discrepancies were found that significantly influenced the final interpretations . Under the conditions of these studies, there was no evidence of carcinogenicity for male and female F344/N rats or for male and female B6C3F1 mice given 8-hydroxyquinoline in feed at concentrations of 1,500 or 3,000 ppm for 103 weeks . Synonyms: 8-quinolinol; oxine; hydroxybenzopyridine

Am J Respir Cell Mol Biol, 2003 Nov, 29(5), 627 - 33 Epub 2003 May 14.
CCL20 is an inducible product of human airway epithelia with innate immune properties; Starner TD et al.; Chemokine ligand 20 (CCL20) and human beta-defensins (HBDs) share structural and functional properties, including antiparallel beta-pleated sheet core structures, charge distribution, and signaling to adaptive immune cells via the highly selective CCR6 receptor . Because of their similarities, we hypothesized that in addition to its known adaptive immune signaling functions, CCL20 has antimicrobial properties and participates in pulmonary innate immunity . We found that primary cultures of human airway epithelial and cultured fetal lung explants expressed CCL20 mRNA . Expression of CCL20 transcripts were significantly induced by interleukin (IL)-1beta and tumor necrosis factor-alpha, and inhibited by dexamethasone . Primary cultures of airway epithelia secreted CCL20 both apically and basolaterally, and CCL20 abundance was increased over 30-fold with IL-1beta stimulation, achieving an estimated concentration of 167 ng/ml in airway surface liquid . CCL20 abundance in bronchoalveolar lavage fluid from patients with cystic fibrosis was nearly 90-fold higher compared with bronchoalveolar lavage fluid from healthy volunteers . Interestingly, CCL20 exhibited salt-sensitive antimicrobial activity, mainly against Gram-negative bacteria in low mug/ml concentrations . Additionally, apical washings from IL-1beta-stimulated primary cultures of human airway epithelia had significantly more antimicrobial activity than unstimulated controls . CCL20 rapidly permeabilized bacterial membranes with a time course intermediate to HBD-2 and HBD-3 . Thus, CCL20 is a bi-functional peptide with both innate and adaptive immune properties that is regulated by inflammatory mediators, expressed by airway epithelia, and increased in cystic fibrosis airway secretions.

J Periodontol, 2003 Apr, 74(4), 411 - 9
Efficacy of controlled-release subgingival chlorhexidine to enhance periodontal regeneration; Reddy MS et al.; BACKGROUND: Periodontal regeneration success may be limited by placing bone grafts and membranes in infected sites . The objective of this study was to test the hypothesis that adjunctive subgingival administration of chlorhexidine gelatin bioresorbable chips enhances bone gain when used in conjunction with guided tissue regeneration . METHODS: This was a single center, blinded, 2-arm parallel design study of 44 subjects with one or more sites with probing depth and clinical attachment loss > or = 5 mm following initial therapy and radiographic evidence of bone loss . The patients were randomly assigned to receive either chlorhexidine (CHX) chip or sham chip placement one week prior to regenerative therapy that included graft placement and site coverage with guided tissue membranes . Patients also received CHX or sham chip placement, per their randomization, adjunctively to scaling and root planing or maintenance procedures . Periodontal examinations were completed at baseline (8 weeks prior to surgery); 1 week prior to surgery; and at 3, 6, and 9 months postsurgery . The major outcomes for the study were changes in bone height and bone mass as measured from standardized radiographs used for quantitative digital subtraction radiography over the 11-month study period . RESULTS: Subjects receiving sham chip placement gained a mean bone height of 1.49 +/- 0.22 mm, while patients receiving the CHX chips gained significantly more bone height (3.54 +/- 0.45 mm; P<0.001) . Similarly, subjects receiving CHX chips as an adjunct gained significantly more bone mass (5.57 +/- 0.69 mg; P<0.001) than the standard therapy (2.59 +/- 0.34 mg) . CONCLUSIONS: These pilot results indicate that locally delivered, controlled-release antimicrobial treatment may improve the amount of bone gain during guided tissue regeneration procedures . These data support the evidence that infection control is an important variable in successful regeneration.

Angew Chem Int Ed Engl, 2003 May 9, 42(18), 2010 - 23
Oxazolidinone structure-activity relationships leading to linezolid; Barbachyn MR et al.; The development of bacterial resistance to currently available antibacterial agents is a growing global health problem . Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings . A number of solutions to the problem of bacterial resistance are possible . The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes . Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity . Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise . Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs . This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.

Clin Infect Dis, 2003 May 15, 36(10), 1284 - 9 Epub 2003 May 09.
Antimicrobial approaches for preventing infections associated with surgical implants; Darouiche RO; Because management of infections associated with surgical implants can be both difficult and costly, prevention of such infections remains a priority . Preventive strategies comprise systemic perioperative administration of antibiotics and local application of antimicrobial agents (antibiotics or antiseptics) . Local antimicrobial prophylaxis can be provided in various forms and aims to prevent implant-associated infections by impeding bacterial adherence to the implant surface and/or reducing the concentration of bacteria in the immediate vicinity of the implant . Analysis of the existing clinical practices and the pertinent medical literature indicates that, although some antimicrobial strategies constitute the standard of care for preventing infections associated with surgical implants, such strategies are often applied in a nonstandardized fashion and without clear evidence of clinical efficacy . This review article concludes with a perspective on assessing and preventing such serious infections.

J Antimicrob Chemother, 2003 Jun, 51(6), 1389 - 96 Epub 2003 May 13.
Adherence to local hospital guidelines for surgical antimicrobial prophylaxis: a multicentre audit in Dutch hospitals; van Kasteren ME et al.; OBJECTIVE: To study the adherence to local hospital guidelines for antimicrobial prophylaxis in surgery, and explore reasons for non-adherence . METHODS: A prospective, multicentre audit of elective procedures, without prior suspicion of infection, was carried out in 13 Dutch hospitals . By reviewing medical, anaesthetic and nursing records, and medication charts, the prescription of antibiotics was compared with the local hospital guideline on antibiotic choice, duration of prophylaxis, dose, dosing interval and timing of the first dose . RESULTS: Between January 2000 and January 2001, 1763 procedures were studied . Antibiotic choice, duration, dose, dosing interval and timing of the first dose were concordant with the hospital guideline in 92%, 82%, 89%, 43% and 50%, respectively . Overall adherence to all aspects of the guideline, however, was achieved in only 28% . The most important barriers to local guideline adherence were lack of awareness due to ineffective distribution of the most recent version of the guidelines, lack of agreement by surgeons with the local hospital guidelines, and environmental factors, such as organizational constraints in the surgical suite and in the ward . CONCLUSION: This study shows that, although adherence to separate aspects of local hospital guidelines for surgical prophylaxis in the Netherlands is favourable, overall adherence to all parameters is hard to achieve . Adherence to guidelines on dosing interval and timing needs improvement, in particular . To increase the quality of antimicrobial prophylaxis in surgery, effort should be put into developing guidelines acceptable to surgeons, in adequately distributing the guidelines and to facilitating logistics . Audits of surgical prophylaxis may help hospitals identify barriers to guideline adherence.

J Antimicrob Chemother, 2003 Jun, 51(6), 1331 - 7 Epub 2003 May 13.
Effects of antimicrobial therapy on the microbial flora of the adenoids; Brook I; The core of the adenoids contains polymicrobial aerobic and anaerobic flora and also includes potential respiratory pathogens . Similar flora, although in higher numbers and with a higher frequency of pathogens, are found in inflamed or hypertrophic adenoids and many of these bacteria are resistant to antimicrobial agents . Exposure to antimicrobial therapy can alter the colonization patterns and select for resistant organisms . Production of beta-lactamase is one of the major mechanisms of resistance of these organisms . The adenoids of healthy individuals, in contrast to those with recurrent respiratory tract infections, are generally colonized by aerobic and anaerobic organisms that are capable of interfering with the growth of potential pathogens . Maintaining the beneficial effects of normal flora by avoiding unnecessary exposure to antimicrobial therapy may be a useful tool in preventing colonization of the adenoids by potential pathogens . This review discusses the unique microbiology of the adenoids in individuals with a variety of pathological conditions, the interactions between the various organisms and the effects of antimicrobial therapy on the microbial flora of the adenoids.

Int J Toxicol, 2003 Mar-Apr, 22(2), 135 - 43
Antimicrobials: modes of action and mechanisms of resistance; McDermott PF et al.; After six decades of widespread antibiotic use, bacterial pathogens of human and animal origin are becoming increasingly resistant to many antimicrobial agents . Antimicrobial resistance develops through a limited number of mechanisms: (a) . permeability changes in the bacterial cell wall/membrane, which restrict antimicrobial access to target sites; (b) . active efflux of the antimicrobial from the cell; (c) . mutation in the target site; (d) . enzymatic modification or degradation of the antimicrobial; and (e) . acquisition of alternative metabolic pathways to those inhibited by the drug . Numerous bacterial antimicrobial resistance phenotypes result from the acquisition of external genes that may provide resistance to an entire class of antimicrobials . These genes are frequently associated with large transferable extrachromosomal DNA elements called plasmids, on which may be other mobile DNA elements such as transposons and integrons . An array of different resistance genes may accumulate on a single mobile element, presenting a situation in which multiple antibiotic resistance can be acquired via a single genetic event . The versatility of bacterial populations in adapting to toxic environments, along with their facility in exchanging DNA, signifies that antibiotic resistance is an inevitable biological phenomenon that will likely continue to be a chronic medical problem . Successful management of current antimicrobials, and the continued development of new ones, is vital to protecting human and animal health against bacterial pathogens.

Int J Toxicol, 2003 Mar-Apr, 22(2), 131 - 4
Animal drug human food safety toxicology and antimicrobial resistance--the square peg; Greenlees KJ; This paper presents the traditional approach for the evaluation of human food safety used for animal drugs intended for food animals, and describes some of the difficulties posed by antimicrobial drug resistance . Like human drugs, animal drugs must be safe and effective for the patient . However, unlike human drugs, food derived from animals treated with the animal drug must also be shown to be safe for human consumption . The Food and Drug Administration has come to realize that antimicrobial drugs used in the treatment of the food animal have the potential to create a unique residue--increased numbers of microorganism that are resistant to antimicrobial drug treatment . The traditional toxicological paradigm for chemical residues does not apply to this unique microbiological residue . Information useful to a food safety evaluation may include the potential for the animal antimicrobial drug to diminish the susceptibility of microorganisms to human antimicrobial drugs, any human medical use of the drug, relationship to other human antimicrobial drugs, and the ability of the animal drug to alter the susceptibility of relevant microorganism to important human antimicrobial drugs . Yet to be developed are standardized approaches to quantify an acceptable level of resistant microorganism in food and to mitigate the hazard to assure that there is a reasonable certainty of no harm following the consumption of the edible food derived from the treated animal.

Int J Toxicol, 2003 Mar-Apr, 22(2), 129 - 30
Antibiotic resistance: who is winning the war? Introductory remarks; Sheldon AT Jr; The evolutionary response of bacteria, fungi, viruses, and parasites to the selective pressure exerted by antimicrobial agents is the emergence of populations that resist the action of the antimicrobial . The emergence and dissemination of such resistance in a variety of these pathogens is a growing public health concern . In response, the scientific community developed an action plan to address this public health issue . Antimicrobial, antifungal, and antiviral drug development for the treatment of diseases caused by resistant pathogens is one component of this strategy . In addition, due to the targeting of specific drugs against resistant pathogens, we may more readily accept a given drugs toxicity profile for the added therapeutic benefit . This symposium provides a discussion of the modes of action and mechanisms of resistance to antimicrobial agents, and the use of surveillance systems to help understand the nature and magnitude of resistance . The goal is to help guide antimicrobial drug product development and use . Specific toxicity issues are presented that should be considered in phase 1 development of antimicrobial drug products for use in clinical medicine and veterinary medicine . Finally, the national and global strategies developed by federal agencies in the Public Health Action Plan to Combat Antimicrobial Resistance are outlined.

Cytotherapy, 2003, 5(1), 19 - 30
Efficacy of granulocyte transfusions for neutropenia-related infections: retrospective analysis of predictive factors; Rutella S et al.; BACKGROUND: The transfusion of G-CSf-primed granulocytes (GTX) might represent an important treatment option for neutropenia-related infections unresponsive to conventional antimicrobial therapies and to recombinant hematopoietic growth factors . However, few studies to date have identified the factors that can predict clinical outcome and the patient populations who are likely to benefit most from GTX . The primary endpoint of the present retrospective study was to evaluate the efficacy of GTX in 22 patients with hematological malignancies who developed neutropenia-related bacterial and fungal infections that were unresponsive to appropriate antimicrobial therapies . METHODS: Peripheral blood granulocytes were collected by continuous-flow leukapheresis from HLA-identical siblings after priming with G-CSF . The response to GTX was classified as 'favorable' if clinical symptoms and signs of infection resolved or 'unfavorable' if clinical symptoms and signs of infection were unchanged or worsened . Control of infection at Day 30 after the enrollment in the GTX program was considered as the outcome variable in multiple regression analysis . RESULTS: Two patients died of infection before receiving the granulocyte concentrates . Bacterial infections (monomicrobial or mixed bacteremias) were documented in 11 patients, whereas fungal infections (fungemia or focal fungal infections) were diagnosed in seven patients . In two patients, no infecting agent could be isolated (clinical infection) . Control of infection at Day 30 after the first GTX was achieved in 10 of 20 assemble patients . Overall, 54% of patients with bacterial infections had a favorable response, compared with 57% of patients with fungal infections . No differences in terms of survival were found when comparing patients with bacterial and those with fungal infections at a median follow-up 90 days from the first GTX . In univariate analysis, disease status before GTX, e.g., complete or partial remission, and spontaneous recovery of the neutrophil count were significantly associated with control of infection . when multivariate regression models were formed, the recovery 0.5 x 10 (9)/L PMN was the only parameter that significantly and independently correlated with a favorable response to GTX . DISCUSSION: GTX can be used to successfully treat bacterial as well as fungal infections in severely neutropenic patients when administered early after the onset of febrile neutropenia in patients with remission of the underlying disease and who are likely to recover marrow function.

J Agric Food Chem, 2003 May 21, 51(11), 3197 - 207
Antimicrobial properties of basil and its possible application in food packaging; Suppakul P et al.; Basil (Ocimum basilicum L.) is a popular culinary herb, and its essential oils have been used extensively for many years in food products, perfumery, and dental and oral products . Basil essential oils and their principal constituents were found to exhibit antimicrobial activity against a wide range of Gram-negative and Gram-positive bacteria, yeast, and mold . The present paper reviews primarily the topic of basil essential oils with regards to their chemical composition, their effect on microorganisms, the test methods for antimicrobial activity determination, and their possible future use in food preservation or as the active (antimicrobial), slow release, component of an active package.

Folia Microbiol (Praha), 2003, 48(1), 51 - 5
Simple synthesis of novel diphenylsulfapyrimidine acetates from chalcones and their antimicrobial activity; Wasfy AA et al.; Given the significant low yield (19-43%) in reported results on the cyclocondensation of sulfaguanidine acetate with chalcones, a careful reinvestigation was carried out . A new series of chalcones, bearing electron-attracting groups in the aromatic moiety, have been used as precursors in the synthesis of diphenylsulfapyrimidine acetates with good yield . All synthesized compounds were active against G(+)- and G(-)-bacteria, and fungi . Combination of substituents (Cl, OMe, NO2, etc.) enhanced antimicrobial activity . Derivative with two NO2 groups exhibits an activity comparable with sulfadiazine.

Postgrad Med J, 2003 Apr, 79(930), 201 - 3
Impact of respiratory viral infections on cystic fibrosis; Wat D; The life expectancy for patients with cystic fibrosis has improved remarkably over the last 20 years . Progressive deterioration of pulmonary function continues despite the aggressive use of antimicrobials . The absence of fever, neutrophilia, and systemic symptoms suggest that during pulmonary exacerbations other non-bacterial factors may have played a part . Some have suggested respiratory viruses as main suspects . So far, few data have illustrated the relationship of respiratory viruses and cystic fibrosis . By gaining further knowledge of this relationship, one may change future clinical practice and boost the survival of these patients.

Contraception, 2003 May, 67(5), 391 - 5
Women's preferences for vaginal antimicrobial contraceptives . V: attitudes of Brazilian women to the insertion of vaginal products; Hardy E et al.; The rapid spread of HIV/AIDS in the female population increases the urgency of developing new formulations that offer protection from this disease as well as other sexually transmitted infections . In many cultures, women do not readily accept touching their genitals or inserting products into their vaginas . Information on this subject was collected during a study involving 635 women in Brazil to determine the preferred attributes of vaginal products . Seventy-six percent would use an idealized contraceptive method that offered dual protection even though it could only be inserted with a finger and 96% would use this method if it could only be placed with an applicator . Qualitative analyses of responses to open questions suggest that the majority of Brazilian women studied did not like to touch their vagina with their finger or to insert devices . Although the introduction of safe and effective vaginal microbicides into many cultural settings can be successful, it should be accompanied by significant efforts to educate women about their bodies.

Diagn Microbiol Infect Dis, 2003 May, 46(1), 9 - 11
Identification of the bacterial etiology of culture-negative endocarditis by amplification and sequencing of a small ribosomal RNA gene; Khulordava I et al.; We report two cases of culture-negative bacterial endocarditis in which the organisms were identified by amplification and sequencing of the bacterial 16S rRNA gene . These results support an important role for polymerase chain reaction followed by direct sequencing to determine the etiology of culture-negative bacterial endocarditis and to guide appropriate antimicrobial therapy.

Gut, 2003 Jun, 52(6), 874 - 8
Administration of protegrin peptide IB-367 to prevent endotoxin induced mortality in bile duct ligated rats; Giacometti A et al.; BACKGROUND: Postoperative morbidity in patients with obstructive jaundice remains high because of increased susceptibility to endotoxin and the inflammatory cascade . AIMS: An experimental study was designed to investigate the efficacy of protegrin peptide IB-367, an antimicrobial positively charged peptide, in neutralising Escherichia coli 0111:B4 lipopolysaccharide (LPS) in bile duct ligated rats . METHODS: Adult male Wistar rats were injected intraperitoneally with 2 mg/kg E coli 0111:B4 LPS one week after sham operation or bile duct ligation (BDL) . Six groups were studied: sham with placebo, sham with 120 mg/kg tazobactam-piperacillin (TZP), sham with 1 mg/kg IB-367, BDL with placebo, BDL with 120 mg/kg TZP, and BDL with 1 mg/kg IB-367 . RESULTS: Main outcome measures were: endotoxin and tumour necrosis factor alpha (TNF-alpha) concentrations in plasma, evidence of bacterial translocation in blood and peritoneum, and lethality . After LPS, TNF-alpha plasma levels were significantly higher in BDL rats compared with sham operated animals . IB-367 caused a significant reduction in plasma endotoxin and TNF-alpha concentrations compared with placebo and TZP treated groups . In contrast, both TZP and IB-367 significantly reduced bacterial growth compared with saline treatment . Finally, LPS induced 60% and 55% lethality in BDL placebo and TZP treated rats and no lethality in sham operated rats, while only IB-367 significantly reduced lethality to 10% . CONCLUSIONS: By virtue of its dual antimicrobial and antiendotoxin properties, IB-367 could be an interesting compound to inhibit bacterial translocation and endotoxin release in obstructive jaundice.

Chest, 2003 May, 123(5), 1664 - 72
Diagnosis and treatment of rhinovirus respiratory infections; Anzueto A et al.; Acute upper viral respiratory infection (VRI) is the number one cause of illness for which patients seek medical care in the United States . Rhinoviruses, members of the family Picornaviridae, are the causative pathogens in more than half of VRIs, and they are associated with acute exacerbations of respiratory disease, including asthma, sinusitis, otitis media, and COPD . Owing to the lack of commercial availability of rapid and cost-effective laboratory tests to confirm the presence of VRI, the diagnosis is most commonly made empirically, based on patient history and physical examination . Currently, no antiviral agents that are active against picornaviruses are available for clinical use . Antimicrobial agents, frequently prescribed for VRIs, are not active against viruses, and their inappropriate and widespread use has contributed to an increase in antimicrobial resistance among bacteria commonly involved in respiratory tract infections . Several newer antiviral agents are being evaluated for treatment of VRIs . Although a variety of mechanisms and agents have been tested, few have shown significant clinical benefit in human trials . The most advanced antiviral agent in clinical trials is pleconaril, a novel viral capsid-binding inhibitor with potent and highly specific in vitro activity against the majority of serotypes of rhinoviruses and enteroviruses . Clinical trials of pleconaril for the treatment of VRIs have been conducted, and the role of pleconaril in patients with chronic lung disease is being evaluated.

Expert Opin Pharmacother, 2003 May, 4(5), 761 - 77
Paediatric community-acquired pneumonia: current concept in pharmacological control; Principi N et al.; Community-acquired pneumonia (CAP) is one of the most frequent infections in childhood but it is not easy to establish a rational therapeutic approach for a number of reasons, including difficulties in identifying the aetiology, the fact that the most frequent bacterial pathogens become resistant to commonly used antibiotics and the lack of certain information concerning the possible preventive role of conjugate vaccines . This leads paediatricians to treat almost all cases of CAP with antibiotics, often using a combination of different antimicrobial classes . In order to avoid unnecessary antibiotic use and limit the spread of antibiotic resistance, consensus guidelines for the management of CAP in childhood should be developed and used by practitioners in their offices and hospitals.

Kansenshogaku Zasshi, 2003 Apr, 77(4), 187 - 94
{Antimicrobial susceptibility tests and resistant strain of Helicobacter pylori}; Wada S et al.; The antimicrobial susceptibility test was necessary for the eradication therapy of Helicobacter pylori infections . This is because, clarithromycin resistant strains has became an increasing problem . In this study, we used the antimicrobial susceptibility test which was compare with the agar gradient method, Etest, and broth microdilution method (dry plate) with 4 antimicrobial agents . The results strongly suggested that broth microdilution method was the best method in order to test the antimicrobial susceptibility of H . pylori . On the other hand, 393 H . pylori stains isolated during 1994-1998 from clinical patients were tested for antimicrobial susceptibility test to amoxicillin, clarithromycin, metronidazole, and minomycin . There were no resistant strains to amoxicillin and minomycin . But clarithromycin and Metronidazole resistant strains were recognized in 85 (22.0%) and 36 (21.7%) strains.

Eur J Clin Microbiol Infect Dis, 2003 May, 22(5), 294 - 6 Epub 2003 May 09.
Non-fatal acute liver injury possibly related to high-dose ciprofloxacin; Goetz M et al.; Fulminant hepatic failure is an uncommon but life-threatening adverse reaction to antibiotic therapy . Reported here is a case of severe liver injury associated with ciprofloxacin administered for treatment of a gram-negative infection in a 79-year-old female . The patient presented with metabolic acidosis 48 hours after the first ciprofloxacin intake . Symptoms resolved after cessation of ciprofloxacin therapy . This report highlights an uncommon side effect of a commonly used antimicrobial agent.

Proc Natl Acad Sci U S A, 2003 May 27, 100(11), 6302 - 7 Epub 2003 May 08.
Interaction of antimicrobial peptide protegrin with biomembranes; Gidalevitz D et al.; The antimicrobial peptide protegrin-1 (PG-1) interacts with membranes in a manner that strongly depends on membrane lipid composition . In this research we use an approach representing the outer layers of bacterial and red blood cell membranes with lipid monolayers and using a combination of insertion assay, epifluorescence microscopy, and surface x-ray scattering to gain a better understanding of antimicrobial peptide's mechanism of action . We find that PG-1 inserts readily into anionic dipalmitoyl-phosphatidylglycerol, palmitoyl-oleoyl-phosphatidylglycerol, and lipid A films, but significantly less so into zwitterionic dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylcholine, and dipalmitoyl-phosphatidylethanolamine monolayers under similar experimental conditions . Epifluorescence microscopy shows that the insertion of PG-1 into the lipid layer results in the disordering of lipid packing; this disordering effect is corroborated by grazing incidence x-ray diffraction data . X-ray reflectivity measurements further point to the location of the peptide in the lipid matrix . In a pathologically relevant example we show that PG-1 completely destabilizes monolayer composed of lipid A, the major component in the outer membrane of Gram-negative bacteria, which is likely to be the mechanism by which PG-1 disrupts the outer membrane, thus allowing it to reach the target inner membrane.

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