Bactericidal

Food Addit Contam, 2003 Mar, 20(3), 221 - 8
Antibodies to the quinolones and fluoroquinolones for the development of generic and specific immunoassays for detection of these residues in animal products; Bucknall S et al.; Several quinolone and fluoroquinolone haptens have been used to raise polyclonal antibodies exhibiting both specific and generic properties for these classes of antimicrobial compounds . The antisera have been assessed in rapid enzyme immunoassays (ELISAs) designed to exploit the specificities obtained . A direct generic ELISA for both the quinolones and fluoroquinolones has been developed that uses the cross-reactivity of an antibody raised against norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid) linked to ovalbumin via a secondary amine group on the piperazinyl moiety to detect nine different drugs in these classes . Specific ELISAs to ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid), enrofloxacin (1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid), flumequin (9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid) and nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid) have also been developed with a high degree of specificity to the individual compounds . The assays measure drug residues in bovine milk and ovine kidney with an interassay relative standard deviation (s(r)) of 10.5% or less and intra-assay s(r) of 11.2% or less . Sensitivity is less than 4 microg x kg(-1) for both the generic and specific assays for all but one of the compounds tested . (Pipemidic acid (8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acid) is detectable at 6 microg x kg(-1) in kidney.)

Structure (Camb), 2003 Mar, 11(3), 329 - 38
Structural basis for the antibiotic activity of ketolides and azalides; Schlunzen F et al.; The azalide azithromycin and the ketolide ABT-773, which were derived by chemical modifications of erythromycin, exhibit elevated activity against a number of penicillin- and macrolide-resistant pathogenic bacteria . Analysis of the crystal structures of the large ribosomal subunit from Deinococcus radiodurans complexed with azithromycin or ABT-773 indicates that, despite differences in the number and nature of their contacts with the ribosome, both compounds exert their antimicrobial activity by blocking the protein exit tunnel . In contrast to all macrolides studied so far, two molecules of azithromycin bind simultaneously to the tunnel . The additional molecule also interacts with two proteins, L4 and L22, implicated in macrolide resistance . These studies illuminated and rationalized the enhanced activity of the drugs against specific macrolide-resistant bacteria.

Arch Intern Med, 2003 Mar 10, 163(5), 601 - 5
Fluoroquinolone utilization in the emergency departments of academic medical centers: prevalence of, and risk factors for, inappropriate use; Lautenbach E et al.; BACKGROUND: Resistance to fluoroquinolone (FQ) antibiotics has risen markedly in recent years and has been associated with increasing FQ use; however, few data exist regarding FQ use patterns . Designing strategies to limit FQ resistance by optimizing FQ use depends on identifying patterns of inappropriate FQ use . Use of FQs in emergency departments (EDs) has not been studied . METHODS: We studied 100 consecutive ED patients who received an FQ and were subsequently discharged . Appropriateness of the indication for use was judged according to existing institutional guidelines . A case-control study was conducted to identify the prevalence of, and risk factors for, inappropriate FQ use . RESULTS: Of 100 total patients, 81 received an FQ for an inappropriate indication . Of these cases, 43 (53%) were judged inappropriate because another agent was considered first line, 27 (33%) because there was no evidence of infection based on the documented evaluation, and 11 (14%) because of inability to assess the need for antimicrobial therapy . Although the prevalence of inappropriate use was similar across various clinical scenarios, there was a borderline significant association between the hospital in which the ED was located and inappropriate FQ use . Of the 19 patients who received an FQ for an appropriate indication, only 1 received both the correct dose and duration of therapy . CONCLUSIONS: Inappropriate FQ use in EDs is extremely common . Efforts to limit emergence of FQ resistance must address the high level of inappropriate FQ use in EDs . Future studies should evaluate the impact of interventions designed to reduce inappropriate FQ use in this setting.

Phytomedicine, 2003 Jan, 10(1), 59 - 61
Antimicrobial activity of various extracts and carvacrol from Lippia multiflora leaf extract; Kunle O et al.; This study examines the antimicrobial activity of the hexane, dichloromethane and methanol extracts of Lippia multiflora and carvacrol isolated from the hexane extract . The result shows the hexane extract to be the most active, while the methanol extract exhibited no antimicrobial activity . The isolated carvacrol from the hexane fraction showed tremendous antimicrobial activity . These results confirm the traditional uses of Lippia multiflora in the treatment of disease conditions due to microbes.

Int J Hyg Environ Health, 2003 Jan, 206(1), 1 - 8
Home hygiene: a risk approach; Bloomfield SF; The need to place "prevention through hygiene" at the core of strategies for infection prevention has been emphasised by recent events . Indications are that re-evaluation of current practice and the promotion of improved hygiene in the domestic setting could have a significant impact in reducing infectious disease . If the public are to play a part however they must be properly informed . Encouraging the concept of the home as a setting in which the whole range of activities occur, including food hygiene, personal hygiene and hygiene related to medical care, provides the opportunity for a rational approach to home hygiene based on risk assessment . In the home surfaces (including hand surfaces) and other sites play an important part in the transmission of infection, especially food-borne infections . From an assessment of the frequency of occurrence of pathogens and potential pathogens at reservoirs, disseminators and hand and food contact sites together with the potential for transfer within the home, the risks of exposure can be assessed . This can be used to develop a rational approach in which effective hygiene procedures involving cleaning and disinfection as appropriate are targeted at these sites to reduce risks of cross contamination . This approach is consistent with the view that good home hygiene is not about "getting rid of household germs" but about targeting hygiene measures appropriately to reduce exposure to germs and thereby prevent cross infection . In motivating change, education programmes must take account of concerns related to antimicrobial resistance, the environment and the "health" of the immune system.

Jpn J Antibiot, 2002 Dec, 55(6), 875 - 81
{Investigation on administration method of carbapenems}; Mikamo H et al.; Seventy-two women diagnosed as parametritis were enrolled in this study and examined on the effective administration method of carbapenems, imipenem/cilastatin (IPM/CS), panipenem/betamipron (PAPM/BP) and meropenem (MEPM) . The total dosage of each carbapenem was 1.5 g/day, and administration frequency was twice a day (0.75 g x 2) or three times a day (0.5 g x 3) . We reviewed the highest body temperature, white blood cell count and CRP value, before treatment and the fourth day after the start of treatment . Three times a day method was statistically superior to twice a day method in the highest body temperature, and CRP value . When we use carbapenem antimicrobial agents, the basis of PK/PD of time above MIC would lead to the increasing clinical effects.

Jpn J Antibiot, 2002 Dec, 55(6), 771 - 7
{Comparative in vitro activities of several antimicrobial agents against Helicobacter pylori}; Sugita K et al.; Comparative in vitro activities of several antimicrobial agents against Helicobacter pylori were evaluated . Minimum inhibitory concentrations against 41 strains of H . pylori were determined by using E test . All 41 strains were isolated from gastric mucosa of patients suspected to have gastric ulcer . The ranges of MIC of amoxicillin was from 0.016 microgram/ml and less to 0.064 microgram/ml . The ranges of MIC of clarithromycin, erythromycin, and azithromycin were from 0.016 microgram/ml and less to 64 micrograms/ml, from 0.016 microgram/ml and less to more than 256 micrograms/ml, from 0.064 to more than 256 micrograms/ml, respectively . The ranges of MIC of ciprofloxacin, sparfloxacin, levofloxacin, norfloxacin were from 0.016 microgram/ml and less to 32 micrograms/ml, from 0.002 microgram/ml and less to more than 32 micrograms/ml, from 0.002 microgram/ml and less to more than 32 micrograms/ml, from 0.064 to more than 32 micrograms/ml, respectively.

Clin Pharmacol Ther, 2003 Mar, 73(3), 242 - 52
Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects; Demolis JL et al.; BACKGROUND: Telithromycin is the first member of a new class of antimicrobials-the ketolides . The main objective of this study was to assess the effect of various oral doses of telithromycin on QT interval during single and repeated administrations . METHODS: Seventeen men and 17 women participated in double-blind, placebo-controlled, crossover studies . Of these subjects, 18 (9 men and 9 women) received single and repeated oral doses of telithromycin (800 mg daily), clarithromycin (500 mg twice daily), or placebo (protocol 1) . The other 16 subjects received a single oral dose (800 mg, 1600 mg, and 2400 mg) of telithromycin or placebo (protocol 2) . At the time of expected telithromycin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test . QT intervals were measured within a wide range of R-R intervals in each subject . RESULTS: ANOVA showed that telithromycin did not increase QT interval at any dose compared with placebo . The greatest effect observed during any study period was a mean (+/-SD) change in QT-interval duration of 4.2 +/- 15.2 ms (ie, +1.2% +/- 4.0%, P not significant) at R-R = 1000 ms after repeated doses of 800 mg telithromycin . Outlier values (change in Bazett QTc from baseline >60 ms) from resting 12-lead electrocardiograms did not differ across treatment groups, including placebo . CONCLUSIONS: Telithromycin administered as repeated doses of 800 mg (recommended doses) or as single doses of up to 3 times this recommended dose did not increase the QT interval at any heart rate at rest and during effort . Telithromycin did not prolong QT-interval duration when administered to healthy young male and female subjects.

Genes Immun, 2003 Mar, 4(2), 87 - 94
Toll-like receptors and their role in experimental models of microbial infection; Qureshi ST et al.; Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response . The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat . Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host . Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.

Chem Biol, 2003 Feb, 10(2), 189 - 96
Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance enzymes; Boehr DD et al.; The action of aminoglycoside antibiotics is inhibited by chemical modification catalyzed by aminoglycoside inactivating enzymes, which bind these cationic saccharides with active site pockets that contain a preponderance of negatively charged residues . In this study, it was observed that several cationic antimicrobial peptides, representing different structural classes, could serve as inhibitors of such aminoglycoside resistance enzymes . The bovine antimicrobial peptide indolicidin and synthetic analogs appeared to be especially effective against a range of resistance enzymes, inhibiting enzymes belonging to both aminoglycoside phosphotransferase and aminoglycoside acetyltransferase classes, where the mode of action was dependent on the class of antibiotic resistance enzyme . These peptides represent the first example of broad-spectrum inhibitors of aminoglycoside resistance enzymes.

Biochem J, 2003 May 1, 371(Pt 3), 663 - 8
Induction of ASABF (Ascaris suum antibacterial factor)-type antimicrobial peptides by bacterial injection: novel members of ASABF in the nematode Ascaris suum; Pillai A et al.; Recently, invertebrate models have been widely used for the study of innate immunity . Nematodes are novel potential candidates because of the experimental advantages of Caenorhabditis elegans . However, whether nematodes have active immune responses is still ambiguous . Previously, we reported ASABF (Ascaris suum antibacterial factor)-type antimicrobial peptides in the parasitic nematode Ascaris suum and the genetic model nematode C . elegans . Further screening of a cDNA library and an expressed-sequence-tag database search detected five novel members of ASABF (ASABF-beta, -gamma, -delta, - epsilon and -zeta) in A . suum . The transcripts for ASABF-alpha, -beta, -gamma, and -delta clearly increased in the body wall, and also in the intestine for ASABF-delta, 4 h after injection of heat-killed bacteria into the pseudocoelom (body cavity), suggesting that these peptides are inducible in the acute phase of immune response . These results also suggest that the nematodes can recognize bacteria in the pseudocoelomic fluid and evoke an active immune response.

Med Trop (Mars), 2002, 62(5), 554 - 60
{Treatment of malaria in children: 1 . Uncomplicated malaria}; Imbert P et al.; Malaria is a worldwide epidemic causing high morbidity and mortality especially in children younger than 5 years . In France the incidence of pediatric malaria has constantly increased up to 1500 cases in the last two years, due to Plasmodium falciparum in more than 80% of cases . According to current recommendations, any patient with clinical suspicion or confirmed diagnosis of malaria must be hospitalized for treatment . Halofantrine is the most widely used antimalarial for treatment of uncomplicated P . falciparum malaria in children . However due to halofontrine-related cardiotoxicity some teams recommend mefloquine as the first-line drug despite disadvantages related to its poorly adapted formulation and adverse gastrointestinal effects in young children . Treatment of malaria involving other plasmodium species is still based on chloroquine . Likewise the World Health Organization continues to recommend chloroquine as the first-line agent for uncomplicated malaria in endemic zones with moderate chloroquine resistance . Amodiaquin or sulfadoxine-pyrimethamine combination may be used either in case of failure or as first-line agents in zones with high chloroquine resistance . In case of multiple resistance, quinine may be used alone or in association with an antimicrobial . Other drug therapies such as combinations using artemisinine derivatives have been shown to be highly effective for control of clinical symptoms and parasitemia . Widespread use of these therapies to prevent the appearance and extension of resistance is now undergoing evaluation.

Laryngoscope, 2003 Mar, 113(3), 432 - 5
Expression of a cathelicidin antimicrobial peptide is augmented in cholesteatoma; Jung HH et al.; OBJECTIVES/HYPOTHESIS: Antimicrobial peptides are active defense components of innate immunity . Their importance was confirmed at epithelial surfaces as immediate barrier effectors in preventing infection . Cathelicidins are peptide antibiotics that are receiving increasing attention . Several studies have shown that overexpression of cathelicidin results in augmented protection against bacterial infection and prevention of local infection and systemic invasion of microbes . The goal of the study was to investigate whether cathelicidin is upregulated in cholesteatoma epithelium compared with normal skin . STUDY DESIGN: Twenty patients from a prospective study of cholesteatoma tissues and normal skins were enrolled in the study . The specimens were divided into two portions . One portion was used for subsequent RNA studies; the other was used for immunohistochemical staining . METHODS: Reverse transcriptase-polymerase chain reaction was used to assess the expression levels of cathelicidin messenger RNA (mRNA) both in cholesteatoma and in normal skin . Presumptive concentration of cathelicidin mRNA and beta2-microglobulin mRNA was evaluated . Ratio of beta2-microglobulin to cathelicidin was analyzed in each group . The expressions of cathelicidin in cholesteatoma and normal skin epithelium were investigated by an immunohistochemical technique . RESULTS: Cathelicidin mRNA in cholesteatoma epithelium was increased 5.5-fold compared with normal skin of the ear canal . In cholesteatoma epithelium, cathelicidin was located in all the layers, but in the normal skin it was expressed only in the granular and prickle cell layers . CONCLUSIONS: Cathelicidin is augmented in cholesteatoma epithelium, and the data in the present study are in agreement with the hypothesis that cathelicidin is likely to act as a key component in the first line of defense at the surface epithelium.

J Antimicrob Chemother, 2003 Mar, 51(3), 545 - 56
Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli; Yang S et al.; Quinolones are widely used, broad-spectrum antimicrobial agents . In screens for genes that, when overexpressed, allow Escherichia coli to grow on otherwise lethal concentrations of the fluoroquinolone norfloxacin, the ydhE gene was identified . We have shown that ydhE encodes a multidrug efflux pump with a narrower substrate range than that of its closest homologue, encoded by norM, and named the gene norE . The relative contributions to drug resistance of NorE compared with the two other known E . coli quinolone pumps, AcrAB and MdfA, have been defined . Overexpression of each of the three pumps separately resulted in roughly similar levels of quinolone resistance, whereas simultaneous overexpression of norE or mdfA in combination with acrAB gave synergic increases in quinolone resistance . The level of quinolone resistance mediated by efflux pumps seems to be constrained to an approximately 10-fold maximum, even with increased production of the pumps . We measured the drug resistance of an isogenic set of strains containing the various permutations of single, double and triple drug efflux pump mutants . The DeltanorE and DeltamdfA mutants were somewhat more susceptible to fluoroquinolones than the parent strain, and acrAB mutants were four- to six-fold more susceptible . Mutants lacking two or all three efflux pumps were not significantly more susceptible to fluoroquinolones than those lacking only one of the three pumps.

J Antimicrob Chemother, 2003 Mar, 51(3), 497 - 511
Drugs of the 21st century: telithromycin (HMR 3647)--the first ketolide; Ackermann G et al.; Telithromycin (HMR 3647) is the first ketolide introduced into clinical practice . Ketolides are semisynthetic derivates of erythromycin A that carry novel biological properties on the erythronolide A ring . This new class of antimicrobials was designed to overcome current resistance mechanisms against erythromycin A within Gram-positive cocci . Ketolides do not induce macrolide-lincosamide-streptogramin B (MLS(B)) resistance and are active against erythromycin resistance methylase gene (erm)-carrying Gram-positive cocci . This review summarizes published data on telithromycin and intends to define the challenge that a new antimicrobial brings to medical practice.

Int J Antimicrob Agents, 2003 Feb, 21(2), 135 - 42
Impact of travel on international spread of antimicrobial resistance; Memish ZA et al.; Antimicrobial resistance, an escalating problem worldwide, affects a broad range of human diseases . Excessive and inappropriate drug usage is the key driver for the emergence of resistant organisms . Travel, trade and mass migration form an important mode for their spread . The use of molecular biology provides the means of understanding the genesis and spread of the genes for drug resistance . Antimicrobial use in veterinary practice as food additives causes selection of resistant zoonotic pathogens that may spread to humans . Comprehensive surveillance systems should be designed and implemented at local and national levels and a national resistance surveillance database operationalized . There is also need for better regulation of the use of antibiotics and education of the medical fraternity, veterinarians and the public in the appropriate use of antimicrobials.

Mol Biochem Parasitol, 2003 Mar, 127(1), 23 - 35
Induction of autophagic cell death in Leishmania donovani by antimicrobial peptides; Bera A et al.; We demonstrate that antimicrobial peptides induce an autophagic cell death in the protozoan pathogen, Leishmania donovani . In our study, three antimicrobial peptides, Indolicidin, and two peptides derived from Seminalplasmin exhibit antileishmanial activity with a 50% lethal dose of 3.5 x 10(-5), 3.8 x 10(-4) and 1.7 x 10(-8) microM, respectively . The action of these antimicrobial peptides on the Leishmania cell involves ionic interactions, which are modulated by lipophosphoglycan on the parasite's surface . Peptide treatment caused dissipation of membrane potential and equilibration of intracellular pH with extracellular environment . However, there was no release of intracellular GFP molecules upon peptide treatment of a GFP expressing Leishmania clone . Transmission electron microscopic studies show extensive intracellular damage including cytoplasmic vacuolization and degeneration of cellular organization without disruption of the plasma membrane . These peptides induce cell death via a non-apoptotic process as shown by lack of nuclear fragmentation or DNA laddering and independent of caspase-like activity . Instead, Monodansylcadaverine (MDC), a biochemical marker of autophagy specifically labels the vacuoles induced by peptides . Collectively, these results indicate that in addition to their effects on the leishmanial membrane, these antimicrobial peptides induce pathway(s) for autophagic cell death in L . donovani.

Mol Biochem Parasitol, 2003 Feb, 126(2), 129 - 42
Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa; Roberts CW et al.; Current treatments for diseases caused by apicomplexan and trypanosomatid parasites are inadequate due to toxicity, the development of drug resistance and an inability to eliminate all life cycle stages of these parasites from the host . New therapeutics agents are urgently required . It has recently been demonstrated that type II fatty acid biosynthesis occurs in the plastid of Plasmodium falciparum and Toxoplasma gondii and inhibitors of this pathway such as triclosan and thiolactomycin restrict their growth . Furthermore, Trypanosoma brucei has recently been demonstrated to use type II fatty acid biosynthesis for myristate synthesis and to be susceptible to thiolactomycin . As this pathway is absent from mammals, it may provide an excellent target for novel antimicrobial agents to combat these diverse parasites . Leishmania and Trypanosoma parasites produce ergosterol-related sterols by a biosynthetic pathway similar to that operating in pathogenic fungi and their growth is susceptible to sterol biosynthesis inhibitors . Thus, inhibition of squalene 2,3-epoxidase by terbinafine, 14alpha-methylsterol 14-demethylase by azole and triazole compounds and delta(24)-sterol methyl transferase by azasterols all cause a depletion of normal sterols and an accumulation of abnormal amounts of sterol precursors with cytostatic or cytoxic consequences . However, Leishmania parasites can survive with greatly altered sterol profiles induced by continuous treatment with low concentrations of some inhibitors and they also have some ability to utilise and metabolise host sterol . These properties may permit the parasites to evade treatment with sterol biosynthesis inhibitors in some clinical situations and need to be taken into account in the design of future drugs .

Rev Med Interne, 2003 Jan, 24(1), 17 - 23
{Lemierre's syndrome: a report of six cases}; Pulcini C et al.; OBJECTIVE: Lemierre's syndrome is a rare but severe condition combining pyrexia, cervical pain and pulmonary signs following a pharyngeal infection, usually tonsillitis . This infectious disease is still present in our country despite wide use of antibiotic therapy in pharyngeal infections . METHODS: In a retrospective study conducted between 1995 and 2000 in two departments (infectious diseases and critical care unit) of Nice university hospital (Nice, France), we collected and analysed six cases of Lemierre's syndrome . RESULTS: We describe a serie of 6 cases, all of them female patients of mean age 27 . We enrolled healthy patients whose initial symptom was tonsillitis . Most of these patients showed signs of severe sepsis and one died of septic shock . All the others recovered with treatment . The mean time between tonsillitis and first sign of sepsis was seven days . In four cases, patients received a beta- lactam antimicrobial agent with metronidazole . In two cases, patients were treated with amoxicillin-clavulanate . All patients were investigated for the presence of internal jugular vein thrombosis and were treated by anticoagulants when research was positive . CONCLUSIONS: A strong presumptive diagnosis can be made on the basis of clinical presentation, secondarily confirmed by para-clinical data . The prognosis depends on the speed and quality of management . We therefore wished to raise awareness of this condition among our colleagues by reporting our personal experience.

Lancet Infect Dis, 2003 Mar, 3(3), 156 - 61
Impact of current transplantation practices on the changing epidemiology of infections in transplant recipients; Singh N; The spectrum of infections in transplant recipients has been substantially affected by novel immunosuppressive regimens and the use of antimicrobial agents . Epidemiology and presentation of traditional opportunistic pathogens has changed . Invasive aspergillosis and cytomegalovirus occur later in the post-transplant period . The incidence of infections that were previously encountered rarely--eg, BK virus nephropathy--has increased, the clinical course of hepatitis C virus recurrence has become more aggressive, the risk factors for invasive aspergillosis have changed, and non-aspergillus moulds are occurring more commonly in transplant recipients . Recognition of these trends as they unfold has significant implications for the clinical care of the transplant recipients, for providing insights into the pathogenesis, and for continually improving the approaches to the management of infections.

Expert Opin Pharmacother, 2003 Mar, 4(3), 369 - 84
Current pharmacotherapy for the treatment of severe burns; Murphy KD et al.; The pharmacotherapy of burn care has evolved from the first topical antibiotics instituted > 30 years ago . These have helped greatly to reduce the incidence of burn wound sepsis, but a better understanding of the principles of burn care has resulted in earlier burn wound excision and complete coverage with autograft, cadaver skin, synthetic dressings, and amnion . This has markedly reduced septic complications and ameliorated the hypermetabolic response to burn injury . The hypermetabolic response, which is mediated by hugely increased levels of circulating catecholamines, prostaglandins, glucagon and cortisol, causes profound skeletal muscle catabolism, immune deficiency, peripheral lipolysis, reduced bone mineralisation, reduced linear growth, and increased energy expenditure . Supportive therapy and pharmacological manipulation, acutely and during rehabilitation, with growth hormone, insulin and related proteins, oxandrolone and propranolol can ameliorate the hypermetabolic response, improving survival and long-term outcome . Despite judicious use of topical and systemic antibiotics, opportunistic nosocomial bacterial resistance threatens to annul the improved survival of patients with severe burns . Patterns of emerging resistance encountered in burn units need to be considered, in light of a decreasing antibiotic armamentarium . A holistic approach to pharmacotherapy of severely burned patients including current practice in antimicrobial control, analgesia, sedation, and anxiety management is required . Current therapy of frequently encountered problems, such as post-burn pruritus, prophylaxis of deep venous thrombosis and peptic ulceration, and pharmacological manipulation of inhalation injury in the burned patient is described . Current pharmacotherapy to ameliorate psychosocial problems associated with burns such as acute stress disorder, depression and post traumatic stress disorder are discussed . Better analgesics, newer antibiotics and immune stimulating drugs are required to reduce mortality and morbidity in large burns.

Rev Soc Bras Med Trop, 2002 Nov-Dec, 35(6), 661 - 3 Epub 2003 Feb 26.
{Typhoid fever: relapse due to antimicrobial resistance . Case report}; Alecrim WD et al.; We report for the first time in the Brazilian Amazon a typhoid fever patient with clinical and laboratorial resistance to chloramphenicol, drug of election for this disease in our region . The relapse was observed at the 7th day after the end of treatment and the patient was treated with ciprofloxacin.

Altern Med Rev, 2003 Feb, 8(1), 28 - 42
Can CAM therapies help reduce antibiotic resistance?
MacKay D.
The Centers for Disease Control and Prevention (CDC) reported the consumption of 235 million doses of antibiotics in 2001 . It is estimated that 20-50 percent of these were unnecessarily prescribed for viral infections . Bacteria that antibiotics have controlled in the past are increasingly developing resistance to these drugs . Today, virtually all important bacterial infections in the United States and throughout the world are becoming resistant . For this reason, antibiotic resistance is among the CDC's top concerns . A large portion of antibiotics are dispensed by pediatricians treating common outpatient infectious diseases . The overuse of antimicrobials is beginning to be discouraged as scientific evidence is emerging to support the use of other therapies . In pediatric practice an emphasis on accurate diagnoses, control of environmental risk factors, and utilization of complementary and alternative medicine (CAM) therapies could reduce antibiotic prescribing . Antibiotic resistance poses a growing threat to health . CAM therapies may provide a safer, more effective treatment for many acute infections of childhood.

Rev Med Suisse Romande, 2002 Dec, 122(12), 606 - 11
{Ambulatory parenteral antibiotics in the treatment of severe pediatric infections}; Krahenbuhl JD et al.; The indications to parenteral antibiotic treatment in paediatrics are frequent . Antibiotic agents with antimicrobial spectrums and pharmacodynamic properties allowing effective and secure outpatient parenteral therapy are now widely available . Outpatient treatment has a number of advantages including important economic benefits . The physician responsible for conducting such treatment should select patients according to strict criteria and never neglect security and quality issues . In this article, the authors discuss different aspects (general, medical, psychosocial, economic and practical) related to outpatient parenteral antibiotic treatment of severe paediatric infections.

Eur J Gastroenterol Hepatol, 2003 Mar, 15(3), 313 - 5
The effect of non-pathogenic Escherichia coli in symptomatic uncomplicated diverticular disease of the colon; Fric P et al.; BACKGROUND: The effect of probiotics in symptomatic uncomplicated diverticular disease of the colon has not been followed . DESIGN: Treatment (T1) with an intestinal antimicrobial (dichlorchinolinol) and absorbent (active coal tablets) was compared with the same set-up supplemented with non-pathogenic Escherichia coli(T2) in a prospective open trial . SETTING: The study was performed at the outpatient department of a tertiary centre . PARTICIPANTS: Fifteen subjects (5 males, 10 females) aged 68-91 years (average 74.8 years) presented with abdominal pain, irregular defecation, bloating and excessive flatulence . Diagnosis was established with colonoscopy, double-contrast barium enema, or both . INTERVENTIONS: The T1 regimen was administered for 1 week . In the T2 regimen, the application of E . coli strain Nissle (Mutaflor capsules, 2.5 x 10(10) viable bacteria/capsule) followed immediately after T1 for an average of 5.2 weeks . MAIN OUTCOME MEASURES: The lengths of two successive remissions with the T1 set-up were compared with the length of remission after T2 . The intensity of symptoms before and after administration of the probiotic was also evaluated.RESULTS The lengths of two successive remissions after T1 amounted to 2.66 and 2.20 months (average 2.43 months) . The average length of remission after T2 was 14.1 months (P < 0.001) . All symptoms after T2 decreased significantly (P < 0.001) . CONCLUSIONS: Non-pathogenic strain Nissle significantly prolonged the remission period and improved the abdominal syndrome in symptomatic uncomplicated diverticular disease . A randomized, placebo-controlled study is recommended.

Microbiol Res, 2003, 158(1), 77 - 81
Combat of iron-deprivation through a plant growth promoting fluorescent Pseudomonas strain GRP3A in mung bean (Vigna radiata L . Wilzeck); Sharma A et al.; Microorganisms and plants sustain themselves under iron-deprived conditions by releasing siderophores . Among others, fluorescent pseudomonads are known to exert extensive biocontrol action against soil and root borne phytopathogens through release of antimicrobials and siderophores . In this study, production and regulation of siderophores by fluorescent Pseudomonas strain GRP3A was studied . Among various media tested, standard succinate medium (SSM) promoted maximum siderophore production of 56.59 mg l(-1) . There were low levels of siderophore in complex media like King's B medium, trypticase soya medium and nutrient medium (41.27, 29.86 and 27.63 mg l(-1)), respectively . In defferrated SSM, siderophore level was quantified to be 68.74 mg l(-1) . Supplementation with iron (FeCl3) resulted in decreased siderophore levels depending on concentration . Siderophore production was promoted by Zn2+ (78.94 mg l(-1)), Cu2+ (68.80 mg l(-1)) whereas Co2+ (57.33 mg l(-1)) and Fe3+ reduced siderophore production (37.44 mg l(-1) as compared to control (55.97 mg l(-1)) . Strain GRP3A showed plant growth promotion under iron limited conditions.

Shokuhin Eiseigaku Zasshi, 2002 Oct, 43(5), 306 - 11
{Effects of veterinary drugs on beta-hexosaminidase release from rat basophilic leukemia cells (RBL-2H3)}; Tanaka Y et al.; Little is known about the effects of residual veterinary drugs on the allergic reaction, except for the antigenicity of antibiotics and synthetic antimicrobials . Therefore, 59 kinds of veterinary drugs were investigated for their effects on the IgE receptor-mediated beta-hexosaminidase release from RBL-2H3 cells as an index of immediate allergic reaction . We found that the antibiotics chlorotetracycline, doxycycline, monensin, the synthetic antimicrobial pyrimethamine and the steroid hormone testosterone inhibited beta-hexosaminidase release . Most of the veterinary drugs showed no action, though the ionophores lasalocid, salinomycin and the steroid hormone hexestrol promoted beta-hexosaminidase release from injured cells . Based on the residual levels of these drugs and the frequencies of detection in actual food samples, it seems unlikely that these drugs have any immediate allergic effect in practice.

Nippon Rinsho, 2003 Jan, 61(1), 129 - 36
{Tailor-made medicine in Helicobacter pylori eradication therapy}; Aoyama N et al.; Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype . The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference . The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole . As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype . CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians . However, we should be aware that the increase of antimicrobial-resistant strains of H . pylori may force us to examine antimicrobial susceptibility of all patients in order to achieve a more than 80% eradication rate at first-line therapy in the near future . We should also have proper knowledge of the influence of the CYP2C19 genetic polymorphism on treatment efficacy according to the variety of PPI and the combination with other drugs.

Nippon Rinsho, 2003 Jan, 61(1), 113 - 8
{A strategy for second-line anti-Helicobacter pylori therapy in eradication-failure patients}; Hojo M et al.; Although available H . pylori eradication regimens in Japan fail to cure 10-20% of patients, an optimal re-treatment therapy for eradication-failure patients has still not been established . Since patient compliance, bacterial resistance and genotypic differences in CYP2C19 influence the eradication rate, re-eradication therapy should be selected, taking them into consideration . In the West, meta-analysis of the second-line treatment of H . pylori infection showed therapies comprising ranitidine bismuth and two antimicrobials are very effective re-treatment therapies irrespective of factors influencing H . pylori eradication . However ranitidine bismuth is not available in Japan and re-eradication therapy consisting of PPI, amoxicillin and metronidazole have been often undertaken and have achieved high eradication rate, even including patients with metronidazole resistant H . pylori.

Nippon Rinsho, 2003 Jan, 61(1), 79 - 83
{The antimicrobial susceptibility test of Helicobacter pylori}; Takahashi S et al.; Now that treatment of H . pylori associated disease is becoming common in Japan, drug resistant--H . pylori has emerged as a problem to be solved . There is no standard method of H . pylori drug susceptibility test in Japan yet . There are several methods available: Disk test, E-test, microplate method and agar plate dilution method . The E-test is being the standard method in European countries and USA . However the microplate method has been reported as a same accuracy as the agar dilution method, and thought as being a new standard method in Japan . In 2000, The Japanese Society of Chemotherapy proposed that drug susceptibility test be standardized and listed the break point of MIC of amoxicillin(AMPC) and clarithromycin(CAM).

Farm Hosp, 2003 Jan-Feb, 27(1), 31 - 7
{Evolution of antimicrobial use during the years 1996-2000 in a general hospital . A detailed ICU study}; Hermosilla Najera L et al.; PURPOSE: Antimicrobials are a mayor part of hospital pharmacy budgets and must be considered in resource planning and spending projections . This study describes the profile of antibiotic use at a medium-sized hospital (by examining the ICU separately) and analyses its evolution over the period 1996-2000 . METHODS: Descriptive and retrospective study . Pharmacy records were reviewed to identify oral and parenteral antimicrobial agents administered to inpatients . Results were expressed in Daily Defined Doses (DDD) per 100 stays and day . RESULTS: During the five-year study period 176.162 DDD / 100 s-d of antibiotics were consumed in the ICU, whereas in the rest of the hospital usage was much lower (54.540 DDD / 100 s-d) . Aminoglycosides, cephalosporins, penicillins, glycopeptides and carbapenems were the most commonly used groups of antimicrobials in the ICU, and penicillins, cephalosporins, trimethoprim/sulfonamide combinations, aminoglycosides and quinolones in the rest of the hospital . CONCLUSIONS: ICUs have some special features which make them different to the rest of inpatient areas . Because of that fact we consider important to study this specific patient-care area separately.

J Biol Chem, 2003 Jun 6, 278(23), 20851 - 9 Epub 2003 Feb 26.
Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data; Kuo MR et al.; Tuberculosis and malaria together result in an estimated 5 million deaths annually . The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties . Although genetically unrelated, both organisms use a type II fatty-acid synthase system . Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target . Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M . tuberculosis and P . falciparum enzyme (referred to as InhA and PfENR, respectively) . The crystal structure of InhA complexed with NAD+ and one of the inhibitors was determined to elucidate the mode of binding . Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR:triclosan structures, or harbored two triclosan molecules bound to the active site . Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M . tuberculosis and P . falciparum . Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization.

Antimicrob Agents Chemother, 2003 Mar, 47(3), 965 - 71
Modulation of the activity of secretory phospholipase A2 by antimicrobial peptides; Zhao H et al.; The antimicrobial peptides magainin 2, indolicidin, and temporins B and L were found to modulate the hydrolytic activity of secretory phospholipase A(2) (sPLA(2)) from bee venom and in human lacrimal fluid . More specifically, hydrolysis of phosphatidylcholine (PC) liposomes by bee venom sPLA(2) at 10 micro M Ca(2+) was attenuated by these peptides while augmented product formation was observed in the presence of 5 mM Ca(2+) . The activity of sPLA(2) towards anionic liposomes was significantly enhanced by the antimicrobial peptides at low {Ca(2+)} and was further enhanced in the presence of 5 mM Ca(2+) . Similarly, with 5 mM Ca(2+) the hydrolysis of anionic liposomes was enhanced significantly by human lacrimal fluid sPLA(2), while that of PC liposomes was attenuated . These results indicate that concerted action of antimicrobial peptides and sPLA(2) could improve the efficiency of the innate response to infections . Interestingly, inclusion of a cationic gemini surfactant in the vesicles showed an essentially similar pattern on sPLA(2) activity, suggesting that the modulation of the enzyme activity by the antimicrobial peptides may involve also charge properties of the substrate surface.

Antimicrob Agents Chemother, 2003 Mar, 47(3), 941 - 7
Alteration of Escherichia coli topoisomerase IV to novobiocin resistance; Hardy CD et al.; DNA gyrase and topoisomerase IV (topo IV) are the two essential type II topoisomerases of Escherichia coli . Gyrase is responsible for maintaining negative supercoiling of the bacterial chromosome, whereas topo IV's primary role is in disentangling daughter chromosomes following DNA replication . Coumarins, such as novobiocin, are wide-spectrum antimicrobial agents that primarily interfere with DNA gyrase . In this work we designed an alteration in the ParE subunit of topo IV at a site homologous to that which confers coumarin resistance in gyrase . This parE mutation renders the encoded topo IV approximately 40-fold resistant to inhibition by novobiocin in vitro and imparts a similar resistance to inhibition of topo IV-mediated relaxation of supercoiled DNA in vivo . We conclude that topo IV is a secondary target of novobiocin and that it is very likely to be inhibited by the same mechanism as DNA gyrase.

Antimicrob Agents Chemother, 2003 Mar, 47(3), 932 - 40
In vivo killing of Porphyromonas gingivalis by toluidine blue-mediated photosensitization in an animal model; Komerik N et al.; Porphyromonas gingivalis is one of the major causative organisms of periodontitis and has been shown to be susceptible to toluidine blue-mediated photosensitization in vitro . The aims of the present study were to determine whether this technique could be used to kill the organism in the oral cavities of rats and whether this would result in a reduction in the alveolar bone loss characteristic of periodontitis . The maxillary molars of rats were inoculated with P . gingivalis and exposed to up to 48 J of 630-nm laser light in the presence of toluidine blue . The number of surviving bacteria was then determined, and the periodontal structures were examined for evidence of any damage . When toluidine blue was used together with laser light there was a significant reduction in the number of viable P . gingivalis organisms . No viable bacteria could be detected when 1 mg of toluidine blue per ml was used in conjunction with all light doses used . On histological examination, no adverse effect of photosensitization on the adjacent tissues was observed . In a further group of animals, after time was allowed for the disease to develop in controls, the rats were killed and the level of maxillary molar alveolar bone was assessed . The bone loss in the animals treated with light and toluidine blue was found to be significantly less than that in the control groups . The results of this study show that toluidine blue-mediated lethal photosensitization of P . gingivalis is possible in vivo and that this results in decreased bone loss . These findings suggest that photodynamic therapy may be useful as an alternative approach for the antimicrobial treatment of periodontitis.

Eur J Biochem, 2003 Mar, 270(5), 911 - 20
Distinguishing between different pathways of bilayer disruption by the related antimicrobial peptides cecropin B, B1 and B3; Chen HM et al.; Different pathways of bilayer disruption by the structurally related antimicrobial peptides cecropin B, B1 and B3, revealed by surface plasma resonance analysis of immobilized liposomes, differential scanning calorimetry of peptide-large unilamellar vesicle interactions, and light microscopic analysis of peptide-treated giant unilamellar vesicles, have been identified in this study . Natural cecropin B (CB) has one amphipathic and one hydrophobic alpha-helix, whereas cecropins B1 (CB1) and B3 (CB3), which are custom-designed, chimaeric analogues of CB, possess either two amphipathic or two hydrophobic alpha-helices, respectively . Surface plasma resonance analysis of unilamellar vesicles immobilized through a biotin-avidin interaction showed that both CB and CB1 bind to the lipid bilayers at high concentration (>10 microm); in contrast, CB3 induces disintegration of the vesicles at all concentrations tested . Differential scanning calorimetry showed the concentration-dependent effect of bilayer disruption, based on the different thermotrophic phase behaviours and the shapes of the thermal phase-transition curves obtained . The kinetics of the lysis of giant unilamellar vesicles observed by microscopy demonstrated that both CB and CB1 effect a continuous process involving loss of integrity followed by coalescence and resolution into smaller vesicles, whereas CB3 induces rapid formation of irregular-shaped, nonlamellar structures which rapidly disintegrate into twisted, microtubule-containing debris before being completely destroyed . On the basis of these observations, models by which CB, CB1 and CB3 induce lysis of lipid bilayers are discussed.

Eur Biophys J, 2002 Dec, 31(7), 554 - 8
Effects of membranotropic agents on mono- and multilayer structures of dipalmitoylphosphatidylcholine; Lisetski LN et al.; We have studied the action of some membranotropic agents (MTAs) on the parameters of mono- and multilayers of dipalmitoylphosphatidylcholine (DPPC) . The MTAs used included an antimicrobial drug, decamethoxinum, the model amphiphilic agent stearoyl-L-alpha-alanine, and cholesterol as a reference substance . Using differential scanning calorimetry and the Langmuir monolayer technique, we measured the temperature and enthalpy of the main phase transition of DPPC, the mean molecular area, the collapse pressure and the free energy of the mixed monolayers of DPPC and MTA . A good correlation has been obtained between the structure of the MTA used and changes in the parameters of both mono- and multilayers . Thus, for cholesterol, its well-known condensing effect in the L alpha phase correlates with its behavior in the mixed monolayers . The disturbing action of decamethoxinum (depression of the phase transition in DPPC multilayers and relatively high free energy of mixing in monolayers) is presumably connected with interaction of its charged ammonium moieties with polar phospholipid heads . At the same time, stearoyl-L-alpha- alpha-alanine condensed the lipid layers and increased the melting point of DPPC, owing to its interaction with both polar and non-polar lipid moieties . One can conclude that the three MTAs used can really be considered as representative examples of three different types of behavior in mono- and multilayers.

Biopolymers, 2003 Mar, 68(3), 407 - 21
Application of the empirical force field to macrocyclic ion carriers, siderophores, and biomimetic analogs; Felder CE et al.; The empirical force field (EFF), developed by Prof . Lifson, was applied to the study of macrocyclic alkali ion carriers and to di- and tripodal and open chain siderophores and synthetic biomimetic molecules binding transition metals . The highly symmetric nature of these structures facilitated a favorable coordination geometry of the ligating groups about the metal, which helped organize the entire molecule into a fairly rigid structure . In our combined experimental-theoretical approach, EFF calculations were used to help predict likely candidates to synthesize, and provided a wealth of structural data to complement what we learned from the spectroscopic measurements, while feedback from these measurements allowed us to continue improving the EFF itself . The simple, highly modular design of the biomimetic analogs allowed rapid synthesis and systematic examination of a large number of related structures, as well as facilitating an efficient, piecewise conformational scanning for the theoretical calculations . In the early years, we focused on macrocyclic polylactones and lactams binding monovalent alkali ions, particularly the natural products enniatin and valinomycin, including inside a crystal lattice . Later we switched to bi- and tridentate siderophores, natural microbial iron carriers, and synthetic biomimetic analogs-in particular, of enterobactin, ferrichrome, and ferrioxamine B . Over the years a large number of biomimetic siderophores have been prepared, some active in a broad range of microorganisms while others are highly species specific . The results of this work have broad applications in many areas, including the design of novel drugs and antimicrobial agents, helical polymeric structures, and polynuclear metal complexes .

J Biomed Mater Res A, 2003 Mar 15, 64(4), 591 - 9
Fibroblast growth on surface-modified dental implants: an in vitro study; Groessner-Schreiber B et al.; A major consideration in designing dental implants is the creation of a surface that provides strong attachment between the implant and bone, connective tissue, or epithelium . In addition, it is important to inhibit the adherence of oral bacteria on titanium surfaces exposed to the oral cavity to maintain plaque-free implants . Previous in vitro studies have shown that titanium implant surfaces coated with titanium nitride (TiN) reduced bacterial colonization compared to other clinically used implant surfaces . The aim of the present study was to examine the support of fibroblast growth by a TiN surface that has antimicrobial characteristics . Mouse fibroblasts were cultured on smooth titanium discs that were either magnetron-sputtered with a thin layer of titanium nitride, thermal oxidized, or modified with laser radiation (using a Nd-YAG laser) . The resulting surface topography was examined by scanning electron microscopy (SEM), and surface roughness was estimated using a two-dimensional contact stylus profilometer . A protein assay (BCA assay) and a colorimetric assay to examine fibroblast metabolism (MTT) were used . Cellular morphology and cell spreading were analyzed using SEM and fluorescence microscopy . Fibroblasts on oxidized titanium surfaces showed a more spherical shape, whereas cells on laser-treated titanium and on TiN appeared intimately adherent to the surface . The MTT activity and total protein were significantly increased in fibroblasts cultured on titanium surfaces coated with TiN compared to all other surface modifications tested . This study suggests that a titanium nitride coating might be suitable to support tissue growth on implant surfaces .

Phytother Res, 2003 Feb, 17(2), 168 - 73
Cytotoxic sesquiterpene lactones from Centaurothamnus maximus and Vicoa pentanema; Muhammad I et al.; The aerial parts of Centaurothamnus maximus yielded three cytotoxic guaianolides, chlorojanerin (1), cynaropicrin (2) and janerin (3) . The structure elucidation of 1-3 was based on (1)H and (13)C NMR data, mainly 2D-NMR (1)H-(1)H COSY and (1)H-(13)C HETCOR experiments . Compounds 1-3 showed in vitro cytotoxic activity against human cancer cell lines of malignant melanoma (SK-MEL), epidermoid (KB), ductal (BT-549) and ovarian (SK-OV-3) carcinomas with IC(50) values of 2-6 microgram/mL . In addition, 12 sesquiterpene lactones (4-15), isolated previously from the aerial parts of Vicoa pentanema, were evaluated for cytotoxic and antimicrobial activities . 2alpha- Acetoxy-3beta-hydroxyalantolactone (10) and 8beta-hydroxyparthenolide (14) were found to be the main cytotoxic agents (IC(50) values of 2-6 microgram/mL against SK-MEL, BT-549 and SK-OV-3), while lactones 4, 5, 11 and 15 selectively inhibited the growth of human malignant melanoma (IC(50) value of 3.6-7.3 microgram/mL) . Cell aggregation and cell adhesion assays, using HL-60 and HeLa cell lines, evaluated the effect of cytotoxic constituents 1-3, 10 and 14 on immune response and inflammation .

Phytother Res, 2003 Feb, 17(2), 152 - 4
Composition and antimicrobial activity of the essential oil of Hypericum rumeliacum subsp . apollinis (Boiss . & Heldr.); Couladis M et al.; The composition and the antimicrobial activity of the aerial parts of Hypericum rumeliacum are reported . Analysis was carried out by GC/MS . The major constituents were alpha-pinene (43.80%), beta-pinene (9.82%), dehydro-aromadendrene (6.81%) and alpha-copaene (5.41%) . The essential oil showed a moderate in vitro activity against the six Gram negative and positive bacteria and a stronger one against the three-tested pathogenic activity .

Ann Hematol, 2003 Feb, 82(2), 98 - 103 Epub 2003 Feb 05.
Procalcitonin: a useful discriminator between febrile conditions of different origin in hemato-oncological patients?
Schuttrumpf S, Binder L, Hagemann T, Berkovic D, Trumper L, Binder C.
Plasma concentrations of procalcitonin (PCT) have been shown to be elevated in bacterial and fungal infections . In contrast to C-reactive protein (CRP), PCT is not elevated in inflammations of noninfectious origin . Febrile inflammatory conditions are frequent in patients with hemato-oncological diseases . A reliable marker to discriminate infectious inflammations from drug-related and tumor-associated fever is still lacking . To evaluate the impact of PCT in this setting, PCT and CRP were prospectively measured in 95 febrile hemato-oncological patients . Infections could be identified in 40 of 95 patients: 38 of 95 had fever of unknown origin (FUO), 9 patients were suspected to suffer from drug-related fever, and 8 patients from tumor-associated fever . In the noninfection group (drug-related and tumor-associated fever), PCT levels were significantly lower than in patients with infections (P<0.001) or FUO (P<0.001) . Differences were still highly significant comparing patients with suspected drug-related or tumor-associated fever alone with the infection or the FUO cohort . All eight patients with tumor-associated fever as well as eight of the nine patients with drug-related fever had PCT levels within the normal range (<0.5 micro g/l) . CRP values only partially allowed discrimination between the various subgroups . Differences were significant between patients with drug-related fever and the infection (P=0.001) or FUO group (P=0.004) . However, as CRP levels were far above the normal range also in the patients with drug-related fever, the significance of individual values was rather limited . In conclusion, PCT may provide useful additional information to assess the clinical significance of febrile conditions . PCT may facilitate the decision on when to initiate antimicrobial or cytotoxic therapy.

Am J Respir Cell Mol Biol, 2003 Jun, 28(6), 738 - 45 Epub 2002 Dec 30.
The antimicrobial activity of the cathelicidin LL37 is inhibited by F-actin bundles and restored by gelsolin; Weiner DJ et al.; Antimicrobial peptides are part of the innate host defense system, and inactivation of these peptides is implicated in airway infections in cystic fibrosis (CF) . The sputum of patients with CF contains anionic polyelectrolytes, including F-actin and DNA not found in normal airway fluid . These anionic filaments aggregate to contribute to the altered viscoelastic properties of CF sputum . We hypothesized that the airway components stabilizing bundles of F-actin and DNA are in part cationic antimicrobial agents, and that appropriate modification of diseased airway fluid of patients with CF might dissociate these bundles and restore antimicrobial activity . We demonstrate that the human cathelicidin peptide LL37 forms bundles with F-actin and DNA, which are dissolved by gelsolin and DNase, respectively . Coincident with bundle formation, antimicrobial activity of LL37 is inhibited by F-actin and DNA . Pseudomonas bacteria were killed by low concentrations of LL37, but killing was significantly reduced in the presence of F-actin . The actin filament-fragmenting protein gelsolin restored bactericidal activity nearly completely . In a growth inhibition assay, the effects of F-actin were confirmed, and DNA was also shown to inhibit the activity of LL37 . When added to CF sputum, gelsolin significantly reduced the growth of bacteria, suggesting activation of endogenous antimicrobial factors . These findings may have therapeutic implications for treatments previously thought to alter only the viscoelastic properties of airway secretions and amplify the possible advantage of gelsolin in CF treatment.

Am J Respir Cell Mol Biol, 2003 Jul, 29(1), 71 - 80 Epub 2003 Jan 23.
ORFeome-based search of airway epithelial cell-specific novel human {beta}-defensin genes; Kao CY et al.; beta-Defensin is one of the major host defense shields produced by various tissues and organs against microbial infection . To date, four human beta-defensins (DEFBs) gene products that share a consensus six-cysteine motif have been discovered . The hidden Markov model (HMM) profile was constructed from the common features of those known beta-defensin peptides to search for additional novel DEFB genes . A genome-wide search of the profile against ORFeome-based peptide databases (e.g., Ensembl project) led to the identification of six new DEFB members that also shared the conserved six-cysteine motif . Phylogenetic analysis supported a close relationship of these six new members with existing DEFB genes . Polymerase Chain Reaction studies of human tissue cDNA panels confirmed the expression of all six novel DEFB genes in various tissues . Two of them, DEFB106 and DEFB109, were expressed in the lung . A pilot study with cRNA probes for in situ hybridization and a synthetic propeptide for the functional characterization demonstrated the tissue-/cell-specific expression and the strong antimicrobial activity of DEFB106 . These results support the utility of ORFeome-based HMM search in gene discovery for members of a specific gene family . The novel DEFB genes identified in this study may significantly contribute to overall antimicrobial host defenses.

Jpn J Antibiot, 2002 Sep, 55 Suppl A, 111 - 8
{Antimicrobial susceptibility and beta-lactamase productivity of recent clinical isolates during the period between December 1999 and February 2000}; Notake S et al.; Antimicrobial susceptibility testings of 24 antimicrobial agents against 605 clinical strains belonging to 10 species were carried out according to the micro-broth dilution method of NCCLS M7-A4 . The productivity of beta-lactamase was also determined against them isolated at 8 medical facilities in Nagano prefecture, Japan during the period between December 1999 and February 2000 . When applied the nitrocefin method, beta-lactamase productivity was demonstrated to be positive for 89.2% of 74 S . aureus, 4.3% of 94 H . influenzae, and 100% of 69 M . (B.) catarrhalis isolates . On the other hand, when used the acidometry method, penicillinase/cephalosporinase were found to be positive for 21.2%/9.6% of 52 E . coli, 29.0%/3.2% of 31 K . pneumoniae, 53.2%/100% of 47 E . cloacae, 0%/11.1% of 99 S . marcescens, and 25.9%/55.6% of 54 P . aeruginosa isolates, respectively . Among the beta-lactamase-producers including P . aeruginosa isolates, only 2 E . coli isolates were found to be ESBL-producers . Besides, 9.6% (9/94) of H . influenzae isolates were proved to be BLNAR strains.

Hua Xi Yi Ke Da Xue Xue Bao, 2002 Jan, 33(1), 87 - 90
{Isolation and purification of antibacterial polypeptides from human LAK cells}; Zhang Q et al.; OBJECTIVE: To isolate and purify new antibiotic peptides from human lymphokine activated killer (LAK) cells . METHODS: Preparative Acid-Urea Polyacrylamide Gel Electrophoresis and Reverse Phase HPLC were performed to isolate and purify polypeptides from the acid extract of human LAK cells . The molecule weight was analyzed by Tricine-SDS-PAGE . Radial agar diffusion assay was used to analyze the antibacterial activities . RESULTS: Several antibiotic peptides were isolated . Two peptides were purified from fractions HLP-2, HLP-3, which had molecular weight of around 7.9 x 10(3) u and 4 x 10(3) u and were named HLP-2b and HLP-3a, respectively . Four peptides with molecular weight of 7.2 x 10(3) u, 10.4 x 10(3) u, 6.2 x 10(3) u and 6.2 x 10(3) u were almost purified and were named HLP-2a, HLP-2c, HLP-3b and HLP-3c, respectively . HLP-2b, HLP-2a, HLP-2c, HLP-3b and HLP-3c all had antimicrobial activities against S . Aureus and C . Albicans, and HLP-3a against S . Aureus only . CONCLUSION: Human LAK cells contained a variety of antimicrobial peptides.

Trends Microbiol, 2003 Feb, 11(2), 80 - 6
The basis of persistent bacterial infections; Rhen M et al.; Selected bacterial pathogens, such as Helicobacter pylori and Mycobacterium tuberculosis, establish persistent infections in mammalian hosts despite activating inflammatory and antimicrobial responses . The strategies used to overcome host defense responses vary with the anatomical location of the infection but often rely on deliberate manipulations of the host cell responses . Phylogenetically unrelated bacteria can share similar strategies for the establishment of persistence and, in selected examples, one even can define homologous "persistence" genes . Such observations suggest that persistent infection is a specific phase in infection pathogenesis rather than a fortuitous imbalance in the host-pathogen interaction.

Chem Phys Lipids, 2003 Jan, 122(1-2), 107 - 20
Interaction of antimicrobial peptides from Australian amphibians with lipid membranes; Marcotte I et al.; Solid-state NMR and CD spectroscopy were used to study the effect of antimicrobial peptides (aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1) from Australian tree frogs on phospholipid membranes . 31P NMR results revealed some effect on the phospholipid headgroups when the peptides interact with DMPC/DHPC (dimyristoylphosphatidylcholine/dihexanoylphosphatidylcholine) bicelles and aligned DMPC multilayers . 2H NMR showed a small effect of the peptides on the acyl chains of DMPC in bicelles or aligned multilayers, suggesting interaction with the membrane surface for the shorter peptides and partial insertion for the longer peptides . 15N NMR of selectively labelled peptides in aligned membranes and oriented CD spectra indicated an alpha-helical conformation with helix long axis approximately 50 degrees to the bilayer surface at high peptide concentrations . The peptides did not appear to insert deeply into PC membranes, which may explain why these positively charged peptides preferentially lyse bacterial rather than eucaryotic cells.

Urology . 2003 Feb;61(2):462.
Osteomyelitis of the pubis: a complication of a chronic indwelling catheter; Stern JA et al.; Pubic osteomyelitis typically occurs after pelvic surgery or trauma . We present a case of pubic osteomyelitis ensuing from a chronic indwelling (for 8 years) urethral catheter in a 40-year-old woman . She presented initially with fever of unknown origin, and broad-spectrum antimicrobial therapy was initiated . Computed tomography of the abdomen and pelvis ultimately revealed cortical destruction of the pubic symphysis, and open biopsy confirmed osteomyelitis . Osteomyelitis of the pubis is a rare entity that typically results from bacteremia, trauma, or the spread of an adjacent focus of infection from previous pelvic surgery . To our knowledge, this is the first report of pubic osteomyelitis resulting from a chronic indwelling urethral catheter.

Crit Care Nurs Clin North Am, 2003 Mar, 15(1), 79 - 87
The role of early enteral nutrition in protecting premature infants from sepsis; Strodtbeck F; Care of critically ill, preterm infants is a major challenge . Because of their small size and complex health problems, preterm infants require long-term hospitalization in the intensive care unit where they are exposed to serious microorganisms and other antigens that can overwhelm their immature immune systems . As smaller and more fragile preterm infants are surviving NICU care, these infants are at increased risk for nosocomial infections . Although modern antimicrobial agents are invaluable in the management of infection, they can result in biologic stress to the immature physiology of the preterm infant . Nonpharmacologic strategies to enhance the immunocompetence of the preterm immune systems provide another alternative in the management of these infants . Because the gastrointestinal tract is one of the largest immune organs within the body, strategies to maximize its immune functions can improve the outcome of these infants and help prevent or minimize the risk of infection . One such strategy is the early introduction of enteral feedings designed to stimulate or prime the gut . Early introduction of enteral feedings in the acutely ill preterm infant appears to be well tolerated in a variety of small clinical studies . Although the studies vary considerably in design and variables measured, collectively they show a solid trend toward improved outcomes . By preventing the negative consequences of a prolonged period of NPO, early enteral feedings promote the normal processes of the gut as a physical, mechanical, physiologic, and immunologic barrier . A solid understanding of the pathophysiology of prolonged NPO status and the physiology of the gut's immune properties enables critical care nurses to improve care of these vulnerable NICU patients.

Surg Infect (Larchmt), 2000, 1(1), 31 - 8
Diagnosis and treatment of intra-abdominal abscesses; Sirinek KR; Despite recent advances in the diagnosis and management of intra-abdominal abscesses, these infections still cause substantial morbidity and mortality . Low pH, large bacterial inocula, poor perfusion, the presence of hemoglobin, and large amounts of fibrin (which impedes antibiotic penetration) make the abscess a cloistered environment that is penetrated poorly by many antimicrobial therapies . Therefore, management of these infections requires prompt recognition, early localization, and effective drainage, as well as appropriate antimicrobial use . Although various imaging techniques, such as ultrasonography, gallium scans, and indium-labeled white-blood-cell scans, can be used for the diagnosis and localization of intra-abdominal abscesses, computer-assisted tomography is the most useful study . Once the diagnosis is made and the abscess is localized, treatment should begin promptly . Percutaneous or open surgical drainage should be used . Broad-spectrum antibiotics should be given until culture and sensitivity data are obtained . Once these data are obtained, a therapy with appropriate coverage that is likely to work in the abscess environment should be chosen . Percutaneous drainage is inappropriate for abscesses in the posterior subphrenic space or in the porta hepatis, for those among loops of small bowel, for suspected echinococcal cysts, and for abscesses containing necrotic or neoplastic tissues . Finally, surgeons need to be cognizant of risk factors, such as advanced age, obesity, complex abscesses, and high Acute Physiology and Chronic Health Evaluation (APACHE) II or APACHE III scores, which correlate with poor outcomes for these patients.

Surg Infect (Larchmt), 2000 Summer, 1(2), 115 - 23; discussion 125-6
Surgeons and infectious disease specialists: different attitudes towards antibiotic treatment and prophylaxis in common abdominal surgical infections; Gorecki PJ et al.; BACKGROUND: The role of medical infectious disease (ID) specialists in the treatment of surgical infections is increasing but no information is available regarding the therapeutic perception held by these non-surgeons treating surgical infections . The purpose of this study was to assess the attitude of the ID specialists towards antibiotic treatment and prophylaxis of common abdominal surgical infections and to compare it with that of surgeons "interested" in this field . METHODS: A questionnaire, polling opinions regarding the management of common surgical infections, was sent to 396 medical ID specialists (New York State) and 515 surgeon members of the Surgical Infection Society (SIS) . The questions covered areas involving choice of antibiotics, and timing and duration of treatment in given clinical scenarios, including elective and emergent colorectal surgery, perforated peptic ulcer, and appendicitis . RESULTS: Response rates for the medical and surgical groups were 10.1% and 15.6%, respectively . Regarding prophylactic use of antimicrobials, the pattern of administration was similar for the two groups . Regarding therapeutic use, on average medical ID specialists used antibiotics twice as long as the surgical group . The main reason identified was the failure of medical ID specialists to understand the conceptual difference between contamination and infection . CONCLUSIONS: Medical ID specialists may overtreat common surgical infections with antibiotics . Surgical infections should be treated by surgeons.

Surg Infect (Larchmt), 2001 Summer, 2(2), 145 - 50; discussion 150-2
Necrotizing soft tissue infections: are we making any progress?
Malangoni MA.
BACKGROUND: Necrotizing soft tissue infections are a group of diseases with significant associated mortality . A wide spectrum of bacteria can be involved, and diagnosis can be difficult . METHODS: Review of pertinent literature of the diagnosis and therapy of necrotizing soft-tissue infection . RESULTS: Mortality and other adverse outcomes are directly related to advanced age, the presence of organ system failure, lactic acidemia, the percentage of body surface area involved with infection, and delays in operative management . Patients usually die early from the consequences of septic shock, whereas late mortality is related to multiple organ failure . CONCLUSION: Early recognition and treatment can lower mortality from necrotizing soft tissue infection . Prompt operative debridement, broad-spectrum antimicrobials, and physiologic support are important components of treatment.

Surg Infect (Larchmt), 2001, 2 Suppl 1, S23 - 32
The role of beta-lactam/beta-lactamase inhibitor combinations in surgical infections; Sayek I; Many surgical infections are characterized by synergistic polymicrobial mixed infection, for which broad-spectrum antimicrobial therapy is usually administered on an empiric basis . Until relatively recently, standard empiric therapeutic regimens have involved the use of two or more antibiotics, such as aminoglycosides and anti-anaerobic agents, to achieve adequate aerobic and anaerobic coverage . There are often substantial drawbacks, however, such as drug-induced toxicity and high costs of treatment . Evidence from a number of clinical studies suggests that single-agent therapy with beta-lactam/beta-lactamase inhibitor combinations is a suitable and cost-effective alternative to multidrug regimens, as well as to monotherapy with cephalosporins or carbapenems in the treatment of intra-abdominal, gynecologic, and diabetic foot infections, and brain abscesses . These agents are also suitable for use in perioperative prophylaxis and may offer benefits over other agents in terms of reduced incidence of surgical wound infections and lower costs.

FASEB J, 2003 Apr, 17(6), 776 - 8 Epub 2003 Feb 19.
The N- and C-terminal fragments of ubiquitin are important for the antimicrobial activities; Kieffer AE et al.; Secretory granules of chromaffin cells contain catecholamines and several antimicrobial peptides derived from chromogranins and proenkephalin-A . These peptides are secreted in the extracellular medium following exocytosis . Here, we show that ubiquitin is stored in secretory chromaffin granules and released into the circulation upon stimulation of chromaffin cells . We also show that the C-terminal fragment (residues 65-76) of ubiquitin displays, at the micromolar range, a lytic antifungal activity . Using confocal laser scan microscopy and rhodamine-labeled synthetic peptides, we could demonstrate that the C-terminal peptide (residues 65-76) is able to cross the cell wall and the plasma membrane of fungi and to accumulate in fungi, whereas the N-terminal peptide (residues 1-34) is stopped at the fungal wall level . Furthermore, these two peptides act synergistically to kill filamentous fungi . Because of the interaction of the C-terminal sequence of ubiquitin with calmodulin, the synthetic peptide (residues 65-76) was tested in vitro against calmodulin-dependent calcineurin, an enzyme crucial for fungal growth . This peptide was found to inhibit the phosphatase activity of calcineurin . Our data show a new property of ubiquitin C-terminal-derived peptide (65-76) that could be used with N-terminal peptide (1-34) as a new potent antifungal agent.

Int J Food Microbiol, 2003 May 15, 82(3), 273 - 9
Isolation of Escherichia coli O157:H7 from foods in Greece; Dontorou C et al.; The presence of Escherichia coli O157:H7 in various foods of animal origin was surveyed in northwestern Greece . Six hundred samples of unpasteurized cows', ewes' and goats' milk, raw minced meat, uncooked frozen beef hamburgers, sandwiches (containing ham or turkey, mixed vegetable salad with mayonnaise and lettuce), fresh traditional Greek pork sausages and swine intestines appropriate for traditional Greek kokoretsi were assayed for E . coli serogroup O157:H7 using the standard cultural method and the immunomagnetic separation technique . The pathogen was detected in 1 out of 100 (1.0%) samples of ewes' milk, 1 out of 75 (1.3%) fresh sausages and 1 out of 50 (2.0%) swine intestines prepared for kokoretsi . The isolated strains were nonsorbitol fermenters, MUG-negative, O157 agglutinating, verotoxin-producing and carried both VT1 and VT2 genes . The three isolated strains were tested for antibiotic resistance and were found to be susceptible to eight antimicrobial agents (ampicillin, chloramphenicol, kanamycin, nalidixic acid, norfloxacin, streptomycin, sulfamethoxazole-trimethoprim and tetracycline).

Eur J Med Chem, 2003 Jan, 38(1), 89 - 100
Synthesis and preliminary evaluation of some N-{5-(2-furanyl)-2-methyl-4-oxo-4H-thieno{2,3-d}pyrimidin-3-yl}-carboxamide and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno{2,3-d}pyrimidin-4-ones as antimicrobial agents; Chambhare RV et al.; Two series of N-{5-(2-furanyl)-2-methyl-4-oxo-4H-thieno{2,3-d}pyrimidin-3-yl}-carboxamide (4a-m) and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno{2,3-d}pyrimidin-4-ones (5a-m) were synthesised using appropriate synthetic route . All the test compounds 4a-m and 5a-m were assayed in vitro for antibacterial activity against two different strains of Gram-negative (Escherichia coli and S . typhi) and Gram-positive (S . aureus, B . subtilis) bacteria and the antimycobacterial activity was evaluated against M . tuberculosis and M . avium strains . The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards . The test compounds have shown significant antibacterial and antimycobacterial activity against all the microbial strains used, when tested in vitro . In general, along with the thienopyrimidinone ring, substituted amido or imino side chain at position 3 is essential for antimicrobial activity . Among the compounds tested, compounds 4c, 4e and 4g in N-{5-(2-furanyl)-2-methyl-4-oxo-4H-thieno{2,3-d}pyrimidin-3-yl}-carboxamide series and compounds 5c, 5e and 5g in 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno{2,3-d}pyrimidin-4-ones series were found to be the most potent . Further the toxicity of most potent compounds 4c, 4e and 4g and 5c, 5e and 5g were assessed using hemolytic assay and minimal hemolytic concentration (MHCs) were determined . In general, test compounds were found to be non-toxic up to a dose level of 200 micromol L(-1) (MHC) .

World Health Organ Tech Rep Ser, 2002, 911, i - vi, 1-66, back cover
Evaluation of certain veterinary drug residues in food; Joint FAO/WHO Expert Committee on Food Additives; This report presents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues in food . The first part of the report considers risk assessment principles and presents the views of the Committee on the FAO/WHO Project to update principles and methods for the risk assessment of chemicals in food . Summaries follow of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: three anthelminthic agents (doramectin, ivermectin and tiabendazole), seven antimicrobial agents (cefuroxime, dihydrostreptomycin and streptomycin, lincomycin, neomycin, oxytetracycline and thiamphenicol), four insecticides (cyhalothrin, cypermethrin and alpha-cypermethrin, and phoxim) and one production aid (melengestrol acetate) . Annexed to the report is a summary of the Committee's recommendations on these drugs, including Acceptable Daily Intakes and Maximum Residue Limits and further information required.

Lijec Vjesn, 2002 Sep, 124 Suppl 1, 72 - 8
{Helicobacter pylori--overview of therapy}; Katicic M et al.; The clinical significance of Helicobacter pylori infection in the etiopathogenesis of many gastroduodenal disorders, especially peptic ulcer disease and current awareness of the benefits of its eradication has entirely changed the current treatment of these diseases . Eradication was already defined as the disappearance of Helicobacter pylori from the gastric mucosa (finding negativization) confirmed at least 4 weeks (or later) after completed antibiotic eradication therapy . The regimen has to be simple, cheap and tolerable so that the patient could carry it out completely and as easy as possible (good compliance is required) . The success of Helicobacter pylori eradication, evaluated by the strict "intention-to-treat" criteria, has to be higher than 80% . Current modern therapy should be triple and not longer than 7 days . One of three proton pump inhibitors is recommended as the antisecretory component (omeprazole, pantoprazole or lansoprazole) . Two of three following antibiotis is added to this therapy: metronidazole/tinidazole, clarithromycin or amoxicillin . Treatment failure and growing number of antimicrobial resistant Helicobacter pylori strains require new ways of therapy and more effective drugs . Our results of 7-, 10- and 14-day therapy consisting of omeprazole, amoxicillin and metronidazole are poorer than those of drug combination including clarithromycin instead of amoxicillin . The results of Clinical Hospital "Merkur" showed that combination of amoxicillin, metronidazole and pantoprazole was more effective than the same combination with omeprazole, and the opposite was true for metronidazole and azithromycin combined with omeprazole and pantoprazole, respectively . The results of other medical centers prescribing the same eradication protocols were completely different . The differences are probably caused by poor patient compliance.

J Allergy Clin Immunol, 2003 Feb, 111(2 Suppl), S548 - 59
10 . Drug allergy; Gruchalla RS; Adverse drug reactions are common, but only 6% to 10% are immunologically mediated . Unlike most adverse drug reactions, allergic drug reactions are unpredictable . Whereas some drug-induced allergic reactions may be easily classified into one of the four Gell and Coombs hypersensitivity categories, many others that appear to have an immunologic component cannot be classified because of our lack of mechanistic information . Theoretically, any drug can induce an immune response . However, some drugs are more likely to elicit clinically relevant immune responses than are others . Drugs in this category include antimicrobial drugs, anticonvulsants, chemotherapeutic agents, heparin, insulin, protamine, and biologic response modifiers . After a drug-disease connection is established, it must be determined whether the reaction was immunologically mediated . Subsequently, confirmatory tests, if available, should be used to determine the allergic status of the patient . If these tests are not available, a graded challenge or desensitization may be considered, depending on the type of clinical reaction previously demonstrated and the need for drug readministration . Education of the patient and primary care physician is an important component of patient management.

Protein Sci, 2003 Mar, 12(3), 438 - 46
Solution structure of termicin, an antimicrobial peptide from the termite Pseudacanthotermes spiniger; Da Silva P et al.; The solution structure of termicin from hemocytes of the termite Pseudacanthotermes spiniger was determined by proton two-dimensional nuclear magnetic resonance spectroscopy and molecular modeling techniques . Termicin is a cysteine-rich antifungal peptide also exhibiting a weak antibacterial activity . The global fold of termicin consists of an alpha-helical segment (Phe4-Gln14) and a two-stranded (Phe19-Asp25 and Gln28-Phe33) antiparallel beta-sheet forming a "cysteine stabilized alphabeta motif" (CSalphabeta) also found in antibacterial and antifungal defensins from insects and from plants . Interestingly, termicin shares more structural similarities with the antibacterial insect defensins and with MGD-1, a mussel defensin, than with the insect antifungal defensins such as drosomycin and heliomicin . These structural comparisons suggest that global fold alone does not explain the difference between antifungals and antibacterials . The antifungal properties of termicin may be related to its marked hydrophobicity and its amphipatic structure as compared to the antibacterial defensins . {SWISS-PROT accession number: Termicin (P82321); PDB accession number: 1MM0.}

Dev Comp Immunol, 2003 Apr, 27(4), 305 - 11
A novel antimicrobial peptide from the sea hare Dolabella auricularia; Iijima R et al.; The sea hare Dolabella auricularia is a marine shell-less gastropod . Four cytotoxic glycoproteins named dolabellanin A, C, E and P were found in the animal previously . An antimicrobial factor was newly isolated from the sea hare's body-wall including skin and mucus . This factor is a novel peptide which consists of 33 amino acid residues, and is called dolabellanin B2 . Dolabellanin B2 was cytotoxically effective against some pathogenic microorganisms at a concentration of 2.5-100 microg/ml.

Dev Comp Immunol, 2003 Apr, 27(4), 291 - 304
Amoebapores, archaic effector peptides of protozoan origin, are discharged into phagosomes and kill bacteria by permeabilizing their membranes; Andra J et al.; Antimicrobial peptides are widespread in animal species and their function as defensive molecules may even have appeared before the evolution of metazoa . The amoeboid protozoon Entamoeba histolytica discharge membrane-permeabilizing polypeptides named amoebapores into the phagosome in which engulfed bacteria are situated as evidenced here by confocal laser microscopy and electron microscopy using specific antibodies . We demonstrate that the purified three isoforms of the amoebic polypeptides exhibit complementary antibacterial activities in vitro . The potency of amoebapores were compared with that of antimicrobial peptides of phylogenetically widespread species by monitoring in parallel their activities against representatives of gram-positive and gram-negative bacteria and liposomes in various assays, and differences in the mechanism of membrane permeabilization became apparent . Northern blot analysis revealed that expression of genes coding for amoebapores and amoebic lysozymes is not dramatically changed upon co-culture of amoebae with bacteria indicating that the antimicrobial arsenal is rather constitutively expressed than induced in these primitive phagocytes.

Dev Comp Immunol, 2003 Apr, 27(4), 283 - 9
Expression of penaeidin antimicrobial peptides in early larval stages of the shrimp Penaeus vannamei; Munoz M et al.; Penaeidins are a family of antimicrobial peptides constitutively produced and stored in the hemocytes of penaeid shrimps . We have determined the expression and the localization of penaeidins in the first early larval stages (Nauplius V, Zoea I, II, III and Mysis II) and in post-larvae (1 and 8) of the shrimp Penaeus vannamei . Using in situ hybridization and immunohistochemical analyses, we localized penaeidin transcripts and peptides in a few hemocytes of larvae from Mysis II stage . However, RT-PCR analyses showed that penaeidin mRNAs are already present in the early stage of Nauplius V . In addition, penaeidin expression could not be detected in other cells than hemocytes . Our observations highlight the potential involvement of penaeidins during larval development and the ontogeny of immune system through hemocytes during this period of life, where shrimps are particularly susceptible to infectious diseases.

Int J Immunopathol Pharmacol, 2002 May, 15(2), 119 - 127
Serum procalcitonin, adenosine deaminase and its isoenzymes in the aetiological diagnosis of pneumonia in children; Hatzistilianou M et al.; A prospective study was undertaken to assess the usefulness of leukocyte count, serum C-reactive protein (CRP), procalcitonin (PCT), and the activities of total adenosine deaminase (tADA) and its isoenzymes ADA1 and ADA2, in the aetiological diagnosis of pneumonia in children . The study included three groups . Group A consisted of 23 children with bacterial pneumonia, group B of 50 children with viral and mycoplasmal pneumonia and group C of 46 healthy children . On the first day of admission in the clinic, blood samples were collected before the start of antimicrobial treatment, for culture, serological tests, leukocyte count and for the determination of CRP and PCT levels as well as tADA activity and its isoenzymes ADA1 and ADA2 . According to our results, the mean leukocyte count and the mean concentrations of PCT and CRP were significantly higher in the children of group A than those in groups B and C . The admission serum PCT concentration has a higher sensitivity, specificity and positive predictive value for bacterial pneumonia than either CRP or the leukocyte count . The mean serum tADA, ADA1 and ADA2 activity in children of group A was not significantly different from those in group C, while the difference between groups B and C was statistically significant . In conclusion, we found that CRP is a good marker for screening various infectious diseases, but it cannot be used to distinguish between bacterial and viral infections . Serum PCT measurement might be a useful tool for the physician for the aetiological diagnosis of pneumonia in children . Measurements of serum tADA and ADA2 activity may provide useful additional diagnostic information on the aetiology of pneumonia so that appropriate antibiotic therapy can be given promptly . Further studies with larger patients groups are required to confirm our results.

J Agric Food Chem, 2003 Feb 26, 51(5), 1215 - 23
Homology similarity analysis of sequences of lactoferricin and its derivatives; Nakai S et al.; A new method, homology similarity analysis (HSA), was developed to investigate homology pattern similarities of selected segments within sequences of peptides . This new approach facilitated elucidation of the structure-function relationships of lactoferricin derivatives . Helix propensity of positions 4-9 in the lactoferricin sequence was the most important in determining the antimicrobial activity of lactoferricin against Escherichia coli, followed by cationic charge pattern at positions 4-9 and 1-3 . The pattern similarity of segments within sequences could be a useful tool for representing the distribution attributes of amino acid residue properties to the structure-function relationships of proteins and peptides, especially when used in conjunction with principal component similarity analysis followed by the regression version of artificial neural networks.

Infection, 2003 Jan, 31(1), 3 - 8
A predictive model for the management of community-acquired pneumonia; Raz R et al.; BACKGROUND: Understanding what determines the prognosis of community-acquired pneumonia (CAP) is especially important for decisions on hospitalization and antimicrobial therapy . The objective of the present study was to compare the predictability of mortality in our patients to that of the pneumonia patient outcomes research team (PORT) study . PATIENTS AND METHODS: Data of 320 patients admitted with CAP were retrospectively evaluated and classified according to the published scheme . RESULTS: One-month mortality was 14.4%; 1-year mortality was 27.8%, two-thirds from new episodes . Univariate logistic regression risk factors for the 1-month mortality rate included leukocytosis, anemia, hypoalbuminemia, elevated blood urea nitrogen, >or= two comorbidities, tachycardia, tachypnea, acidosis, stupor, age > 65 years and high serum lactic dehydrogenase . These variables, except the last two, plus pleural effusion and bilateral infiltration were also risk factors for 1-year mortality . In the multivariate models, eight of these factors were significant risk factors, four for 1-month mortality and six for 1-year mortality . Our model for prediction of 1-month mortality had a sensitivity of 65%, specificity of 95% and accuracy of 91% . CONCLUSION: Agreement between predictions by our model and the published model was considerable, showing that most patients in the low score groups should not have been hospitalized.

Auris Nasus Larynx, 2003 Feb, 30(1), 65 - 9
Effects of topical chlorhexidine applied to the rabbit nasal mucosa; Cankaya H et al.; OBJECTIVE: To search the effects of administration of various concentrations of a wide-spectrum antimicrobial agent, chlorhexidine, to the nasal mucosa . MATERIAL AND METHODS: About 0.20, 0.12, 0.06 and 0.03% concentrations of chlorhexidine gluconate were applied to the rabbit nasal mucosa as one puff twice a day throughout 5 days . Another group, treated with serum saline to the nose, behaved as the control group . On the fifth day following drug administration, specimens were taken from nasal mucosa of the rabbits and examined under light microscope . RESULTS: As a result of comparison between drug treated group and control group, with increasing drug concentrations progressively increased neutrophil infiltration in mucosa, ciliary loss in cells, and occasional metaplasia were observed . CONCLUSION: There is a linear, positive and strong association between concentrations of chlorhexidine and its irritative effects on rabbit nasal mucosa . While 0.20 and 0.12% concentrations of chlorhexidine cause excess irritation on the nasal cavity, 0.06 and 0.03% concentrations of chlorhexidine gluconate causes lower irritation and effects on the animals which have experimentally induced rhinosinusitis must be evaluated.

Br J Dermatol, 2003 Feb, 148(2), 229 - 32
Antimicrobial photodynamic therapy: assessment of genotoxic effects on keratinocytes in vitro; Zeina B et al.; BACKGROUND: Work has shown that cutaneous microbial species associated with skin conditions of microbial aetiology are susceptible to killing by antimicrobial photodynamic therapy (APDT) using visible light and methylene blue . OBJECTIVES: To evaluate immediate and delayed genotoxicity of APDT on keratinocytes in vitro . METHODS: A combination of methylene blue (100 microg mL(-1)) and visible light (42 mW cm(-2)), as used in studies of microbe and keratinocyte cytotoxicity, was employed to test a human keratinocyte cell line (H103) for genotoxic damage by comet assay . RESULTS: The comet assay was able to detect genotoxic damage in H2O2-treated keratinocytes (positive control) . APDT did not cause either immediate or delayed genotoxic damage in keratinocytes following APDT of up to 180 min . CONCLUSIONS: APDT sufficient to reduce microbes by seven log cycles showed no detectable genotoxic effects on keratinocytes . APDT applied in vivo may represent a useful low-risk alternative to conventional antimicrobial treatment in dermatology.

Acta Microbiol Pol, 2002, 51(3), 265 - 73
Antimicrobial activity of substituted 2-trifluoromethyl- and 2-pentafluoroethylbenzimidazoles; Wolinowska R et al.; Antibacterial and antifungal activity of 2-trifluoromethyl- and 2-pentafluoroethylbenzimidazoles, including a number of newly obtained derivatives, were examined by diffusion method (inhibition area diameter in solid agar medium) and minimum inhibitory concentration (MIC, in liquid and agar medium) . Some of the derivatives tested affected fungal colony morphology and exerted genotoxic effects in bacteria . Of the tested compounds, 5,6-dichlorosubstituted derivatives appeared the most active against the majority of microorganisms used.

Acta Microbiol Pol, 2002, 51(3), 255 - 63
Primary resistance of Helicobacter pylori to antimicrobial agents in Polish children; Rozynek E et al.; Helicobacter pylori resistance to antimicrobial agents is an important factor compromising the efficacy of treatment . Therefore the aims of our study were: to determine the prevalence of H . pylori resistance to clarithromycin, metronidazole, amoxycillin and tetracycline in children prior to eradication therapy, to compare different methods of susceptibility testing and to detect mutations responsible for clarithromycin resistance . During 1996-2000, 259 H . pylori strains were isolated from antral gastric biopsies . Susceptibility to antimicrobials was determined by the agar dilution method and the Etest . Mutations in the 23S rRNA gene associated with clarithromycin resistance were analysed by PCR-RFLP and direct sequencing . Overall, ninety-six strains (37%) were resistant to metronidazole, 50 strains (19.3%) were resistant to clarithromycin, and 20 strains (7.7%) were simultaneously resistant to both drugs . All cultured isolates were sensitive to amoxycillin and only one isolate (0.4%) was resistant to tetracycline . The agar dilution method and the Etest showed a perfect category correlation for clarithromycin and 4% discrepancies for metronidazole . Primary resistance to clarithromycin was mainly associated with an A2143G mutation in the 23S rRNA gene of H . pylori . The study highlights the high prevalence of H . pylori primary resistance to clarithromycin in Polish children, which implies a need for pretreatment susceptibility testing.

Pharmacotherapy, 2003 Feb, 23(2), 159 - 64
Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy; Carver PL et al.; STUDY OBJECTIVE: To evaluate risk factors for the development of arthralgias or myalgias associated with quinupristin-dalfopristin . DESIGN: Retrospective chart review and case-control analysis . SETTING: An 850-bed tertiary care medical center . PATIENTS: All adult and pediatric patients who had received quinupristin-dalfopristin through either a compassionate-use protocol (February 1996-October 1999) or in the year after quinupristin-dalfopristin was added to the hospital formulary (November 1999-October 2000) were included in this study . Case patients were those who developed arthralgias or myalgias while receiving quinupristin-dalfopristin therapy; control patients were those who received quinupristin-dalfopristin but did not develop arthralgias or myalgias . INTERVENTION: Medical records, pharmacy dispensing information, and microbiology data were reviewed by a physician and a pharmacist, both of whom specialized in infectious diseases . Presence or absence of arthralgias or myalgias was the primary outcome assessed . MEASUREMENTS AND MAIN RESULTS: Quinupristin-dalfopristin was administered to 68 patients during the period defined by the study . Arthralgias and myalgias could not be assessed in 18 of the 68 patients because they were sedated and paralyzed, or they were young children who could not communicate the presence of pain . Univariate analysis demonstrated that significant risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin were female sex, chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, major surgery, and receipt of either mycophenolate or cyclosporine . Multivariate analysis demonstrated a strong association with chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate . Of 50 evaluable patients receiving quinupristin-dalfopristin, 25 had pain that may have been associated with this antimicrobial agent . CONCLUSION: The mechanism for development of arthralgias or myalgias associated with quinupristin-dalfopristin remains unknown, but these adverse events are more likely to occur in patients with chronic liver disease and those who have received a liver transplant or are receiving cyclosporine or mycophenolate.

Lik Sprava, 2002, (7), 114 - 7
{Microbiological validation of the composition of "decaceol", an antiseptic prolonged-release drug}; Dykyi IL et al.; With the aid of different microbiological methods, antimicrobal properties of decametoxine, a home-produced antiseptic, were studied together with those of the synthetic zoelite NaA-base drug preparation . The antimicrobial activity of the above drug has been shown to be of a synergistic character that makes it a very promising medical agent which will, we believe, come to be widely used in medical practice.

Rev Esp Quimioter, 2002 Dec, 15(4), 306 - 12
{The bacteriophages and their gene products as antimicrobial agents}; Garcia E et al.; The viruses that infect bacteria (bacteriophages or phages) were first isolated about 90 years ago . Phages have been fundamental tools in the development of molecular biology . Phages were early hypothesized as therapeutic agents for combatting pathogenic bacteria . However, the discovery and successful use of antibiotics to treat infectious diseases hindered this aim . the development of bacterial resistance to most available drugs has recently led researchers to test the possibilities of using phages as therapeutic agents . We review here recent achievements in this field, taking into consideration former bias in handling phages as well as previous achievements carried out in Eastern Europe where bacteriophages have been employed for decades as an alternative to antibiotics.

J Hosp Infect, 2003 Feb, 53(2), 129 - 35
Pharmacokinetics of the antimicrobial agents rifampicin and miconazole released from a loaded central venous catheter; Rump AF et al.; The time course of rifampicin and miconazole concentrations after insertion of a polyurethane catheter loaded with these antibiotics were studied . Data from controlled release experiments in vitro were used, and the concentration time courses of the antimicrobials in serum were calculated by pharmacokinetic simulations . Systemic therapy using typical dosages (rifampicin 600 mg/day iv, miconazole 3 x 200 mg/day iv) results in rifampicin concentrations between 54 and 8424 microg/L, and miconazole concentrations between 3567 and 4676 microg/L . After insertion of a polyurethane catheter loaded with these antibiotics, the maximal concentrations after catheter placement were determined as 6 microg/L at 10.7h for rifampicin, and 13 microg/L at 28.6 h for miconazole . Assuming that the total amount of antibiotics incorporated in the catheter matrix were bioavailable ('worst case'), the resulting maximal concentrations calculated by simulation are 10 microg/L for rifampicin and 65 microg/L for miconazole . Maximal concentrations of rifampicin or miconazole resulting from the insertion of a polyurethane catheter loaded with these antibiotics are, therefore, far below the concentrations resulting from a systemic therapy with the same antimicrobial agents . Even in the worst case, the danger of selecting resistant bacterial strains seems remote because the systemic drug levels are magnitudes of order below subinhibitory concentrations .

J Hosp Infect, 2003 Feb, 53(2), 91 - 6; quiz 149
Principles of good use of antibiotics in hospitals; Guven GS et al.; Rational use of antimicrobials is a key element for a successful strategy against development of resistance to antimicrobials . The physician should establish the need and the reason for therapy, select the appropriate antimicrobial agent, and then decide on the optimum dose and dosing interval, duration, as well as route of administration . In a particular hospital, the present status of antimicrobial use should be determined, and a strategy should be developed to improve it . This usually encompasses a combination of educative, facilitative and restrictive measures . Good infection control practice is a critical component for success of such a programme .

J Hosp Infect, 2003 Feb, 53(2), 85 - 90
Multidisciplinary antimicrobial management and the role of the infectious diseases pharmacist--a UK perspective; Knox K et al.; Improved clinical outcome, patient safety, cost savings and a reduction in the burden of antimicrobial resistance are outcomes associated with optimizing antimicrobial use . Despite this, the misuse of antimicrobials in the hospital setting remains a huge problem . The development of antimicrobial management teams and the promotion of the role of the clinical pharmacist in antimicrobial prescribing are recommended strategies for improving prescribing practice . It is recognized that there is a lack of published evidence-based research looking at the effects of antimicrobial control programmes and there is a need for more data . In the UK, the role of the hospital pharmacist in promoting responsible antimicrobial prescribing has been largely undervalued and needs to be encouraged and formalized in line with current directives . Managerial structures within hospitals need to endorse multidisciplinary antimicrobial management schemes with appropriate authoritative, administrative and information technology support .

Nitric Oxide, 2003 Feb, 8(1), 1 - 6
Effect of amidine derivatives on nitric oxide production by Leishmania amazonensis promastigotes and axenic amastigotes; Genestra M et al.; The effects of pentamidine isethionate (reference drug) and N,N'-diphenyl-4-methoxy-benzamidine (test compound) on NO . production by Leishmania amazonensis promastigotes and axenic amastigotes were investigated by measuring nitrite, a by-product of nitric oxide released into culture supernatants . The NO . production by infective promastigotes was inhibited by OCH(3)-amidine in about 23.53% and by pentamidine in only 3.78% . In axenic amastigotes, the inhibition of NO . production by OCH(3)-amidine was significantly higher (52.94%; p=0.01) than that by pentamidine, which inhibited this radical production nonsignificantly (25.29%; p=0.1) . The mechanism of amidine derivatives, as an antimicrobial agent, is unknown . However, other amidines, such as a diamidine (pentamidine), contain chemical structures shared by the guanidino group of the nitric oxide synthase substrate L-arginine, suggesting the possibility of an interaction with this enzyme or electronic factors (substituent constant) that alter physical and chemical properties significant for biological activity.

FEBS Lett, 2003 Feb 11, 536(1-3), 215 - 9
Synthetic and structural studies on Pyrularia pubera thionin: a single-residue mutation enhances activity against Gram-negative bacteria; Vila-Perello M et al.; The thionin from Pyrularia pubera (Pp-TH), a 47-residue peptide with four internal disulfide bonds, was efficiently produced by chemical synthesis . Its antimicrobial activity in vitro against several representative pathogens (EC(50)=0.3-3.0 microM) was identical to that of natural Pp-TH . This peptide has a unique Asp(32) instead of the consensus Arg found in other thionins of the same family . In order to evaluate the effect of this mutation, the Arg(32) analogue (Pp-TH(D32R)) was also synthesized and showed a significant increase in antibiotic activity against several Gram-negative bacteria, whereas it retained the same activity against other pathogens . The overall structure of Pp-TH(D32R) was maintained, though a slight decrease in the helical content of the peptide was observed.

Enferm Infecc Microbiol Clin, 2003 Feb, 21(2), 93 - 100
{Cyclic rotation of antibiotics . Is all that glitters gold?}; Sandiumenge A et al.; Antibiotic cycling refers to the rotation of antimicrobial agents; that is, one specific agent or class of agents is withdrawn from use during a predefined time period, switched to another, and reintroduced at a later time . This strategy of periodic restriction attempts to reduce the selective pressure that antibiotic agents exert on microbial flora, thereby reducing antimicrobial resistance . Such control of antibiotic use has been proposed as an effective measure for preventing the emergence and spread of resistant pathogens, particularly in areas with high levels of antibiotic pressure . Although the first works on antibiotic cycling were published more than two decades ago, the experience with rotational therapy is limited . Most studies on this subject report intriguing and promising results . Nevertheless, a detailed examination of the literature discloses differences in the objectives proposed, the variables analyzed, and the methods for quantification, making generalization of the results difficult . The association between antibiotic use and emergence of multi-drug resistant pathogens has been extensively demonstrated, but the influence of several factors on the mechanisms of emergence and spread of antibiotic resistance in microorganisms makes it difficult to establish a cause-effect relationship . In this article several methodological considerations are suggested for future studies testing this new antibiotic strategy.

Rev Med Brux, 2002, 23 Suppl 2, 93 - 6
{The infective diseases clinic}; Jacobs F et al.; The Clinic of Infectious Diseases was created at Erasme Hospital in 1980 . Its main activity consists in taking care of patients with infectious complications in various hospital departments . Its main scientific contributions concern the evaluation of new treatments, pharmacokinetics of antimicrobial agents and physiopathology of sepsis . The evaluation of the impact of infectious diseases on the appropriateness of antimicrobial therapy and the control of infection is a major contribution of the clinic . Several works concern the study of the immune response in case of infection due to an intracellular pathogen and in response to vaccination.

Med Pregl, 2002 Sep-Oct, 55(9-10), 397 - 400
{Treatment of acute upper respiratory tract infections in children}; Roncevic N et al.; INTRODUCTION: Acute respiratory tract infections are the most common diseases of childhood . A preschool child suffers up to 5-7 infections of upper airways during a year . Upper airway infections make 80-90% of all respiratory infections . ETIOLOGY AND TREATMENT: In 75% of all cases respiratory infections are of viral etiology, 15% of bacterial and 10% are caused by mycoplasma, rickettsiae, fungi, parasites . The treatment of respiratory infections includes antimicrobial therapy (causal), relief of symptoms (symptomatic) and application of general principles of child treatment . The choice of antimicrobial drug is based on the evidence of agents and their sensitivity to antimicrobial drugs, age, patient's condition, previous treatment and possible allergic reactions to the drug . In cases where adequate specimen cannot be obtained for microbiologic tests, when these tests do not reveal the agent, or therapy must start before evidence of the agent is available, we must decide about the therapy, taking in consideration the most frequent agents, and those that would cause the most devastating clinical picture . This therapy can be modified later, according to the isolated agent and its sensitivity to the drug . Considering the incidence and importance of respiratory infections in morbidity and mortality of children, the aim of this article was to present guidelines in treatment of respiratory infections . The main point remains that the treatment should take into consideration the individual patient before all.

FEMS Microbiol Lett, 2003 Jan 21, 218(1), 135 - 41
Organization of the biosynthetic gene cluster for the polyketide macrolide mycinamicin in Micromonospora griseorubida; Anzai Y et al.; Mycinamicin, composed of a branched lactone and two sugars, desosamine and mycinose, at the C-5 and C-21 positions, is a 16-membered macrolide antibiotic produced by Micromonospora griseorubida A11725, which shows strong antimicrobial activity against Gram-positive bacteria . The nucleotide sequence (62 kb) of the mycinamicin biosynthetic gene cluster, in which there were 22 open reading frames (ORFs), was completely determined . All of the products from the 22 ORFs are responsible for the biosynthesis of mycinamicin II and self-protection against the compounds synthesized . Central to the cluster is a polyketide synthase locus (mycA), which encodes a seven-module system comprised of five multifunctional proteins . Immediately downstream of mycA, there is a set of genes for desosamine biosynthesis (mydA-G and mycB) . Moreover, mydH, whose product is responsible for the biosynthesis of mycinose, lies between mydA and B . On the other hand, eight ORFs were detected upstream of the mycinamicin PKS gene . The myrB, mycG, and mycF genes had already been characterized by Inouye et al . The other five ORFs (mycCI, mycCII, mydI, mycE, and mycD) lie between mycA1 and mycF, and these five genes and mycF are responsible for the biosynthesis of mycinose . In the PKS gene, four regions of KS and AT domains in modules 1, 4, 5, and 6 indicated that it does not show the high GC content typical for Streptomyces genes, nor the unusual frame plot patterns for Streptomyces genes . Methylmalonyl-CoA was used as substrate in the functional units of those four modules . The relationship between the substrate and the unusual frame plot pattern of the KS and AT domains was observed in the other PKS genes, and it is suggested that the KS-AT original region was horizontally transferred into the PKS genes on the chromosomal DNA of several actinomycetes strains.

Vet Hum Toxicol, 2003 Feb, 45(1), 20 - 3
Effects of Lantana camara (Verbenaceae) on rat fertility; de Mello FB et al.; Lantana camara, widely used in folk medicine, possesses several pharmacological properties, including antipyretic, antimicrobial and antimutagenic properties . Lantana poisoning causes livestock mortality and morbidity; and also has adverse effects on humans working in lantana-infested forests, pastures or orchards . We examined the effects of a hydroalcoholic extract from Lantana camara var aculeata leaves on fertility of male rats . The extract did not interfere with overall weight or internal organ weights, but interfered with sperm count, daily sperm production and sperm morphology in a dose-dependent manner.

J Chemother, 2002 Dec, 14(6), 547 - 53
A comparison between disk diffusion and microdilution for susceptibility testing of Mycobacterium fortuitum complex; Esteban J et al.; We evaluated a disk diffusion method using Mueller-Hinton agar for susceptibility testing of Mycobacterium fortuitum complex organisms . Ninety-five strains were tested both by broth microdilution and disk diffusion . Global results showed good correlation for all antimicrobials except for clarithromycin and erythromycin . However, when the results were analyzed according to species, correlation was poor except for a few antimicrobials . The analysis of the resistant/susceptible results was good for all the antimicrobials tested except azithromycin and erythromycin . In conclusion, the disk diffusion technique could be useful as a screening technique for some antibiotics, but the results must be confirmed by using an accepted reference technique.

J Am Acad Dermatol, 2003 Feb, 48(2 Suppl), S5 - 6
Development of an idlike reaction during treatment for acute pulmonary histoplasmosis: a new cutaneous manifestation in histoplasmosis; Crum N et al.; Id reactions often occur secondary to release of antigens after initiation of antimicrobial therapy . This reaction commonly occurs during treatment of Trichophyton infections . The diagnosis is usually made clinically and is supported in the presence of an infection and/or initiation of therapy . We report an idlike reaction during therapy for pulmonary histoplasmosis.

Prev Vet Med, 2003 Mar 20, 57(3), 105 - 15
VETSTAT-the Danish system for surveillance of the veterinary use of drugs for production animals; Stege H et al.; The Danish Ministry of Food, Agriculture and Fisheries funds a monitoring system based on drug usage information collected at the herd level: VETSTAT . VETSTAT is constructed as a relational database and data originates from three sources: pharmacies, veterinarians and feed mills . All administration of drugs for use in animal production is reported on a monthly basis.Pharmacies provided 95% of the total weight antimicrobial compounds used in Denmark in 2001 . More than 80% of the antimicrobial compounds reported by pharmacies were sold on prescription to end-users (owners) and included information on animal species, age-group and diagnostic grouping; >90% of the total amount of antimicrobials sold on prescription was used for pigs . In 2001, sales of 96,500 kg of antimicrobials were reported.

Drug Saf, 2003, 26(3), 187 - 95
Safety of celecoxib in individuals allergic to sulfonamide: a pilot study; Shapiro LE et al.; OBJECTIVE: To evaluate cross reactivity between sulfonamide antimicrobials and celecoxib in patients with histories of allergies to sulfonamide antimicrobials . METHODS: Immunocompetent patients with a history of sulfonamide antimicrobial allergy who were being considered for therapy with celecoxib were prospectively enrolled . Sulfamethoxazole and trimethoprim skin prick and intradermal testing and/or an in vitro lymphocyte toxicity assay were performed . If skin testing was negative, an oral challenge with sulfamethoxazole and trimethoprim was performed . Oral challenges with celecoxib were administered to all patients . RESULTS: Twenty-eight immunocompetent patients (26 female; mean age 60 years) were evaluated . History of sulfonamide antimicrobial allergy included urticaria (n = 7), cutaneous eruptions (n = 9), and other (n = 12) . Four of the 28 patients who were skin prick tested were positive to sulfamethoxazole and two of the ten patients who underwent in vitro testing were positive to sulfamethoxazole . All 28 patients were administered celecoxib and tolerated the medication . Phone call follow up in 25 patients disclosed that 15 patients continued to take celecoxib, while five patients did not take celecoxib following the oral challenge, and five discontinued celecoxib due to adverse effects, lack of drug efficacy or physician preference . CONCLUSIONS: Confusion exists regarding the potential for cross reactivity between sulfonamide antimicrobials and other sulfonamide-containing compounds . The six sulfonamide-allergic patients tolerated celecoxib uneventfully . This pilot study supports the hypothesis that the potential for cross-reactivity between celecoxib and sulfonamide antimicrobials appears to be low . However, further investigations are required to confirm this.

J Am Chem Soc, 2003 Feb 19, 125(7), 1877 - 87
Total synthesis of the ramoplanin A2 and ramoplanose aglycon; Jiang W et al.; Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon are disclosed . Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1, 2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon . Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected l-threo-beta-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 degrees C) . The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist beta-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure . By altering the order of final couplings, two macrocyclization sites, Phe(9)-d-Orn(10) and Gly(14)-Leu(15), were examined . Macrocyclization at the highly successful Phe(9)-d-Orn(10) site (89%) may benefit from both beta-sheet preorganization as well as closure at a d-amine terminus within the confines of a beta-turn at the end of the H-bonded antiparallel beta-strands . A more modest, but acceptable macrocyclization reaction at the Gly(14)-Leu(15) site (40-50%) found at the other end of the H-bonded antiparallel beta-strands within a small flexible loop may also benefit from preorganization of the cyclization substrate, is conducted on a substrate incapable of competitive racemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications . Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn(1) side-chain introduction provides future access to analogues of the aglycons which themselves are equally potent or more potent than the natural products in antimicrobial assays.

J Vet Diagn Invest, 2003 Jan, 15(1), 26 - 9
Antimicrobial susceptibility of Riemerella anatipestifer isolated from ducks and the efficacy of ceftiofur treatment; Chang CF et al.; The in vitro susceptibilities of 50 field isolates of Riemerella anatipestifer from ducks to ceftiofur and 16 other commonly used antimicrobials were determined . The MIC90 values (MIC refers to minimum inhibitory concentrations) for the antimicrobials used in this study are as follows: penicillin was 16 microg/ml; ceftiofur was 32 microg/ml; cephalothin, chloramphenicol, flumequine, and kanamycin were 64 microg/ml; nalidixic acid, nitrofurantoin, and sulfamethoxazole were 128 microg/ml; amikacin, ampicillin, gentamicin, lincomycin, spectinomycin, streptomycin, tetracycline, and trimethoprim were > or = 256 microg/ml . The therapeutic efficacy of ceftiofur against a highly lethal experimental R . anatipestifer infection in ducks was also evaluated . All experimental ducks were infected through the infraorbital sinus with 1 ml of 9 x 10(9) CFU of R . anatipestifer . Ceftiofur (0, 0.25, 0.5, 1, and 2 mg/kg) was injected subcutaneously 5 hours after infection . A single dose of 2 mg/kg resulted in 73% survival as compared with 10% survival in the infected, but untreated controls.

Arch Otolaryngol Head Neck Surg, 2003 Feb, 129(2), 211 - 4
Expression of cathelicidin in human salivary glands; Woo JS et al.; BACKGROUND: Salivary secretions play a critical role in maintaining oral health via innate host defense mechanisms and secretion of secretory IgA . One of the antimicrobial peptides, LL-37, is the only cathelicidin protein that has yet been identified in humans . Cathelicidins are a family of peptides thought to provide an innate defensive barrier against a variety of potential microbial pathogens . OBJECTIVES: To examine the expression of cathelicidin in human salivary glands and to investigate up-regulation of cathelicidin in inflammatory conditions . DESIGN: Reverse transcriptase-polymerase chain reaction and immunohistochemical staining were performed on 20 salivary gland tissues, 10 from normal salivary glands and 10 from glands with chronic sialadenitis . RESULTS: Cathelicidin messenger RNA transcripts were detected in the tissues from the normal salivary glands and the glands with chronic sialadenitis . The level of cathelicidin messenger RNA in glands with chronic sialadenitis was significantly increased compared with that in normal salivary glands . Cathelicidin protein was expressed in the glandular epithelium of the normal salivary glands and the glands with chronic sialadenitis . CONCLUSION: The results indicate that cathelicidin might play an important role in innate host defense of human salivary glands.

New Microbiol, 2003 Jan, 26(1), 57 - 63
Analysis of an outbreak due to Chryseobacterium meningosepticum in a neonatal intensive care unit; Tekerekoglu MS et al.; The aim of this study was to describe the epidemiological and clinical features of an outbreak due to Chryseobacterium meningosepticum . During a 11-day period, the outbreak was observed among four newborns in a neonatal intensive care unit (NICU) in a teaching hospital . All patients yielded C . meningosepticum in their blood cultures, in addition one was colonised in the throat . Antimicrobial susceptibility assay showed complete resistance to penicillins, cephalosporins, aminoglycosides, imipenem, aztreonam, and tetracycline, sensitivity to ciprofloxacin and trimethoprim-sulfamethoxazole . All patients were empirically treated with amikacin and meropenem . The neonate who was the first to develop sepsis died before the culture result . When C . meningosepticum was identified, antimicrobial therapy was changed to a combination of ciprofloxacin, rifampicin and vancomycin, and three neonates were treated successfully . Environmental screening recovered C . meningosepticum from two venous catheter lines and one nutritional solution that was opened by health care staff and used for two neonates . Arbitrary primed polymerase chain reaction and antibiogram typing indicated that all isolates were epidemiologically related . This study demonstrates that rapid selection of appropriate antibiotics is critical for clinical cure and standard precautions should be reconsidered to limit the spread of this bacterium on the NICU in our hospital.

Boll Chim Farm, 2002 Nov-Dec, 141(6), 461 - 5
Novel 4-aminopyrimido{4,5-b}quinoline derivatives as potential antimicrobial agents; el-Sayed OA et al.; Two series of 4-aminopyrimido{4,5-b}quinoline derivatives substituted in the 2-position 6a-c and/or in 1-position 9a-e have been prepared by facile routes starting from 2-amino-3-cyanoquinoline 2,2-chloro-3-cyanoquinoline 4 and 2-arylamino-3-cyanoquinolines 8a-d . The reactions involved simple fusion with thiourea or urea and, in some cases, with guanidine . The prepared compounds were in vitro tested for antimicrobial activities against some selected Gram-positive, Gram-negative bacteria and fungi . The products containing the thio-function were the most active followed by those containing the imino-function while the carbonyl containing derivatives were without significant antimicrobial effect.

Boll Chim Farm, 2002 Nov-Dec, 141(6), 443 - 6
A facile synthesis of 2-aryl-4,5-di(2-thienyl)imidazoles under microwave irradiation and their antimicrobial activities; Demirayak S et al.; In this study, some 2-aryl-4,5-dithienylimidazoles were synthesized by reacting di-(2-thienyl)ethandione and a suitable aromatic aldehyde in the presence of ammonium acetate in acetic acid . Either the classical reflux method or microwave irradiation method were applied as alternative reaction conditions . The antimicrobial activities of the compounds obtained were investigated in vitro and appreciable activities were obtained.

Anaesthesist, 2003 Jan, 52(1), 3 - 22
{Clinical management of patients with sepsis}; Weigand MA et al.; Sepsis and septic shock are the leading causes of death in non-cardiological intensive care units in developed countries despite recent advances in critical care medicine.Sepsis is the systemic inflammatory response to infection, often associated with hypoperfusion followed by tissue injury and organ failure.Activation of monocytes/macrophages and neutrophils with consecutive release of proinflammatory mediators and activation of the coagulation cascade, seem to play a key role in the pathogenesis of sepsis.Elimination of the septic focus,antimicrobial therapy and supportive treatment are the cornerstones of sepsis therapy.Adequate and rapid volume replacement and if necessary application of catecholamines are of highest priority to optimize tissue perfusion.Norepinephrine is the vasopressor of choice and dobutamine the preferred inotropic agent . Most experts recommend hemoglobin levels of 8-10 g/dl in severe sepsis.In addition,lung protective ventilatory strategies as well as enteral and parenteral nutrition are part of the clinical management of septic patients.In mechanically ventilated patients intensive insulin therapy to maintain blood glucose at a level between 80 and 110 mg/dl has significantly reduced mortality.Furthermore,prophylaxis of deep vein thrombosis and of stress ulcer bleeding are individually applied to septic patients.Treatment of septic patients with anti-mediator strategies or high dose AT III were not successful so far.In contrast,now two new promising treatment options may be emerging: application of small doses hydrocortisone and activated protein C {drotrecogin alfa (activated)} . Large and in part multicentric studies especially in the last 2 years now allow the practicing clinician to perform a partially evidence-based management of patients with sepsis.In addition, for the first time two options for specific therapy of sepsis,application of small doses hydrocortisone and activated protein C {drotrecogin alfa (activated)},are available which may further improve prognosis for septic patients.

Crit Care Med, 2003 Feb, 31(2), 608 - 16
Appropriate use of antimicrobial agents: challenges and strategies for improvement; Niederman MS; The use of inadequate empirical antimicrobial therapy is common in intensive care unit patients and contributes to a number of poor outcomes . Selecting appropriate antimicrobial therapy is complicated by many factors, including the large number of agents available, the presence of resistant organisms, and the general desire among practitioners to use the most focused therapy available . An important aspect of appropriate antimicrobial use is prompt initiation of adequate empirical therapy, which has been shown to improve mortality rates in hospitalized patients with pneumonia and other serious infections . Other key strategies include streamlining antimicrobial therapy when a pathogen is identified and switching from intravenous to oral therapy when clinically indicated . In addition, antibiotic rotation (or cycling) has been evaluated in several trials as a means to minimize resistance . Promoting appropriate antimicrobial therapy ultimately will require a multidisciplinary, system-oriented, institution-specific approach because each intensive care unit has its own unique flora and antimicrobial resistance patterns.

Crit Care Med, 2003 Feb, 31(2), 462 - 7
Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome; Leone M et al.; OBJECTIVE: To assess the adequacy of empirical antimicrobial therapy prescribed in septic shock patients and to evaluate the relationship between inadequate antimicrobial therapy and 30-day mortality . DESIGN: Prospective observational study . SETTING: Medical-surgical (16-bed) intensive care unit in an urban teaching hospital . PATIENTS: A total of 107 patients requiring intensive care admission were prospectively evaluated during the 3-yr period of the study . INTERVENTIONS: Prospective patient surveillance and data collection and assessment of antimicrobial therapy according to microbiological documentation . MEASUREMENTS AND MAIN RESULTS: A source of infection associated with a microbiological documentation was identified in 78 of the 107 patients (72%) . Empirical antimicrobial therapy consisted of a pivotal antibiotic (beta-lactam) associated with an aminoglycoside (59 patients) or a fluoroquinolone (21 patients) . Vancomycin was added in 14 patients . Sixty-nine of the 78 patients (89%) received an adequate antimicrobial therapy . The mortality rate of patients receiving an adequate antimicrobial therapy was 56%, and seven of the nine patients (78%) receiving an inadequate antimicrobial therapy died (p =.2) . Among the 81 patients who were alive on day 3, antimicrobial therapy was modified in agreement to clinical status and microbiological documentation in 80% of cases, with de-escalation in 64% of cases . De-escalation consisted of withdrawing the nonpivotal antibiotic in 42% of patients or switching to a narrow-spectrum beta-lactam antibiotic (22% of cases) . CONCLUSION: The prescription of empirical antimicrobial therapy by a senior physician in agreement with practice guidelines made it possible to achieve a crude rate of 89% of adequate antimicrobial therapy in study patients . Inadequate antimicrobial therapy was associated with a 39% excess of mortality . A de-escalation of the empirical therapy was possible in 64% of patients.

Medicina (Kaunas), 2003, 39(1), 30 - 5
{Drug-resistant tuberculosis in Kaunas region 1997-2001}; Naudziunas A et al.; Two thousand four hundred thirty nine cases of tuberculosis were confirmed by the method of culture of the sputum at Kaunas Romainiai tuberculosis hospital during the period of 1997-2001 . Out of them, 669 of them were diagnozed for the first time (not treated or treated for less than 1 month) . Out of confirmed cases, 1601 of confirmed cases were the "old" ones (treatment failures, relapses, treated with one or two courses of antimicrobial therapy) . The resistance to H, R, E, S and multidrug resistance have been investigated . We have revealed that among the "new" cases of tuberculosis the resistance of M . tuberculosis has decreased . In 1997 the resistance to H was 27.5 percent . However, it decreased 5.3 percent in 2000 and to 8.7 percent in 2001 . In 1997 the resistance to R was 19.9 percent and it has decreased to 9.0 percent and 1.9 percent in 1998 and 1999, respectively . No R resistance cases were diagnozed in 2000 and 2001 . In 1997 the resistance to E was 1.1 percent . It reached 1.5 percent in 1998 and there was no resistance to E in 1999-2001 . In 1997 the resistance to S was 15.6 percent . In 1998 it was 26.3 percent and dropped to 1.8 percent in 2000.

Microbiology, 2003 Jan, 149(Pt 1), 239 - 47
Expressed sequence tag (EST) analysis of two subspecies of Metarhizium anisopliae reveals a plethora of secreted proteins with potential activity in insect hosts; Freimoser FM et al.; Expressed sequence tag (EST) libraries for Metarhizium anisopliae, the causative agent of green muscardine disease, were developed from the broad host-range pathogen Metarhizium anisopliae sf . anisopliae and the specific grasshopper pathogen, M . anisopliae sf . acridum . Approximately 1,700 5' end sequences from each subspecies were generated from cDNA libraries representing fungi grown under conditions that maximize secretion of cuticle-degrading enzymes . Both subspecies had ESTs for virtually all pathogenicity-related genes cloned to date from M . anisopliae, but many novel genes encoding potential virulence factors were also tagged . Enzymes with potential targets in the insect host included proteases, chitinases, phospholipases, lipases, esterases, phosphatases and enzymes producing toxic secondary metabolites . A diverse array of proteases composed 36 % of all M . anisopliae sf . anisopliae ESTs . Eighty percent of the ESTs that could be clustered into functional groups had significant matches (E<10(-5)) in other ascomycete fungi . These included genes reported to have specific roles in pathogens with plant or vertebrate hosts . Many of the remaining ESTs had their best BLAST match among animal, plant and bacterial sequences . These include genes with plant and microbial counterparts that produce potent antimicrobials . The abundance of transcripts discovered for different functional groups varied between the two subspecies of M . anisopliae in a manner consistent with ecological adaptations of the two pathogens . By hastening gene discovery this project has enhanced development of improved mycoinsecticides . In addition, the M . anisopliae ESTs represent a significant contribution to the extensive database of sequences from ascomycetes that are saprophytes or plant and vertebrate pathogens . Comparative analyses of these sequences is providing important information about the biology and evolutionary history of this clade.

Med Clin North Am, 2003 Jan, 87(1), 59 - 75
Antimicrobial prophylaxis in the surgical patient; Weed HG; The primary prophylactic measure against postoperative infection is antiseptic technique in patient preparation, during surgery, and in postoperative patient care . Antimicrobial prophylaxis against postoperative infection is not indicated for procedures with a low infection rate because the expected benefit of antimicrobial treatment is less than the risk of an adverse medication reaction . Antimicrobial prophylaxis has been demonstrated to be of greater benefit than risk in some procedures with higher infection rates; however, because the problem is complex and the data are limited, extra-polating these findings to the practitioner's setting and the individual patient remains a challenge (Table 1) . Although antimicrobial prophylaxis for bacterial endocarditis is not effective for most patients, the seriousness of the potential infection has driven the creation of guidelines recommending prophylaxis for at-risk patients undergoing at-risk procedures . Applying these guidelines appropriately could help to reduce unwarranted use of antimicrobials . In the prophylactic use of antimicrobials, as in many medical interventions, the difficulty is balancing the risks of the intervention with the potential benefits . Although we do not have either the randomized, controlled trials or the detailed, patient-specific information to estimate this balance precisely, there are general guidelines to help the clinician choose treatment for most patients.

Ann Hematol, 2003 Jan, 82(1), 24 - 9 Epub 2002 Nov 29.
Low infectious morbidity in patients with heavily pretreated hematological malignancies receiving autologous peripheral blood stem cell transplantation without antimicrobial prophylaxis; Yeh SP et al.; The use of prophylactic antimicrobials during autologous peripheral blood stem cell transplantation (APBSCT) remains controversial . A prospective study was therefore conducted to examine whether the use of prophylactic antimicrobials is necessary . In this study, all the antimicrobials were given therapeutically rather than prophylactically . Twenty-three consecutive patients with heavily pretreated hematological malignancies were enrolled . All of the 23 patients had at least one episode of fever during APBSCT and most were fever of unknown origin (78.3%) . Clinically or microbiologically documented infections occurred in only five patients (21.7%) . These included bacteremias (three patients), perianal abscess (one patient), and catheter-related phlebitis (one patient) . No death, invasive fungal infection, or serious adverse events occurred . The medium duration of fever, intravenous antimicrobial therapy, and hospital stay after transplantation were 5, 10, and 17 days, respectively . In conclusion, without using prophylactic antimicrobials, the infectious morbidity during APBSCT is low even in patients with heavily pretreated hematological malignancies.

Trends Biotechnol, 2003 Feb, 21(2), 70 - 3
Radiopharmaceuticals: new antimicrobial agents; Lupetti A et al.; Small antimicrobial peptides are good candidates for new antimicrobial agents . A scintigraphic approach to studying the pharmacokinetics of antimicrobial peptides in animals has been developed . The peptides were safely and reproducibly labelled with technetium-99m and, after intravenous injection of the radiolabelled peptides into infected animals, scintigraphy allowed real-time quantification of the peptide in the various body compartments . Antimicrobial peptides rapidly accumulated at sites of infection but not at sites of sterile inflammation, indicating that radiolabelled antimicrobial peptides could be used in detection of infection . These radiopharmaceuticals enabled the efficacy of antibacterial therapy in animals to be monitored . The scintigraphic approach provides a useful method for investigating the pharmacokinetics of small peptides in animals.

Vet J, 2003 Mar, 165(2), 104 - 18
Pharmacokinetics and PK-PD modelling of danofloxacin in camel serum and tissue cage fluids; Aliabadi FS et al.; The pharmacokinetics and pharmacodynamics of danofloxacin were studied in the camel in a two period cross-over study . After intravenous (i.v.) administration at a dose rate of 1.25 mg/kg, the pharmacokinetics of danofloxacin indicated a high volume of distribution (V(d(area))=3.43 L/kg), relatively rapid clearance (0.44 L/kg/h) and half-life of 5.37 h . After intramuscular (i.m.) dosing absorption was complete (F=114.5) and rapid (T((1/2)abs)=0.12 h) and terminal half-life was 5.71 h . Danofloxacin penetrated fairly slowly into both inflamed (exudate) and non-inflamed (transudate) tissue cage fluids and was cleared slowly from these fluids, elimination half-life being at least twice that for serum for both exudate and transudate after both i.v . and i.m . dosing . The antibacterial actions of danofloxacin against the camel pathogen Escherichia coli 0157-H7 were determined by measurement of minimum inhibitory concentration (MIC) in vitro (single measurement) and ex vivo measurements of bacterial count at nine times between one and 48 h after i.m . dosing in each of the fluids, serum, exudate, and transudate . Using in vitro MIC data and in vivo pharmacokinetic parameters, the surrogate markers of antimicrobial activity, C(max)/MIC, AUC/MIC and T>MIC, were determined for all three fluids . The ex vivo serum AUC(24 h)/MIC data were integrated with reduction in bacterial count to provide values producing a bacteriostatic action (no change in bacterial count), inhibition of bacterial count by 50%, reduction in bacterial count by 99.9% (bactericidal action) and elimination of bacteria . Mean AUC(24h)/MIC values were 17.20, 20.07, 21.24, and 68.37 h, respectively . To describe the latter, the introduction of a new term to supplement MIC and minimum bactericidal concentration (MBC) is proposed, namely minimum elimination concentration (MEC) . A novel means of designing antimicrobial drug dosage schedules for evaluation in clinical trials is proposed, using ex vivo AUC(24h)/MIC values for bactericidal activity and elimination of bacteria together with MIC(90) data for camel pathogens.

Biochim Biophys Acta, 2003 Feb 21, 1645(2), 172 - 82
A Leu-Lys-rich antimicrobial peptide: activity and mechanism; Park Y et al.; To develop novel antibiotic peptides useful as therapeutic drugs, the analogues were designed to increase not only net positive charge by Lys substitution but also hydrophobic helix region by Leu substitution from cecropin A (1-8)-magainin 2 (1-12) hybrid peptide (CA-MA) . In particular, CA-MA analogue P5 (P5), designed by flexible region (GIG-->P) substitution, Lys (positions 4, 8, 14, 15) and Leu (positions 5, 6, 12, 13, 16, 17, 20) substitutions, showed an enhanced antimicrobial and antitumor activity without hemolysis . Confocal microscopy showed that P5 was located in the plasma membrane . The antibacterial effects of analogues were further confirmed by using 1,6-diphenyl-1,3,5-hexatriene as a plasma membrane probe . Flow cytometric analysis revealed that P5 acted in an energy-independent manner . This interaction is also independent of the ionic environment . Furthermore, P5 causes significant morphological alterations of the bacterial surfaces as shown by scanning electron microscopy and showed strong membrane disrupting activity when examined using liposomes (phosphatidyl choline/cholesterol; 10:1, w/w) . Its potent antibiotic activity suggests that P5 is an excellent candidate as a lead compound for the development of novel antiinfective agents.

Surg Infect (Larchmt), 2002, 3 Suppl 1, S45 - 53
Chemistry and safety of triclosan, and its use as an antimicrobial coating on Coated VICRYL* Plus Antibacterial Suture (coated polyglactin 910 suture with triclosan); Barbolt TA; BACKGROUND: The safety of the antimicrobial agent triclosan was reviewed, and the biocompatibility of coated polyglactin 910 suture with triclosan was evaluated . METHODS: Acute single exposure LD(50) values for triclosan were determined in multiple species by several routes of administration . Subacute to chronic toxicity for dermal and oral exposure to triclosan was determined in multiple species in studies of up to one year's duration . Chronic oral toxicity/carcinogenicity potential was determined in 2-year studies in rodents and non-rodents . The genotoxicity potential of triclosan was determined using a battery of standard assays . Reproductive toxicity and teratology studies were conducted in rodents and non-rodents . Immunotoxicity studies in guinea pigs and the repeat-insult patch test in humans were conducted to assess the potential for sensitization reactions . Pharmacokinetic studies were conducted in animals and humans to understand the metabolic profile of triclosan . Preclinical biocompatibility studies conducted on coated polyglactin 910 suture with triclosan included in vitro cytotoxicity, in vivo intracutaneous reactivity, material-mediated pyrogenicity, and intramuscular tissue reaction/absorption studies . RESULTS: The oral LD(50) values for triclosan ranged from 3,750 to 5,000 mg/kg, whereas the LD(50) after subcutaneous injection was >14,600 mg/kg . Safety factors calculated from repeated daily dosing studies ranged from 1,000 to 25,000 times the no-observed-effect levels . There was no evidence of carcinogenic potential in either species, and genotoxicity studies were negative . Reproductive toxicity studies did not reveal any evidence of teratogenic potential . There was no evidence of skin sensitization potential in controlled studies . Pharmacokinetic studies in animals and humans have shown that triclosan is rapidly absorbed, well distributed in the body, metabolized in the liver, and excreted by the kidneys, with no indication of accumulation over time . Biocompatibility studies showed that coated polyglactin 910 suture with triclosan was non-cytotoxic, non-irritating, and not a chemical pyrogen . In addition, an intramuscular implantation study demonstrated a tissue reaction, a healing response, and an absorption profile comparable to current polyglactin 910 suture . CONCLUSION: The extensive toxicology database supporting the safety of triclosan and the biocompatibility studies conducted on coated polyglactin 910 suture with triclosan demonstrate the safety of this suture for clinical use . Considering the clinical relevance of surgical site infections and the relatively low level of triclosan required to inhibit bacterial colonization of the suture, the use of this antimicrobial technology is well suited to this application.

Jpn J Antibiot, 2000 Jun, 53 Suppl B, 43 - 59
{Pharmacokinetics and tissue distribution of azithromycin in humans}; Shiba K; Azithromycin(AZM) is a new macrolides antibiotic developed by Pfizer Inc . of the US . It has a 15-membered ring structure obtainable by introducing methyl-substituted nitrogen into a 14-membered ring lactone of erythromycin(EM) . An effective drug concentration is sustained long owning to its superiority in tissue distribution and long half life(T1/2) . AZM is also demonstrated to be twice to three times more powerful than the existing macrolides owning to its reinforced antimicrobial activity against Gram-negative microorganisms including influenza virus . AZM is already used in clinical practice in foreign countries and its excellent clinical performance has been demonstrated by the data . As for the domestic basic and clinical studies of AZM, Phase I study was initiated in 1991 following completion of nonclinical studies, and general clinical studies, a dose-setting study and Phase III controlled studies were conducted between 1992 and 1994 . Usefulness of AZM is substantiated by the data from those studies.

Proc Natl Acad Sci U S A, 2003 Feb 18, 100(4), 1879 - 84 Epub 2003 Feb 05.
STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity; Welte T et al.; Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development . We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis . This specific STAT3 deletion causes death of these mice within 4-6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation . Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of the myeloid lineage, both in vivo and in vitro . Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses . Although inflammatory cytokines, including tumor necrosis factor alpha and IFN-gamma, are overly produced in these mice, the NAPDH oxidase activity, which is involved in antimicrobial and innate immune responses, is inhibited . The signaling responses to lipopolysaccharide are changed in the absence of STAT3, leading to enhanced NF-kappa B activation . Our results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.

Appl Environ Microbiol, 2003 Feb, 69(2), 1051 - 8
Bacteriocin detection from whole bacteria by matrix-assisted laser desorption ionization-time of flight mass spectrometry; Hindre T et al.; Class I bacteriocins (lantibiotics) and class II bacteriocins are antimicrobial peptides secreted by gram-positive bacteria . Using two lantibiotics, lacticin 481 and nisin, and the class II bacteriocin coagulin, we showed that bacteriocins can be detected without any purification from whole producer bacteria grown on plates by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) . When we compared the results of MALDI-TOF-MS performed with samples of whole cells and with samples of crude supernatants of liquid cultures, the former samples led to more efficient bacteriocin detection and required less handling . Nisin and lacticin 481 were both detected from a mixture of their producer strains, but such a mixture can yield additional signals . We used this method to determine the masses of two lacticin 481 variants, which confirmed at the peptide level the effect of mutations in the corresponding structural gene.

Curr Protein Pept Sci, 2003 Feb, 4(1), 21 - 9
Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents; Khandekar SS et al.; As a result of increasing drug resistance in pathogenic bacteria, there is a critical need for novel broad-spectrum antibacterial agents . As fatty acid synthesis (FAS) in bacteria is an essential process for cell survival, the enzymes involved in the FAS pathway have emerged as promising targets for antimicrobial agents . Several lines of evidence have indicated that bacterial condensing enzymes are central to the initiation and elongation steps in bacterial fatty acid synthesis and play a pivotal role in the regulation of the entire fatty acid synthesis pathway . beta-ketoacyl-acyl carrier protein (ACP) synthases (KAS) from various bacterial species have been cloned, expressed and purified in large quantities for detailed enzymological, structural and screening studies . Availability of purified KAS from a variety of bacteria, along with a combination of techniques, including combinatorial chemistry, high-throughput screening, and rational drug design based on crystal structures, will undoubtedly aid in the discovery and development of much needed potent and broad-spectrum antibacterial agents . In this review we summarize the biochemical, biophysical and inhibition properties of beta-ketoacyl-ACP synthases from a variety of bacterial species.

Curr Drug Targets Infect Disord, 2002 Dec, 2(4), 331 - 8
Novel intervention strategies for Helicobacter pylori treatment; Noonan B et al.; Helicobacter pylori infects the gastric mucosa of almost half of the worlds population and infection is associated with several gastrointestinal diseases, ranging in severity from superficial and chronic gastritis to duodenal ulceration and gastric adenocarcinoma . Developing new therapeutics against a bacterium with such a unique niche has proven challenging, and the current therapy is complex and increase of bacterial resistance to current antimicrobials and treatment failure has identified a need for newer, more potent compounds . Access to the genomic sequence of several H . pylori isolates has allowed a more focused, target-specific approach to the development of new therapeutics.

Curr Drug Targets Infect Disord, 2002 Dec, 2(4), 279 - 90
Bioinformatics and the discovery of novel anti-microbial targets; Volker C et al.; Genomic research is playing a critical role in the discovery of new anti-microbial drugs . The rapid increase in bacterial and eukaryotic genome sequences allows for new and innovative ways for obtaining antimicrobial protein targets . Here, we describe a two level strategy for target identification and validation using computers (in silico) . First, large scale comparative analyses of genome sequences were used to identify highly conserved genes which might be essential for in vitro and/or in vivo survival of bacterial pathogens . Lab-based experiments provided confirmation or validation of the hypothesis of in silico essentiality for over 350 individual genes . Over 200 validated, broad spectrum; yet highly specific gene targets, were identified in community infection pathogens . The second part of the target discovery strategy is an in-depth evolutionary, structural and cellular analysis of key drug targets . As an example, phylogenetic and structural analyses suggest that sequence and binding-pocket conservation in FabH (beta-ketoacyl-ACP synthase III) would allow for the development of small molecule inhibitors not only effective against a broad species spectrum of community bacterial pathogens but also as potential new therapies for tuberculosis and malaria.

Curr Drug Targets Infect Disord, 2003 Mar, 3(1), 55 - 63
A review of macrolide treatment of atherosclerosis and abdominal aortic aneurysms; Lindholt JS et al.; Seroepidemiological studies have shown an association between Chlamydia pneumoniae and atherosclerosis, the risk of acute myocardial infarction and abdominal aortic aneurysms (AAA) . Several studies have detected C . pneumoniae in atherosclerotic lesions from coronary and carotid arteries, in AAA, and in sclerotic aortic valves . However, culturing of C . pneumoniae is difficult and has seldomly succeeded from atherosclerotic lesions . Thus, the pathogenicity is unknown, and the significance of detecting the organism is unresolved . Nevertheless, in a large observational study comparing the risk of cardiovascular events among recipients of macrolide versus pencillins, macrolide treatment reduced the risk of such events after relevant adjustment . Furthermore, in two out of three minor randomized clinical trials were patients with ischaemic heart disease were randomized into antibiotic treated and placebo groups, a significant reduction in serious end-points were noticed in patients receiving macrolide . Similarly, two other minor randomized trials showed that macrolide treatment inhibited growth of small AAA . Macrolide therapy thus seems potential to improve the outcome of severe ischaemic heart disease, and growth of AAA . If true, it not known whether this is transient because of macrolide's non-specific anti-inflammatory effect or latent infection, or permanent because of eradicating C . pneumoniae organisms . In order to clarify this, large and long term randomized trials are needed, as well as diagnostic methods that can differentiate between individuals who are or are not infected with C . pneumoniae . The latter are needed in order to clarify the impact of the presence of C . pneumoniae and to avoid overconsumption of antimicrobials, which can result in serious ecological problems.

Curr Drug Targets Infect Disord, 2003 Mar, 3(1), 1 - 8
Mode of action of plant defensins suggests therapeutic potential; Thomma BP et al.; Higher vertebrates can rely both on an innate as well as an adaptive immune system for defense against invading pathogens . In contrast, plants can only employ an innate immune system that largely depends on the production of antimicrobial compounds such as plant defensins and other pathogenesis-related proteins . Plant defensins are ubiquitous, cationic, cysteine-rich plant peptides and have a folding pattern that shares high similarity to defense peptides of mammals and insects, suggesting an ancient and conserved origin . A large number of plant defensins appear to display antifungal activity . Some of these defensins have been found to interact with fungal-specific components in the plasmamembrane, resulting in membrane permeabilization . This makes them an attractive source of potential therapeutics to treat fungal infections.

Curr Med Chem, 2003 Feb, 10(3), 211 - 23
Polyene macrolide antibiotics and their applications in human therapy; Zotchev SB; Fungal infections represent a serious problem for patients with immune systems compromized either by HIV infection, or administration of immunosuppressive drugs during cancer therapy and organ transplantation . High dissemination and proliferation rates of many pathogenic fungi along with their insusceptibility to common antimicrobial drugs urge implementation of efficient and reliable antifungal therapy . Up to date, polyene macrolide antibiotics proved to be the most effective antifungal agents due to their potent fungicidal activity, broad spectrum, and relatively low frequency of resistance among the fungal pathogens . However, polyene macrolides are rather toxic, causing such serious side effects as renal failure, hypokalemia and thrombophlebitis, especially upon intravenous administration . Current views on the biosynthesis of polyene macrolides, their mode of action and structure-function relationship, as well as strategies used to overcome the toxicity problem are discussed in this review . In addition, some of the new potential applications for polyene macrolides in therapy of prion diseases, HIV infection and cancer are highlighted.

Curr Pharm Des, 2003, 9(2), 159 - 74
Antimicrobial compounds of low molecular mass are constitutively present in insects: characterisation of beta-alanyl-tyrosine; Meylaers K et al.; The number of bacterial and fungal strains that have developed resistance against the classical antibiotics continues to grow . The intensified search for new antibiotic lead compounds has resulted in the discovery of numerous endogenous peptides with antimicrobial properties in plants, bacteria and animals . Their possible applications as anti-infective agents are often limited by their size, in reference to production costs and susceptibility to proteases . In this article, we report recent isolations of antimicrobial compounds from insects, with molecular masses less than 1 kDa . Experimental approaches are discussed and the first data on the antimicrobial properties of beta-alanyl-tyrosine (252 Da), one of such low molecular mass compounds isolated from the fleshfly Neobellieria bullata, are presented . We also offer evidence for the constitutive presence of antimicrobial compounds in insects of different orders, in addition to the previously identified inducible antimicrobial peptides.

Curr Cancer Drug Targets, 2003 Feb, 3(1), 67 - 81
Garlic {Allium sativum}: a review of its potential use as an anti-cancer agent; Thomson M et al.; Garlic {Allium sativum} is among the oldest of all cultivated plants . It has been used as a medicinal agent for thousands of years . It is a remarkable plant, which has multiple beneficial effects such as antimicrobial, antithrombotic, hypolipidemic, antiarthritic, hypoglycemic and antitumor activity . In this review, we will discuss particularly the largely preclinical use of this agent in the treatment and prevention of cancer . A number of studies have demonstrated the chemopreventive activity of garlic by using different garlic preparations including fresh garlic extract, aged garlic, garlic oil and a number of organosulfur compounds derived from garlic . The chemopreventive activity has been attributed to the presence of organosulfur compounds in garlic . How this is achieved is not fully understood, but several modes of action have been proposed . These include its effect on drug metabolizing enzymes, antioxidant properties and tumor growth inhibition . Most of these studies were carried out in the animal models . Also, recent research has focused on the antimutagenic activity of garlic . Recently, it has been observed that aged garlic extract, but not the fresh garlic extract, exhibited radical scavenging activity . The two major compounds in aged garlic, S-allylcysteine and S-allylmercapto-L-cysteine, had the highest radical scavenging activity . In addition, some organosulfur compounds derived from garlic, including S-allylcysteine, have been found to retard the growth of chemically induced and transplantable tumors in several animal models . Therefore, the consumption of garlic may provide some kind of protection from cancer development.

Eur Respir J, 2003 Jan, 21(1), 135 - 43
Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia; Torres A et al.; Based on recent guidelines for the management of community-acquired pneumonia, this study was designed to evaluate the effectiveness of a new fluoroquinolone compared with standard antimicrobial regimens, in conditions relating as closely as possible to the real world setting . In this study, 564 patients were randomised to either oral moxifloxacin (400 mg o.d.) or to standard oral therapy (amoxicillin 1 g t.i.d . or clarithromycin 500 mg b.i.d . alone or in combination) for up to 14 days using a double-blind procedure . The choice between the three standard regimens was made by the clinician prior to randomisation . Clinical response, quality of life, symptoms, healthcare resources and safety were assessed . In the per-protocol population, clinical success was reported for 201 of 215 (93.5%) and 217 of 231 (93.9%) in the moxifloxacin and standard groups, respectively, at 7-10 days post-therapy . At 28-35 days follow-up, continued clinical cure was observed in 183 of 192 (95.3%) moxifloxacin and 207 of 221 (93.7%) standard groups . Drug-related adverse events were reported in 55 of 274 (20%) moxifloxacin and 86 of 279 (31%) standard patients with diarrhoea >5% . Oral moxifloxacin monotherapy was as effective as, and better tolerated than, optimal antibiotic strategy represented either by mono- or combination therapy (amoxicillin and/or clarithromycin) in community-acquired pneumonia management.

Planta, 2003 Feb, 216(4), 587 - 96 Epub 2002 Dec 06.
MSI-99, a magainin analogue, imparts enhanced disease resistance in transgenic tobacco and banana; Chakrabarti A et al.; Magainin is one of the earliest reported antimicrobial peptides isolated from skin secretions of the African clawed frog Xenopus laevis . A synthetic substitution analogue of magainin, MSI-99, is employed in this study to impart disease resistance in transgenic tobacco ( Nicotiana tabacumL.) and banana {( Musaspp . cv . Rasthali (AAB)} . This peptide inhibited the growth and spore germination of Fusarium oxysporumf.sp . cubenseat 16 micro g/ml . MSI-99 has been subcloned into plant expression vectors pMSI164 and pMSI168, targeting the peptide into the cytoplasm and extracellular spaces, respectively . Tobacco plants transformed with pMSI168 showed enhanced resistance against Sclerotinia sclerotiorum, Alternaria alternataand Botrytis cinerea . Transgenic banana pants were obtained for both pMSI164 and pMSI168 transformations and showed resistance to F . oxysporumf.sp . cubenseand Mycosphaerella musicola . The transgenic nature of the transformants and expression of this peptide was confirmed through polymerase chain reaction (PCR) and reverse transcription (RT)-PCR . The results suggest that MSI-99 can be useful in imparting enhanced disease resistance in transgenic plants.

Novartis Found Symp, 2002, 248, 20 - 6; discussion 27-37, 277-82
Post-secretory fate of host defence components in mucus; Salathe M et al.; Airway mucus is a complex mixture of secretory products that provide a multifaceted defence against infection . Among many antimicrobial substances, mucus contains a peroxidase identical to milk lactoperoxidase (LPO) that is produced by goblet cells and submucosal glands . Airway secretions contain the substrates for LPO, namely thiocyanate and hydrogen peroxide, at concentrations sufficient for production of the biocidal compound hypothiocyanite, a fact confirmed by us in vitro . In vivo, inhibition of airway LPO in sheep significantly inhibits bacterial clearance, suggesting that the LPO system is a major contributor to host defences . Since secretory products including LPO are believed to be steadily removed by mucociliary clearance, their amount and availability on the surface is thought to be controlled solely by secretion . In contrast to this paradigm, new data suggest that LPO and other substances are retained at the ciliary border of the airway epithelium by binding to surface-associated hyaluronan, thereby providing an apical, fully active enzyme pool . Thus, hyaluronan, secreted from submucosal gland cells, plays a previously unrecognized pivotal role in mucosal host defence by retaining LPO and possibly other substances important for first line host defence at the apical surface 'ready for use' and protected from ciliary clearance.

Cell Mol Life Sci, 2002 Dec, 59(12), 2023 - 32
Association of different mobile elements to generate novel integrative elements; Rice LB; Among the more important problems in modern hospitals is the prevalence of bacterial pathogens expressing resistance to multiple antimicrobial agents . The frequency of multiresistance suggests mechanisms by which bacterial species can concentrate and efficiently exchange a variety of resistance determinants . Mechanisms by which this occurs include insertion of transposons within transposons, coalescence through the activity of insertion sequences and the employment of integrons . In some instances, more than one of these mechanisms is involved in creating large multiresistance genetic elements . The association of the elements with transferable elements or transposons may promote rapid dissemination among clinical strains, and create further opportunities for inclusion of additional resistance determinants.

Clin Infect Dis, 2003 Feb 15, 36(4), 453 - 60 Epub 2003 Jan 31.
Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus; Murray MF; Coinfection with Mycobacterium tuberculosis and human immunodeficiency virus (HIV) is responsible for one-third of all deaths due to acquired immunodeficiency syndrome . More than 99% of cases of HIV-M . tuberculosis coinfection occur in the developing world, where limited resources add urgency to the search for effective and affordable therapies . Although antimicrobial agents against each of these infections are available, single agents that have activity against both M . tuberculosis and HIV are uncommon . The activity of nicotinamide has been evaluated in 2 different eras: in anti-M . tuberculosis studies performed during 1945-1961 and in anti-HIV studies performed from 1991 to the present . This review brings together these 2 bodies of inquiry and raises the possibility that, with more study, this small molecule could emerge at the beginning of the 21st century either as a therapeutic agent in itself or as the lead compound for a new class of agents with activity against both M . tuberculosis and HIV.

Planta Med, 2003 Jan, 69(1), 80 - 3
Antimicrobial activity and chemical composition of the essential oil of Lippia graveolens from Guatemala; Salgueiro LR et al.; The composition and the antimicrobial activity of the essential oil of Lippia graveolens H.B.K . collected in Guatemala were studied . Two samples of essential oils were obtained from the aerial parts of the plant by hydrodistillation and analyzed by GC and GC-MS . The oils were characterized by their high content of monoterpenes (70.0-87.2 %) . Important differences between the major constituents were found, particularly for carvacrol (0.2 vs . 44.8 %), thymol (18.1 vs . 7.4 %) and p-cymene (6.8 vs . 21.8 %) . Both oils showed significant activity against all tested Gram-positive and Gram-negative bacteria, as well as against fungi . Nevertheless, the oil with the higher carvacrol content was found to be more active than the thymol type, with MICs ranging from 0.25 to 0.83 microL/mL and 0.12 to 0.27 microL/mL for bacteria and fungi, respectively.

Dermatology, 2003, 206(1), 29 - 36
Topical treatment in acne: current status and future aspects; Gollnick HP et al.; During the last 20 years, the number of topical and systemic drugs for the treatment of acne vulgaris has been enriched . Topical drugs on the one hand have been newly discovered or further developments of already available agents such as in the group of retinoids or galenic formulation have improved efficacy or local tolerance . Topical retinoids are a mainstay in acne treatment since 1962 . All-trans retinoic acid was the first and is still in use . Its irritative potential has led to the new galenics, i.e . incorporation in microsponges and in propolyomers, which increased the tolerability significantly . The isomer of tretinoin, isotretinoin, has the same clinical efficacy, but also a lower irritancy . A real breakthrough was adapalene, a retinoid-like agent, with a different retinoid receptor-binding profile, but in addition to the same clinical efficacy on inflammatory and non-inflammatory acne lesions compared to tretinoin, a better tolerability and, therefore, compliance . Unfortunately, over the past years topical retinoids have been less used in inflammatory acne than they should be, taking the the mechanisms of action into account . Topical antimicrobials, in particular topical antibiotics, should be used less often than in the past and only for short periods to avoid the development of resistances . It seems better to combine those agents with topical retinoids, with BPO or with azelaic acid to enhance the efficacy and slow down the development of resistance . BPO is still the gold standard for papular-pustular acne of mild-to-moderate type in concentrations of 2-5% . Azelaic acid is an alternative with efficacy on the comedo and is antibacterial without development of resistances . Finally, the physical removal by electrocautery or CO(2) laser of multiple densely packed closed comedones, macrocomedones and microcysts is necessary to enhance the efficacy of topical comedolytic agents and to speed up the therapeutic results . Photodynamic therapy has not yet been proven efficacious in controlled studies . Blue and red light can probably be used in association with local agents but enhancement of the irritative potential of topical and systemic agents has to be considered .

Biochem Biophys Res Commun, 2003 Feb 7, 301(2), 551 - 7
Redox properties of the couples compound I/compound II and compound II/native enzyme of human myeloperoxidase; Furtmuller PG et al.; Myeloperoxidase (MPO) is an important component of the neutrophil's antimicrobial armory and has been implicated in promoting tissue damage in numerous inflammatory diseases . For the first time the standard reduction potential of the redox couple compound II/native enzyme has been determined to be (0.97+/-0.01)V at pH 7.0 and 25 degrees C . This was achieved by rapid mixing of preformed compound II with either tyrosine or nitrite by using the sequential-mixing stopped-flow technique and measuring spectrophotometrically the concentrations of the reacting species and products at equilibrium . Using the recently determined standard reduction potential for the couple compound I/native enzyme (1.16 V), the reduction potential of the couple compound I/compound II was calculated to be 1.35 V at pH 7 and 25 degrees C . These data reveal substantial differences between the two known heme peroxidase superfamilies and reflect the dramatic differences observed in the oxidisability of substrates by the MPO redox intermediates compound I and compound II.

Int J Clin Pharmacol Ther, 2003 Jan, 41(1), 36 - 41
Trends in ophthalmic antimicrobial utilization pattern in Bahrain between 1993 and 2000: a resurgence of chloramphenicol?
Jassim Al Khaja KA, Sequeira RR, Mathur VS.
OBJECTIVES: The occurrence of aplastic anemia following topical administration of ophthalmic chloramphenicol is controversial and debated internationally . We have determined the influence of such debate on the utilization of ophthalmic chloramphenicol in Bahrain, through studying the utilization patterns of ophthalmic antimicrobial preparations by the Ministry of Health, with an emphasis on chloramphenicol, between 1993 and 2000 . Cost-implications of these patterns are examined . MATERIAL AND METHODS: Information on the annual purchase of ophthalmic antimicrobial drug preparations and their unit price was obtained from the Directorate of Materials Management, Ministry of Health, and analyzed . RESULTS: In 1993, the 3 most commonly purchased ophthalmic antibacterial preparations were oxytetracycline 1% eye ointment (40.1%); sulfacetamide 10% and 20% eye drops (25.3%); and chloramphenicol 0.5% eye drops and 1% eye ointment (10.8%) . In 2000, oxytetracycline remained the most frequently purchased preparation (33%), followed by chloramphenicol (21.2%) . Between 1993 and 1999, chloramphenicol purchases fluctuated between 10% to 16.4% with a remarkable increase to 21.2%, in 2000 . Chloramphenicol accounted for 8.6% and 15.1% of cost of total ophthalmic preparations purchased in 1993 and 2000, respectively . CONCLUSION: Despite continued concerns of potential risks of ophthalmic chloramphenicol, this preparation is extensively utilized in Bahrain . We are of the opinion that for minor infections, chloramphenicol ophthalmic preparations should be replaced by safer alternatives . Further, we recommend that their use be reserved for ocular infections that are resistant to other antimicrobials, and that ophthalmologists, at the secondary care level, should supervise such treatment.

J Am Vet Med Assoc, 2003 Feb 1, 222(3), 346 - 50, 316
Intraosseous regional perfusion for treatment of septic physitis in a two-week-old foal; Kettner NU et al.; A 2-week-old Morgan filly examined because of lameness of 5 days' duration was found, on the basis of clinical and radiographic findings, to have septic physitis of the distal end of the radius . The foal was treated by means of intraosseous regional perfusion with penicillin and amikacin and systemic administration of antimicrobials . Intraosseous regional perfusion was performed 3 times . The foal was anesthetized for the first episode of intraosseous regional perfusion, but was only sedated for the subsequent 2 episodes . Antimicrobials were administered systemically for 22 days . Foals with septic physitis are typically considered to have a guarded to poor prognosis for recovery; however, this treatment regimen resulted in relatively fast and uncomplicated resolution of the infection in this foal.

Dan Medicinhist Arbog . 2002;:164-70.
{The human in the art: Henrik Have's painting for a medical thesis}; Kristiansen JE et al.; A painting made by the Danish painter and author Henrik Have (born 1946) illustrates the front page of Jette E . Kristiansen's medical thesis The Antimicrobial Activity of Psychotherapeutic Drugs and Stereo-isomeric Analogues (1990) . The painting illustrates beautifully that art and science can go hand in hand . Even very complicated chemical, pharmacological and microbiological questions can be expressed by means of colours and by means of symbols used in everyday life, such as a spiral (DNA), or a pair of hands expressing working together . Prayers, wishes and the most difficult questions in receptor stereo-chemistry in eucaryotic and procaryotic cell-systems are illustrated in this painting . Synthetic chemistry and pharmacology are linked in the development of the synthetic dyes . The chemical colours are often the same in dyes and drugs . The red colour in the pharmacology is associated with the antibiotic drugs as sulfonamides as well as with the staining of Gram-negative bacteria . The yellow colour is associated with the antibiotic drugs, quinolones and the Ziehl-Neelsen staining for tubercle bacillii . The blue colour is associated with the psychoactive drugs, phenotiazines, as well as with methylenblue staining and the staining of Gram-positive bacteria . These association and symbols have been used in this painting.

Neurol Res, 2003 Jan, 25(1), 27 - 30
Nocardial cerebral abscess: report of three cases and review of the current neurosurgical management; Valarezo J et al.; Nocardia asteroides cerebral abscesses are rare but challenging intracranial lesions . Early diagnosis, institution of appropriate antimicrobial therapy, lack of underlying systemic disease and limited intracranial disease are recognized factors leading to good outcome . However, the optimal treatment approach has not been established and nocardial brain abscesses have been managed either conservatively, with steroetactic aspirations or with open craniotomy and enucleation . We present three cases of Nocardia asteroides cerebral abscesses cured only after neurosurgical enucleation, and discuss the current management alternatives and conclude that a more aggressive approach than that currently preferred for this entity may be more effective.

Neurol Res, 2003 Jan, 25(1), 22 - 6
Linezolid: implications for neurosurgical infections; Nguyen CM et al.; Nosocomial infections affect a significant number of intensive care unit (ICU) patients including those in the neurosurgical ICU . Gram-positive organisms are responsible for many of these infections and often these pathogens are resistant to some of the older antimicrobial agents . Two new classes of antibiotics have been developed: streptogramins and oxazolidinones . Linezolid is an oxazolidinone, which has been shown to be effective against methicillin- and vancomycin-resistant Gram-positive pathogens . It may be administered orally or parenterally, and displays favorable pharmacokinetic properties, with rapid and complete absorption after oral administration . Linezolid is generally well tolerated with mild gastrointestinal related adverse effects . Linezolid provides a useful alternative in the treatment of Gram-positive infections, particularly those caused by resistant organisms . It has tremendous clinical utility, especially in the ICU where infections and multi-drug resistant rates are high and treatment options become limited.

Radiology, 2003 Feb, 226(2), 399 - 404
Nephrotoxicity of iopamidol in pediatric, adolescent, and young adult patients who have undergone allogeneic bone marrow transplantation; Haight AE et al.; PURPOSE: To assess the effects of the low-osmolar contrast agent iopamidol and antimicrobial drugs on renal function in pediatric, adolescent, and young adult patients who have undergone bone marrow transplantation (BMT) . MATERIALS AND METHODS: A retrospective review of records of 120 consecutive pediatric patients who underwent allogeneic BMT in 1997 or 1998 was performed . Eighty-nine patients (median age, 8.1 years) fulfilled study eligibility criteria . Cumulative doses of nephrotoxic antimicrobial drugs were recorded, as well as serum creatinine and blood urea nitrogen concentrations from 24 hours before to 72 hours after each administration of iopamidol during a computed tomographic examination performed within 100 days after BMT . Random coefficient models were used to estimate nephrotoxic effects . RESULTS: Mean baseline glomerular filtration rate was 130.2 mL/min/1.73 m(2), and mean baseline creatinine concentration was 0.51 mg/dL (45 micro mol/L) . Older age at BMT (P <.001), use of foscarnet (P =.003), and receipt of iopamidol (P =.073) each prompted a rise in serum creatinine concentration . The antiviral drug foscarnet was associated with the largest increase in the creatinine level; the use of iopamidol effected a relatively small rise in creatinine level . CONCLUSION: Iopamidol nephrotoxicity was negligible in this cohort of pediatric patients who had undergone allogeneic BMT, even in the presence of elevated renal function levels.

J Biol Chem, 2003 Apr 11, 278(15), 13110 - 7 Epub 2003 Jan 31.
NMR study of mersacidin and lipid II interaction in dodecylphosphocholine micelles . Conformational changes are a key to antimicrobial activity; Hsu ST et al.; Mersacidin belongs to the type B lantibiotics (lanthionine-containing antibiotics) that contain post-translationally modified amino acids and cyclic ring structures . It targets the cell wall precursor lipid II and thereby inhibits cell wall synthesis . In light of the emerging antibiotics resistance problem, the understanding of the antibacterial activity on a structural basis provides a key to circumvent this issue . Here we present solution NMR studies of mersacidin-lipid II interaction in dodecylphosphocholine (DPC) micelles . Distinct solution structures of mersacidin were determined in three different states: in water/methanol solution and in DPC micelles with and without lipid II . The structures in various sample conditions reveal remarkable conformational changes in which the junction between Ala-12 and Abu-13 (where Abu is aminobutyric acid) effectively serves as the hinge for the opening and closure of the ring structures . The DPC micelle-bound form resembles the previously determined NMR and x-ray crystal structures of mersacidin in pure methanol but substantially deviates from the other two states in our current report . The structural changes delineate the large chemical shift perturbations observed during the course of a two-step (15)N-(1)H heteronuclear single quantum coherence titration . They also modulate the surface charge distribution of mersacidin suggesting that electrostatics play a central role in the mersacidin-lipid II interaction . The observed conformational adaptability of mersacidin might be a general feature of lipid II-interacting antibiotics/peptides.

J Antimicrob Chemother, 2003 Feb, 51(2), 447 - 51
A national surveillance of antimicrobial resistance in Escherichia coli isolated from food-producing animals in Japan; Kijima-Tanaka M et al.; A nationwide investigation of antimicrobial susceptibility in Escherichia coli isolated from food-producing animals was performed in Japan . MICs of 18 antimicrobial agents were determined for a total of 1018 isolates . Higher resistance rates were observed against sulfadimethoxine, oxytetracycline and dihydrostreptomycin, followed by ampicillin and kanamycin . Resistance was more frequently observed among broiler isolates, followed by isolates from pigs . Almost 10% of broiler isolates were resistant to fluoroquinolones and extremely high MICs (100 mg/L) were observed . In general, antimicrobial resistance rates in E . coli have declined in recent years, with the exception of resistance to fluoroquinolones among broiler isolates, which has increased.

J Antimicrob Chemother, 2003 Feb, 51(2), 439 - 42
Antimicrobial activity of esomeprazole versus omeprazole against Helicobacter pylori; Gatta L et al.; OBJECTIVE: Esomeprazole is an enantiomorph of omeprazole, which inhibits gastric acid secretion more effectively than omeprazole . As proton pump inhibitors also exert an antibacterial activity, we aimed to compare esomeprazole and omeprazole for their antimicrobial activity against Helicobacter pylori in vitro . METHODS: We studied 52 H . pylori isolates obtained from gastric biopsies and inoculated onto agar plates containing the acid-converted drugs at different concentrations . The minimal concentrations that inhibited the growth of 50% and 90% of isolates were defined as MIC(50) and MIC(90) . RESULTS: The MIC(50) and MIC(90) of esomeprazole were 16 and 32 mg/L; and those of omeprazole were 32 and 64 mg/L . Overall, 63.5% of isolates showed the same susceptibility to both drugs; 17 isolates were two- to 64-fold more susceptible to esomeprazole and two isolates were two-fold more susceptible to omeprazole . CONCLUSIONS: The increased antimicrobial activity in vitro of esomeprazole against H . pylori could contribute to improving the outcome of the eradication treatment of such an infection.

J Antimicrob Chemother, 2003 Feb, 51(2), 367 - 71
Monotherapy with mastic does not eradicate Helicobacter pylori infection from mice; Loughlin MF et al.; OBJECTIVE: To determine the ability of mastic monotherapy to eradicate Helicobacter pylori infection from mice . MATERIALS AND METHODS: The susceptibility of H . pylori SS1 to mastic was assessed by broth dilution determination of the MIC and MBC . Mice were inoculated intragastrically with either a suspension of H . pylori SS1 (n = 70) or brain-heart infusion broth alone (n = 10) . Mice were given antimicrobial chemotherapy 4 weeks after infection and were administered the mouse equivalent of either 2 g of mastic twice daily for 7 days or a triple therapy regimen containing the mouse equivalent of 400 mg of metronidazole, 250 mg of clarithromycin and 20 mg of omeprazole twice daily for 7 days . Mice were killed either immediately or 1 month after the completion of treatment, and their stomachs cultured for H . pylori . RESULTS: The mastic MIC and MBC of H . pylori SS1 were 7.80 and 31.25 mg/L, respectively . The triple therapy regimen eradicated infection from 19 of 20 SS1-infected mice . Mastic failed to eradicate infection from any of the 18 SS1-infected mice (P < 0.001) and there was no signifi- cant reduction in gastric bacterial load in mice treated with this regimen . CONCLUSION: Despite reported beneficial effects in ulcer patients and the good in vitro activity of mastic against H . pylori, this compound is unable to eradicate H . pylori infection from mice.

J Antimicrob Chemother, 2003 Feb, 51(2), 275 - 80
Development and mechanism of fluoroquinolone resistance in Legionella pneumophila; Jonas D et al.; The potential for selection in vitro of Legionella pneumophila mutants resistant to fluoroquinolones was investigated . Six distinct clinical isolates of L . pneumophila were subcultured in subinhibitory concentrations of ciprofloxacin, levofloxacin, clinafloxacin, trovafloxacin and moxifloxacin until MICs increased at least eight-fold . The numbers of serial passages required in microbroth dilution series were determined . The gyrA gene of the six parental strains, and 12 selected mutant strains, was sequenced . The five quinolones differed markedly in their ability to select mutants with decreased susceptibility . The average number of serial passages required was low in the cases of clinafloxacin (n = 10.6), ciprofloxacin and levofloxacin (both n = 13), but notably higher for trovafloxacin (n = 26.6) and moxifloxacin (n = 22.5) . Five mutants treated with ciprofloxacin and three treated with moxifloxacin showed Thr83-->Lys or Thr83-->Ile amino acid changes in the gyrA gene . In conclusion, different quinolones lose their antimicrobial effect after a varying number of passages . This study demonstrated, for the first time to our knowledge, that gyrA in L . pneumophila is a possible target of fluoroquinolones.

Indian J Pathol Microbiol, 2001 Jan, 44(1), 45 - 8
Candidemia in neonatal intensive care unit; Gupta N et al.; The present study was conducted over a period of 6 months to determine the Candida species causing candidemia in a neonatal intensive care unit and to analyse the risk factors associated with acquisition of significant fungemia . Speciation of the 19 isolated Candida spp was done by the standard techniques . Antimicrobial susceptibility of these isolates was determined by disc diffusion method against Amphotericin B, Fluconazole, Ketoconozole and 5-Flucytosine . Candida glabrata was the most common species involved (42.1%) . Other species isolated were C . tropicalis (31.6%) . Calbicans (21.1%) and C.parapsilosis (5.2%) . All the isolates were sensitive to Amphotericin B . Resistance to other antigungal agents was seen only in C . globrata . Significant candidemia was seen in 14/19 (72.6%) of neonates . Risk factors found to be associated with significant candidemis in these neonates included intake of multiple broad-spectrum antibiotics (p<0.0001), use of total parenteral nutrition (p<0.045) and ventilators (p<0.0001).

Support Care Cancer, 2003 Feb, 11(2), 101 - 6 Epub 2002 Nov 12.
Granulocyte transfusions from G-CSF-stimulated donors for the treatment of severe infections in neutropenic pediatric patients with onco-hematological diseases; Cesaro S et al.; From March 1994 to January 2001, 15 courses of granulocyte transfusion (GTX) were administered to 13 neutropenic patients (6 male and 7 female patients; median age 7 years, range 3 months to 14 years) affected by: acute lymphoblastic leukemia (ALL) in 6 cases, acute myeloid leukemia (AML) in 5, very severe aplastic anemia in 1, and familial erythrophagocytic lymphohistiocytosis (FEL) in 1 . Infections were classified as microbiologically defined and clinically defined infections in 8 and 7 episodes, respectively . Before the GTX transfusions, broad-spectrum antibacterial and antifungal therapy had been administered for a median of 12 (range 5-28) and 8 days (range 2-50), respectively, with no improvement . G-CSF was administered prior to GTX in 9 episodes of infection, with a median of 9 days of treatment (range 4-30) . Leukapheresis was obtained from 15 related donors (father, 10; mother, 3; sister, 1; aunt, 1) after s.c . stimulation with G-CSF, 300 micro g daily, starting from day -3 (where day 0 was the day of the first granulocyte collection) and continuing throughout the period of GTX treatment . The donors' median white blood cell (WBC) count at leukapheresis was 31.6 x 10(9)/l (range 12-56), and the median yield was 31.39 x 10(9) WBC (range 2.96-64.73 x 10(9)), with a proportion of PMN of 90-95% . Overall, 70 GTX were administered, with a median of 4 GTX per episode of infection (range 2-11) . The combination of GTX with antimicrobial therapy led to complete or partial recovery in 6 and in 3 of 15 episodes (60%), respectively . Priming of the donor with G-CSF was well tolerated, the most common side-effects being bone pain, malaise and paresthesia . All donors are alive and well after a median of 4.5 years (range 0.8-7.7) from donation . We conclude that GTX is potentially useful when the severity of the infection and the host's immunodeficiency make any other antimicrobial treatment ineffectual . Long-term safety data on the stimulation of donors with G-CSF have been reassuring to date . Further controlled studies are needed to assess the exact role of GTX in the outcome of neutropenic patients with severe infection and any criteria for patient selection and the timing of GTX administration.

Ann Surg, 2003 Feb, 237(2), 235 - 45
Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial; Solomkin JS et al.; OBJECTIVE: To examine the clinical efficacy and safety of ertapenem, a novel beta-lactam agent with wide activity against common pathogens encountered in intraabdominal infection . SUMMARY BACKGROUND DATA: Ertapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections.METHODS This prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections . RESULTS: Six hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population . Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population) . A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability . For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam . One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam . CONCLUSIONS: In this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections . Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam . A formal process for review of adequacy of source control was found to be of benefit . The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.

J Mol Biol, 2003 Feb 14, 326(2), 467 - 74
The differentially spliced mouse tagL gene, homolog of tag7/PGRP gene family in mammals and Drosophila, can recognize Gram-positive and Gram-negative bacterial cell wall independently of T phage lysozyme homology domain; Kibardin AV et al.; Tag7/PGRP, a recently characterized antimicrobial protein, is conserved from insects to mammals . Recently its involvement in Toll signalling in Drosophila was demonstrated . A number of genes representing a new family homologous to PGRP were identified in Drosophila and human . Here we describe a splicing pattern of the tagL gene, mouse member of tag7/PGRP family . Some of the identified splice variants lacked characteristics for the family T phage lysozyme homology domain (also known as PGRP domain) . Accordingly to the predicted transmembrane domains, mouse TagL may be secreted as inducible proteins or retained on intracellular membranes . All detected splice variant isoforms of TagL bound Gram-positive, Gram-negative bacteria and peptidoglycan . This binding did not depend on the presence of T phage lysozyme homology domain but was associated with the C-terminal portion of the polypeptides . Thus, this variety of isoforms of a single gene may play a role in circulating bacteria recognition in mammals.

Drugs, 2003, 63(4), 389 - 406
Antimicrobial peptides: current status and therapeutic potential; Koczulla AR et al.; Antimicrobial peptides (AMPs) are effector molecules of the innate immune system . A variety of AMPs have been isolated from species of all kingdoms and are classified based on their structure and amino acid motifs . AMPs have a broad antimicrobial spectrum and lyse microbial cells by interaction with biomembranes . Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cell proliferation, immune induction, wound healing, cytokine release, chemotaxis and protease-antiprotease balance . AMPs qualify as prototypes of innovative drugs that may be used as antimicrobials, anti-lipopolysaccharide drugs or modifiers of inflammation . Several strategies have been followed to identify lead candidates for drug development, to modify the peptides' structures, and to produce sufficient amounts for pre-clinical and clinical studies . This review summarises the current knowledge about the basic and applied biology of AMPs.

Bull Mem Acad R Med Belg, 2002, 157(5-6), 301 - 8; discussion 308-9
{Evolutionary strategy of antibiotic resistance}; Courvalin P; Antibiotics have reduced the mortality from infectious diseases, but not the prevalence of these diseases . Use, and often abuse, of antimicrobial agents encourages the evolution of bacteria toward resistance, often resulting in therapeutic failure . This evolution is due to the emergence of "new" resistance mechanisms and to the spread of well-characterized mechanisms of resistance, to the majority of bacterial species . Bacterial resistance can be intrinsic or acquired . Intrinsic resistance is species or genus specific and delineates the spectrum of activity of the antibiotic . Acquired resistance is present in only certain strains of a species or of a genus . The latter results from mutation in a gene located in the host chromosome, or a plasmid, or from acquisition of new genetic information by a bacterium mainly by conjugation or transformation.

Mol Cell Biol, 2003 Feb, 23(4), 1358 - 67
Signal-induced transcriptional activation by Dif requires the dTRAP80 mediator module; Park JM et al.; The Mediator complex is the major multiprotein transcriptional coactivator complex in Drosophila melanogaster . Mediator components interact with diverse sets of transcriptional activator proteins to elicit the sophisticated regulation of gene expression . The distinct phenotypes associated with certain mutations in some of the Mediator genes and the specific in vitro interactions of Mediator gene products with transcriptional activator proteins suggest the presence of activator-specific binding subunits within the Mediator complex . However, the physiological relevance of these selective in vitro interactions has not been addressed . Therefore, we analyzed dTRAP80, one of the putative activator-binding subunits of the Mediator, for specificity of binding to a number of natural transcriptional activators from DROSOPHILA: Among the group of activator proteins that requires the Mediator complex for transcriptional activation, only a subset of these proteins interacted with dTRAP80 in vitro and only these dTRAP80-interacting activators were defective for activation under dTRAP80-deficient in vivo conditions . In particular, activation of Drosophila antimicrobial peptide drosomycin gene expression by the NF-kappa B-like transcription factor Dif during induction of the Toll signaling pathway was dependent on the dTRAP80 module . These results, and the indirect support from the dTRAP80 artificial recruitment assay, indicate that dTRAP80 serves as a genuine activator-binding target responsible for a distinct group of activators.

J Antimicrob Chemother, 2002 Dec, 50 Suppl S2, 87 - 92
Implications of antimicrobial resistance in the empirical treatment of community-acquired respiratory tract infections: the case of macrolides; Lonks JR et al.; Macrolide resistance among pneumococci is increasing worldwide and is associated with increasing macrolide use . Recent studies show that use of macrolides and azalides increases nasopharyngeal carriage of both macrolide-resistant and penicillin-resistant pneumococci . Carriage of a resistant pneumococcus may foster dissemination . The clinical relevance of in vitro resistance has been debated . However, recent data from a matched case-control study showed that 18 (24%) of 76 patients had breakthrough bacteraemia with an erythromycin-resistant pneumococcus while taking a macrolide, whereas none of the 136 matched controls with an erythromycin-susceptible pneumococcal bacteraemia was taking a macrolide (P = 0.0000001) . Moreover, five (24%) of 21 patients bacteraemic with the low-level resistant M phenotype and none of the 40 matched controls were taking a macrolide (P = 0.00157) . These data indicate that macrolide resistance due to both the efflux and the methylase mechanisms is clinically relevant . Furthermore, they favour guidelines for the empirical treatment of outpatients with community-acquired pneumonia that recommend high-dose oral amoxicillin and reserve coverage of atypical pathogens for selected high-risk populations.

J Antimicrob Chemother, 2002 Dec, 50 Suppl S2, 13 - 9
Antimicrobial susceptibility and pneumococcal serotypes; Fenoll A et al.; The increase in antibiotic resistance and the possible changes in serotype prevalence as a consequence of a new conjugated vaccine have contributed to renewed interest in the study of pneumococcal serotypes and their antibiotic resistances . Spain still has one of the highest penicillin resistance rates, but in the past 4-5 years a slight decrease has been observed . The level of resistance has not increased either, 12.7% of the 11 165 isolates studied showed high-level penicillin resistance but 94% of these had an MIC of only 2 mg/L . Serotypes 6, 9, 14, 19 and 23 included 83% of the penicillin-resistant pneumococci; the remaining 17% belonged to 18 different serotypes . We analysed these minor penicillin-resistant serotypes in view of their potential increase following a possible child vaccination programme . Four of these serotypes (11, 15, 21 and 35) were the most prevalent, and among them serotype 15 was particularly frequent with >50% of its strains resistant . The effective control of these minor penicillin-resistant serotypes should be based on continuous surveillance of pneumococcal epidemiology.

J Am Vet Med Assoc, 2003 Jan 15, 222(2), 168 - 73
Survey of antimicrobial susceptibility testing practices of veterinary diagnostic laboratories in the United States; Brooks MB et al.; OBJECTIVE: To describe antimicrobial susceptibility testing practices of veterinary diagnostic laboratories in the United States and evaluate the feasibility of collating this information for the purpose of monitoring antimicrobial resistance in bacterial isolates from animals . DESIGN: Cross-sectional study . PROCEDURES: A questionnaire was mailed to veterinary diagnostic laboratories throughout the United States to identify those laboratories that conduct susceptibility testing . Nonrespondent laboratories were followed up through telephone contact and additional mailings . Data were gathered regarding methods of susceptibility testing, standardization of methods, data management, and types of isolates tested . RESULTS: Eighty-six of 113 (76%) laboratories responded to the survey, and 64 of the 86 (74%) routinely performed susceptibility testing on bacterial isolates from animals . Thirty-four of the 36 (94%) laboratories accredited by the American Association of Veterinary Laboratory Diagnosticians responded to the survey . Laboratories reported testing > 160,000 bacterial isolates/y . Fifty-one (88%) laboratories reported using the Kirby-Bauer disk diffusion test to evaluate antimicrobial susceptibility; this accounted for 65% of the isolates tested . Most (87%) laboratories used the NCCLS (National Committee for Clinical Laboratory Standards) documents for test interpretation . Seventy-five percent of the laboratories performed susceptibility testing on bacterial isolates only when they were potential pathogens . CONCLUSIONS: The veterinary diagnostic laboratories represent a comprehensive source of data that is not easily accessible in the United States . Variability in testing methods and data storage would present challenges for data aggregation, summary, and interpretation.

J Am Dent Assoc, 2003 Jan, 134(1), 43 - 51; quiz 117-8
The effect of diabetes mellitus on endodontic treatment outcome: data from an electronic patient record; Fouad AF et al.; BACKGROUND: The authors used a custom-built electronic record system to investigate endodontic diagnostic and treatment outcome data in patients with and without diabetes . METHODS: The medical histories and endodontic treatment data for nonsurgical endodontic patients treated in predoctoral and postgraduate specialty clinics were entered into an electronic record system . A total of 5,494 cases (including 284 cases in patients with diabetes) were treated, and 540 cases (including 73 cases in patients with diabetes) had follow-up data two years or more postoperatively . The authors performed univariate and multivariate analyses to determine important factors affecting endodontic diagnosis and treatment outcome . RESULTS: Patients with diabetes had increased periodontal disease of teeth with endodontic involvment compared with patients who did not have diabetes . There was a trend toward increased symptomatic periradicular disease in patients with diabetes who received insulin, as well as flareups in all patients with diabetes . Two years or longer postoperatively, 68 percent of cases followed were successful . Older age, the absence of preoperative lesions, the presence of permanent restorations and longer postoperative evaluation periods all were associated with a successful outcome . A multivariate analysis showed that in cases with preoperative periradicular lesions, a history of diabetes was associated with a significantly reduced successful outcome . CONCLUSIONS: Patients with diabetes have increased periodontal disease in teeth involved endodontically and have a reduced likelihood of success of endodontic treatment in cases with preoperative periradicular lesions . CLINICAL IMPLICATIONS: Patients with diabetes who are treated endodontically should be assessed carefully and be treated with effective antimicrobial root canal regimens, particularly in cases with preoperative lesions.

Quintessence Int, 2002 Nov-Dec, 33(10), 731 - 5
Preliminary evaluation of salivary pellicle on nickel-chromium alloy in vivo; Ozden AN et al.; OBJECTIVE: The composition of the salivary interface (pellicle) between dental restorations and oral mucosa may be critical to the biocompatibility of the restoration . The purpose of this study was to examine the molecular composition of the salivary pellicle on nickel-chromium alloy in vivo . METHOD AND MATERIALS: The molecular components of nickel-chromium pellicle was examined with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analyses . RESULTS: Only limited numbers of salivary proteins were found to participate in the formation of nickel-chromium pellicle in vivo . Salivary amylase and secretory immunoglobulin A were among the proteins identified in the pellicle . CONCLUSION: In vivo, nickel-chromium pellicle consists of selectively adsorbed salivary proteins . Because both salivary amylase and secretory immunoglobulin A are antimicrobial proteins, it is possible that they play a role in modulating the microbial flora on the nickel-chromium prosthesis.

Ann Med, 2002, 34(7-8), 606 - 13
Management of septic shock; Vincent JL et al.; Severe sepsis is a common disease process affecting some 2-11% of hospital admissions in the US . Severe sepsis and septic shock are associated with considerable morbidity and mortality, and account for a large part of intensive care unit costs . Until recently, the management of septic shock relied on the treatment of underlying infection with antimicrobial agents and surgical removal of any infectious source, and individual support of failing organs . However, in the last few years we have seen huge strides being made in our understanding of the pathophysiology of the sepsis response, and in our ability to manipulate that response . In the last couple of years these advances have come to fruition with the development of a drug, drotrecogin alfa, which specifically reduces mortality from this all too often fatal disease . While intensive early resuscitation remains the cornerstone of management, new approaches are beginning to form part of sepsis management protocols and will lead to improved outcomes for patients with this disease process.

Intensive Care Med, 2003 Apr, 29(4), 642 - 5 Epub 2003 Jan 28.
High glucose impairs superoxide production from isolated blood neutrophils; Perner A et al.; OBJECTIVE: Superoxide (O(2)(-)), a key antimicrobial agent in phagocytes, is produced by the activity of NADPH oxidase . High glucose concentrations may, however, impair the production of O(2)(-) through inhibition of glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the formation of NADPH . This study measured the acute effects of high glucose or the G6PD inhibitor dehydroepiandrosterone (DHEA) on the production of O(2)(-) from isolated human neutrophils . DESIGN: Laboratory studies of short-term cultures of neutrophil granulocytes . PARTICIPANTS: Healthy subjects . INTERVENTIONS: Neutrophils were isolated from peripheral blood and incubated for 1 h in Krebs-Ringer buffer containing 5, 10, or 25 mM glucose, 5 mM glucose with 0, 5, or 20 mM mannitol, or 5 mM glucose with 0, 1, 10, or 100 micro M DHEA . O(2)(-) production was induced by N-formyl-methionyl-leucyl-phenylalanine and measured by the cytochrome c reduction assay . Potential scavenging of O(2)(-) by glucose, mannitol, or DHEA was assessed in a cell free system using the pyrogallol assay . MEASUREMENTS AND RESULTS: Incubation of neutrophils with glucose dose-dependently reduced O(2)(-) production, which was 50% decreased at 25 mM glucose . Also DHEA reduced the production of O(2)(-) dose-dependently, whereas production rates were unaffected by mannitol . Neither glucose, mannitol, nor DHEA scavenged O(2)(-) . CONCLUSIONS: High extracellular glucose concentrations acutely reduce O(2)(-) production from activated neutrophils possibly through inhibition of G6PD . If this occurs in vivo, microbial killing by neutrophils may be impaired during acute hyperglycemia, as observed after major surgery, trauma, or severe infection.

Int J Pharm, 2003 Feb 18, 252(1-2), 149 - 57
Does ciprofloxacin interact with neutral bilayers? An aspect related to its antimicrobial activity; Hernandez-Borrell J et al.; Ciprofloxacin (CPX) physicochemical properties, mainly hydrophobicity and microspeciation, appear to be related with the ability of this drug to adsorb and diffuse through lipid environments . We have combined the information from fluorescence anisotropy, quenching and epifluorescence of phospholipid monolayers, to explore effects of CPX at the phospholipid-buffer interface . Two fluorescent probes (TMA-DPH and PA-DPH) located at surface level were used for anisotropy experiments . The results evidenced that CPX interact with liposomes at surface level and induce a moderate decrease in the bilayer anisotropy . By using two hydrophobic quenchers (iodobenzene and iododecanoic acid) the presence of CPX in the core of the bilayer was excluded . Mixed monolayers of DPPC and CPX evidenced the ability of CPX to compress the monolayer and the epifluorescence observations showed that CPX modifies lipid distribution and surface phase transition . The surface activity of CPX is reviewed from the physicochemical properties of the drug and in relation to its pharmacological activity.

J Nutr Biochem, 2002 Nov, 13(11), 636 - 644
Major phenolic compounds in olive oil: metabolism and health effects; Tuck KL et al.; It has been postulated that the components in olive oil in the Mediterranean diet, a diet which is largely vegetarian in nature, can contribute to the lower incidence of coronary heart disease and prostate and colon cancers . The Mediterranean diet includes the consumption of large amounts of olive oil . Olive oil is a source of at least 30 phenolic compounds . The major phenolic compounds in olive oil are oleuropein, hydroxytyrosol and tyrosol . Recently there has been a surge in the number of publications that has investigated their biological properties . The phenolic compounds present in olive oil are strong antioxidants and radical scavengers . Olive "waste water" also possesses compounds which are strong antioxidant and radical scavengers . Typically, hydroxytyrosol is a superior antioxidant and radical scavenger to oleuropein and tyrosol . Hydroxytyrosol and oleuropein have antimicrobial activity against ATTC bacterial strains and clinical bacterial strains . Recent syntheses of labeled and unlabelled hydroxytyrosol coupled with superior analytical techniques have enabled its absorption and metabolism to be studied . It has recently been found that hydroxytyosol is renally excreted unchanged and as the following metabolites as its glucuronide conjugate, sulfate conjugate, homovanillic acid, homovanillic alcohol, 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylacetaldehyde . Studies with tyrosol have shown that it is excreted unchanged and as its conjugates . This review summarizes the antioxidant abilities; the scavenging abilities and the biological fates of hydroxytyrosol, oleuropein and tyrosol which have been published in recent years.

Biochemistry, 2003 Feb 4, 42(4), 1101 - 8
Lipopolysaccharides in bacterial membranes act like cholesterol in eukaryotic plasma membranes in providing protection against melittin-induced bilayer lysis; Allende D et al.; Melittin is a small, cationic peptide that, like many other antimicrobial peptides, lyses cell membranes by acting on their lipid bilayers . However, the sensitivity to antimicrobial peptides varies among cell types . We have performed direct binding and vesicle leakage experiments to determine the sensitivity to melittin of bilayers composed of various physiologically relevant lipids, in particular, key components of eukaryotic membranes (cholesterol) and bacterial outer membranes (lipopolysaccharide or LPS) . Melittin binds to bilayers composed of both zwitterionic and negatively charged phospholipids, as well as to the highly charged LPS bilayers . The magnitude of the free energy of binding (deltaG degrees ) increases with increasing bilayer charge density; deltaG degrees = -7.6 kcal/mol for phosphatidylcholine (PC) bilayers and -8.9 to -11.0 kcal/mol for negatively charged bilayers containing phosphatidylserine (PS), phospholipids with covalently attached polyethylene glycol (PEG-lipids), or LPS . Comparisons of these data show that binding is not markedly affected by the steric barrier produced by the PEG in PEG-lipids or by the polysaccharide core of LPS . The addition of equimolar cholesterol to PC bilayers reduces the level of binding (deltaG degrees = -6.4 kcal/mol) and reduces the extent of melittin-induced leakage by 20-fold . LPS and 1:1 PC/cholesterol bilayers have similar high resistance to melittin-induced leakage, indicating that cholesterol in eukaryotic plasma membranes and LPS in Gram-negative bacteria provide strong protection against the lytic effects of melittin . We argue that this resistance is due at least in part to the similar tight packing of the lipid acyl chains in PC/cholesterol and LPS bilayers . The addition of bacterial phospholipids to LPS bilayers increases their sensitivity to melittin, helping to explain the higher sensitivity of deep rough bacteria compared to smooth phenotypes.

Am J Infect Control, 2003 Feb, 31(1), 49 - 53
Microbial contamination of enteral feed administration sets in a pediatric institution; Matlow A et al.; BACKGROUND: Enteral feeding tubes have been associated with outbreaks of antimicrobial-resistant organisms, but the pathogenesis of this association has not been investigated . We hypothesized that the enteral feed administration sets become colonized externally by microbes grown from the enteral tube hub, and therefore serve as a reservoir of organisms that can be crosstransmitted . METHODS: We conducted a prospective observational cohort pilot study, obtaining bacterial cultures from the external enteral feed administration set and from the hub of nasogastric, gastric, or gastrojejunal tubes in children receiving enteral feeding while hospitalized in a tertiary care pediatric hospital . RESULTS: Thirty-six of 37 hubs cultured had bacterial growth . Twenty-nine of 36 administration sets (78%) sampled had at least 1 microbe isolated that was also cultured from the hub . No significant risk factors for colonization were identified . CONCLUSIONS: Enteral feed administration sets are frequently colonized by organisms in the enteral tube hub . These sets can serve as a reservoir of organisms that can be crosstransmitted between patients . Adherence to Standard Precautions is critical when handling enteral feeding apparatuses.

Am J Infect Control, 2003 Feb, 31(1), 1 - 8
Which antimicrobial impregnated central venous catheter should we use? Modeling the costs and outcomes of antimicrobial catheter use; Marciante KD et al.; BACKGROUND: Catheter-related bloodstream infections are costly and associated with substantial morbidity and mortality . Trials suggest that central venous catheters impregnated with minocycline/rifampin, although more expensive, are clinically superior to chlorhexidine/silver sulfadiazine impregnated catheters . It remains unclear whether minocycline/rifampin catheters are cost-effective for all high-risk patients or only those requiring longer-term catheterization . METHODS: We developed a series of decision models with patient-level clinical trial data to determine whether minocycline/rifampin catheters are cost-effective for patients requiring various durations of catheterization . We calculated incremental cost-effectiveness ratios for patients catheterized for durations ranging from 1 to 25 days . RESULTS: The data were too sparse to estimate cost-effectiveness for patients catheterized less than 8 days . The probability that minocycline/rifampin catheters were cost-effective compared with chlorhexidine/silver sulfadiazine catheters in patients catheterized for 8 days was 91% . The probability that the minocycline/rifampin catheters in patients catheterized 13 days or longer resulted in cost savings was more than 95% . CONCLUSIONS: Our analysis suggests that central venous catheters coated with minocycline/rifampin are cost-effective for patients catheterized for at least 1 week and lead to overall cost savings when patients are catheterized for 2 weeks or longer . Policies for the use of antimicrobial catheters in high-risk patients should reflect patients' expected duration of catheterization.

J Pediatr Gastroenterol Nutr, 2003 Feb, 36(2), 190 - 9
Expression, characterization, and biologic activity of recombinant human lactoferrin in rice; Suzuki YA et al.; BACKGROUND: Lactoferrin has been suggested to have many biologic activities, such as facilitating iron absorption and having antimicrobial and antiinflammatory effects . In humans, several of these activities are likely to only be facilitated by human lactoferrin because they depend on the binding of human lactoferrin to specific receptors . Rice may be a useful vehicle to introduce recombinant human lactoferrin to infant foods because it has low allergenicity and is likely to be safer than using microorganisms or transgenic animals . METHODS: Recombinant human lactoferrin was expressed in the rice cell culture system, and its biologic activity was assessed by iron-binding and -releasing properties, antimicrobial activity, and binding and uptake to Caco-2 cells . The authors also compared the stability of recombinant and native human lactoferrins against heat, low pH, and in vitro digestion . RESULTS: Biologic activity of rice-expressed recombinant human lactoferrin was similar to that of native human lactoferrin . Heat-treated proteins retained their functional activities except with severe treatment at 100 degrees C for 8 seconds, which disturbed the iron-binding capacity of recombinant human lactoferrin . Both types of proteins retained their functional activities between pH 2 and 7.4 . After in vitro digestion, 50% of both proteins were detectable by enzyme linked immunosorbent assay . The remaining native and recombinant lactoferrins retained antimicrobial and Caco-2 binding and uptake activities . CONCLUSIONS: The results indicate recombinant human lactoferrin has stability similar to native human lactoferrin when exposed to thermal treatment, pH treatment, and in vitro digestion, suggesting it may be active when added to infant formula.

J Feline Med Surg, 2003 Feb, 5(1), 19 - 26
Panniculitis, due to Mycobacterium smegmatis, in two Finnish cats; Alander-Damsten YK et al.; Pyogranulomatous panniculitis due to infection by Mycobacterium smegmatis was diagnosed in two cats in Finland, a country with a rather cold climate . The diagnosis was confirmed by sequencing of the 16S rRNA gene, which gave a perfect match with the M smegmatis strain ATCC 19420 . Gene sequencing makes it possible to distinguish M smegmatis from closely related mycobacteria such as M goodii sp.nov . Diagnosing this entity seems to be a question of having a high index of suspicion . The appearance of the disease as well as sampling is described in detail . In our first case an initial erroneous diagnosis of Nocardia species considerably delayed our arriving at the right diagnosis . The first patient has now been followed for more than 7 years . Her disease is chronic, but she is not systemically affected . Several antimicrobials were tried . Probable side effects of enrofloxacin medication are described.

Blood Cells Mol Dis, 2002 Nov-Dec, 29(3), 361 - 6
Decreased liver hepcidin expression in the Hfe knockout mouse; Ahmad KA et al.; Hepcidin is a circulating antimicrobial peptide which has been proposed to regulate the uptake of dietary iron and its storage in reticuloendothelial macrophages . Transgenic mice lacking hepcidin expression demonstrate abnormalities of iron homeostasis similar to Hfe knockout mice and to patients with HFE-associated hereditary hemochromatosis (HH) . To identify any association between liver hepcidin expression and the iron homeostasis abnormalities observed in HH, we compared liver hepcidin mRNA content in wild type and Hfe knockout mice . Because the iron homeostasis abnormalities in the Hfe knockout mice are greatest early in life, we analyzed mice at different ages . At four weeks of age, Hfe knockout mice had significantly decreased liver hepcidin mRNA expression compared to wild type mice . The decreased hepcidin expression was associated with hepatic iron deposition, elevated transferrin saturations, and decreased splenic iron concentrations . At 10 weeks of age, despite marked hepatic iron loading, Hfe knockout mice demonstrated liver hepcidin mRNA expression similar to that observed in wild type mice . Placing 8 week-old wild type and Hfe knockout mice on a 2% carbonyl iron diet for 2 weeks led to a similar degree of hepatic iron loading in each group . However, while the wild type mice demonstrated a mean five-fold increase in liver hepcidin mRNA, no change was observed in the Hfe knockout mice . The lack of an increase in liver hepcidin expression in these iron-loaded Hfe knockout mice was associated with sparing of iron deposition into the spleen . These data indicate that the normal relationship between body iron stores and liver hepcidin mRNA levels is altered in Hfe knockout mice, such that liver hepcidin expression is relatively decreased . We speculate that decreased hepcidin expression relative to body iron stores contributes to the iron homeostasis abnormalities characteristic of HH.

Drug Discov Today, 2002 Nov 1, 7(21), 1092 - 101
Rapid molecular theranostics in infectious diseases; Picard FJ et al.; The increasing availability of rapid and sensitive nucleic acid testing assays for infectious diseases will revolutionize the practice of medicine by gradually reducing the need for standard culture-based microbiological methods that take at least two days . Molecular theranostics in infectious diseases is an emerging concept in which molecular biology tools are used to provide rapid and accurate diagnostic assays to enable better initial management of patients and more efficient use of antimicrobials . Essential conditions and the quality control required for the development and validation of such molecular theranostic assays are reviewed.

J Card Surg, 2002 Jul-Aug, 17(4), 301 - 6
Wei Lun Visiting Professorial Lecture: Nitric oxide in the regulation of vascular function: an historical overview; Ignarro LJ; The field of nitric oxide (NO) research has developed in explosive proportions since the discovery of endogenous NO in 1986 . The biological importance of NO was first shown by the findings that nitroglycerin causes vasodilation by liberating NO in the smooth muscle, and activating guanylate cyclase to raise smooth muscle levels of cyclic GMP . NO also inhibits platelet aggregation by cyclic GMP mechanisms . NO activates guanylate cyclase by heme dependent mechanisms involving the formation of a nitrosyl-heme complex . The high pharmacological potency of NO was finally understood when NO was shown to be formed endogenously, and to be the same as EDRF . Based on these properties of NO, new drugs can be developed as vasodilators and antiplatelet agents for the treatment of a variety of vascular disorders including impotency . NO elicits many other actions in mammalian systems including inhibition of cell proliferation, airway bronchodilation, antimicrobial effects, other host defense effects, and also modulates learning and memory as well as other central functions . This allows for an extensive opportunity to develop novel drugs for the diagnosis, prevention, and treatment of a number of different diseases, many of which are vascular in origin.

Hua Xi Yi Ke Da Xue Xue Bao, 2000 Sep, 31(3), 285 - 8
{Enhancement of BCG-induced hBD-1 mRNA expression in human pulmonary gland epithelial cells}; Feng Y et al.; Using reverse-transcription PCR (RT-PCR) and Northern blot analysis, the present authors found an enhanced expression of the human beta-defensin 1 (hBD-1) gene in the SPC-A-1 cells challenged with heat-killed M . Bovis Bacille Calmette-Guerin (BCG) . The enhanced expression of hBD-1 mRNA was dose- and time-dependent . This result indicated a significant progress in the work of developing a new antimicrobial strategy that enhances mucosa antibiotic peptide expression for the prevention and treatment of mucosal infections.

Eur J Gastroenterol Hepatol, 2003 Jan, 15(1), 27 - 33
Impact of clarithromycin resistance and CYP2C19 genetic polymorphism on treatment efficacy of Helicobacter pylori infection with lansoprazole- or rabeprazole-based triple therapy in Japan; Miki I et al.; OBJECTIVE: Helicobacter pylori treatment failure is thought to be due mainly to polymorphic cytochrome P450 2C19 (CPY2C19) genetic polymorphism, associated with proton pump inhibitor metabolism, and antimicrobial susceptibility . This report has ascertained which was more important, CPY2C19 polymorphism or antimicrobial susceptibility, when using 1-week lansoprazole-based or rabeprazole-based triple therapy in Japan . DESIGN: An open, randomized, parallel group study . SETTING: One hundred and forty-five subjects with H . pylori-positive gastritis or peptic ulcers were randomly assigned to receive 30 mg lansoprazole twice daily (LAC group), 10 mg rabeprazole twice daily (RAC20 group), or 20 mg rabeprazole twice daily (RAC40 group), with 1000 mg amoxicillin twice daily and 400 mg clarithromycin twice daily for 1 week . Antimicrobial resistance testing was performed by E-test . More than 4 weeks after completion of treatment, H . pylori status was assessed by 13C-urea breath test, histology, and culture . RESULTS: Cure rates expressed as intention-to-treat and per-protocol analyses, respectively, were 79.6 and 83.0% with LAC, 85.4 and 89.1% with RAC20, and 83.3 and 88.9% with RAC40 . In the case of clarithromycin-sensitive strains, the cure rates were more than 97%, regardless of CPY2C19 polymorphism . However, treatment succeeded in only one out of 16 clarithromycin-resistant strains . CONCLUSIONS: The key to successful eradication of H . pylori, using lansoprazole or rabeprazole with clarithromycin and amoxicillin, is clarithromycin susceptibility, not CPY2C19 polymorphism .

Am J Med Sci, 2003 Jan, 325(1), 31 - 3
Hepatitis associated with amoxicillin/clavulanic acid and/or ciprofloxacin; Zaidi SA; We describe an elderly patient with normal pre-existing liver functions who was treated with amoxicillin/clavulanic acid and later ciprofloxacin for acute bronchitis . He developed a pattern of liver dysfunction consistent with hepatocellular injury, with clinical features of a hypersensitivity reaction, which may be attributable to either or both of the antimicrobial agents used . This gradually resolved over a 4-week time period, with conservative management . A review of the relevant literature on drug-induced hepatotoxicity is also presented.

J Med Microbiol, 2003 Feb, 52(Pt 2), 155 - 62
Antibiotic resistance among verocytotoxigenic Escherichia coli (VTEC) and non-VTEC isolated from domestic animals and humans; Bettelheim KA et al.; Two hundred verocytotoxigenic and 216 non-verocytotoxigenic Escherichia coli (VTEC and non-VTEC), isolated from a variety of sources were tested for their resistances to 11 antimicrobial agents . The strains included isolates from domestic food animals and both symptomatic and asymptomatic infections in man . A much higher level of resistance was found among the non-VTEC than among the VTEC, regardless of source . The resistant VTEC isolated from animals were predominantly from specimens associated with sick animals . Antibiotic resistance was detected in only four of the 59 (6.8 %) VTEC of human origin, whereas more of the human non-VTEC possessed antibiotic resistance determinants . It was particularly noteworthy that 24/87 (28 %) strains isolated from healthy babies, who had neither contact with antibiotics nor had gastrointestinal symptoms for at least 2 weeks prior to the specimen being taken, were resistant to one or more of the antibiotics tested.

Antimicrob Agents Chemother, 2003 Feb, 47(2), 636 - 42
Methodologies and cell lines used for antimicrobial susceptibility testing of Chlamydia spp; Suchland RJ et al.; In vitro susceptibility testing was performed on strains of Chlamydia trachomatis, Chlamydia pneumoniae, and Chlamydia psittaci under various conditions, including the cell line utilized, the time between infection and the addition of an antimicrobial, the concentration of inoculum, and the effect of multiple passage on the minimal chlamydicidal concentrations for the antibiotics doxycycline, azithromycin, erythromycin, ofloxacin, and tetracycline . With macrolides, the MIC varied depending upon the cell line utilized . With all antimicrobials, the MIC was related to the time at which the antimicrobial was added after infection . By an optimized cell culture passage method, all strains of chlamydia tested demonstrated survival after exposure to high levels (>100 times the MIC) of antimicrobials . Furthermore, upon retest, these surviving organisms did not demonstrate increased MICs . Thus, this phenomenon does not reflect selection of antimicrobial-resistant mutants but rather survival of some organisms in high antimicrobial concentrations (heterotypic survival) . An additional 44 clinical isolates of C . trachomatis from patients with single-incident infections were tested against those from patients with recurrent or persistent infections, and heterotypic survival was seen in all isolates tested; hence, in vitro resistance did not correlate with the patient's apparent clinical outcome.

Antimicrob Agents Chemother, 2003 Feb, 47(2), 626 - 35
Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of danofloxacin in sheep biological fluids; Aliabadi FS et al.; The fluoroquinolone antimicrobial drug danofloxacin was administered to sheep intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1.25 mg/kg of body weight in a two-period crossover study . The pharmacokinetic properties of danofloxacin in serum, inflamed tissue cage fluid (exudate), and noninflamed tissue cage fluid (transudate) were established by using a tissue cage model . The in vitro and ex vivo activities of danofloxacin in serum, exudate, and transudate against a pathogenic strain of Mannheimia haemolytica were established . Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 60.5, 85.6, and 45.7 h, respectively, after i.v . dosing and 55.9, 77.9, and 49.1 h, respectively, after i.m . dosing . After i.m . dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 10.8, 3.0, and 1.6, respectively . The ex vivo growth inhibition data after i.m . dosing were fitted to the inhibitory sigmoid E(max) equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria . The respective values for serum were 17.8, 20.2, and 28.7 h, and slightly higher values were obtained for transudate and exudate . It is proposed that use of these data might provide a novel approach to the rational design of dosage schedules.

Antimicrob Agents Chemother, 2003 Feb, 47(2), 607 - 13
NK-lysin and its shortened analog NK-2 exhibit potent activities against Trypanosoma cruzi; Jacobs T et al.; Antimicrobial peptides are widespread in nature and have been evolutionarily conserved as essential tools for combating a variety of pathogens . Among the plethora of natural peptides and synthetic analogs thereof studied in recent years for their antimicrobial activities, only a very few are known to be effective against protozoan parasites . In the present study we investigated the activity of NK-lysin, a broad-spectrum effector polypeptide of mammalian cytotoxic lymphocytes, against trypomastigotes of the human pathogen Trypanosoma cruzi in vitro . Moreover, the activity of a synthetic peptide named NK-2 that corresponds to the cationic core region of NK-lysin was tested in parallel against this parasite . T . cruzi was found to be highly susceptible to both peptides, as evidenced by inhibition of the mobility of trypomastigotes . The peptides rapidly permeabilized the plasma membrane of the parasite since micromolar concentrations resulted in the release of cytosolic enzymes within minutes . NK-lysin and NK-2 were even found to kill trypanosomes residing inside the human glioblastoma cell line 86HG39, but only NK-2 left the host cells apparently unharmed.

Antimicrob Agents Chemother, 2003 Feb, 47(2), 533 - 40
Activities of tigecycline (GAR-936) against Legionella pneumophila in vitro and in guinea pigs with L . pneumophila pneumonia; Edelstein PH et al.; The activities of tigecycline (Wyeth Research) against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L . pneumophila pneumonia were studied . The tigecycline MIC at which 50% of strains are inhibited for 101 different Legionella sp . strains was 4 micro g/ml versus 0.125 and 0.25 micro g/ml for azithromycin and erythromycin, respectively . Tigecycline was about as active as erythromycin (tested at 1 micro g/ml) against the F889 strain of L . pneumophila grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain . Azithromycin (0.25 micro g/ml) was more active than (F889) or as active as (F2111) tigecycline (1 micro g/ml) in the macrophage model . When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with L . pneumophila pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 micro g/ml (1.2 and 1.5 micro g/g) at 1 and 2 h postinjection, respectively . The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 micro g . h/ml, respectively . Thirteen of 16 guinea pigs with L . pneumophila pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days) . None of 12 guinea pigs treated with saline survived . Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 x 10(6) CFU/g (range, 2.5 x 10(4) to 3.2 x 10(6) CFU/g) versus <1 x 10(2) CFU/g for azithromycin (range, undetectable to 100 CFU/g) . A second guinea pig study examined the ability of tigecycline to clear L . pneumophila from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log(10) 4.2 to log(10) 5.5 CFU/g for four different dosing regimens . Tigecycline is about as effective as erythromycin against intracellular L . pneumophila, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data . Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.

Burns, 2003 Feb, 29(1), 15 - 24
What's new in burn microbiology? James Laing Memorial Prize Essay 2000; Edwards-Jones V et al.; A variety of factors contribute to the development of infection in burned patients . The role of wound management procedures, risk factors associated with infection, typical bacterial pathogens and associated exotoxins, current problems with antibiotic resistance, wound sampling and rare complications of infection are described . The use of new novel treatments that are currently being developed, such as cell signalling molecules and the increasing use of natural antimicrobial agents, for example honey, papaya fruit and tea-tree oil are discussed . The impact of new methods for earlier detection of infectious agents that could change future practices in burn care is also described.

Surg Infect (Larchmt), 2002 Autumn, 3(3), 259 - 267
Economic Consequences of Antimicrobial Resistance; Paladino JA et al.; BACKGROUND: In the past two decades, a dramatic increase in the frequency and prevalence of antimicrobial-resistant pathogens has challenged clinicians and researchers . MATERIALS AND METHODS: A review of the literature was conducted . Available data identifying the costs and consequences of resistance are summarized while the issues and limitations of research assessing the economics of resistance are acknowledged . RESULTS: Microbial resistance is a complex, multifactorial phenomenon, but the single most powerful influence is antimicrobial use . Treatment guidelines, clinical pathways, and other directives exert widespread influences on individual selection of antimicrobial agents . However, use of an empiric regimen that does not provide effective coverage, or a targeted regimen that is dosed too low to provide optimal therapy, will delay eradication of the pathogen, increase the potential for resistance to emerge, extend and increase morbidity, and expose the patient to an increased risk of mortality . Coincident with these untoward clinical events are economic consequences secondary to increased duration of treatment, and for some, an extended duration of hospitalization . CONCLUSION: Resistant gram-negative and gram-positive bacteria have been associated with increased direct medical costs ranging from several thousand dollars to tens of thousands of dollars per patient.

Surg Infect (Larchmt), 2002 Autumn, 3(3), 161 - 173
The Surgical Infection Society Guidelines on Antimicrobial Therapy for Intra-Abdominal Infections: An Executive Summary; Mazuski JE et al.; The Surgical Infection Society last published guidelines on antimicrobial therapy for intra-abdominal infections in 1992 (Bohnen JMA, et al., Arch Surg 1992;127:83-89) . Since then, an appreciable body of literature has been published on this subject . Therefore, the Therapeutics Agents Committee of the Society undertook an effort to update the previous guidelines, primarily using data published over the past decade . An additional goal of the Committee was to characterize its recommendations according to contemporary principles of evidence-based medicine . To develop these guidelines, the Committee carried out a systematic search for all English language articles published between 1990 and 2000 related to antimicrobial therapy for intra-abdominal infections . This literature was reviewed individually and collectively by the Committee, and categorized according to the type of study and its quality . Additional articles published prior to 1990 were also utilized when necessary . By a process of iterative consensus, the Committee developed provisional guidelines for antimicrobial therapy for intra-abdominal infections based on this evidence . Following extensive review by members of the Society, these guidelines were approved for publication in final form by the Council of the Surgical Infection Society . This executive summary delineates the Society's current recommendations for antimicrobial therapy of patients with intra-abdominal infections . Topics discussed include the selection of patients needing therapeutic antimicrobials, duration of antimicrobial therapy, acceptable antimicrobial regimens, and identification and treatment of higher-risk patients . Guidelines for patient selection and specific antimicrobial regimens were based on relatively good evidence, but those regarding optimal duration of therapy and treatment of higher-risk patients relied mostly on expert opinion, since there was a paucity of high-quality studies on those issues . Relevant areas for future investigation include the safety, convenience, and cost-effectiveness of available antimicrobial regimens for lower-risk patients, and better means for identifying and treating higher-risk patients with intra-abdominal infections.

J Endotoxin Res, 2002, 8(6), 403 - 17
Antimicrobial and immunoregulatory functions of lactoferrin and its potential therapeutic application; Caccavo D et al.; Lactoferrin is an iron-binding glycoprotein present in various secretions (eg . milk, tears, saliva,pancreatic juice, etc.) . It is also stored in specific granules of polymorphonuclear granulocytes from which it is released following activation . Lactoferrin exerts a bactericidal activity by damaging the outermembrane of Gram-negative bacteria, as well as immunoregulatory functions by decreasing the release of interleukin-l (IL- 1), IL-2 and tumor necrosis factor-alpha INF-alpha) and enhancing monocyte and natural killer cell cytotoxicity . Lactoferrin binds with high affinity to lipid A, the toxic moiety of the lipopolysaccharide, or endotoxin from Gram-negative bacteria Lipopolysacchride interaction with monocytes/ma phages results in the production and release of TNF-alpha, that plays an important role in inducing septic shock In this respect, it has recently been demonstrated that lactoferrin inhibits the lipopolysaccharide interaction with CD14 on monocytes/macrophages by competition with the lipopolysaccharide binding protein . Therefore, besides its bactericidal activity, lactoferrin may also act by neutralizing the toxic effects of lipopolysaccharide and this protective role against endotoxin lethal shock has been demonstrated in animal models . Moreover, in vitro and in vivo neutralization of endotoxin by a human lactoferrin-derived peptide was also reported and lactoferrin or lactoferrin-derived peptides could represent useful tools for the treatment of endotoxin-induced septic hock . The recent production and characterization of monoclonal antibodies against different epitopes of human lactoferrin, including monoclonal antibodies selectively neutralizing lactoferrin binding to lipid A, may allow a better elucidation of the consequence of lactoferrin-lipopolysaccharide interaction.

Insect Mol Biol, 2003 Feb, 12(1), 93 - 7
Hidden from the host: Spiroplasma bacteria infecting Drosophila do not cause an immune response, but are suppressed by ectopic immune activation; Hurst GD et al.; Insects and other arthropods have an effective innate immune system that can clear infections with bacteria and other microorganisms . Despite this ability, one group of bacteria, the spiroplasmas, survive unharmed within the haemolymph of a wide range of arthropod hosts . We investigated the interaction between one member of this clade, a relative of Spiroplasma poulsonii, and the immune system of its Drosophila host . Expression of antimicrobial genes in spiroplasma-infected flies did not differ from wild-type controls either in the naturally infected state, nor after septic shock . We therefore concluded that spiroplasma infection did not induce an immune response in its host, but that this absence of response was unlikely to be because the bacterium inhibited response . Further experiments revealed immune reactions induced ectopically did reduce parasite titre . We therefore conclude that this bacterium has a novel form of interaction with its host, being hidden from the host immune system, but potentially suppressible by it.

Cell Microbiol, 2003 Jan, 5(1), 41 - 51
Francisella tularensis inhibits Toll-like receptor-mediated activation of intracellular signalling and secretion of TNF-alpha and IL-1 from murine macrophages; Telepnev M et al.; Microbial ligands, including lipopolysaccharide (LPS) and bacterial lipoproteins, activate Toll-like receptors (TLR) of mononuclear phagocytes, thereby inducing proinflammatory cytokines and antimicrobial activity . We show that Francisella tularensis, an intracellular pathogen, is capable of inhibiting this macrophage response . Infection with the live vaccine strain F . tularensis LVS rendered cells of the murine macrophage-like cell line J774A.1 incapable of secreting TNF-alpha or IL-1beta and mobilizing an antimicrobial activity in response to bacterial lipopeptide or Escherichia coli-derived LPS . Inhibition of TNF-alpha secretion occurred also when J774 cells were infected with F . tularensis LVS in the presence of chloramphenicol, but not when they were infected with a mutant of F . tularensis LVS defective in expression of a 23 kDa protein that is upregulated during intracellular infection . Purified F . tularensis LPS did not show an agonistic or antagonistic effect on the E . coli LPS-induced activation of the J774 cells . Francisella tularensis LVS suppressed the capability of the cells to respond to LPS or bacterial lipopeptide (BLP) with activation of nuclear factor kappa B (NF-kappaB), and degradation of the in-hibitor of NF-kappaB, IkappaB, was blocked during the infection . Also the LPS- or BLP-induced phosphorylation of the mitogen-activated protein kinase p38 and the transcription factor c-Jun was inhibited by F . tularensis LVS but not by the 23 kDa protein mutant . In conclusion, F . tularensis appears capable of abrogating the TNF-alpha and IL-1 responses of macrophages induced by E . coli LPS or BLP via a mechanism that involves suppression of several intracellular pathways and is dependent on expression of a bacterial 23 kDa protein.

J Nat Prod, 2003 Jan, 66(1), 103 - 7
Chemical and biological investigation of the fungus Pulveroboletus ravenelii; Duncan CJ et al.; Two new compounds, pulveraven A (1) and pulveraven B (2), as well as vulpinic acid (3) and its previously unreported polymorph were isolated from the fruiting body of Pulveroboletus ravenelii . The structures were determined using a combination of NMR, MS, IR, optical rotation, molecular modeling, and X-ray analysis . The isolates were evaluated for antimicrobial activity as well as their potential to inhibit cyclooxygenase (COX) activity and carcinogen-induced preneoplastic lesion formation with mouse mammary organ culture (MMOC).

Expert Opin Ther Targets, 2001 Aug, 5(4), 465 - 475
Microbial genomics - new targets, new drugs; Schmid MB; Genomics has changed our view of the biological world in the past decade, providing both new information and new tools to characterise biological systems . Over 100 microbial genomes - including many of substantial clinical importance - have been fully or partially sequenced, pushing the search for novel antimicrobial compounds into the post-genomic era . Genomic information and associated new technologies have the potential to revolutionise the drug discovery process . Genomic methods have created a wealth of potential new antimicrobial targets; strategies are evolving to provide validation for these targets before chemical inhibitors are identified . The ability to obtain large amounts of purified target proteins and advances in X-ray crystallography have caused significant increases in available protein structures, which may foreshadow an increased effort in structure-based drug design . The post-genomics strategies used in antimicrobial drug discovery may have application for small molecule drug discovery in numerous therapeutic areas.

Hua Xi Kou Qiang Yi Xue Za Zhi, 2000 Oct, 18(5), 301 - 3
{The neutralizing effect of histidine-rich-polypeptides on LPS from suspected periodontal pathogens}; Luo H et al.; OBJECTIVE: Human parotid histidine-rich-polypeptides (HRPs) are a family of lowmolecular-weight, cationic polypeptides . HRP-1, HRP-3 and HRP-5 comprise 85%-90% of the total HRPs and are called major HRPs . There were many researches indicating the antimicrobial activities of HRPs . Recently, HRPs were reported to have an inhibitory action on the lipopolysaccharide (LPS) of E . coli, with HRP-5 being the most effective one among the three major HRPs . Since the LPS of oral gram-negative bacteria is thought to be one of the important etiological factors during the development of periodontal diseases, our experiment was aimed to investigate the neutralizing effect of human parotid HRP-5 on the LPS of anaerobic suspected periodontal pathogens, which have different chemical structures and biological activities compared with LPS of aerobic E . coli . METHODS: By using of preparative acid urea polyacrylamide gel electrophoresis (AU-PAGE), HRP-5 was purified from parotid saliva collected from healthy adults . Two stains of suspected periodontal pathogens, Porphyromonas gingivalis (P.g, 47-A) and Fusobacterium nuceatum (F . n, separated from subgingival plaque of a patient with adult periodontitis) were mass cultured . After harvested in the midlogarithmic phase, they were washed and lyophilized . The LPS of dried bacteria were extracted by the modified Westphal hot phenol-water procedures and purified by the enzyme digestion plus ultracentrifugation . Limulus test was applied to test the neutralizing effect of HRP-5 on the LPS-induced gelation of Limulus amoebocyte lysate . In brief, the standard LPS of E . coli, or extracted LPS of P . g or F . n, was preincubated with HRP-5 in a tube separately in room temperature for 10 minutes . Then the reagent of Limulus amoebocyte lysate was added in all the tubes, continued the incubation in 37 degrees C for one hour . After that, the gelation level of every tube was observed . RESULTS: LPS extracted from P . g and F . n both showed good purity and strong activities to induce gelation of Limulus amoebocyte lysate . The gelation induced by LPS (1 ng/ml) of these two anaerobic suspected periodontal pathogens were weakly inhibited by HRP-5 (10 micrograms/ml), similar to that observed with standard LPS of E . coli . To get a complete neutralizing effect on LPS, it may be important to increase the concentration of HRP-5 . CONCLUSION: It appeared that HRPs could neutralize the endotoxic properties of LPS of suspected periodontal pathogens, therefore may contribute to periodontal health . The present investigation further confirmed that HRPs are important components of the host non-immune defense system.

J Clin Ultrasound, 2003 Feb, 31(2), 108 - 10
Sonographic detection of a malpositioned feeding tube causing esophageal perforation in a neonate; Maruyama K et al.; We report a case of esophageal perforation caused by a malpositioned feeding tube in a neonate of extremely low birth weight, 632 g . The infant had respiratory distress, which increased rapidly when he was 6 days old . Radiography revealed right-sided hydrothorax that had not been evident a day earlier but no sign of a perforated esophagus . We performed sonography, which revealed fluid in the right pleural cavity and extra-esophageal placement of the feeding tube . Analysis of a fluid specimen obtained on thoracocentesis indicated that the fluid was feeding formula . The feeding tube's misplacement was confirmed sonographically by injecting a small amount of sterile distilled water into the tube and visualizing its entry into the pleural cavity . The feeding tube was removed, and antimicrobial agents were administered . When the infant was 15 days old, feeding resumed through another tube, the placement of which was verified radiographically . The infant was discharged when he was 118 days old with no severe complications, although he had mild chronic lung disease . Because radiography did not reveal the tube's misplacement in this case, we believe that the use of sonography can contribute to an early diagnosis of esophageal perforation in such cases .

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2003 Jan, 95(1), 101 - 8
The hemolytic and cytotoxic properties of a zeolite-containing root filling material in vitro; Thom DC et al.; OBJECTIVE: This in vitro study characterized the hemolysis and cytotoxicity of ZUT, an experimental glass ionomer cement (GIC) sealer with an added antimicrobial-containing zeolite (0.2% Zeomic w/w) . STUDY DESIGN: ZUT, Ketac-Cem (GIC component of ZUT), Ketac-Endo, and two AH 26 sealer formulations were tested at various times after mixing . Hemolysis produced by standardized specimens was determined spectrophotometrically (n = 6/material) . Cytotoxicity was assessed by using a Millipore Filter test with a HeLa cell monolayer (n = 10/material) . Tests were repeated, and results were analyzed with a one-way analysis of variance (alpha = .05) . RESULTS: Disks of AH 26 containing silver produced the most hemolysis of all test groups (P < .0001) . Compared to controls, GICs and AH 26 formulations were noncytotoxic at 1 and 6 hours after mixing, respectively (P > .05) . Addition of Zeomic did not increase the cytotoxic and hemolytic activity of Ketac-Cem (P > .05) . CONCLUSION: Overall results suggest ZUT is less cytotoxic than AH 26 and possesses characteristics similar to the other GIC formulations tested.

Ann N Y Acad Sci, 2002 Dec, 975, 192 - 201
Chlamydiae host cell interactions revealed using DNA microarrays; Mahony JB; Chlamydiae are obligate intracellular bacterial parasites that infect eukaryotic cells and live their entire life cycle within a cytoplasmic vacuole or inclusion . We have employed cDNA microarray and conventional biological approaches to study the pathogen-host cell interaction during C . pneumoniae infection of eukaryotic cells . Two host cell signaling pathways, MEK/ERK and PI 3-kinase/Akt, were activated within 5 and 20 minutes, respectively, following infection with chlamydiae . Pharmacological inhibition of these pathways blocked invasion of HEp2 cells indicating that activation of these pathways was required for infection . Rho family GTPase activity was essential for invasion, since the pan-Rho GTPase inhibitor, compactin, blocked infection of HEp2 cells . cDNA microarrays and reverse transcriptase PCR were used to study host cell and chlamydial gene expression during the replication cycle . Analysis of host cell gene expression following infection with C . pneumoniae indicated that genes coding for cytokines, growth factors, and signaling molecules were upregulated, as early as 2 hours postinfection . Analysis of chlamydial gene expression indicated a temporal regulation of transcription with distinct early-, mid-, and late-cycle classes of RNA transcripts . Newly discovered genes encoding three Ser/Thr protein kinases and one protein phosphatase were upregulated 6-12 hours postinfection . One protein kinase, designated CpnPK1, was first detected at 12 hours postinfection, accumulated in the inclusion throughout the replication cycle, and may be a type III effector molecule . An increased understanding of chlamydial host cell interactions, in particular the role of various chlamydial proteins in infection and identification of essential virulence factors should provide novel targets for the development of new antimicrobials.

Bioorg Med Chem, 2003 Feb 20, 11(4), 515 - 20
Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212; Biava M et al.; During the course of our investigations in the field of azole antimicrobial agents, we have identified BM 212, a pyrrole derivative with good in vitro activity against mycobacteria and candidae . These findings prompted us to prepare new pyrrole derivatives 1-10 in the hope of increasing the activity . The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.

Genet Test, 2002 Winter, 6(4), 261 - 9
Single-nucleotide polymorphisms and haplotype analysis in beta-defensin genes in different ethnic populations; Jurevic RJ et al.; Beta-defensins are cationic antimicrobial peptides expressed by epithelial cells and exhibit antibacterial, antifungal, and antiviral properties . The defensins are part of the innate host defense network and may have a significant protective role in the oral cavity and other mucosa . Defects or alteration in expression of the beta-defensins may be associated with susceptibility to infection and mucosal disorders . We examined the occurrence of single-nucleotide polymorphisms (SNPs) in the human beta-defensin genes DEFB1 and DEFB2 encoding human beta-defensin-1 and -2 (hBD-1, hBD-2), respectively, in five ethnic populations and defined haplotypes in these populations . Fifteen SNPs were identified in both DEFB1 and DEFB2 . Coding region SNPs were found in very low frequency in both genes . One nonsynonymous DEFB1 SNP, G1654A (Val --> Ile), and one nonsynonymous DEFB2 SNP, T2312A (Leu --> His), were identified . Seven sites in each gene exhibited statistically significant differences in frequency between ethnic groups, with the greatest variation in the promoter and in the 5'-untranslated region of DEFB1 . DEFB1 displayed 10 common haplotypes, including one cosmopolitan haplotype . Eight common haplotypes were found in DEFB2, including one cosmopolitan haplotype shared among all five ethnic groups . Our results show that genotypic variability among ethnic groups will need to be addressed when performing associative genetic studies of innate defense mechanisms and susceptibility to disease.

Chem Commun (Camb), 2002 Dec 21, (24), 3018 - 9
Hybrids of silver nanoparticles with amphiphilic hyperbranched macromolecules exhibiting antimicrobial properties; Aymonier C et al.; Hybrids of silver particles of 1 to 2 nm in size with highly branched amphiphilically modified polyethyleneimines adhere effectively to polar substrates providing environmentally friendly antimicrobial coatings.

J Appl Microbiol, 2003, 94(2), 240 - 7
Activity and mechanisms of action of selected biocidal agents on Gram-positive and -negative bacteria; Walsh SE et al.; AIMS: This study investigates the antimicrobial activity and mode of action of two natural products, eugenol and thymol, a commonly utilized biostatic agent, triclocarban (TCC), and two surfactants, didecyldimethylammonium chloride (DDDMAC) and C10-C16 alkyldimethyl amine N-oxides (ADMAO) . METHODS AND RESULTS: Methods used included: determination of minimum inhibitory concentrations (MICs), lethal effect studies with suspension tests and the investigation of sub-MIC concentrations on growth of E . coli, Staph . aureus and Ps . aeruginosa using a Bioscreen microbiological analyser . Leakage of intracellular constituents and the effects of potentiating agents were also investigated . Only DDDMAC was bactericidal against all of the organisms tested . Eugenol, thymol and ADMAO showed bacteriostatic and bactericidal activity, but not against Ps . aeruginosa . TCC was only bacteristatic against Staph . aureus, but like the other agents, it did affect the growth of the other organisms in the Bioscreen experiments . All of the antimicrobial agents tested were potentiated by the permeabilizers to some extent and leakage of potassium was seen with all of the agents except TCC . CONCLUSIONS: DDDMAC was bactericidal against all organisms tested and all compounds had some bacteriostatic action . Low level static effects on bacterial growth were seen with sub-MIC concentrations . Membrane damage may account for at least part of the mode of action of thymol, eugenol, DDDMAC and ADMAO . SIGNIFICANCE AND IMPACT OF THE STUDY: The ingredients evaluated demonstrated a range of bactericidal and bacteriostatic properties against the Gram-negative and -positive organisms evaluated and the membrane (leakage of intracellular components) was implicated in the mode of action for most (except TCC) . Sub-MIC levels of all ingredients did induce subtle effects on the organisms which impacted bacterial growth, even for those which had no true inhibitory effects.

Br J Dermatol, 2003 Jan, 148(1), 30 - 8
Adrenomedullin: expression and possible role in human skin and hair growth; Muller FB et al.; BACKGROUND: Adrenomedullin (AM) is a regulatory peptide that is synthesized and secreted by a wide number of cells and tissues . AM is a potent vasodilator, but also exerts other functions, such as regulating cell growth and antimicrobial defence . Two receptors, L1 and calcitonin receptor-like receptor (CRLR), which are able to bind AM, have been cloned and characterized . OBJECTIVES: To investigate expression of AM protein and its receptors in human skin and during different stages of the human hair cycle and, moreover, because of the suggested antimicrobial function of AM in skin, to investigate AM immunoreactivity (IR) in inflammatory acne lesions compared with healthy pilosebaceous follicles . METHODS: We used immunohistochemistry to determine the distribution of AM and its receptors in human skin and during different stages of the human hair cycle . AM IR in inflammatory acne lesions was investigated to evaluate the antimicrobial function of the protein, and hair follicle cultures were performed to examine the role of AM in differentiation and proliferation of hair follicle keratinocytes . RESULTS: Strong IR for AM and its receptors was present in the suprabasal epidermis, in the melanocytes of the epidermis, and in sweat and sebaceous glands . In the hair follicle, AM protein was strongly expressed in the basal and suprabasal layers of the hair bulb and the proximal outer root sheath (ORS) . In the distal ORS, AM expression was increasingly suprabasal, especially in proximity to the bulge region where the basal cell layer was free of IR . IR for the CRLR revealed a similar expression pattern to that seen for AM . In contrast, L1 IR showed a suprabasal pattern of IR throughout the ORS . Similar expression of AM and its receptors was observed in catagen and early anagen follicles . AM expression was not markedly upregulated in acne lesions, suggesting a minor role for this antimicrobial peptide in acne . Despite its well-documented mitogenic effects, particularly in oral and skin keratinocytes, AM had no significant effect on hair follicle growth in vitro . CONCLUSIONS: AM and its receptors are expressed in human hair follicles, and both AM and its receptors are colocalized in the same compartments and cell types of the skin . This finding is consistent with the proposed autocrine/paracrine mechanism in the physiology of AM.

Environ Microbiol, 2002 Dec, 4(12), 787 - 98
Diversity of siderophore-mediated iron uptake systems in fluorescent pseudomonads: not only pyoverdines; Cornelis P et al.; Fluorescent pseudomonads are gamma-proteobacteria known for their capacity to colonize various ecological niches . This adaptability is reflected by their sophisticated and diverse iron uptake systems . The majority of fluorescent pseudomonads produce complex peptidic siderophores called pyoverdines or pseudobactins, which are very efficient iron scavengers . A tremendous variety of pyoverdines has been observed, each species producing a different pyoverdine . This variety can be used as an interesting tool to study the diversity and taxonomy of fluorescent pseudomonads . Other siderophores, including newly described ones, are also produced by pseudomonads, sometimes endowed with interesting properties in addition to iron scavenging, such as formation of complexes with other metals or antimicrobial activity . Factors other than iron limitation, and different regulatory proteins also seem to influence the production of siderophores in pseudomonads and are reviewed here as well . Another peculiarity of pseudomonads is their ability to use a large number of heterologous siderophores via different TonB-dependent receptors . A first genomic analysis of receptors in four different fluorescent pseudomonads suggests that their siderophore ligand repertoire is likely to overlap, and that not all receptors recognize siderophores as ligands.

Acta Psychiatr Scand, 2003 Feb, 107(2), 96 - 101
The importance of the QT interval: a review of the literature; Elming H et al.; OBJECTIVE: QT interval (QTi) prolongation is generally associated with increased risk of ventricular arrhythmias such as torsade de pointes (TdP) and death . METHOD: Literature review based on publications identified by means of electronic and manual search . RESULTS: It has recently become apparent that not only antiarrhythmic drugs such as sotalol and quinidine, but also a variety of non-antiarrhythmic drugs such as certain antihistamines, antimicrobial drugs, psychiatric drugs and cisapride, may have the ability to induce prolongation of the QTi and TdP . Special concern should be drawn to the coadministration of drugs that inhibit the metabolism of these drugs such as ketoconazole, itraconazol and erythomycin . Patients with congenital long QT syndrome, patients with heart disease, with hypokalemia or hypomagnesemia, and women have an increased risk . Every sign of dizziness or syncope should be regarded as a warning sign of possible arrhythmia in patients treated with drugs that potentially prolong the QTi . CONCLUSION: Measurement of the QTi before and during treatment is generally recommended in high-risk patients.

Drug Saf, 2003, 26(2), 109 - 20
Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions; Leone R et al.; OBJECTIVE: To analyse and compare with one another and with other antibacterial drugs the adverse drug reactions (ADRs) of the different fluoroquinolones currently used in Italy, spontaneously reported from doctors in three northern Italian regions . METHODS: The data on fluoroquinolones and other antibacterials were obtained from the spontaneous reporting system database of Emilia Romagna, Lombardy and the Veneto, which are the principal contributors to the Italian spontaneous surveillance system . The fluoroquinolone ADRs with a causality assessment of certain, probable or possible (according to WHO criteria), reported between January 1999 and December 2001, were selected and toxicity profiles of individual drugs were described and compared with one another . The reports were also correlated with sex and age of patients and with regional prescription data to estimate individual fluoroquinolone reporting rate of adverse events . RESULTS: During the study period, 10 011 reports were received by the system (a mean annual reporting rate of approximately 185 per million inhabitants): 1920 referred to systemic antimicrobials, of which 432 (22.5%) involved fluoroquinolones . Pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin (221) and lomefloxacin (196) . The most frequently reported reactions to fluoroquinolones involved the skin, but their percentage (25%) was significantly lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas the percentages of reactions involving the central nervous (12.2 vs 3.6%), musculoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were significantly higher (p < 0.01) . We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05) . Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin . CONCLUSIONS: The differences in the safety profiles should be taken into account when prescribing a fluoroquinolone to individual patients.

Am J Health Syst Pharm, 2003 Jan 1, 60(1), 69 - 74
Characterization of an extemporaneous liquid formulation of lisinopril; Thompson KC et al.; The stability of lisinopril in an extemporaneously prepared suspension stored at or below 25 degrees C for 28 days under ambient light exposure was studied . A formulation of 1-mg/mL oral suspension was prepared from commercially available 20-mg lisinopril tablets, using Bicitra and Ora-Sweet SF as the compounding vehicles to make a final volume of 200 mL . Individual samples, stored in 8-oz amber polyethylene terephthalate bottles, were used for each test performed . All samples were stored at 25 degrees C . Appropriateness of the extemporaneous preparation method was performed by shaking three lots of each suspension for 30, 60, and 90 seconds . To test the robustness and reproducibility of the method, two chemists prepared the suspensions from the same three lots of lisinopril tablets . Chemical and physical stability were established by analyzing duplicate samples at time zero and after one, two, four, and six weeks . The solubility of lisinopril was tested from suspensions stored for four weeks . In-use stability was also examined over four weeks . Photochemical stability was examined by exposing three batches of the suspension to maximum light stress in accordance with the International Conference on Harmonization . Antimicrobial-effectiveness testing was also conducted with freshly prepared suspensions and suspensions stored for six weeks . The preparation method used was appropriate and effective . Lisinopril is fully dissolved in the suspension matrix . Satisfactory chemical, physical, and microbiological results were obtained after the suspensions were stored for six weeks at 25 degrees C and 35% relative humidity . Lisinopril suspensions extemporaneously prepared from tablets are stable for at least four weeks when stored at or below 25 degrees C under ambient light exposure.

Epidemiol Mikrobiol Imunol, 2002 Nov, 51(4), 156 - 60
{Deep necrotizing soft tissue infections . Necrotizing fasciitis and necrotizing myositis}; Plodr M et al.; The authors present a review on deep soft tissue infections--necrotizing fasciitis and necrotizing myositis, incl . the classification of myositis into sub-groups according to the causal agent . The authors describe the incidence of these diseases, basic clinical symptoms and therapeutic principles . Therapy is based on surgical treatment, antimicrobial treatment and in indicated cases on hyperbaric oxygen therapy (HBO).

Rev Inst Med Trop Sao Paulo, 2002 Nov-Dec, 44(6), 341 - 4 Epub 2003 Jan 02.
Perinephric and renal abscesses in children: a study of three cases; Fernandes RC et al.; Perinephric and renal abscesses are rare in childhood, but they must be remembered in the differential diagnosis of fever and abdominal or flank pain . This paper reports three cases whose solution was found after clinical and surgical treatment . The importance of ultrasound and computerized tomography (CT) in prompt diagnosis is highlighted in this work . The use of these methods along the improved antimicrobial therapy may result in decrease in mortality due to this pathology.

Arch Environ Health, 2002 Jul-Aug, 57(4), 366 - 70
Mercury in saliva and the risk of exceeding limits for sewage in relation to exposure to amalgam fillings; Leistevuo J et al.; The concentration of total mercury in stimulated saliva was studied in humans with dental amalgam fillings and in 2 nonamalgam groups . The probability of exceeding the limits of mercury permitted in wastewater increased proportionally as the number of amalgam-filled surfaces increased . The mercury limit for sewage is 0.05 mg/l (= 250 nmol/l) effluent, according to the Council of European Communities directive 84/156/EEC . In neither of the nonamalgam groups was this limit exceeded, but 20.5% in the amalgam group exceeded the limit (p < .001) . The risk of exceeding the limit increased 2-fold for every 10 additional amalgam-filled surfaces (odds ratio = 2.0; 95% confidence interval = 1.3, 3.3) . These results demonstrate that humans, especially in populated areas, can be a significant source of mercury pollutants . As a consequence of mercury release, bacteria may acquire mercury resistance, as well as resistance to other antimicrobial agents, thus resulting in failure of antibiotic treatment.

Cell Mol Life Sci, 2002 Nov, 59(11), 1928 - 33
Cellular and molecular aspects of drugs of the future: meropenem; Cottagnoud P; Meropenem, first synthesized in the late eighties, has become one of the most important beta-lactam antibiotics of the carbapenem subclass used for the treatment of a variety of life-threatening infections . Due to its unique chemical structure, meropenem is not inactivated by the kidney dehydropeptidase I and the majority of microbial beta-lactamases . Its antimicrobial activity is based on its high affinity for the majority of cell wall-synthesizing enzymes, the so-called penicillin-binding proteins, of Gram-positive and -negative bacteria . However, bacteria have evolved several approaches to resist meropenem: (i) by reducing the affinity of the penicillin-binding proteins for the antibiotics, (ii) by decreasing the permeability of the outer membrane of Gram-negative bacteria, (iii) by using efflux pumps, and (iv) by activating zinc-dependent carbapenemases . Meropenem has a low toxicity profile and, in contrast to imipenem, no central nervous system toxicity.

Contrib Microbiol, 2003, 10, 164 - 82
CD1 antigen presentation and infectious disease; Dascher CC et al.; Taken together, the data generated thus far strongly suggest that CD1 plays a role in the immune response against various infections (table 1) . For obvious reasons, the data gathered thus far using model infection systems have focused primarily on the mouse and therefore only examine the role of CD1d . This leaves an important gap in our understanding of the CD1 antigen presentation pathway given the potential role of CD1a, CD1b and CD1c for contributing to antimicrobial immunity . The functional dichotomy between group 1 and group 2 CD1 isoforms obviously requires further analysis . However, we propose that the group 1 CD1 (CD1a, CD1b, CD1c) antigen presentation pathway is closer to the traditional adaptive immune response mechanisms with the capacity to present unique foreign antigens to specific T cells . This broadens the universe antigens that T cells can use to target pathogens and provides important antimicrobial effector mechanisms that may be critical for combating some types of infections . Lipid antigens may also provide a more effective means of targeting intracellular pathogens by T cells since CD1 is able to sample almost all of the intracellular reservoirs that are exploited by this class of pathogen and may provide an important component of the cytotoxic T cell response {80} . On the other hand, the group 2 CD1 protein (CD1d) may be more intermediate in terms of lying functionally between the innate and adaptive immune systems . The activation of CD1d-restricted T cells may, therefore, help bridge the temporal gap between the onset of innate immunity and the purely adaptive responses typified by the MHC-restricted T cells . Hence, the CD1d-restricted {table: see text} T cells are primed for rapid high-level cytokine release . In addition, the interaction of CD1d-restricted T cells with CD1d on DCs can trigger the release of IL-4 and GM-CSF to promote maturation of tissue-resident DC at the site of infection . The maturation of tissue DC would lead to migration of the activated DC to regional lymph nodes and initiation of MHC-restricted T cell responses . Subsequent IL-12 production by the DC in response to CD1d-mediated T cell stimulation could then drive IFN-gamma production by CD1d-restricted T cells and influence the polarization of the T cell response to infection . In addition, early bursts of IFN-gamma by CD1d-restricted T cells could also upregulate antimicrobial activity in macrophages and activate other important effector cells such as NK cells prior to MHC-restricted T cell responses . In the constant struggle between the microbial pathogen and its host, the evolutionary balance almost always favors the microbe . The rapid rate of evolution and adaptation of the microbe accounts for most of this advantage . Hence, it is not surprising that the host immune system has evolved a complex set of pathways, in addition to the MHC, that are able to recognize and target the unique molecular signatures of infectious microorganisms . The lipid antigens presented by CD1 add to this array and thus provide a further layer of immune defense to the host for combating pathogens.

Kulak Burun Bogaz Ihtis Derg, 2003 Jan, 10(1), 39 - 44
{Nitric oxide and the upper airways: recent discoveries}; Vural C et al.; Nitric oxide (NO) is produced from L-arginine in mammalian tissues . Nitric oxide synthase (NOS) catalyzes this reaction in human tissues . It has been shown that NO serves as an important signaling molecule in the cardiovascular system and is responsible for vasoregulation . In 1991, NO was discovered in exhaled air . More recently, it has been shown that the main production site of exhaled NO is the nose and sinuses . In the upper airways NO upregulates ciliary motility and provides a first-line defense mechanism against microorganisms by antiviral and antimicrobial activity . In the lungs it is involved in ventilation/perfusion matching . Nitric oxide is also a marker for inflammation, with increased nasal output in allergic rhinitis, and a decreased output in sinusitis, nasal polyps and Kartagener's syndrome . This report reviews some aspects of the origin, metabolism, and functions of NO in the upper airways, together with the techniques for, and implications of, nasal NO measurement.

Paediatr Drugs, 2003, 5(2), 71 - 80
Acute sinusitis in children: current treatment strategies; Contopoulos-Ioannidis DG et al.; Acute sinusitis is a very common infection in childhood, but its management remains a controversial issue . Antibacterials may be effective in selected children, but direct evidence is limited . One randomized, placebo-controlled trial has shown that amoxicillin or amoxicillin/clavulanate are better than placebo for children with symptoms of nasal discharge and cough that are persistent (over 10 days) and not improving . However, another placebo-controlled trial of the same agents did not demonstrate any benefit from antibacterials in a patient population selected with a clinical diagnosis of sinusitis of moderate severity, based on a composite clinical symptom score . A systematic assessment of cure rates with various antibacterials shows no consistent differences between classes . Evidence on the use of ancillary measures and nasal corticosteroids is also limited . The only randomized, placebo-controlled trial of antihistamines and decongestants has shown no incremental benefit when given in addition to amoxicillin . Another placebo-controlled randomized trial showed some transient symptomatic improvement with the use of nasal corticosteroids . No randomized trials exist on the use of antral lavage in children with acute sinusitis . The current rates of antimicrobial resistance among commonly implicated pathogens should be considered in therapeutic decisions . However, there is no evidence from well-designed trials on specifically how to manage children at high risk of carrying resistant organisms . The inaccuracy of clinical signs and symptoms in documenting the diagnosis further complicates therapeutic decisions . Nevertheless, radiographic assessment does not meaningfully improve the accuracy of the diagnosis for uncomplicated cases, and it is not cost effective . In the absence of definitive evidence, treatment with amoxicillin 45 mg/kg/day in two divided doses may be used in selected patients with symptoms that are persistent and not improving . High doses (90 mg/kg in two divided doses) may also be considered, and amoxicillin/clavulanate may be a more appropriate choice when there is high risk of resistant pathogens, e.g . in a child attending a childcare center, or recent use of antibacterials . However, a considerable proportion of children, especially those with mild or improving symptoms, may not have to be treated at all.

Keio J Med, 2002 Dec, 51 Suppl 2, 33 - 7
Gastric spirochaetes: 100 years of discovery before and after Kobayashi; Marshall B; The discovery of Helicobacter pylori, by Warren and Marshall in 1982, was preceded by nearly 100 years of inconspicuous publications relating to spiral bacteria, achlorhydria, gastritis, gastric urease, and antimicrobial therapy for ulcers . Japanese investigators, notably Kasai and Kobayashi, should be acknowledged for their pioneering work showing that spiral bacteria could infect many animals, could cause haemorrhagic erosions, and would be effectively cured with various antimicrobials.

Am J Gastroenterol, 2003 Jan, 98(1), 21 - 8
Gastroenterologist specialist care and care provided by generalists--an evaluation of effectiveness and efficiency; Provenzale D et al.; OBJECTIVE: In this era of cost containment, gastroenterologists must demonstrate that they provide effective and efficient care . The aim of this study was to evaluate the process and outcomes of care provided by gastroenterologists and generalist physicians (internists, family physicians, general surgeons) for GI conditions . METHODS: We conducted a systematic literature review using a MEDLINE search of English language articles (January 1980 to September 1998) . A total of 2157 articles were identified; 10 met inclusion criteria for systematic review . In addition, there were nine articles that described the results of physician surveys, and examined the process of care among gastroenterologists and generalist physicians . RESULTS: Care provided by gastroenterologists for GI bleeding and diverticulitis resulted in significantly shorter length of hospital stay . Gastroenterologists diagnosed celiac disease more accurately than generalists, and more adequately diagnosed colorectal cancer and prescribed antimicrobials for peptic ulcer disease . There was no difference between gastroenterologists and generalists in terms of colonoscopy procedure time, and family physicians detected a greater number of cancers . Furthermore, there was no difference in the outcomes of gastroesophageal reflux disease therapy in patients seen by gastroenterologists, versus those educated by nurses . The survey articles suggested that gastroenterologists were more likely to test and treat for Helicobacter pylori in patients with peptic ulcer disease, and were more likely recommended for medical versus surgical therapy . Gastroenterologists had a lower threshold for ordering ERCP before cholecystectomy than surgeons, but had similar responses regarding indications for surgery in inflammatory bowel disease . Finally, primary care physicians were less likely to associate symptoms of profuse watery diarrhea with cryptosporidium infection compared with gastroenterologists and infectious disease specialists . CONCLUSIONS: We reached the following conclusions: 1) The results suggest that gastroenterologists deliver effective and efficient care for GI bleeding and diverticulitis and provide more effective diagnosis in certain disorders . 2) Studies are limited by retrospective design, small sample size, and lack of control groups . 3) To fully evaluate care by gastroenterologists, prospective comparisons with greater attention to methodology are needed.

Pediatr Pulmonol, 2003 Feb, 35(2), 99 - 107
Antimicrobial susceptibility profile of molecular typed cystic fibrosis Stenotrophomonas maltophilia isolates and differences with noncystic fibrosis isolates; Canton R et al.; Multiresistance in Stenotrophomonas maltophilia limits the effectiveness of antimicrobial therapy for infections due to this organism . It can be of special concern in cystic fibrosis (CF) patients due to frequent antimicrobial administration . The in vitro activity of 41 antimicrobial agents against 76 epidemiologically defined CF S . maltophilia isolates by pulsed-field-gel electrophoresis (PFGE) technique under XbaI and SpeI restriction was compared with that obtained with 51 non-CF strains recovered from respiratory sources . Minimal inhibitory concentrations (MICs) were determined with the standard National Committee for Clinical Laboratory Standards agar dilution technique, but with 24-hr incubation . Forty-seven different PFGE profiles were observed within 76 S . maltophilia CF isolates . Minocycline (resistance rate, 0%; MIC(90), 1 microg/ml), doxycycline (6.4%; 8 microg/ml), trovafloxacin (4.2%; 2 microg/ml), moxifloxacin (6.3%; 2 microg/ml), clinafloxacin (6.3%; 2 g/ml), and moxalactam (17.0%; 64 g/ml) displayed low resistance rates . On the contrary, resistance rates were higher with ceftazidime (70.0%; 256 microg/ml), cefepime (83.0%; 128 microg/ml), piperacillin (87.2%; >1,024 microg/ml), ticarcillin (87.2%; >512 microg/ml), and aztreonam (95.7%; >1,024 microg/ml) . Clavulanate reverted resistance to ticarcillin and aztreonam in 40.4% and 31.7% of strains, respectively . Aminoglycosides displayed reduced activities with susceptibility rates lower than 20% and MIC(90) higher than 128 microg/ml . With the exception of trimethoprim-sulfamethoxazole (25.4 vs . 31.3%), CF isolates were more resistant than non-CF isolates . Remarkably, resistance was enhanced in S . maltophilia isolates persistently recovered in chronically colonized patients . Susceptibility analysis demonstrated higher resistance rates among CF S . maltophilia isolates when compared with respiratory isolates from non-CF patients . Moreover, persistently recovered CF S . maltophilia isolates were more resistant than sporadic non-CF isolates .

Biochemistry, 2003 Jan 21, 42(2), 440 - 9
Fourier transform infrared spectroscopic study of the interactions of a strongly antimicrobial but weakly hemolytic analogue of gramicidin S with lipid micelles and lipid bilayer membranes; Lewis RN et al.; Cyclo{VKLdKVdYPLKVKLdYP} (GS14dK(4)), a synthetic tetradecameric ring-size analogue of the naturally occurring antimicrobial peptide gramicidin S (GS), retains the strong antimicrobial activity of GS but is 15-20 times less hemolytic . To characterize its interaction with lipid membranes and to understand the molecular basis of its capacity to lyse bacterial cells, in preference to erythrocytes, we have investigated the interactions of GS14dK(4) with detergent micelles and with lipid bilayer model membranes by Fourier transform infrared spectroscopy and compared our results with those of a similar study of GS {Lewis, R . N . A . H., et al . (1999) Biochemistry 38, 15193-15203} . In both aqueous and organic solvent solutions, GS14dK(4) adopts a beta-sheet conformation that is somewhat distorted and more sensitive to the polarity of its environment than GS . Like GS, GS14dK(4) is completely or partially excluded from gel-state lipid bilayers but interacts strongly with liquid-crystalline lipid bilayers and detergent micelle, and interacts more strongly with more fluid liquid-crystalline lipid systems . However, its interactions are more strongly influenced by membrane lipid order and fluidity, and unlike GS, it is essentially excluded from cholesterol-containing phospholipid bilayers . Also, GS14dK(4) is excluded from cationic lipid bilayers, but partitions more strongly and/or penetrates more deeply into anionic lipid bilayers than into those composed of either zwitterionic or nonionic lipids . Anionic lipids also facilitate GS14dK(4) interactions with multicomponent lipid bilayers which are predominantly zwitterionic or nonionic . Although GS14dK(4) generally penetrates and/or partitions into zwitterionic or uncharged lipid bilayers less strongly than does GS, its greater size and altered distribution of positive charges make it intrinsically more perturbing with regard to membrane organization once associated with lipid bilayers . This fact, combined with its relatively strong interactions with anionic phospholipids, may explain why GS14dK(4) retains relatively high antimicrobial activity . However, its low hemolytic activity is probably largely attributable to its low propensity to penetrate and/or partition into cholesterol-containing zwitterionic lipid membranes.

Biochemistry, 2003 Jan 21, 42(2), 402 - 9
Enhanced membrane permeabilization and antibacterial activity of a disulfide-dimerized magainin analogue; Dempsey CE et al.; A cysteine substitution analogue of magainin-2 amide (magainin-F12W, N22C; denoted here as mag-N22C), and a disulfide-linked dimer prepared by air oxidation {(mag-N22C)(2)}, were compared in their ability to release carboxyfluorescein (CF) from 100-nm large unilamellar vesicles (LUV) and to kill the Gram negative bacteria Stenotrophomonas maltophilia and Escherichia coli . The disulfide-dimerized peptide showed enhanced permeabilization and antimicrobial activity, when compared with the monomeric peptide, that was particularly marked at very low peptide concentrations . The enhanced CF-releasing activity of the dimer at low concentrations in vesicles results from (i) enhanced binding to negatively charged membrane surfaces and (ii) a low concentration dependence for permeabilization in the dimer compared to the monomer . The unique properties of the dimeric peptide suggest a role for structural diversity of antimicrobial peptides in frog skin, including the recent identification of a heterodimer composed of disulfide-linked amphipathic helical peptides {Batista et al . (2001) FEBS Lett . 494, 85-89} . Disulfide-dimerization of pore-forming, positively charged, amphipathic helical peptides may be a useful general approach to the generation of peptide antimicrobials having activity at very low concentrations.

Annu Rev Immunol, 2003, 21, 335 - 76 Epub 2001 Dec 19.
Toll-like receptors; Takeda K et al.; The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms . In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway . In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms . Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity . The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88 . However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Arch Intern Med, 2003 Jan 13, 163(1), 76 - 80
Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics; Reyes M et al.; BACKGROUND: Genital herpes is epidemic in the United States; long-term acyclovir therapy is common; and long-term use of antimicrobials in suppressive doses favors development of resistance . OBJECTIVE: To determine the prevalence of and risk factors for acyclovir-resistant genital herpes . METHODS: We identified and attempted to enroll all patients 18 years or older with suspected genital herpes who attended 22 sexually transmitted disease and human immunodeficiency virus (HIV) clinics in the United States between October 1996 and April 1998 . We conducted standardized interviews of all consenting patients . Lesions were cultured, and isolates were typed as herpes simplex virus (HSV) 1 or HSV-2 and tested for acyclovir sensitivity (using a 50% inhibitory concentration of 2 microg/mL) by plaque reduction, which was independently confirmed . RESULTS: Herpes simplex virus was isolated from 2088 of 3602 patients, and 90.2% of isolates were HSV-2 . Fifteen isolates, all HSV-2, were acyclovir resistant . Three (0.18%) of 1644 HIV-negative patients had acyclovir-resistant isolates (95% confidence interval {CI}, 0.04%-0.5%); resistance was associated with oral (P<.006) and topical (P<.001) acyclovir use . Twelve (5.3%) of 226 HIV-positive patients yielded resistant HSV isolates (95% CI, 2.8%-9.1%); resistance was associated with oral acyclovir use (P<.001), duration of the current episode (P<.001), history of recurrent genital herpes (P<.01), and low CD4 cell count (P<.05) . CONCLUSIONS: In the 15 years following licensure of acyclovir, resistance to the drug remains low among immunocompetent patients . However, 5% of HIV-positive patients had resistant HSV-2 isolates . Continued surveillance is essential to monitor changes in acyclovir resistance and to characterize the clinical and public health importance of acyclovir-resistant HSV.

J Comb Chem, 2003 Jan-Feb, 5(1), 33 - 40
Automated mass spectrometric sequence determination of cyclic peptide library members; Redman JE et al.; Cyclic peptides have come under scrutiny as potential antimicrobial therapeutic agents . Combinatorial split-and-pool synthesis of cyclic peptides can afford single compound per well libraries for antimicrobial screening, new lead identification, and construction of quantitative structure-activity relationships (QSAR) . Here, we report a new sequencing protocol for rapid identification of the members of a cyclic peptide library based on automated computer analysis of mass spectra, obviating the need for library encoding/decoding strategies . Furthermore, the software readily integrates with common spreadsheet and database packages to facilitate data visualization and archiving . The utility of the new MS-sequencing approach is demonstrated using sonic spray ionization ion trap MS and MS/MS spectrometry on a single compound per bead cyclic peptide library and validated with individually synthesized pure cyclic D,L-alpha-peptides.

Microb Drug Resist, 2002 Winter, 8(4), 245 - 51
Mutations in gyrA and parC QRDRs are not relevant for quinolone resistance in epidemiological unrelated Stenotrophomonas maltophilia clinical isolates; Ribera A et al.; Clinical strains of Stenotrophomonas maltophilia are often highly resistant to multiple antibiotics and this resistance is steadily rising . Quinolones are included in the group of antimicrobial agents to which this microorganism is developing resistance . Therefore, the aim of this study was to analyze the epidemiological relationship among 22 clinical isolates of S . maltophilia as well as the molecular mechanisms responsible for the acquisition of quinolone-resistance in these strains . The results of the pulsed-field gel electrophoresis (PFGE) showed an heterogenicity of 82% among the strains used in the study . On the other hand, no amino acid changes were found in the quinolone resistance-determining region (QRDR) of either gyrA and parC genes among quinolone-susceptible and -resistant S . maltophilia strains . Besides, the amino acid of the GyrA found in the position equivalent to Ser-83 of E . coli was Gln instead of a Ser or Thr, the amino acids usually encountered in this position among Gram-negative bacteria . The results suggest that there is not a relationship between the presence of this Gln and the resistance to quinolones in S . maltophilia . We can conclude that, contrary to what has been described in other microorganisms, in these S . maltophilia isolates, the development of resistance to quinolones was not related to mutations in the QRDR of gyrA and parC genes . Thus, to our knowledge, this is the first report describing this phenomenon.

Ann Med, 2002, 34(6), 419 - 27
Wound pathophysiology, infection and therapeutic options; Bowler PG; Wound healing is a complex and highly regulated process that can be compromised by both endogenous factors (pathophysiological) and exogenous factors (micro-organisms) . Microbial colonisation of both acute and chronic wounds is inevitable, and in most situations endogenous bacteria predominate, many of which are potentially pathogenic in the wound environment . The risk of wound infection increases as local conditions favour bacterial growth rather than host defence . Consequently a primary objective in wound management is to redress the host-bacterial balance, and this is most effectively achieved by ensuring that the wound is cleared of devitalised tissue and foreign bodies, the bacterial load and inflammation are controlled, and that adequate tissue perfusion is maintained . Although surgical debridement is the most rapid and effective technique for removing devitalised tissue, topical enzymes, moisture-retentive dressings, biosurgical therapy and vacuum therapy have been used as alternative approaches to wound cleansing and preparation . Topical antimicrobial agents continue to be used widely for preventing wound infection and current interest is focused on alternatives to antibiotics, such as antimicrobial moisture-retentive dressings, honey, essential oils and cationic peptides . In addition to the need to control wound microflora, unregulated inflammation caused by both micro-organisms and underlying abnormal pathophysiological conditions is a major factor associated with poor healing in chronic wounds . Consequently, therapeutic strategies that target chronic inflammatory processes are critical to wound progression . The success of future therapies will be dependent on a growing understanding of the pathophysiological processes and the host-bacterial interactions that significantly influence wound healing.

Environ Sci Technol, 2002 Dec 1, 36(23), 4998 - 5004
Triclosan: occurrence and fate of a widely used biocide in the aquatic environment: field measurements in wastewater treatment plants, surface waters, and lake sediments; Singer H et al.; Triclosan is used as an antimicrobial agent in a wide range of medical and consumer care products . To investigate the occurrence and fate of triclosan in the aquatic environment, analytical methods for the quantification of triclosan in surface water and wastewater, sludge, and sediment were developed . Furthermore, the fate of triclosan in a wastewater treatment plant (biological degradation, 79%; sorption to sludge, 15%; input into the receiving surface water, 6%) was measured during a field study . Despite the high overall removal rate, the concentration in the wastewater effluents were in the range of 42-213 ng/L leading to concentrations of 11-98 ng/L in the receiving rivers . Moreover, a high removal rate of 0.03 d(-1) for triclosan in the epilimnion of the lake Greifensee was observed . This is due to photochemical degradation . The measured vertical concentration profile of triclosan in a lake sediment core of lake Greifensee reflects its increased use over 30 years . As the measured concentrations in surface waters are in the range of the predicted no effect concentration of 50 ng/L, more measurements and a detailed investigation of the degradation processes are needed.

Urology, 2002 Dec, 60(6 Suppl), 42 - 3; discussion 44
Bladder training biofeedback and pelvic floor myalgia; Nadler RB; Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating condition, traditionally treated with antimicrobials, nonsteroidal anti-inflammatory drugs, and alpha-blockers . Pelvic floor tension myalgia is hypothesized to be a contributing factor in CPPS . Biofeedback training for CPPS is based on the principle that maximum muscle contraction prompts maximum muscle relaxation . Similar chronic pain conditions have been treated successfully with biofeedback-assisted techniques of neuromuscular reeducation . Preliminary study by our group has shown biofeedback, pelvic floor reeducation, and bladder training to be helpful in the treatment of CP/CPPS . Overall, 8 of 11 patients had improvement in either pain scores or their chronic prostatitis pain index scores . With no cure for CP/CPPS available, biofeedback and pelvic floor reeducation merit further evaluation in the treatment of this condition.

Urology, 2002 Dec, 60(6 Suppl), 24 - 6; discussion 26
Antimicrobial therapy for bacterial and nonbacterial prostatitis; Fowler JE Jr; Antimicrobial therapy is the standard of care for the unusual man with true chronic bacterial prostatitis but does not have much of a role in the treatment of men with nonbacterial prostatitis . The fluoroquinolone antibiotics given for 2 to 4 weeks will cure about 70% of chronic bacterial infections of the prostate . If this treatment fails, the symptomatic manifestations of the infections can almost always be eliminated with suppressive antimicrobial therapy using trimethoprim-sulfamethoxazole, a fluoroquinolone antibiotic, or nitrofurantoin.

Med Tr Prom Ekol, 2002, (11), 31 - 4
{Use of antimicrobial articles in the prevention of pyoderma and dermatomycoses}; Astaf'eva IP et al.; The authors present results of experimental and clinical studies of antimicrobial articles (underwear, socks, insoles and gloves) containing catamine AB and base use of these articles for prevention of pyoderma and dermatomycoses.

Chem Pharm Bull (Tokyo), 2003 Jan, 51(1), 53 - 7
Determination of ofloxacin in tablets by room-temperature phosphorimetry on a poly(vinyl alcohol) solid substrate; Kitade T et al.; An easy and sensitive method for the quantitative determination of ofloxacin (OFLX), a new fluoroquinolone antimicrobial agent, in a pharmaceutical formulation, tablet, was developed by using solid-substrate room-temperature phosphorimetry (RTP) on a poly(vinyl alcohol) substrate . The method did not require a dry gas flush during the measurement of phosphorescence . The influence of different conditions such as solution pH and concentrations of heavy atoms, used as the enhancer, were studied . The phosphorescence intensity of OFLX was enhanced using NaOH and KI as enhancers . A linear relationship between concentration and RTP intensity for each standard solution was obtained in the concentration range of 4-18000 ng/ml, and the determination limit was 4 ng/ml . The proposed method was applied to a determination of OFLX in a commercial tablet, and the results were compared with those of fluorescence and UV methods . It was proven that OFLX in a commercial tablet can be accurately measured by this method with a very small amount of sample solution.

Mol Med, 2002 Nov, 8(11), 686 - 94
Involvement of {beta}-glucans in the wide-spectrum antimicrobial activity of Williopsis saturnus var . mrakii MUCL 41968 killer toxin; Guyard C et al.; BACKGROUND: Williopsis saturnus var . mrakii MUCL 41968 secretes a 85-kDa glycoprotein killer toxin (WmKT) that displays a cytocidal activity against a wide range of microorganisms, making WmKT a promising candidate for the development of new antimicrobial molecules . Although the killing mechanism of WmKT is still unknown, the toxin was recently proposed to bind to the surface of sensitive microorganisms through the recognition of beta-glucans . Indeed, Saccharomyces cerevisiae strains sensitive to the toxin become resistant when mutated in their beta-glucan synthesis pathway . MATERIALS AND METHODS: To investigate the interaction of WmKT with beta-glucans, we examined in agar diffusion assays the WmKT activity in the presence of enzymes displaying beta-glucanase activity . The toxin activity was also investigated using spheroplasts derived from sensitive yeast cells . The hydrolytic activity of WmKT was studied using specific glucosidase inhibitors as well as various sugar molecules covalently linked to p-nitrophenyl as potential substrates . Finally, the ultrastructural modifications induced by WmKT activity on sensitive yeasts were assessed by scanning electron microscopy . RESULTS: The data reported here support the hypothesis that WmKT binds to sensitive cells using surface-exposed beta-glucans . Indeed beta-glucanase exerts an antagonistic effect on WmKT activity and spheroplasts derived from WmKT-sensitive yeast cells are shown to be resistant to WmKT, suggesting that cell wall beta-glucans are required for WmKT lethal effect . Because WmKT exhibits amino acid sequence similarities with proteins suspected to be glucanase, we also investigated the effect of castanospermine, a potent glucosidase inhibitor, on WmKT activity . Castanospermine completely abolished WmKT killer activity as well as its hydrolytic enzymatic activity against p-nitrophenyl beta-D-glucopyranoside . The scanning electron microscopy analysis of sensitive yeast cells treated with the toxin reveals that WmKT causes cell wall modifications similar to those observed with zymolyase . CONCLUSION: The results reported in this study show that WmKT activity requires an interaction between the mycocin and the cell wall beta-glucans . Moreover, they indicate that WmKT acts on sensitive yeast cells through a hydrolytic activity directed against cell wall beta-glucans that disrupts the yeast cell wall integrity leading to death.

Clin Exp Immunol, 2003 Jan, 131(1), 190 - 6
Increased expression of the secretory leukocyte proteinase inhibitor in Wegener's granulomatosis; Ohlsson S et al.; The secretory leucocyte proteinase inhibitor (SLPI) is a low molecular weight, tissue-specific inhibitor of proteases, such as elastase and cathepsin G . It is the major local protease inhibitor in the upper airways . Proteinase 3, the main autoantigen in Wegener's granulomatosis (WG), can degrade SLPI proteolytically . In addition, SLPI is sensitive to oxidative inactivation by myeloperoxidase-generated free oxygen radicals . SLPI also has an antimicrobial capacity that can be of interest, as infection is considered to play a role in the pathogenesis of WG . This study focuses on SLPI expression in patients suffering from WG, something that to our knowledge has not been explored hitherto . Serum samples and nasal biopsies were obtained from 12 Swedish WG patients, while buffy coats were obtained from 33 American WG patients . SLPI levels in serum were measured by means of ELISA and the protein was detected by means of immunohistochemistry in nasal biopsies . mRNA expression was studied by means of in situ hybridization on nasal biopsies and RT-PCR on leucocytes . IL-6 or ESR were measured as markers of inflammatory activity . Cystatin C or creatinine was measured as a marker of renal filtration . White blood cell counts were registered . In serum, we found close to normal SLPI levels, without any correlation to IL-6 . Two patients had greatly elevated values, both of them suffering from severe renal engagement . Strong SLPI mRNA expression was found in nasal biopsies . RT-PCR on leucocyte mRNA showed normal or greatly elevated expression of SLPI mRNA, correlating with disease activity . Leukocyte SLPI expression seems to be up-regulated in active WG . Serum levels were measured in a small number of patients and were found to be close to normal . Lack of correlation to the acute phase response indicates a specific regulation . This might be linked to an altered protease/antiprotease balance . These findings could indicate that SLPI locally participates in the anti-inflammatory and perhaps antimicrobial response in WG.

Clin Exp Immunol, 2003 Jan, 131(1), 90 - 101
Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis; Fahlgren A et al.; The impact of chronic inflammation on the expression of human alpha-defensins 5 and 6 (HD-5, HD-6), beta-defensins 1 and 2 (hBD-1, hBD-2) and lysozyme in epithelial cells of small and large intestine was investigated . Intestinal specimens from 16 patients with ulcerative colitis (UC), 14 patients with Crohn's disease (CD) and 40 controls with no history of inflammatory bowel disease were studied . mRNA expression levels of the five defence molecules were determined in freshly isolated epithelial cells by real-time quantitative RT-PCR . Specific copy standards were used allowing comparison between the expression levels of the different defensins . HD-5 and lysozyme protein expression was also studied by immunohistochemistry . Colonic epithelial cells from patients with UC displayed a significant increase of hBD-2, HD-5, HD-6 and lysozyme mRNA as compared to epithelial cells in controls . Lysozyme mRNA was expressed at very high average copy numbers followed by HD-5, HD-6, hBD-1 and hBD-2 mRNA . HD-5 and lysozyme protein was demonstrated in metaplastic Paneth-like cells in UC colon . There was no correlation between hBD-2 mRNA levels and HD-5 or HD-6 mRNA levels in colon epithelial cells of UC patients . Colonic epithelial cells of Crohn's colitis patients showed increased mRNA levels of HD-5 and lysozyme mRNA whereas ileal epithelial cells of Crohn's patients with ileo-caecal inflammation did not . Chronic inflammation in colon results in induction of hBD-2 and alpha-defensins and increased lysozyme expression . hBD-1 expression levels in colon remain unchanged in colitis . The high antimicrobial activity of epithelial cells in chronic colitis may be a consequence of changes in the epithelial lining, permitting adherence of both pathogenic bacteria and commensals directly to the epithelial cell surface.

Afr J Med Med Sci, 2002 Jun, 31(2), 171 - 3
Seasonal accumulation of anthraquinones in leaves of cultivated Cassia podocarpa Guill et Perr; Abo KA et al.; Seasonal variations and spectrophotometric determination of anthraquinones in cultivated Cassia podocarpa are presented . The study shows that combined anthraquinones are concentrated in the leaves at peak flowering (2.43%) and lowest in the bark (0.21%) . Anthraquinone glycosides reached peak levels during the months of October to March (dry season), the maximum being recorded during January to March . There was significant drop in glycosidic content during the period April to September (rainy season) . There was slight increase in concentration of aglycones during the rainy season which may be due to inter-conversion of some glycosides to the aglycones . However, the free aglycone content is much lower than the glycosides . This is desirable for optimum laxative activity and reduced toxicity . This study is significant because it provides useful information on the seasonal distribution of anthraquinones and the best period for harvesting leaves of C . podocarpa for drug development . The inclusion of C . podocarpa in the African Pharmacopoeia will, no doubt, enhance its commercialization as laxative and for its antimicrobial effect.

Am J Vet Res, 2003 Jan, 64(1), 88 - 92
Effects of topical application of antimicrobials and bandaging on healing and granulation tissue formation in wounds of the distal aspect of the limbs in horses; Berry DB 2nd et al.; OBJECTIVE: To determine whether povidone iodine ointment or 2 forms of silver sulfadiazine applied topically to wounds of the distal aspect of the limbs in horses affect the rate of second intention healing and to evaluate the additional influence of bandaging with these antimicrobials on granulation tissue formation . ANIMALS: 6 healthy adult horses . PROCEDURE: Six standardized 2.5-cm2 skin wounds/horse were distributed between the dorsomedial surfaces of the metacarpi and metatarsi . One of the following 6 treatments was applied to each wound: 1% silver sulfadiazine cream with bandage, 1% silver sulfadiazine slow-release matrix with bandage, 1% silver sulfadiazine slow-release matrix without bandage, povidone-iodine ointment with bandage, untreated control with bandage, and untreated control without bandage . Wound area, granulation tissue area, and perimeter were measured by use of planimetry software applied to digital images . Exuberant granulation tissue was excised when present . Days until healing, rate of healing parameter, rate of contraction, and epithelialization were compared among wound treatment groups . RESULTS: Healing parameters and mean days to healing did not differ significantly among any of the wound treatment groups . Percentage wound contraction and rate of epithelialization were similar among wound treatments . All bandaged wounds produced exuberant granulation tissue, which was surgically excised; none of the unbandaged wounds produced exuberant granulation tissue . CONCLUSIONS AND CLINICAL RELEVANCE: When exuberant granulation tissue is removed, rates of epithelialization and wound contraction were not different among wound treatment groups, whether bandaged or unbandaged . Topical application of 1% silver sulfadiazine slow-release matrix on unbandaged wounds induced the same result as medications applied beneath bandages, but without exuberant granulation tissue formation.

J Clin Dent, 2002, 13(6), 240 - 8
A clinical methods study of the effects of triclosan dentifrices on gingivitis over six months; Winston JL et al.; The basic design for human clinical trials which examine prevention of gingivitis recurrence is well known . However, the anti-gingivitis efficacy of triclosan-containing dentifrices has not been routinely demonstrated using this design, regardless of formulation . In an effort to better understand the subtleties of design which show triclosan efficacy, a study was undertaken to prospectively test how subjects with a range of baseline disease levels (which encompassed the range of gingivitis severity documented in the triclosan literature) benefit from a triclosan dentifrice . This trial was a randomized, double-blind, parallel group, six-month study where subjects brushed twice daily with either triclosan/pyrophosphate, triclosan/copolymer, triclosan placebo or sodium fluoride control (NaF) dentifrice following a prophylaxis . Both gingivitis and bleeding were measured using the Loe-Silness Gingival Index (GI) and plaque was measured using the Turesky Plaque Index . Comparisons between treatments were performed using an analysis of covariance . At month 3, the triclosan/pyrophosphate group had a relative mean plaque benefit of 14.4% versus the triclosan placebo group (with an associated p-value of 0.004), and subjects using triclosan/copolymer had a mean reduction in GI bleeding sites of 16.2% relative to those brushing with the NaF control (with an associated p-value of 0.031) . The overall results did not demonstrate a treatment effect for gingivitis or plaque for either triclosan-containing dentifrice at month 6 . There was evidence of modest anti-gingivitis efficacy in the triclosan placebo . In an effort to better understand how baseline disease severity may have impacted the trial outcome, additional analyses were performed to investigate whether the magnitude of a triclosan effect was related to baseline gingivitis levels . An analysis of covariance model incorporating a baseline group interaction effect indicated that the magnitude of the treatment differences depended on the baseline scores The effect was most pronounced for GI bleeding sites . Further analysis showed that differences between triclosan dentifrices and the NaF control dentifrice were only present for subjects with more than 33 to 63 bleeding sites, depending on the specific comparison . These findings were illustrated through a series of subset analyses on subjects with > or = 20 (entire study population), > or = 31, > or = 40 and > or = 45 baseline GI bleeding sites . The magnitude of the treatment effect for both GI and GI bleeding sites increased with each succeeding subset . Unlike that required for other antimicrobial agents used in oral care products, these findings suggest that a study design which includes subjects with more severe gingivitis at baseline has the required sensitivity to demonstrate treatment benefits for triclosan dentifrices.

J Clin Microbiol, 2003 Jan, 41(1), 495 - 7
Detection and treatment of bloodstream infection: laboratory reporting and antimicrobial management; Munson EL et al.; We analyzed antimicrobial use in 509 episodes of clinically significant bloodstream infection to assess the impact that microbiology laboratory reporting had on antimicrobial management . Most therapy interventions occurred at the time of phlebotomy and after notification of Gram stain results by telephone . Release of antimicrobial susceptibility data had the least impact on antimicrobial management.

J Clin Microbiol, 2003 Jan, 41(1), 90 - 6
Single-nucleotide polymorphisms (SNPs) in human beta-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls; Jurevic RJ et al.; beta-Defensins are cationic antimicrobial peptides expressed in epithelia . They exhibit antibacterial, antifungal, and antiviral properties . Defensins are a component of the innate immune response, and it has been proposed that they have a protective role in the oral cavity . Previous studies have shown that human beta-defensin 1 (hBD-1) is constitutively expressed in oral epithelial cells but that expression varies between individuals . We tested the hypothesis that genetic variations in defensin peptide expression may be associated with opportunistic infections . This may be critical in the immunocompromised patient population, in which innate immune responses may have a relatively more important role . Oral Candida carriage status and the presence of six single-nucleotide polymorphisms (SNPs) in the DEFB1 gene encoding hBD-1 were evaluated in type I diabetic patients (n = 43) and nondiabetic controls (n = 50) . Genomic DNA was obtained from buccal swabs . Portions of the DEFB1 gene were amplified, and each SNP was analyzed by a TaqMan assay, standardized with control DNA of known genotype . Candida carriage status was determined from unstimulated saliva on CHROMagar plating medium . A low level of Candida carriage was defined as < or = 350 CFU/ml . A high level of Candida carriage was seen in 44% of the diabetic subjects but only in 28% of the nondiabetic controls (P < 0.05) . C . albicans predominated; however, diabetic subjects, especially those with high levels of carriage, showed an increased proportion of Candida glabrata and C . tropicalis . There was a strong association between an SNP in the 5' untranslated region (C-->G at position -44) and Candida carriage in both groups . Among individuals in the diabetic population who had the SNP allele 2 (G), 58% had low CFU, while 6% had high CFU . The C-->G SNP at position -44 is associated with low levels of Candida carriage . The resultant odd ratios are statistically significant for a protective effect (odd ratios, 25 for diabetic subjects and 8.5 for nondiabetic subjects) . These results indicate that genetic variations in the DEFB1 gene encoding hBD-1 may have a major role in mediating and/or contributing to susceptibility to oral infection.

Expert Opin Biol Ther, 2002 Dec, 2(8), 929 - 42
Antigen-based immune modulation: DNA vectors and beyond; Bot A et al.; The ultimate goal for autoimmune immunotherapy is to achieve a specific downregulation or modification of autoaggressive immune responses while leaving in place the normal repertoire, capable of mediating antimicrobial responses . A multitude of preclinical studies, particularly during the last 15 years, raised hopes that self-antigens could be used to achieve the goal of specific immune modulation . Difficulties associated with the translation of this concept to the clinic revealed inherent limitations of antigen-based immune modulation . To increase the efficiency of antigen-dependent immune modulation, researchers started to investigate novel vectors for antigen delivery . Plasmid vectors, as opposed to protein antigens or peptides, have the ability to trigger prolonged production of limited amounts of antigen in the periphery . However, one complicating factor may be the inherent "danger" signal stimulated by the nature of the unmethylated CpG motifs on bacterial plasmid . Currently, various approaches are being explored to improve the efficacy of response while ameliorating the safety concerns of plasmids as immunotherapeutic tools . This manuscript offers a perspective on such efforts and outlines how the knowledge accumulated in the process will help scientists advance to the next generation of immunotherapeutics.

Infect Control Hosp Epidemiol, 2002 Dec, 23(12), 725 - 9
An outbreak of bloodstream infections in an outpatient hemodialysis center; Price CS et al.; OBJECTIVES: Investigate and control an increase in bloodstream infections (BSIs) in an outpatient hemodialysis center . PATIENTS AND DESIGN: A retrospective cohort study was conducted for patients receiving dialysis at the center from February 2000 to April 2001 . A case-control study compared microbiological data for all BSIs that occurred during the study period with those for BSIs that occurred during a baseline period January 1999 to January 2000) . BSI rates before and after a 1-month intervention (May 2001) were assessed . A case was defined as a new BSI during the study period . RESULTS: The outbreak was polymicrobial, with approximately 30 species . The baseline BSI rate was 0.7 per 100 patient-months . From February 2000 to April 2001, the BSI rate increased to 4.2 per 100 patient-months . Overall, 75% of the BSIs were associated with central venous catheters (CVCs), but CVC use did not fully explain the increase in BSIs . In January 2000, when the center changed ownership, prepackaged CVC dressing kits and biweekly infection control monitoring were discontinued . Beginning in May 2001, staff were educated on CVC care, chlorhexidine replaced povidone-iodine for cutaneous antisepsis, gauze replaced transparent dressings, antimicrobial ointments containing polyethylene glycol at CVC exit sites were discontinued, and patients with CVCs were educated on cutaneous hygiene . After the intervention period, by October 2001, rates decreased to less than 1 BSI per 100 patient-months . CONCLUSIONS: Proper cutaneous antisepsis and access site care is crucial in preventing BSIs in patients receiving hemodialysis . Infection control programs, staff and patient education, and use of optimal antisepsis agents or prepackaged kits are useful toward this end.

Microbiol Immunol, 2002, 46(11), 741 - 9
Antimicrobial activity and stability to proteolysis of small linear cationic peptides with D-amino acid substitutions; Hamamoto K et al.; Antimicrobial peptides contribute to innate host defense against a number of bacteria and fungal pathogens . Some of antimicrobial synthetic peptides were systemically administered in vivo; however, effective protection has so far not been obtained because the effective dose of peptides in vivo seems to be very high, often close to the toxic level against the host . Alternatively, peptides administered in vivo may be degraded by certain proteases present in serum . In this study, D-amino acids were substituted for the L-amino acids of antimicrobial peptides to circumvent these problems . Initially a peptide (L-peptide) rich in five arginine residues and consisting of an 11-amino acid peptide (residues 32-42) of human granulysin was synthesized . Subsequently, the L-amino acids of the 11-amino acid peptide were replaced partially (D-peptide) or wholly (AD-peptide) with D-amino acids . Activity and stability to proteolysis, in particular, in the serum of antimicrobial peptides with D-amino acid substitutions were examined . Peptides with D-amino acid substitutions were found to lyse bacteria as efficiently as their all-L-amino acid parent, L-peptide . In addition, the peptide composed of L-amino acids was susceptible to trypsin, whereas peptides containing D-amino acid substitutions were highly stable to trypsin treatment . Similarly, the peptide consisting of L-amino acids alone was also susceptible to fetal calf serum (FCS), however, protease inhibitors restored the lowered antimicrobial activity of the FCS-incubated peptide . Thus, D-amino acid substitutions can make antimicrobial peptides resistant to proteolysis, suggesting that the antimicrobial peptides consisting of D-amino acids are potential candidates for clinical therapeutic use.

Clin Perinatol, 2002 Dec, 29(4), 799 - 826
Perinatal infections and brain injury: current treatment options; Sanchez PJ; Antimicrobial therapy can ameliorate infection and prevent long-term morbidity caused by several pathogens that infect the fetus and neonate . Ultimately, however, preventive strategies need to be developed and incorporated into routine preconceptional care . The future of prevention lies in immunizations, and if past and current successes with smallpox, polio, rubella, and measles vaccination programs are any indication, the future is bright for the developing fetus.

Clin Infect Dis, 2003 Jan 15, 36(Suppl 1), S42 - 50
Prevention of resistance: a goal for dose selection for antimicrobial agents; Drusano GL; Drug-resistant microorganisms have become a major problem around the world . In nosocomial and community settings, many important pathogens have demonstrated high-grade resistance to many of our most important agents . In addition, the adverse impact of resistance has not been limited to the bacterial realm . In chemotherapy to treat human immunodeficiency virus (HIV) and other viral diseases, resistance has become a major problem . We are starting to see the beginnings of a resistance problem, even among fungi . Strangely, little attention has been focused on the impact of dosing on the probability with which emergence of resistance occurs . After delineation of the pharmacodynamically linked variable, it is possible to generate dosing regimens that can lower the probability of resistance . In addition, circumstances exist in which combination therapy may be required (e.g., therapy of HIV and tuberculosis) . Here, too, it is possible to optimize therapy to prevent resistance by understanding how the drugs in the regimen interact . We can do better with our choices of dose, schedule, and combinations of agents . We will need to lower the probability of resistance and maintain the utility of the drugs currently in our therapeutic armamentarium.

Hum Pathol, 2002 Dec, 33(12), 1227 - 33
CCR6 is a functional chemokine receptor that serves to identify select B-cell non-Hodgkin's lymphomas; Rodig SJ et al.; Several recent studies have revealed important contributions of chemokines and their receptors to the development and progression of both hematopoietic and nonhematopoietic neoplasms . The chemokine receptor CCR6 is unusual in that it mediates leukocyte chemotaxis in response to a single chemokine, CCL20 (macrophage inhibitory factor-3alpha), as well as in response to a family of antimicrobial peptides termed "beta-defensins." CCR6 is critical for mucosal immunity, and expression of the receptor is tightly regulated on hematopoietic cells . Here we characterize the expression of CCR6 on B cells and B-cell non-Hodgkin's lymphomas . We demonstrate that CCR6 expression is limited to cells comprising the mantle and marginal zones of the secondary lymphoid tissues and serves to identify the majority of mantle cell, marginal zone, and mucosa-associated lymphoid tissue lymphomas . Furthermore, we show that CCR6 serves as a functional chemokine receptor when expressed by neoplastic cells . Finally, we establish that the cognate ligand for CCR6 is present on mucosal epithelium infiltrated by neoplastic cells in select extranodal lymphomas . Thus, CCR6 is a useful new marker identifying a subset of B-cell non-Hodgkin's lymphomas and likely contributes to the localization of select extranodal lymphomas at mucosal sites .

Genes Dev, 2003 Jan 1, 17(1), 115 - 25
Nitric oxide contributes to induction of innate immune responses to gram-negative bacteria in Drosophila; Foley E et al.; Studies in mammals uncovered important signaling roles of nitric oxide (NO), and contributions to innate immunity . Suggestions of conservation led us to explore the involvement of NO in Drosophila innate immunity . Inhibition of nitric oxide synthase (NOS) increased larval sensitivity to gram-negative bacterial infection, and abrogated induction of the antimicrobial peptide Diptericin . NOS was up-regulated after infection . Antimicrobial peptide reporters revealed that NO triggered an immune response in uninfected larvae . NO induction of Diptericin reporters in the fat body required immune deficiency (imd) and domino . These findings show that NOS activity is required for a robust innate immune response to gram-negative bacteria, NOS is induced by infection, and NO is sufficient to trigger response in the absence of infection . We propose that NO mediates an early step of the signal transduction pathway, inducing the innate immune response upon natural infection with gram-negative bacteria.

Pharm World Sci, 2002 Dec, 24(6), 247 - 55
Intravenous and oral antibiotics in respiratory tract infection: an international observational study of hospital practice; Cooke J et al.; BACKGROUND: Hospitalised patients with respiratory tract infections (RTI) frequently receive intravenous (i.v.) antibiotics followed by a short course of oral treatment . OBJECTIVES: To observe antibiotic use in hospitals in Germany, Spain, France, Italy and the UK and the reasons for choosing the i.v . route and switching to oral treatment . METHODS: Research pharmacists sought the opinions of physicians and senior nurses in the completion of a semi-structured questionnaire on the treatment of RTI with i.v . antibiotics . Questions focussed on antimicrobials of choice, reasons for choosing i.v., reasons for changing to oral administration, and duration of treatment . RESULTS: This study recruited 796 patients with RTI, usually pneumonia . Prescribing patterns varied widely between the five hospitals . Accepted clinical criteria were only commonly cited in Germany, Spain and the UK as reasons for choosing the i.v . route at the beginning of the study . These were more commonly cited at the time of switch, although other criteria such as improved condition, were other significant reasons . The mean duration of i.v . treatment ranged from 4 days in the UK to 10 days in Italy, where most patients received the full course of treatment by the i.v . route . Unlike the other hospitals studied, the few patients in Italy who were switched to another form of treatment were as likely to receive intramuscular as oral administration (13% and 11%, respectively) . CONCLUSIONS: The practice of and reasons for prescribing i.v . antibiotics varied in the hospitals studied . Objective clinical criteria were inconsistently cited as reasons for administering i.v . antibiotics and in general these reasons were unrelated to those given for the switch from i.v . to oral administration . In order for guidelines for switching from i.v . to oral antimicrobials to be routinely employed, explicit physiological criteria need to be recorded in a routine fashion . Closer co-operation between pharmacists and physicians may help in developing and implementing guidelines at a local level.

Ophthalmology, 2003 Jan, 110(1), 138 - 43
Trends in contact lens-associated microbial keratitis in Southern India; Sharma S et al.; OBJECTIVE: To review the microbiologic profile, clinical course, treatment, and outcome in patients with contact lens-associated microbial keratitis in the setting of a tertiary eye care center in a developing country in the Tropics . DESIGN: Retrospective noncomparative case series selected from an ongoing prospective series . PARTICIPANTS: Twenty-eight subjects examined in the contact lens clinic of L . V . Prasad Eye Institute, Hyderabad, south India, between February 1991 and September 2000, who presented with corneal stromal infiltrate on slit-lamp examination, were included in the study . INTERVENTION: All patients underwent standard diagnostic microbiologic evaluation and smear and culture-guided topical antimicrobial therapy . Penetrating keratoplasty was performed in some patients . MAIN OUTCOME MEASURES: Culture results and clinical response to antimicrobial therapy . RESULTS: Twenty eight (0.11%) of 23,889 contact lens-wearing patients presented with laboratory-proven infectious keratitis; this constituted 0.56% of 4967 corneal ulcer patients seen during the same period . Most (15/28) of the patients wore soft contact lenses on a daily basis . Rigid gas-permeable lenses were worn by six patients, therapeutic bandage contact lenses by four, and Silsoft lenses by four . Laboratory results showed bacterial infections in 25 patients (89.2%); Pseudomonas was the most common organism (13/25; 52%) . Acanthamoeba, herpes simplex virus, and Aspergillus niger were isolated in one case each . Laboratory-based medical therapy led to the healing of ulcers in 24 (85.7%) of 28 patients, whereas 4 patients required penetrating keratoplasty . Most of the organisms were sensitive to antibiotics . CONCLUSIONS: Contact lens-associated microbial keratitis is rare in southern India . Soft contact lens wear is the most common risk factor; Pseudomonas keratitis is the predominant causative agent . Fungal, viral, and Acanthamoeba keratitis are rare . The offending bacteria are usually sensitive to antibiotics, and the treatment outcome with medical therapy is good.

Med Clin North Am, 2002 Nov, 86(6), 1447 - 66, viii
Pathogenesis and therapy of gastric and duodenal ulcer disease; Shiotani A et al.; Despite the decreasing frequency of Helicobacter pylori-induced peptic ulcers, peptic ulcer disease remains a major clinical problem partly because nonsteroidal anti-inflammatory drug ulcers have increased in frequency . The reduction in nonsteroidal anti-inflammatory drug ulcers by use of selective cyclooxygenase-2 inhibitors will not eliminate the problem because of increased use of aspirin for cardiovascular prophylaxis . This article reviews current concepts of peptic ulcer pathogenesis and therapy according to ulcer etiology; discusses potential interactions between etiologies; and considers the therapy for H pylori infection including the effects of antimicrobial resistance, and the role of bismuth quadruple therapy or furazolidone salvage therapy.

Protein Expr Purif, 2003 Jan, 27(1), 55 - 62
EGFP as a fusion partner for the expression and organic extraction of small polypeptides; Skosyrev VS et al.; Green fluorescent protein (GFP) is widely used as an excellent reporter module of the fusion proteins . The unique structure of GFP allows isolation of the active fluorescent protein directly from the crude cellular sources by extraction with organic solvents . We demonstrated the stable expression of four short polypeptides fused to GFP in Escherichia coli cells, including antimicrobial cationic peptides, which normally kill bacteria . EGFP module protected fusion partners from the intracellular degradation and allowed the purification of the chimerical proteins by organic extraction . The nature of the polypeptide fused to GFP, as opposed to the order of GFP and the polypeptide modules in the fusion protein, influenced the efficiency of the described purification technique.

Int J Antimicrob Agents, 2003 Jan, 21(1), 75 - 8
Antimicrobial activity of magainin analogues against anaerobic oral pathogens; Genco CA et al.; Magainins are a family of potent antimicrobial cationic peptides that possess antimicrobial activity against a wide range of target organisms . In this study, the antimicrobial activity of synthetic magainin-mimetic compounds MSI-751 and MSI-774 was investigated against the periodontal pathogens Porphyromonas gingivalis, Fusobacterium nucleatum, Actinobacillus actinomycetemcomitans, Eikenella corrodens, Prevotella loescheii and Prevotella intermedia . P . gingivalis was more susceptible to MSI-751 than to MSI-774, whereas the other oral pathogens showed little difference in susceptibility to the two compounds . MSI-751 exhibited a rapid, dose-dependent bactericidal effect on P . gingivalis . Electron microscopy of MSI-751-treated P . gingivalis revealed intact cell wall vesicles devoid of cell contents, suggesting perturbation of the cytoplasmic membrane by this compound, perhaps equivalent to formation of membrane-disruptive ion channels by magainin peptides . These studies demonstrate that synthetic magainin derivatives exhibit antimicrobial activity against oral pathogens by disruption of cell membrane integrity.

Int J Antimicrob Agents, 2003 Jan, 21(1), 13 - 9
The increased bactericidal activity of a fatty acid-modified synthetic antimicrobial peptide of human cathepsin G correlates with its enhanced capacity to interact with model membranes; Mak P et al.; The bactericidal potency of a synthetic peptide (CG 117-136) of human lysosomal cathepsin G (cat G) can be substantially increased by covalent attachment to its N- or C-termini, of saturated, linear fatty acids (FAs), namely those with C-8, C-10 and C-12 hydrocarbon chains . In order to understand better the mechanism by which FA moieties increase the bactericidal activity of CG 117-136, the interaction of N-terminally FA-modified peptides with artificial membranes was studied . First, the content of secondary structure motifs in the modified and unmodified peptides was determined by circular dichroism (CD) . A marked increase in the propensity of FA-modified CG 117-136 to form an alpha-helix structure was observed for the C-8, C-10 and C-12 derivatives compared with unmodified/short-chain and long-chain (C-14, C-16, C-18) derivatives . These effects were observed both in the presence of large unilamellar liposomes or in trifuluoroethanol, a membrane-stimulating agent . Second, the capacity of peptides to insert into large unilamellar liposomes as a function of FA length was determined by their ability to release a trapped fluorescent dye . FA derivatives with the highest alpha-helical content were found to be the most effective in releasing a fluorescent dye, compared with an unmodified peptide and/or derivatives having a low alpha-helical content . The ability of the peptides to attain alpha-helical structure in the membrane-like environment and the ability to disrupt the liposomal membrane, therefore correlate remarkably well with their increased ability to kill bacteria . A plausible explanation for improved bactericidal action of the modified peptide is that the FA moiety facilitates formation of the peptide with an alpha-helical structure formation in membranes, which is essential for disrupting the integrity of the bacterial cytoplasmic membrane.

AIDS Alert, 2002 Dec, 17(12), 149 - 53
New drugs and drug types boost hope for the future . Report from ICAAC.
{Myeloperoxidase in the human placenta at preterm labor}
Prokopenko VM, Aleshina GM, Frolova EV, Anan'eva VV, Kokriakov VN, Arutiunian AV.

Ott Research Institute of Obstetrics and Gynecology RAMS, Mendeleev Line 3, St . Petersburg, 199034 RussiaIn the present study the level of myeloperoxidase in the human placenta at premature was investigated . Mycloperoxidase content did not depend on its localization in placenta and decreased at premature labour . It is suggested that the decrease in the myeloperoxidase content in placenta results in the weakening of antimicrobial barrier in the system mother-placenta-fetus and plays an important role in pathogenesis of premature delivery at later term.

Vopr Med Khim, 2002 Jul-Aug, 48(4), 361 - 7
{Genetic heterogeneity of cytochrome CYP51 in clinical strains of Mycobacterium tuberculosis}; Shavkunov AS et al.; Information on the complete genome sequences of a number of organisms available recently offers essentially new opportunities for the development of new, highly effective antimicrobial compounds . In particular, the search for new effective antituberculosis drugs remains an important problem, due to the recent increase of number of patients suffering with tuberculosis . In this respect considerable attention is paid to the cyp51-like gene Rv0764c encoding sterol-14 alpha-demethylase belonging to the cytochrome P450 superfamily, which has been discovered by computer analysis of the Mycobacterium tuberculosis genome sequence . We have screened 64 clinical isolates of M . tuberculosis for functionally relevant mutations in the coding sequence of the gene encoding Cyp 51-demethylase by single-strand conformation polymorphism analysis (SSCP) and sequencing of PCR-amplified gene fragments . Structural analysis of the gene in the isolates revealed no mutations leading to amino acid substitutions in the corresponding protein . 10 isolates had a silent nucleotide substitution 114 GCT-->GCC . Computer analysis of cyp51 sequence of the CDC1551 strain also revealed a similar nucleotide substitution, which has not been mentioned previously . The data obtained demonstrate that the sequence of the gene is highly conserved, supporting the advisability of M . tuberculosis Cyp51 protein to be considered as a molecular target for new antitubercular drugs . The SNP found in the gene coding sequence may be employed in the studies of M . tuberculosis population genetics.

Lancet Infect Dis, 2003 Jan, 3(1), 28 - 32
Mutation rate and the efficacy of antimicrobial drug treatment; Gerrish PJ et al.; Despite rapid progress in drug development, microbial infections in general are becoming increasingly difficult to treat as a result of the emergence of drug-resistant strains . In some cases, such as HIV-1, the early goal of eradicating infections with antimicrobial drugs is, for now, being replaced with the more pragmatic goal of controlling infections over long periods of time through a succession of transiently effective treatments . Because treatment efficacy is often incomplete, studying the degree of treatment efficacy has great relevance to clinical disease management . We derived a model describing the association between the mutation rate of the pathogen and the degree of treatment efficacy . We found that drug treatment is most effective when the mutation rate of the pathogen is either very low or, perhaps counterintuitively, very high . We discuss this finding in the light of a promising new treatment strategy for RNA viruses that combines antiviral compounds with a mutagen.

Biomaterials, 2003 Mar, 24(6), 1075 - 80
Surface effects and desorption of tetracycline supramolecular complex on bovine dentine; Pataro AL et al.; The aim of this in vitro study was to evaluate the antimicrobial activity, the substantivity, and surface effects of the inclusion compound tetracycline: beta-cyclodextrin on bovine roots . The antimicrobial activity was assessed by dentine slabs which had been immersed in the inclusion complex in concentrations 8.0%, 4.0%, 2.0%, 1.0%, 0.5% and 0.25% for 5min compared to a control of tetracycline hydrochloride . Each slab was tested in a broth of overnight culture of Actinobacillus actinomycetemcomitans (Y4-FDC) . The inclusion complex significantly inhibited the A . actinomycetemcomitans (p<0.01) verified at concentrations from 1.0% to 8.0% . The substantivity of tetracycline was evaluated by the measure of desorption from the slabs previously immersed in solution samples and removed at 24h intervals . The tetracycline encapsulated in beta-cyclodextrin showed a flow rate near to zero order in comparison to free tetracycline . The surface morphology determined by SEM showed a more homogeneous and integrated layer with the complex compared to the effect of free tetracycline . We concluded that the root surfaces treated with tetracycline: beta-cyclodextrin release lower concentrations of active drug over 5 days at inhibitory concentrations against A . actinomycetemcomitans with enhanced disponibility in comparison to tetracycline.

Biomed Pharmacother, 2002 Dec, 56(10), 503 - 10
The chitinase system from Trichomonas vaginalis as a potential target for antimicrobial therapy of urogenital trichomoniasis; Loiseau PM et al.; Chitinolytic activities in Trichomonas vaginalis membrane extracts were assessed by assays of three enzyme systems: N-acetyl-beta-D-hexosaminidase (NAHase), chitobiosidase and chitotriosidase . N-acetyl-beta-D-hexosaminidase was the enzyme that showed the highest specific activity . After successive subcutaneous inoculations into mice and parasite recovery in culture, the enzyme activities increased significantly with the number of inoculations for up to eight passages . In addition, enzyme activities were maximum at the logarithmic phase of growth . Glycol chitin, a chitinase substrate, enhanced all chitinolytic activities by about 30% and a clear-cut correlation is shown between the capacity for erythrocyte lysis by parasites and NAHase expression . Chitobiosidase and chitotriosidase activities were both inhibited at 58% and 100%, respectively, by allosamidine, a chitinase inhibitor used at 3 microM, whereas NAHase activity was not affected . Seven putative NAHase inhibitors (compounds n, 1-7), ureido and thioureido derivatives of 2-amino-2-deoxy-D-glucose were evaluated and five of them had K(i) values in the range 30-70 microM . The most active compound (compound 6) was functionally competitive with respect to the substrate with a K(i) value of 30 microM . The IC(50) values of the most active compounds on T . vaginalis were in the range 62-85 microM . These results indicate that chitinases of T . vaginalis are involved in pathogenicity and they could be an interesting target for drugs since chitinase inhibitors also inhibit parasite growth.

Anesthesiology, 2003 Jan, 98(1), 164 - 9
Comparison of povidone iodine and DuraPrep, an iodophor-in-isopropyl alcohol solution, for skin disinfection prior to epidural catheter insertion in parturients; Birnbach DJ et al.; BACKGROUND: Although rare, infectious sequelae of epidural analgesia can occur . A recently marketed antiseptic solution (DuraPrep) which contains an iodophor in isopropyl alcohol, may provide enhanced and longer-lasting antimicrobial activity and thus be useful in the obstetric setting . The purpose of this study was to evaluate the antisepsis achieved with DuraPrep compared with povidone iodine (PI) . METHODS: Sixty women in active labor who requested epidural analgesia were randomly assigned to receive skin preparation with either PI or DuraPrep solution . A total of three cultures were obtained from each subject . The first was obtained just prior to skin disinfection, the second was obtained immediately following antisepsis, and the third was obtained just before removal of the catheter . In addition, the distal tip of the catheter was also submitted for culture . RESULTS: The clinical characteristics and the risk factors for infection were similar in the two groups . The proportion of subjects with positive skin cultures immediately after skin disinfection differed significantly between the PI and DuraPrep groups (30 3%, respectively, P = 0.01) . The number of subjects with any positive skin cultures at the time of catheter removal was greater in the PI group as compared to the DuraPrep group (97 50%, respectively, P = 0.0001), as was the number of organisms cultured from skin (log CFU 1.93 +/- 0.40 0.90 +/- 0.23, respectively, P = 0.03) . Six catheters, all from the PI group, yielded positive cultures by the roll-plate technique . CONCLUSION: As compared to PI, DuraPrep solution was found to provide a greater decrease in the number of positive skin cultures immediately after disinfection, as well as in bacterial regrowth and colonization of the epidural catheters.

J Agric Food Chem, 2003 Jan 1, 51(1), 63 - 7
Antimicrobial and antioxidant activity of the essential oil and methanol extracts of Thymus pectinatus Fisch . et Mey . Var . pectinatus (Lamiaceae); Vardar-Unlu G et al.; The essential oil, obtained by using a Clevenger distillation apparatus, and water-soluble (polar) and water-insoluble (nonpolar) subfractions of the methanol extract of Thymus pectinatus Fisch . et Mey . var . pectinatus were assayed for their antimicrobial and antioxidant properties . No (or slight) antimicrobial activity was observed when the subfractions were tested, whereas the essential oil showed strong antimicrobial activity against all microorganisms tested . Antioxidant activities of the polar subfraction and the essential oil were evaluated using 2,2-diphenyl-1-picrylhydrazyl, hydroxyl radical, superoxide radical scavenging, and lipid peroxidation assays . The essential oil, in particular, and the polar subfraction of the methanol extract showed antioxidant activity . The essential oil was analyzed by GC/MS, and 24 compounds, representing 99.6% of the essential oil, were identified: thymol, gamma-terpinene, p-cymene, carvacrol, and borneol were the main components . An antimicrobial activity test carried out with fractions of the essential oil showed that the activity was mainly observed in those fractions containing thymol, in particular, and carvacrol . The activity was, therefore, attributed to the presence of these compounds . Other constituents of the essential oil, such as borneol, gamma-terpinene, and p-cymene, could be also taken into account for their possible synergistic or antagonistic effects . On the other hand, thymol and carvacrol were individually found to possess weaker antioxidant activity than the crude oil itself, indicating that other constituents of the essential oil may contribute to the antioxidant activity observed . In conclusion, the results presented here show that T . pectinatus essential oil could be considered as a natural antimicrobial and antioxidant source.

Biochemistry, 2002 Dec 31, 41(52), 15468 - 76
The crystal structure of the H48Q active site mutant of human group IIA secreted phospholipase A2 at 1.5 A resolution provides an insight into the catalytic mechanism; Edwards SH et al.; The human group IIA secreted PLA(2) is a 14 kDa calcium-dependent extracellular enzyme that has been characterized as an acute phase protein with important antimicrobial activity and has been implicated in signal transduction . The selective binding of this enzyme to the phospholipid substrate interface plays a crucial role in its physiological function . To study interfacial binding in the absence of catalysis, one strategy is to produce structurally intact but catalytically inactive mutants . The active site mutants H48Q, H48N, and H48A had been prepared for the secreted PLA(2)s from bovine pancreas and bee venom and retained minimal catalytic activity while the H48Q mutant showed the maximum structural integrity . Preparation of the mutant H48Q of the human group IIA enzyme unexpectedly produced an enzyme that retained significant (2-4%) catalytic activity that was contrary to expectations in view of the accepted catalytic mechanism . In this paper it is established that the high residual activity of the H48Q mutant is genuine, not due to contamination, and can be seen under a variety of assay conditions including assays in the presence of Co(2+) and Ni(2+) in place of Ca(2+) . The crystallization of the H48Q mutant, yielding diffraction data to a resolution of 1.5 A, allowed a comparison with the corresponding recombinant wild-type enzyme (N1A) that was also crystallized . This comparison revealed that all of the important features of the catalytic machinery were in place and the two structures were virtually superimposable . In particular, the catalytic calcium ion occupied an identical position in the active site of the two proteins, and the catalytic water molecule (w6) was clearly resolved in the H48Q mutant . We propose that a variation of the calcium-coordinated oxyanion ("two water") mechanism involving hydrogen bonding rather than the anticipated full proton transfer to the histidine will best explain the ability of an active site glutamine to allow significant catalytic activity.

Otolaryngol Head Neck Surg, 2002 Dec, 127(6), 558 - 68
Use of nebulized antibiotics for acute infections in chronic sinusitis; Vaughan WC et al.; OBJECTIVE: Infections in patients with chronic sinusitis after surgery can be difficult to treat . Nebulized antimicrobial therapy was studied as a treatment option . Study Design: Patients with chronic sinusitis, previous sinus surgery, and an acute infection were offered nebulized antibiotics or standard therapy . Cultures were taken and sensitivity testing was performed . Retrospective chart reviews were also performed . RESULTS: Forty-two patients were included . The most common side effects were sore throat and cough . Symptomatic and endoscopic data before and after nebulized therapy showed a longer infection-free period (average, 17 weeks) compared with standard therapy (average, 6 weeks) . Improvements in posterior nasal discharge, facial pain/pressure, and emotional consequences were noted . CONCLUSION: Nebulized therapy was safe and effective in this cohort . Endoscopy and outcome measure changes showed consistent improvements . SIGNIFICANCE: A novel therapy for acute sinus infections in patients with chronic sinusitis and previous endoscopic sinus surgery is presented.

Biofizika, 2002 Nov-Dec, 47(6), 1116 - 29
{Medusomyces (tea fungus): scientific history, composition, physiology, and metabolism}; Iurkevich DI et al.; The literature data on medusomyces published since 1913 are discussed . Different versions of appearance and distribution of this microorganism are considered . The features of its structure, metabolism and growth conditions are analyzed . It is shown that the tea fungus is a symbiosis is of several sorts of yeast and acetic acid bacteria . Evidence is presented indicating that fermented tea fungus has a therapeutic effect and can be applied in medicine . It was proved, that the antimicrobial properties of tea fungus metabolic products are due to the presence of particular antibiotic substances . The regularities of the biosynthesis of these substances and the pathways of its stimulation were studied . The results obtained will lead to the large-scale use of tea fungus in biotechnology . The fungus has unique adaptation properties, as confirmed by experiments on cultivation of the organism on deuterium oxide (D2O) and in the conditions of "cold stress" . It is suggested that medusomyces is a unique model for the investigation of the phenomenon of symbiosis.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 360 - 2
Activities of moxifloxacin alone and in combination with other antimicrobial agents against multidrug-resistant Mycobacterium tuberculosis infection in BALB/c mice; Fattorini L et al.; The activity of moxifloxacin was enhanced by the addition of ethionamide but not by that of cycloserine, thiacetazone, capreomycin, para-aminosalicylic acid, or linezolid in BALB/c mice infected with a strain of Mycobacterium tuberculosis resistant to isoniazid, rifampin, and six other drugs . These observations are important for the therapy of multidrug-resistant tuberculosis.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 302 - 8
Reactivity of reduced {2Fe-2S} ferredoxins parallels host susceptibility to nitroimidazoles; Vidakovic M et al.; The kinetics of the electron transfer reaction between reduced {2Fe-2S} ferredoxins and select nitroimidazole antimicrobial agents is reported . The ferredoxins from the protozoan Trichomonas vaginalis and the cyanobacterium Anabaena sp . strain 7120 were studied because they are the proximal electron donors to nitroimidazoles in these two organisms with significantly different nitroimidazole susceptibilities . The rates of electron transfer from Anabaena ferredoxin to all nitroimidazoles were 1 to 2 orders of magnitude lower than for T . vaginalis ferredoxin . Quantitative structure-activity analysis of the kinetic data showed that the size of the alkyl substituent on the N-1 position of the imidazole ring strongly influenced the magnitude of the electron transfer rate constant . This implies that the distance between the iron-sulfur cluster and the nitro group of the imidazole is the critical variable in determining the rate of electron transfer . A correlation between the magnitude of the one-electron transfer rate constant with the susceptibility of the host organism to the cytotoxic effects of nitroimidazoles was also discovered . These results demonstrate that reductive activation is the most crucial step in determining the toxicity of nitroimidazoles.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 161 - 5
In vitro susceptibilities to and bactericidal activities of garenoxacin (BMS-284756) and other antimicrobial agents against human mycoplasmas and ureaplasmas; Waites KB et al.; The in vitro susceptibilities to garenoxacin (BMS-284756), an investigational des-fluoroquinolone, and eight other agents were determined for 63 Mycoplasma pneumoniae, 45 Mycoplasma hominis, 15 Mycoplasma fermentans, and 68 Ureaplasma sp . isolates . Garenoxacin was the most active quinolone, inhibiting all isolates at <or=1 microg/ml . The garenoxacin MIC at which 90% of isolates are inhibited (MIC(90)s; <or=0.008 microg/ml) was at least 4-fold less than those of moxifloxacin and clindamycin, 8-fold less than that of sparfloxacin, and 64-fold less than those of levofloxacin and ciprofloxacin for M . pneumoniae . For M . hominis, the garenoxacin MIC(90) (<or=0.008 microg/ml) was 4-fold less than those of clindamycin and moxifloxacin, 8-fold less than that of sparfloxacin, and 64-fold less than those of levofloxacin and ciprofloxacin . All 15 M . fermentans isolates were inhibited by garenoxacin at concentrations <or=0.008 microg/ml, making it the most active drug tested against this organism . For Ureaplasma spp., the garenoxacin MIC(90) (0.25 microg/ml) was equivalent to those of moxifloxacin and doxycycline, 4-fold less than those of levofloxacin and sparfloxacin, 8-fold less than that of azithromycin, and 32-fold less than that of ciprofloxacin . Garenoxacin and the other fluoroquinolones tested were demonstrated to have bactericidal activities against M . pneumoniae and M . hominis by measurement of minimal bactericidal activities and by time-kill studies . Further study of garenoxacin is required, as it has great potential for use in the treatment of infections due to mycoplasmas and ureaplasmas.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 39 - 42
In vitro activities of ABT-773 and other antimicrobials against human mycoplasmas; Waites KB et al.; The in vitro susceptibilities of 103 Mycoplasma pneumoniae isolates, 14 Mycoplasma hominis isolates, 12 Mycoplasma fermentans isolates, and 24 Ureaplasma species to ABT-773, an investigational ketolide, and seven other agents were determined . For M . pneumoniae, the ABT-773 MIC at which 90% of isolates are inhibited (MIC(90); <or=0.001 microg/ml) was comparable to those of azithromycin, clarithromycin, and erythromycin and at least 128-fold lower than those of levofloxacin, gatifloxacin, moxifloxacin, and doxycycline . For M . fermentans, the ABT-773 MIC(90) (<or=0.008 microg/ml) was 2- to 128-fold lower than those of all other agents tested . For M . hominis, the ABT-773 MIC(90) (0.031 microg/ml) was equivalent to that of moxifloxacin, 2-fold lower than those of gatifloxacin and clindamycin, and 16-fold lower than that of levofloxacin . ABT-773 was equally active against doxycycline-susceptible and doxycycline-resistant organisms . The ABT-773 MICs (0.016 microg/ml) for Ureaplasma species were the lowest of those of any drug tested . The MIC(90) was 4- to 64-fold lower than those of clarithromycin, azithromycin, and erythromycin and >or=16-fold lower than those of all three fluoroquinolones . Minimal bactericidal concentrations determined for a subgroup of organisms were <or=0.063 micro g/ml for M . pneumoniae and 0.25 microg/ml for M . fermentans, but they were several dilutions higher for M . hominis and Ureaplasma spp . ABT-773 has great potential for further study for the treatment of infections due to mycoplasmas and ureaplasmas.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 1 - 6
Transcriptional profile of the Escherichia coli response to the antimicrobial insect peptide cecropin A; Hong RW et al.; Cationic antimicrobial peptides are believed to exert their primary activities on anionic bacterial cell membranes; however, this model does not adequately account for several important structure-activity relationships . These relationships are likely to be influenced by the bacterial response to peptide challenge . In order to characterize the genomic aspect of this response, transcription profiles were examined for Escherichia coli isolates treated with sublethal and lethal concentrations of the cationic antimicrobial peptide cecropin A . Transcript levels for 26 genes changed significantly following treatment with sublethal peptide concentrations, and half of the transcripts corresponded to protein products with unknown function . The pattern of response is distinct from that following treatment with lethal concentrations and is also distinct from the bacterial response to nutritional, thermal, osmotic, or oxidative stress . These results demonstrate that cecropin A induces a genomic response in E . coli apart from any lethal effects on the membrane and suggest that a complete understanding of its mechanism of action may require a detailed examination of this response.

J Ethnopharmacol, 2003 Jan, 84(1), 57 - 78
Traditional herbal drugs of Southern Uganda, II: literature analysis and antimicrobial assays; Hamill FA et al.; Continuing field interviews brought the total species used for disease treatment by herbalists of the majority Baganda Tribe of southern Uganda to 168 . Literature searches provided support for the ethnomedical claims for a number of these species, and provided criteria for the species classification into four categories of use validation . They also helped guide the selection of species for recollection, for chemical extraction and further testing in laboratories of the Uganda Ministry of Health and the University of Illinois at Chicago . Many species proved active against microorganisms in several susceptibility assays conducted in Uganda and the US .

PDA J Pharm Sci Technol, 2002 Nov-Dec, 56(6), 300 - 11
Development of the antimicrobial effectiveness test as USP chapter <51>; Sutton SV et al.; The antimicrobial effectiveness test first appeared as a USP General Chapter in the 18th revision, official September 1, 1970 . This chapter, at the beginning, was designed to evaluate the performance of antimicrobials added to inhibit the growth of microorganisms that might be introduced during or subsequent to the manufacturing process . As Good Manufacturing Practices (GMPs) became a governing principal in pharmaceutical manufacturing, the purpose of the test was refined to focus on activity of the preservative system as a protection against inadvertent contamination during storage and usage of the product . This article will review the history of the antimicrobial test; its function, technique, and the background discussions that resulted in the changes from the test that appeared in USP XVIII to that of the current USP 25.

Semin Respir Infect, 2002 Dec, 17(4), 291 - 302
Infectious pulmonary complications in lung transplant recipients; Chan KM et al.; Pulmonary infections are the most common cause of morbidity in the lung transplant population . Prompt recognition and treatment is necessary to prevent poor outcomes . An understanding of the temporal relationship between immunosuppression and the risk for developing infection can assist the clinician with appropriate treatment . Bacterial pneumonia is common within the first 4 months after transplantation whereas cytomegalovirus (CMV) infection or disease becomes prevalent after the discontinuation of prophylaxis in at-risk patients . Fungal infections, especially aspergillosis, can be fatal if not treated early and the risk for infection is present throughout the transplant period . Community-acquired viral infections present with upper-respiratory symptoms and wheezing that may lead to a chronic decline in lung function . Suspicion of a pulmonary infection in these immunosuppressed individuals should lead to an urgent diagnostic bronchoscopy and empiric antimicrobial therapy . Copyright 2002, Elsevier Science (USA) . All rights reservedPublication Types:

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