Antimicrobial

Int J Dermatol, 2000 Oct, 39(10), 784 - 8
Adapalene: an update on newer comparative studies between the various retinoids; Millikan LE; BACKGROUND: Extensive modification of the retinoic acid molecular skeleton has resulted in the development of adapalene, a more stable, less irritating compound with receptor selectivity . Adapalene selectively targets nuclear retinoic acid receptors found primarily in the epidermis . Pharmacologic and preclinical studies have demonstrated excellent follicular penetration, comedolytic activity, and anti-inflammatory activity . METHODS: Recent comparative trials were reviewed . RESULTS: Adapalene is a useful new agent because of its tolerability and stability . It is a good therapeutic choice for combination with other topical anti-acne medications, such as antimicrobials or benzoyl peroxide . Patient compliance with either combination or single-agent adapalene regimens is likely to be enhanced because of the greater comfort and reduced skin irritation associated with the new compound . Other investigators have confirmed that adapalene gel produces consistent and significantly reduced irritation . CONCLUSIONS: Recent comparative trials on retinoids have provided new data to aid in the selection of the appropriate combination of topical agents for individual patients.

Anaesth Intensive Care, 2000 Oct, 28(5), 475 - 90
Can we achieve consensus on central venous catheter-related infections?
Fraenkel DJ, Rickard C, Lipman J.
Central venous catheter-related bacteraemia is a substantial and preventable source of iatrogenic morbidity and mortality . A single episode of catheter-related bacteraemia has an estimated cost of A$50,000, with an attributable mortality between 10 and 35% . Catheter colonization is diagnosed with standard culture techniques . Diagnostic criteria for catheter-related bacteraemia include the results of cultures from the catheter tip, the peripheral blood and other possible sites of infection . The presence of clinical symptoms and subsequent defervescence may assist in making the diagnosis . This review explores the existing definitions of catheter-related infections and proposes a new and more rigorous classification with criteria for definite, probable and possible catheter-related bacteraemia . The authors hope that this classification will enhance the interpretation of the literature and the planning of new investigations . Infection rates can be reduced by appropriate site selection, adequate skin preparation, sterile technique and appropriate dressings . Decreased manipulation of administration sets, with more careful technique and less frequent set replacement, may reduce hub contamination . Infection rates increase with the duration in situ of the catheter, however are not reduced by regular scheduled catheter replacement or guide-wire exchanges . A range of antimicrobial catheter materials and coatings are under investigation, some of which are effective in reducing the rate of catheter-related bacteraemia . Chorhexidine-silver sulphadiazine and rifampicin-minocycline are the best studied combinations to date . Further developments are expected, although none are likely to be as effective as not inserting or removing the central venous catheter when it is not required.

Curr Treat Options Gastroenterol, 1999 Jun, 2(3), 251 - 257
Diarrhea in the International Traveler; Duchini A et al.; International travelers to developing countries have a 40% risk of developing a diarrheal illness, usually acute and occasionally chronic . Preventive measures, including diet and lifestyle modifications, are highly recommended but may not be sufficient . Prophylaxis with bismuth subsalicylate or an antimicrobial should be considered in travelers with immunodeficiencies, co-morbid conditions, achlorhydria, or those who cannot afford a loss of time . Oral rehydration is the primary goal of therapy . Bismuth-subsalicylate is a first-line agent for treatment of milder cases with less than three watery bowel movements per day and prominent nausea . Use of an antibiotic is indicated for more severe cases or in the presence of fever, dysentery, or severe dehydration . A short course of a quinolone is highly effective, safe and well tolerated . Antimicrobial resistance among enteropathogens is growing and appropriate therapeutic modifications should be considered according to specific geographic areas . Metronidazole may be empirically added in those cases that do not respond to quinolones . Specific guidelines for particular pathogens are highlighted.

Curr Treat Options Neurol, 1999 May, 1(2), 157 - 166
Brain Abscess; Davis LE et al.; Optimal treatment of a brain abscess requires early clinical suspicion, and the diagnosis is usually made by identification of the abscess on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) . The immediate first step is to reduce the potentially life-threatening brain mass (abscess and surrounding cerebral edema) and secure the diagnosis with culture specimens . This is usually accomplished by reducing the increased intracranial pressure (ICP) through surgical aspiration with or without drainage of the abscess pus . The surgical procedure chosen depends on several factors, including the location and type of abscess, multiplicity, and the medical condition of the patient . In addition, dexamethasone and hyperventilation may be required if brain herniation is imminent . The dexamethasone dose should be reduced as soon as the ICP is reduced because steroid administration may retard abscess capsule formation and decrease antibiotic concentrations within the abscess cavity . Antibiotic therapy should be started as soon as the diagnosis is made . Penicillin G or third-generation cephalosporins plus metronidazole are commonly given to treat both anaerobic and aerobic bacteria . The initial choice of antibiotic will vary on the basis of the suspected source of the brain organisms, which is most often either contiguous spread from a sinus or mastoid infection or hematogenous spread from a pulmonary, gastrointestinal, cardiac, or dental infection . Isolation and determination of the antibiotic sensitivities of the organism from abscess pus allow definitive antibiotic therapy . Patients should be managed in an intensive care unit . Phenytoin is often given to prevent seizures, which could further elevate the ICP . The duration of antimicrobial treatment is 4 to 8 weeks, during which time the patient should be monitored clinically and with repeated neuroimaging studies to ensure abscess resolution.

Curr Interv Cardiol Rep, 2000 Nov, 2(4), 342 - 348
Infectious Agents, Antibiotics, and Coronary Artery Disease; Muhlestein JB; Atherosclerotic cardiovascular disease, the major cause of death in the Western world, is a multi-factorial process with a large number of interacting variables . Despite a significant understanding of many of these variables, the underlying causes of atherosclerosis are still not clearly defined . Recent studies have documented a possible association between chronic inflammation and a variety of chronic bacterial infections (including Chlamydia pneumoniae, Helicobacter pylori, and a variety of periodontal infectious agents) and the development or progression of atherosclerosis . Because these bacterial agents are sensitive to a variety of antibiotic agents, it has been proposed that antimicrobial therapy might be useful in the primary or secondary prevention of atherosclerosis . This article reviews the evidence supporting an association between chronic bacterial infection and atherosclerosis, describes the results of preliminary secondary prevention antibiotic treatment trials, and discusses a variety of ongoing and planned large multicenter clinical trials of antibiotics in patients with atherosclerotic heart disease . Potential pitfalls associated with the broad use of antibiotics to treat heart disease are also discussed.

Curr Treat Options Gastroenterol, 1998 Dec, 1(1), 1 - 7
Diabetic and Nondiabetic Gastroparesis; McCallum RW et al.; Nutritional support is essential in treating patients with gastroparesis . Initially, dietary changes should be instituted to reduce extra fat and bulk, and patients should be encouraged to eat frequent small meals with liquid supplementation . Enteral feeding should be introduced in the event of weight loss or persistent vomiting . Medical therapy is usually necessary early in treatment . Cisapride is the initial agent of choice and may be combined with an antiemetic agent, such as promethazine or chlorpromazine or, if side effects occur, ondansetron and granesitron . If cisapride is ineffective or contraindicated, metoclopramide is a reasonable option, though limited by side effects . Erythromycin is useful in the acute treatment of postoperative ileus and hospitalized gastroparetic patients, but its role is limited based on concerns about poor long-term effectiveness and antimicrobial resistance . Once domperidone becomes available in the United States, it will be useful for its promotility and antiemetic qualities . Combination therapy should be considered if monotherapy with cisapride or metoclopramide alone is ineffective . While not yet well studied, combination therapy has the potential to offer dramatic benefit for patients with refractory gastroparesis . Metoclopramide may be added to cisapride for patients with breakthrough symptoms or refractory chronic symptoms . Other combinations include metoclopramide with erythromycin, domperidone with cisapride, and domperidone with erythromycin . In the future, gastric pacing may become an effective option for patients not responding to medical therapy . Total gastrectomy should be performed only for end-stage gastroparesis when all other therapy has failed . Both procedures should be reserved for centers that specialize in severe gastric motility disorders.

Curr Infect Dis Rep, 2000 Oct, 2(5), 409 - 416
Impact of Antibiotic Resistance on the Treatment of Gram-negative Sepsis; Baden LR et al.; Resistance among gram-negative organisms has greatly complicated the care of the septic patient . An understanding of the likely source of infection, the epidemiologic risk of the patient being exposed to an antibiotic-resistant organism, and the specific vulnerabilities of the host are essential to the proper selection of empiric antimicrobial therapy . In this report, we discuss the epidemiology, antibiotic resistance mechanisms, microbiology, treatment strategies, and diagnostic and therapeutic innovations in the approach to the septic patient.

Curr Infect Dis Rep, 2000 Aug, 2(4), 365 - 370
HIV Treatment in Developing Countries; Mason PR et al.; Diagnostic, prognostic and therapeutic advances have had a major impact on HIV at both the individual and community levels in wealthy nations . However, more than 95% of HIV infections occur in developing countries, where personal or national economies cannot support these measures . Therefore, HIV treatment in developing countries must focus on particular aspects of infection, especially prevention and treatment of those opportunistic infections for which inexpensive antimicrobial agents are available and effective . At present, the focus in developing countries is on tuberculosis, Pneumocystis carinii pneumonia (PCP), and pneumococcal pneumonia . The spread of antimicrobial resistance in mycobacteria and pneumococci is of special concern for developing countries, and strategies to limit the spread of resistance should take high priority . The use of specific antiretroviral agents is limited, because of cost, to prevention of mother-to-child transmission, and notable successes have been achieved . While it is unlikely that these agents will become widely available to the general population, targeting treatment at high-risk groups, through a program of post-exposure prophylaxis, may be an affordable strategy in some situations.

Curr Infect Dis Rep, 1999 Dec, 1(5), 488 - 494
"Essentiality" Testing: Looking for New Antimicrobial Targets; Knowles D et al.; After a gap of some 30 years, the prospect of finding completely new agents with which to combat infectious disease is promising . New discovery approaches based on the application of genomics and associated technologies are leading to the identification of genes essential for bacterial viability and pathogenesis . This article reviews the current status of the search for new antimicrobial targets and points to future developments and issues.

Curr Infect Dis Rep, 1999 Dec, 1(5), 480 - 487
Quinupristin-Dalfopristin; Linden P; The incidence of infection with multidrug-resistant or pan-resistant gram-positive bacteria has drastically limited or eliminated the conventional antimicrobial options available to clinicians . Quinupristin-dalfopristin, a unique parenteral streptogramin that lacks cross-resistance with other antimicrobials, has shown clinical efficacy against many of these important bacteria . This review focuses on quinupristin-dalfopristin"s mechanism of action, in vitro spectrum of activity, clinical efficacy and toxicity, and likely future role in the management of serious gram-positive infections.

Curr Infect Dis Rep, 1999 Dec, 1(5), 464 - 469
Superbugs: How They Evolve and Minimize the Cost of Resistance; Low DE et al.; The increasing frequency with which antimicrobial-resistant microorganisms have emerged in hospitals and communities has alarmed public health officials worldwide . The emergence of resistance results from the evolution of the sometimes elegant resistance mechanisms that create so-called superbugs, which disseminate by clonal spread or exchange resistance traits with other microorganisms . One major contributor to the emergence of resistance is selection intensity, which is determined by the volume of drug consumption by humans and the agriculture industry . De novo or acquired resistance is often initially associated with a cost to fitness of the microorganism . It therefore seems reasonable to assume that reducing the volume of drug use would slow the evolution and reduce the prevalence of resistance . This assumption has led to worldwide attempts to control the inappropriate use of antimicrobials in the hope of controlling the pandemic of antibiotic resistance . However, microorganisms have learned to adapt in order to survive in ever-changing environments . Superbugs have evolved numerous mechanisms that reduce or eliminate the cost of resistance, and such adaptations may minimize the potential benefits of programs aimed at reducing the volume of drug use . It therefore behooves us to look to other disciplines--such as population genetics, ecology, and mathematical biology--to help us tackle this perplexing and important problem.

Curr Infect Dis Rep, 1999 Oct, 1(4), 334 - 337
Role of Antimicrobial Stewardship in Prevention and Control of Antibiotic Resistance; Shlaes DM; Evidence linking antimicrobial use with resistance is compelling on the local, national, and international levels . That resistance levels can be influenced by changing patterns of use also seems clear . We must now determine how, as a global society, to best use the resource of antimicrobials and how to protect novel compounds that are just now becoming available from emerging resistance . We must act not only within the arena of human use but also on use in animals and for crops.

Curr Infect Dis Rep, 1999 Aug, 1(3), 218 - 223
Colony-Stimulating Factors in the Therapeutic Approach to Sepsis; Alcid DV et al.; Sepsis and its complications continue to be a leading cause of death in the United States despite availability of potent broad-spectrum antimicrobial agents . Current in vitro, ex vivo, animal, and human data are reviewed . Present data shows that colony-stimulating factors (CSFs), granulocyte CSFs, and granulocyte-macrophage CSFs are very effective in raising the leukocyte count and shortening the number of neutropenic days . CSFs in some studies improved outcome of neutropenic septic patients especially when given very early . However, there are studies that do not show any benefit . CSFs appear to be safe and should be limited to septic, neutropenic patients whose duration of neutropenia is anticipated to be prolonged, or to patients who are seriously ill.

Curr Infect Dis Rep, 1999 Jun, 1(2), 166 - 171
Brain Abscess, Subdural Empyema, and Intracranial Epidural Abscess; Calfee DP et al.; Brain abscess, subdural empyema, and intracranial epidural abscess are three of the most commonly encountered focal suppurative processes of the central nervous system . A great deal has been known about the epidemiology and pathogenesis of these entities for quite some time, but until recent years the associated morbidity and mortality remained very high . New imaging techniques have allowed for more rapid detection and more precise localization of these lesions for surgical drainage . Empiric antimicrobial regimens that are effective within the abscess environment and that are directed against the most likely pathogens have also contributed to the improved outcomes seen in the current literature . This article will discuss some of the more recent advances in the diagnosis and treatment of these suppurative lesions within the central nervous system.

Curr Infect Dis Rep, 1999 Jun, 1(2), 119 - 125
Infective Endocarditis: Current Guidelines on Prophylaxis; Levison ME et al.; Prevention of infective endocarditis is a priority because this disease is associated with considerable morbidity and mortality both during the acute phase of the illness and subsequently, despite modern medical and surgical treatment . The American Heart Association has published recommendations for prevention by antimicrobial prophylaxis since 1955; the most recent revision of these guidelines appeared in 1997 . All practicing physicians should know their content and understand their underlying concepts and assumptions.

Curr Infect Dis Rep, 1999 Apr, 1(1), 99 - 104
Immune Reconstitution and the Consequences for Opportunistic Infection Treatment and Prevention; Powderly WG; Effective antiretroviral therapy that suppresses HIV replication is associated with dramatic increases in CD4 counts . Recent evidence suggests that this CD4 cell increase is biphasic in nature, with an initial phase (in the first 2 to 3 months) that represents redistribution of lymphocytes into the periphery and a second phase that is associated with true immunologic recovery and reconstitution . Immunologically there is evidence of increase in naive T cells, recovery of in vitro responses to microbial antigens, and repair of the damaged diversity of T cells . Clinically, this immune recovery has been characterized by decreasing morbidity and mortality from opportunistic infections, an ability to treat previously intractable infections, immune-mediated syndromes, and increasing reports of the ability to discontinue primary and secondary prophylaxis . Although there are still unresolved questions about the completeness of the immune recovery, most available evidence suggests in most patients the degree of immune reconstitution with effective antiretroviral therapy is sufficient to be protective against most opportunistic infections, and ultimately additional antimicrobial prophylaxis will be unnecessary.

Shock, 2000 Nov, 14(5), 555 - 60
Proinflammatory kupffer cell alterations after femur fracture trauma and sepsis in rats; Huynh T et al.; This study examined effects of trauma and sepsis on Kupffer cell function . When CBA/J mice had femur fracture (FFx), no deaths occurred . After cecal ligation and puncture (CLP), 44% died . Following combined injuries (FFx + CLP), mortality increased to 60%, suggesting a deleterious effect between FFx + CLP . Kupffer cell ablation with GdCI3 decreased mortality to 13% after CLP and 5% after FFx + CLP . After FFx, CLP, and FFx + CLP, Kupffer cells isolated from Sprague-Dawley rats produced 720%, 1,100%, and 2,130% more O2 . than sham, respectively . Phagocytosis increased 320%, 610%, and 150% . Kupffer cell PGE2 production also increased 300%, 510%, and 300% over sham . After FFx alone, TNF-alpha production decreased 40% . By contrast, CLP and FFx + CLP increased TNF-alpha release 25% and 100%, respectively . After FFx, NO . production decreased 44%, whereas NO increased 280% and 260% after CLP and FFx + CLP . These findings indicate that Kupffer cells mediate mortality after CLP and FFx + CLP . Increased mortality is associated with a more proinflammatory and less antimicrobial Kupffer cell phenotype.

Bioorg Med Chem, 2000 Nov, 8(11), 2539 - 48
The interaction of analogues of the antimicrobial lipopeptide, iturin A2, with alkali metal ions; Rautenbach M et al.; Electrospray mass spectrometry was employed as a tool in this first study on the molecular interaction between the alkali metal ions and antifungal lipopeptide iturin A, and some analogues . Cationisation by sodium and signal intensity of lipopeptide species depended on sodium concentration, but was independent of sample solvent, carrier solvent polarity and sample pH between 4 and 11 . 8-Beta, a linear analogue of iturin A2 (8-Beta; beta-aminotetradecanoyl-NYNQPNS), and its shorter linear lipopeptide analogues, associated either one or two alkali metal cations, while the N-->C cyclic peptides associated with only one cation . The chirality of the beta-NC14 residue had a limited influence on the cationisation . It was observed that 8-Beta contained at least four interaction sites for a cation of which two, the C-terminal carboxylate and the side-chain of tyrosine, can take part in ionic interaction with a cation . It is proposed that the remaining two interaction centres of alkali metal ions are within the two type II beta-turns found in conformation of natural iturin A . This was corroborated by the diminished capacity of the shorter peptides, in which one of the beta-turns was eliminated to bind a second larger cation . All the lipopeptides showed the same order of alkali metal ion selectivity: Na+ > K+ > Rb+ . These results indicated a size limitation in the interaction cavity or cavities . The absence of, or observation of only low abundance, di-cationised complexes of cyclic peptides the indicated association of the cation in the interior of the peptide ring . It is thus hypothesised that alkali metal ions can bind in one of the two beta-turns in the natural iturin A molecule.

Microbiol Immunol, 2000, 44(9), 749 - 54
Effect of ions on antibacterial activity of human beta defensin 2; Tomita T et al.; Human beta defensin 2 (HBD-2), the most recently discovered human defensin, has been considered to work as a host defense substance against microbial infection . Using Escherichia coli ATCC 25922, we investigated how some cations and anions influenced the antimicrobial activity of HBD-2 . This activity, measured in 10 mM phosphate buffer at a concentration of 20 microg/ml, reduced significantly in the presence of 100 and 150 mM sodium or potassium chloride . The reduction was not significantly different when the total amounts of sodium and potassium ions were equal . The kind and the valence of anions (chlorine and sulfate ions) did not affect the bactericidal activity as long as the concentrations of sodium ions were equal . Divalent ions (calcium and magnesium ions) added to 10 mM of Tris buffer significantly inactivated HBD-2 at much lower concentrations (more than or equal to 0.01 mM and 0.05 mM, respectively) than the monovalent ions did . These findings suggest that HBD-2 kills the bacteria through at least two phases, which are affected independently by either monovalent or divalent ions and unaffected by anions.

Int J Antimicrob Agents, 2000 Nov, 16(3), 303 - 7
The role of antimicrobial policies in neutropenic patients; Martino P et al.; Antimicrobial policies in neutropenic patients are under continual review . The development of more potent broad spectrum antibiotics has allowed new approaches to empiric antibiotic therapy, including the use of a single agent rather than an antibiotic combination . The standard clinical approach in cancer patients with persistent, severe neutropenia, is hospitalization until the infective complication has resolved, but an accurate clinical stratification of patients based on different medical risks could suggest different approaches to infective complications . The desire of cancer patients to spend as much time as possible at home during the palliative or terminal phase of their illness and the high costs of hospitalization are the main motives behind the early discharge of patients from hospital and the development of strategies that move traditionally inpatient problems or therapies, to the outpatient setting.

Int J Antimicrob Agents, 2000 Nov, 16(3), 295 - 9
Impact of an antimicrobial formulary and restriction policy in the largest hospital in Italy; Bassetti M et al.; We have analysed the expenditure on antimicrobial drugs in the largest hospital in Italy; over this period, a committee prepared an antibiotic policy document . This formulary lists all antimicrobial drugs available in the hospital . Some drugs were removed from the list and others are only available on special request for a named patient . In the hope of optimising drug utilisation, we included all the reasons for the choice of agent in the document . The introduction of this formulary resulted in an immediate saving and perhaps in the future we shall also observe an improvement in bacterial resistance patterns.

Int J Antimicrob Agents, 2000 Nov, 16(3), 191 - 7
Development and persistence of multi-resistance to antibiotics in bacteria; an analysis and a new approach to this urgent problem; van der Waaij D et al.; The intestinal microflora may have more influence on infectious diseases, than the mere control of growth of opportunistic micro-organisms by colonisation resistance (CR) and unspecific stimulation of the immune system . In compromised patients the CR may become decreased for several reasons but mostly because antibiotics reach the intestine during treatment . The consequence of a CR-decrease is that antibiotic-resistant opportunistic micro-organisms may increase in numbers in the gut . In this context, it is hypothesised that if the CR could be maintained at a normal level, the risk for maintenance and spread of resistant strains could be mitigated . Such maintenance requires absence of active antibiotic substance in the gut . This might be brought by the inactivation of antimicrobial agents by intestinal contents . Intra-intestinal inactivation has been described to occur along two possible routes: (1) inactivation by chemical binding or absorption and (2) by enzymatic destruction . Secondly, the composition of the intestinal microflora should be maintained at a normal level in case of other reasons for CR-decrease than antibiotic activity . Comprehensive study of the composition of normal microflora and the strains of species which play a role in CR with techniques which have become available during last decade, is recommended as well as the application of certain pre- and probiotics . It is concluded that antibiotic inactivation may be an ancient strategy of nature which should become incorporated in antibiotic treatment . Antibiotic use and development of resistance may have occurred when ecosystems formed several billions of years ago . Protection against antibiotics produced by newcomers into the ecosystem may have developed as it was necessary to maintain locally available nutrients for the inhabitants of the ecosystem . Should this hypothesis be correct, it is plausible that antimicrobial inactivation by antibiotic inactivating molecules is ubiquitous . In the ecosystem of the digestive tract, molecules involved in inactivation may predominantly be formed by microorganisms.

Peptides, 2000 Nov, 21(11), 1681 - 6
Sequence of a gene from Bombina orientalis coding for the antimicrobial peptide BLP-7; Miele R et al.; The structure of a gene coding for bombinin-like peptides (BLP) in Bombina orientalis was determined . It comprises two exons separated by a 1337 bp intron . Exon 1 codes for the signal peptide, while exon 2 contains the genetic information for BLP-7 and a bombinin H-type peptide (GH-2) . The promoter region contains putative recognition sites for nuclear factors, such as NF-IL6 and NF-kappaB . The analysis of the structure of this gene, compared with that of the previously reported BLP-3 gene sequence, suggests the occurrence of a gene duplication event, rather than an alternative splicing mechanism, which leads to the generation of both inter- and intra-families variability in this class of cytolytic peptides . Furthermore, chromosome walking analysis indicates that this gene family is not densely clustered.

Peptides, 2000 Nov, 21(11), 1673 - 9
Structure-function relationships in bombinins H, antimicrobial peptides from Bombina skin secretions; Mangoni ML et al.; Skin secretions of amphibia of the Bombina genus contain two families of antimicrobial peptides, the bombinins (bombinin-like peptides) and the bombinins H (H for hydrophobic and hemolytic) . The latter family includes a number of peptides containing a D-amino acid in the second position, in addition to their corresponding all L-isomers . The antimicrobial activity of three pairs of bombinin H isomers, H2/H4, H6/H7 and GH-1D/GH-1L, has been investigated . The first two pairs of peptides were actually isolated from the secretion, whereas the third was synthesized according to the sequence deduced from a gene coding for a bombinin-like peptide in Bombina orientalis.

Aquat Toxicol, 2001 Jan, 51(3), 351 - 62
Combined effects of pentachlorophenol and salinity stress on chemiluminescence activity in two species of abalone; Martello LB et al.; The effect of pentachlorophenol (PCP) combined with salinity stress on hemocyte microbicidal activity was examined in two species of abalone . Microbicidal phagocytic function was determined in red (Haliotis rufescens) and black (Haliotis cracherodii) abalone after in vivo exposure to 25, 35 and 45 per thousand seawater salinity plus 1.2 mg/l PCP using luminol-dependent chemiluminescence (CL) . Red and black abalone exposures of 3.5 and 6.5 h, respectively, were based on species-specific metabolic endpoints (MEPs) derived from previous nuclear magnetic resonance spectroscopy (NMR) data . Endpoints examined include total CL (CL(total)), peak CL (CL(max)), and the time to reach peak CL (T(max)) . Overall, black abalone CL was significantly greater than red abalone CL particularly at ambient and high salinities . High salinity alone had a dramatic effect on red abalone whereas black abalone demonstrated few salinity effects . While the addition of PCP stimulated CL(max) and CL(total) among red abalone at ambient and high salinities, PCP exposure inhibited CL(max) at each salinity and inhibited CL(total) at ambient salinity among black abalone . Black abalone generally did not demonstrate effects of PCP within the 3.5 h exposure period except at high salinity plus PCP, which caused a reduction of CL(total) . T(max) was greatly increased after PCP exposure at each salinity among red abalone but did not effect T(max) at any salinity tested among black abalone . No lysozyme activity was detected among red or black abalone after exposure to any of four different target particles tested either in the presence or absence of PCP . Overall, PCP in combination with salinity stress causes a modulation in the production of reactive oxygen species and this modulation varies between abalone species . Agents that decrease CL activity in hemocytes may reduce the antimicrobial potential of these cells thereby increasing susceptibility to infectious disease.

Arch Intern Med, 2000 Nov 27, 160(21), 3234 - 40
Impact of zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults; Kaiser L et al.; BACKGROUND: Influenza infections commonly lead to respiratory tract complications that result in antibiotic treatment . OBJECTIVES: To determine frequency of respiratory events leading to antibiotic use following influenza illness in adolescents and adults, and to assess whether treatment with topical zanamivir prevents these complications . METHODS: Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal zanamivir, inhaled zanamivir, or corresponding placebos . Twelve percent of enrolled subjects were high-risk patients . The main outcome was the incidence of respiratory events leading to antibiotic prescriptions in patients with proven influenza . RESULTS: Influenza infections were laboratory confirmed in 2499 (66%) of 3815 patients (influenza A in 88% and B in 12%) . Placebo recipients developed a respiratory event leading to antibiotic use in 17% of cases, mainly for acute bronchitis or acute sinusitis . Among zanamivir-treated patients (n = 1494) the incidence of respiratory events leading to the use of antimicrobials was 11% (relative risk {RR} compared with placebo, 0.69; 95% confidence interval {CI}, 0.57-0.84) . Intranasal and inhaled zanamivir seemed to reduce the number of upper (RR, 0.59; 95% CI, 0.36-0.97) and lower respiratory tract events (RR, 0.64; 95% CI, 0.38-1.08) . Inhaled zanamivir reduced the number of lower respiratory tract events (RR, 0.60; 95% CI, 0.42-0.85), but the reduction in the number of upper respiratory tract events was not statistically significant (RR, 0.90; 95% CI, 0.63-1.27) . CONCLUSIONS: Respiratory complications or worsening of symptoms leading to antibiotic use occurred in about 17% of adolescents or adults with influenza infection . Early treatment of influenza illness with zanamivir reduced the number of these antibiotic prescriptions . Arch Intern Med . 2000;160:3234-3240.

Biochim Biophys Acta, 2000 Nov 30, 1543(1), 95 - 105
Multiple antimicrobial peptides and peptides related to bradykinin and neuromedin N isolated from skin secretions of the pickerel frog, Rana palustris; Basir YJ et al.; The skin secretions of the North American pickerel frog Rana palustris are toxic to both microorganisms and predators . A total of 22 peptides with differential growth-inhibitory activity towards bacteria and yeast were isolated from the electrostimulated secretions of R . palustris skin and were characterized structurally . Thirteen of the antimicrobial peptides belong to five of the known families previously identified in the skins of other species of Ranid frogs: brevinin-1 (3 peptides), esculentin-1 (2 peptides), esculentin-2 (1 peptide), ranatuerin-2 (6 peptides), and temporin (1 peptide) . Nine peptides show little structural similarity towards other known antimicrobial peptides and so are classified in new families: palustrin-1 (4 peptides) with 27-28 amino acid residues and a cystine-bridged heptapeptide ring; palustrin-2 (3 peptides) with 31 amino acids and a cyclic heptapeptide region and palustrin-3 (2 peptides) with 48 amino acids and a cyclic hexapeptide region . Peptides belonging to the esculentin-1, esculentin-2 and palustrin-3 families are the most potent (minimal inhibitory concentrations approximately 1 microM against Escherichia coli) whereas peptides of the brevinin-1 and esculentin-2 families show the broadest spectrum of activity . As well as bradykinin that is identical to the human peptide, a further 4 peptides structurally related to {Leu(8)}bradykinin and two peptides related to neuromedin-N (the hexapeptide KKPYIL and a larger, cystine-containing form HLRRCGKKPYILMACS) were purified from the skin secretions.

J Nat Prod, 2000 Nov, 63(11), 1524 - 6
Nostocyclyne A, a novel antimicrobial cyclophane from the cyanobacterium Nostoc sp; Ploutno A et al.; A novel acetylene-containing para-{14}-cyclophane, nostocyclyne A (1), possessing antimicrobial activity, is the major active metabolite of the natural bloom of the cyanobacterium Nostoc sp . (TAU strain IL-220) . Homonuclear and heteronuclear 2D NMR techniques as well as HREIMS determined the gross structure of 1.

J Agric Food Chem, 2000 Nov, 48(11), 5702 - 9
Cinnamaldehyde content in foods determined by gas chromatography-mass spectrometry; Friedman M et al.; trans-Cinnamaldehyde, the principal component of cinnamon flavor, is a potent antimicrobial compound present in essential oils such as cinnamon . In the course of studies designed to discover its maximum microbial lethality under food-processing conditions, a gas chromatographic-mass spectrophotometric procedure was developed for the extraction and analysis of essential oil components such as cinnamaldehyde from commercial cinnamon-containing foods (several brands of cinnamon breads, cereals, cookies, puddings, applesauces, and fruit juices) . The cinnamaldehyde content ranged from trace amounts in orange juice to 12.2 mg/100 g (122 ppm) in apple cinnamon cereals and 31.1 mg/100 g (311 ppm) for cinnamon swirl bread (highest value) . To ascertain the heat stability of cinnamaldehyde, pure cinnamaldehyde, pure eugenol, cinnamon oil, and mixtures consisting of cinnamaldehyde plus eugenol or cinnamon oil were heated at graded temperatures up to 210 degrees C and 60 min, and then possible compositional changes were examined . Eugenol was stable to heat, as were the components of cinnamon oil: carvone, eugenol, and linalool . In contrast, starting at approximately 60 degrees C, pure cinnamaldehyde undergoes a temperature-dependent transformation to benzaldehyde under the influence of heat . Eugenol, both pure and in cinnamon oil, when added to pure cinnamaldehyde protected the aldehyde against heat destruction . The protection may due to an antioxidative action of eugenol . The possible mechanism of this effect and the significance of these findings for food chemistry and microbiology are discussed.

Biochemistry, 2000 Nov 28, 39(47), 14436 - 47
Solution structure and activity of the synthetic four-disulfide bond Mediterranean mussel defensin (MGD-1); Yang YS et al.; MGD-1 is a 39-residue defensin-like peptide isolated from the edible Mediterranean mussel, Mytilus galloprovincialis . This peptide is characterized by the presence of four disulfide bonds . We report here its solid-phase synthesis and an easy way to improve the yield of the four native disulfide bonds . Synthetic and native MGD-1 display similar antibacterial activity, suggesting that the hydroxylation of Trp28 observed in native MGD-1 is not involved in the antimicrobial effect . The three-dimensional solution structure of MGD-1 has been established using (1)H NMR and mainly consists of a helical part (Asn7-Ser16) and two antiparallel beta-strands (Arg20-Cys25 and Cys33-Arg37), together giving rise to the common cystine-stabilized alpha-beta motif frequently observed in scorpion toxins . In MGD-1, the cystine-stabilized alpha-beta motif is stabilized by four disulfide bonds (Cys4-Cys25, Cys10-Cys33, Cys14-Cys35, and Cys21-Cys38), instead of by the three disulfide bonds commonly found in arthropod defensins . Except for the Cys21-Cys38 disulfide bond which is solvent-exposed, the three others belong to the particularly hydrophobic core of the highly constrained structure . Moreover, the C4-P5 amide bond in the cis conformation characterizes the MGD-1 structure . MGD-1 and insect defensin A possess similar bactericidal anti-Gram-positive activity, suggesting that the fourth disulfide bond of MGD-1 is not essential for the biological activity . In agreement with the general features of antibacterial peptides, the MGD-1 and defensin A structures display a typical distribution of positively charged and hydrophobic side chains . The positively charged residues of MGD-1 are located in three clusters . For these two defensin peptides isolated from insects and mollusks, it appears that the rather well conserved location of certain positively charged residues and of the large hydrophobic cluster are enough to generate the bactericidal potency and the Gram-positive specificity.

Biochemistry, 2000 Nov 21, 39(46), 14150 - 9
Interaction between heat shock proteins and antimicrobial peptides; Otvos L Jr et al.; Drosocin, pyrrhocoricin, and apidaecin, representing the short (18-20 amino acid residues) proline-rich antibacterial peptide family, originally isolated from insects, were shown to act on a target bacterial protein in a stereospecific manner . Native pyrrhocoricin and one of its analogues designed for this purpose protect mice from bacterial challenge and, therefore, may represent alternatives to existing antimicrobial drugs . Furthermore, this mode of action can be a basis for the design of a completely novel set of antibacterial compounds, peptidic or peptidomimetic, if the interacting bacterial biopolymers are known . Recently, apidaecin was shown to enter Escherichia coli and subsequently kill bacteria through sequential interactions with diverse target macromolecules . In this paper report, we used biotin- and fluorescein-labeled pyrrhocoricin, drosocin, and apidaecin analogues to identify biopolymers that bind to these peptides and are potentially involved in the above-mentioned multistep killing process . Through use of a biotin-labeled pyrrhocoricin analogue, we isolated two interacting proteins from E . coli . According to mass spectrometry, Western blot, and fluorescence polarization, the short, proline-rich peptides bound to DnaK, the 70-kDa bacterial heat shock protein, both in solution and on the solid-phase . GroEL, the 60-kDa chaperonin, also bound in solution . Control experiments with an unrelated labeled peptide showed that while binding to DnaK was specific for the antibacterial peptides, binding to GroEL was not specific for these insect sequences . The killing of bacteria and DnaK binding are related events, as an inactive pyrrhocoricin analogue made of all-D-amino acids failed to bind . The pharmaceutical potential of the insect antibacterial peptides is underscored by the fact that pyrrhocoricin did not bind to Hsp70, the human equivalent of DnaK . Competition assay with unlabeled pyrrhocoricin indicated differences in GroEL and DnaK binding and a probable two-site interaction with DnaK . In addition, all three antibacterial peptides strongly interacted with two bacterial lipopolysaccharide (LPS) preparations in solution, indicating that the initial step of the bacterial killing cascade proceeds through LPS-mediated cell entry.

Mycopathologia, 1999, 148(1), 25 - 31
Antimicrobial susceptibility testing of dematiaceous filamentous fungi: effect of medium composition at different temperatures and times of reading; Llop C et al.; We examined the effects of the composition of five media on the MICs of three antifungal agents (amphotericin B, flucytosine and ketoconazole) against 24 dematiaceous fungi at different temperatures and times of reading . Media studied were RPMI 1640, tryptic soy broth (TSB), yeast nitrogen broth (YNB), casein-yeast-glucose broth (CYG) and high-resolution medium (HR) . The degree of reproducibility was determined with ketoconazole and 5-fluorocytosine and the media TSB and RPMI showed the best results with ketoconazole, while the best results for flucytosine were in CYG . Reproducibility was higher at 25 degrees than at 30 degrees C . The media and incubation time were shown to have a significant influence on the MICs of the three antifungals, but there were no interactions between these variables and temperature, except in the case of ketoconazole, where media-temperature and media-incubation time interactions were significant . There were noteworthy differences between the MICs obtained with the different media.

Braz J Infect Dis, 1999 Oct, 3(5), 180 - 183
Pharmacy Distribution of Advice, Symptomatic Treatment and Antimicrobial Drugs to Patients with Cough; Cadore LP et al.; It is an accepted fact that, in many countries, pharmacies are the predominant source of medical advice over-the-counter drugs, and supplies of "prescription-only" drugs for sale without a prescription . To assess the activities conducted by pharmacists or pharmacy counter assistants in response to a common health problem, a cross-sectional study was done at 114 pharmacies in Porto Alegre, Brazil . A fictitious case-history of cough was used by trained personnel entering the pharmacy and the subsequent activities by the pharmacist or pharmacy counter assistant were analyzed . Some kind of medication was provided in 101 (88.5%) of the pharmacies . Pharmacists gave medication in 80% of pharmacies, and pharmacy assistants in 95.5% (p<0.03) . The class of medication most frequently dispensed was the expectorants (97 times, 92.4%), however, systemic antibiotics were provided in 11 pharmacies (10.5%) . Of note, the pharmacists provided antibiotics more frequently than did pharmacy assistants (p=0.016) . We conclude that pharmacy advice and symptomatic medical care (expectorants) are very common and that pharmacy assistants are more likely than pharmacists to provide medication . Of concern, when pharmacists were the drug dispensers of antibiotics which should be provided by prescription only, drugs were provided without proper diagnosis, and often in incorrect dosages . This reflects a potentially dangerous practice in need of careful evaluation, education and supervision.

Infect Immun, 2000 Dec, 68(12), 6879 - 82
Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung; Cooper AM et al.; The interleukin-12 and gamma interferon (IFN-gamma) pathway of macrophage activation plays a pivotal role in controlling tuberculosis . In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-gamma-activated macrophages . Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controlling Mycobacterium tuberculosis in the lung . In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals . This is in contrast to the rapid progression of disease in mice lacking IFN-gamma or a key member of the IFN signaling pathway, interferon regulatory factor 1 . Thus while IFN-gamma is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene . The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

Infect Control Hosp Epidemiol, 2000 Oct, 21(10), 674 - 9
The burden of infection in long-term care; Strausbaugh LJ et al.; Available data, although fragmentary, indicate that infections impose a large burden on long-term-care facilities (LTCFs) in the United States . Endemic infections occur with frequencies estimated to range between 1.64 and 3.83 million per year . These estimates rival or exceed the annual tally for nosocomial infections in acute-care settings . Infections associated with outbreaks caused by respiratory, gastrointestinal, and antimicrobial-resistant pathogens burden LTCFs even further . As judged by antimicrobial use, transfers to hospital, and mortality figures, infections in LTCFs are not trivial . Moreover, annual costs associated with these infections appear to exceed $1 billion . Recognition of the burden associated with infection in LTCFs helps to identify research priorities for this rapidly growing area of healthcare.

Acta Otorhinolaryngol Belg, 2000, 54(3), 373 - 90
Humoral immunodeficiency in recurrent upper respiratory tract infections . Some basic, clinical and therapeutic features; Daele J et al.; Adequate surface protection of the upper airway tract depends on intimate co-operation between natural non specific defence mechanisms such as ciliary function and acquired adaptative immunity . The latter is mediated by specific antibodies mainly belonging to secretory immunoglobulin A (SIgA) and to lesser extent secretory IgM (SigM) as well as by serum derived and locally produced IgG . Immunoglobulin's deficiency may exist in a significant percentage of patients with chronic or recurrent infections of the upper respiratory tract . So an immunologic screening should be extended to patients who have persistent sinus infection, despite normal mucocilary and ventilation patterns, inadequate response to antimicrobial therapy, culture of unusual pathogens from the upper respiratory tract or history of infection at other side, mainly bronchopulmonary . The therapeutic aspects include immunoglobulin replacement or mucosal immunogens whose efficacy is related with both an unspecific and a specific way . In the future, cytokines will probably become the strongest therapy of the immunoglobulin's deficiency.

Phytomedicine, 2000 Oct, 7(5), 427 - 48
Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica; Brinkhaus B et al.; Centella asiatica is a medicinal plant that has been in use since prehistoric times . Its active constituents include pentacyclic triterpene derivatives . Studies have been conducted in particular to investigate the madecassosides and asiaticosides . In common with most traditional phytotherapeutic agents, Centella asiatica is used in folk medicine to treat a wide range of indications . In contrast to other medicinal plants, however, Centella asiatica has been subjected to quite extensive experimental and clinical investigations . Studies done in accordance with standardized scientific criteria have shown it to have a positive effect in the treatment of venous insufficiency and striae gravidarum . Centella asiatica also appears to be effective in the treatment of wound healing disturbances . At the present time, clinical studies aimed at investigating the sedative, analgesic, antidepressive, antimicrobial, antiviral and immunomodulatory effects that have been demonstrated experimentally, are still lacking . However, the therapeutic potential of this plant in terms of its efficacy and versatility is such that further detailed research would appear worthwhile.

Structure Fold Des, 2000 Oct 15, 8(10), 1049 - 58
Catalytic center assembly of HPPK as revealed by the crystal structure of a ternary complex at 1.25 A resolution; Blaszczyk J et al.; BACKGROUND: Folates are essential for life . Unlike mammals, most microorganisms must synthesize folates de novo . 6-Hydroxymethyl-7, 8-dihydropterin pyrophosphokinase (HPPK) catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP), the first reaction in the folate pathway, and therefore is an ideal target for developing novel antimicrobial agents . HPPK from Escherichia coli is a 158-residue thermostable protein that provides a convenient model system for mechanistic studies . Crystal structures have been reported for HPPK without bound ligand, containing an HP analog, and complexed with an HP analog, two Mg(2+) ions, and ATP . RESULTS: We present the 1.25 A crystal structure of HPPK in complex with HP, two Mg(2+) ions, and AMPCPP (an ATP analog that inhibits the enzymatic reaction) . This structure demonstrates that the enzyme seals the active center where the reaction occurs . The comparison with unligated HPPK reveals dramatic conformational changes of three flexible loops and many sidechains . The coordination of Mg(2+) ions has been defined and the roles of 26 residues have been derived . CONCLUSIONS: HPPK-HP-MgAMPCPP mimics most closely the natural ternary complex of HPPK and provides details of protein-substrate interactions . The coordination of the two Mg(2+) ions helps create the correct geometry for the one-step reaction of pyrophosphoryl transfer, for which we suggest an in-line single displacement mechanism with some associative character in the transition state . The rigidity of the adenine-binding pocket and hydrogen bonds are responsible for adenosine specificity . The nonconserved residues that interact with the substrate might be responsible for the species-dependent properties of an isozyme.

Fitoterapia, 2000 Dec, 71(6), 710 - 2
Antimicrobial activity of flowers from Anthemis cotula; Quarenghi MV et al.; The flavonoid containing total extract of Anthemis cotula flowers, tested at the concentration of 200 microg/ml, showed interesting antimicrobial activity against both Gram-negative and Gram-positive microorganisms.

Fitoterapia, 2000 Dec, 71(6), 704 - 6
Antimicrobial activity and cytotoxicity of Trapa bispinosa; Rahman MM et al.; The extracts of Trapa bispinosa showed interesting antimicrobial activity against Gram-positive and Gram-negative test organisms and significant cytotoxic activity.

Trop Doct, 2000 Oct, 30(4), 197 - 200
The incidence of Legionella pneumophila: a prospective study in a tertiary care hospital in India; Chaudhry R et al.; The prevalence of Legionella pneumophila causing community-acquired pneumonia (CAP) in patients who were admitted to hospital was investigated . Between April 1997 and December 1998, 60 patients admitted to the All India Institute of Medical Sciences with CAP, were included in the study . Aetiological diagnosis was based on the results of routine microbiological blood culture for bacteria and serological test by enzyme linked immunosorbent assay (ELISA) for L . pneumophila serogroup 1-7 . Eight (13%) patients had a conventional bacterial aetiology and nine (15%) had serological evidence of recent infection with L . pneumophila . Legionella pneumophila may be an important cause of CAP in adults in developing countries . Empiric antimicrobial treatment should include a combination of agents to cover both atypical agents and bacterial pathogens.

Health Technol Assess, 2000, 4(21), 1 - 237
Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration; O'Meara S et al.; BACKGROUND: Chronic wounds, including pressure sores, leg ulcers, diabetic foot ulcers and other kinds of wounds, healing by secondary intention are common in both acute and community settings . The prevention and treatment of chronic wounds includes many strategies, including the use of various wound dressings, bandages, antimicrobial agents, footwear, physical therapies and educational strategies . This review is one of a series of reviews, and focuses on the prevention and treatment of diabetic foot ulcers and the role of antimicrobial agents in chronic wounds in general . OBJECTIVES: To assess the clinical- and cost-effectiveness of (1) prevention and treatment strategies for diabetic foot ulcers and (2) systemic and topical antimicrobial agents in the prevention and healing of chronic wounds . METHODS - DATA SOURCES: Nineteen electronic databases were searched, including MEDLINE, CINAHL, Embase and the Cochrane Library . Relevant journals, conference proceedings and bibliographies of retrieved papers were hand-searched . An expert panel was consulted . METHODS - STUDY SELECTION: Randomised and non-randomised trials with a concurrent control group, which evaluated any intervention for the prevention or treatment of diabetic foot ulcers, or systemic or topical antimicrobials for chronic wounds (diabetic foot ulcers, pressure ulcers, leg ulcers of various aetiologies, pilonidal sinuses, non-healing surgical wounds, and cavity wounds) and used objective measures of outcome such as: (1) development or resolution of callus; (2) incidence of ulceration (for diabetic foot ulcer prevention studies); (3) incidence of pressure sores (pressure sore prevention studies); (4) any objective measure of wound healing (frequency of complete healing, change in wound size, time to healing, rate of healing); (5) ulcer recurrence rates; (6) side-effects; (7) amputation rates (diabetic foot ulcer treatment studies); (8) healing rates and recurrence of disease, among others, for pilonidal sinuses . Studies reporting solely microbiological outcomes were excluded . Decisions on the inclusion of primary studies were made independently by two reviewers . Disagreements were resolved through discussion . Data were extracted by one reviewer into structured summary tables . Data extraction was checked independently by a second reviewer and discrepancies resolved by discussion . All included studies were assessed against a comprehensive checklist for methodological quality . INCLUDED STUDIES - DIABETIC FOOT ULCERS: Thirty-nine trials which evaluated various prevention and treatment modalities for diabetic foot ulcers: footwear (2), hosiery (1), education (5), screening and foot protection programme (1); podiatry (1) for the prevention of diabetic foot ulcers; and footwear (1), skin replacement (2), hyperbaric oxygen (2), ketanserin (3), prostaglandins (3), growth factors (5), dressings and topical applications (9), debridement (2) and antibiotics (2) for the treatment of diabetic foot ulcers . INCLUDED STUDIES - ANTIMICROBIALS: Thirty studies were included, 25 with a randomised design . There were nine evaluations of systemic antimicrobials and 21 of topical agents . QUALITY OF STUDIES: The methodological and reporting quality was generally poor . Commonly encountered problems of reporting included lack of clarity about randomisation and outcome measurement procedures, and lack of baseline descriptive data . Common methodological weaknesses included: lack of blinded outcome assessment and lack of adjustment for baseline differences in important variables such as wound size; large loss to follow-up; and no intention-to-treat analysis . RESULTS - PREVENTION OF DIABETIC FOOT ULCERS: There is some evidence (1 large trial) that a screening and foot protection programme reduces the rate of major amputations . The evidence for special footwear (2 small trials) and educational programmes (5 trials) is equivocal . A single trial of podiatric care reported a significantly greater reduction in callus in patients receiving podiatric care . RESULTS - TREATMENT OF DIABETIC FOOT ULCERS: Total contact casting healed significantly more ulcers than did standard treatment in one study . There is evidence from 5 trials of topical growth factors to suggest that these, particularly platelet-derived growth factor, may increase the healing rate of diabetic foot ulcers . Although these studies were of relatively good quality, the sample sizes were far too small to make any definitive conclusions, and growth factors should be compared with current standard treatments in large, multicentre studies . Topical ketanserin increased ulcer healing rate in 2 studies, while systemic hyperbaric oxygen therapy reduced the rate of major amputations in 1 study . Preliminary research into the effects of iloprost and prostaglandin E1 (PGE1) on diabetic foot ulcer healing suggests possible benefits . However, good quality, large-scale confirmatory research is needed . (ABSTRACT TRUNCATED)

Eur J Obstet Gynecol Reprod Biol, 2000 Dec, 93(2), 193 - 7
Wound complications in patients with carcinoma of the vulva . Comparison between radical and modified vulvectomies; Leminen A et al.; OBJECTIVE: To evaluate complications after different vulvectomies performed because of vulvar cancer . STUDY DESIGN: Retrospective analysis of 149 patients who underwent vulvectomy . RESULTS: Wound infections was found in 58% . Overweight, central or bilateral location of the tumor, and non-radical surgery were significant predictors of wound infections . Patients with a wound infection had more often wound breakdown (P<0.001), prolonged healing time (P<0.000), and lymphedema (P<0.001) than patients without infection . Antimicrobial prophylaxis did not prevent wound infection . Wound infections were found in 75% after radical en bloc vulvectomy (RV) and in 47% after modified vulvectomies (MV) (P<0.001) . Also wound breakdown (47 versus 20%) (P<0.001) and lymphedema (48 versus 12%) (P<0.0001) were more common in RV group than in MV group . Lymphocysts were found in 7%, and showed no association with wound infection or type of operation . The mean hospital stay was 26 days in patients with wound infection and 12 days in patients without infection, 31 days in RV group and 12 days in MV group, respectively . CONCLUSIONS: Wound infections are major determinants for both acute and late complications . Postoperative complications reduce with increasing use of modified vulvectomies.

Clin Infect Dis, 2000 Nov, 31(5), 1188 - 95 Epub 2000 Nov 07.
Toxoplasmosis after hematopoietic stem cell transplantation; Martino R et al.; Forty-one cases of toxoplasmosis were diagnosed in 15 European transplantation centers in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT) from 1994 through 1998 . Most patients (39 {94%}) were seropositive for Toxoplasma gondii before they underwent transplantation, and 30 (73%) had developed moderate to severe acute graft-versus-host disease before they developed toxoplasmosis . Thirty-five (85%) patients had Toxoplasma disease with evidence of organ involvement, whereas 6 (15%) patients had Toxoplasma infection, as defined by fever and a positive polymerase chain reaction (PCR) finding for T . gondii in blood . Nine patients were diagnosed at autopsy . Thirty patients (73%) had not received antimicrobial prophylaxis with anti-Toxoplasma activity after undergoing transplantation . The median day of onset of disease after HSCT was 64 . Twenty-two (63%) patients died from toxoplasmosis, and 23 (66%) received adequate anti-Toxoplasma therapy for > or =3 days . Among these 23 patients, 11 (48%) showed a complete response and 3 (13%) showed improvement . In univariate and multivariate analyses, having received adequate therapy and experiencing late infection (>63 days after HSCT) were associated with a lower risk of dying from toxoplasmosis . Toxoplasmosis after HSCT is a severe infection with a high mortality rate even when diagnosed soon after HSCT, and PCR may help establish the diagnosis earlier.

J Hosp Infect, 2000 Nov, 46(3), 230 - 5
Use and misuse of antimicrobial agents in a general hospital in the AIDS era; Rivero M et al.; A prevalence study was carried out to ascertain the pattern of antimicrobial use, costs and relevance in a general hospital during the AIDS era . All patients receiving antimicrobials were studied . Antimicrobials were divided into antibacterial drugs and others and the costs evaluated in US dollars . Of 1526 patients surveyed, 455 (29.8%) were receiving 664 courses of antimicrobials: 109 (7.2%) as prophylaxis and 346 (22.6%) as treatment . Fifteen percent of courses involved non-antibacterial drugs . In 188 patients (40.9% of those treated) treatment was inadequate, usually because of incorrect drug choice . Daily cost of antimicrobials was $14953 . AIDS accounted for 3% of all patients, 9% of those receiving antimicrobials, 19.7% of antimicrobial usage and 9.6% of the antimicrobial expenditure . Misuse occurred in 43% of non-HIV patients and 17% of those with HIV . Thus, despite a disproportionate contribution of patients with AIDS, adequacy of use of antimicrobials was better in this population .

Ned Tijdschr Geneeskd, 2000 Oct 21, 144(43), 2049 - 55
{Optimizing antibiotics policy in the Netherlands . V . SWAB guidelines for perioperative antibiotic prophylaxis . Foundation Antibiotics Policy Team}; van Kasteren ME et al.; The Stichting Werkgroep Antibioticabeleid (SWAB, Foundation Antibiotics Policy Team) has issued guidelines for perioperative antibiotic prophylaxis in Dutch hospitals . Antibiotic prophylaxis is generally recommended for surgical procedures with relatively high postoperative infection rates and those in which consequences of infection are really serious . Studies have revealed that prophylaxis given within two hours before incision is most effective . Short-term, preferably single-dose prophylaxis, is as effective as multiple-dose prophylaxis in most procedures . For reasons of cost effectiveness and prevention of induction of resistance, single-dose prophylaxis is recommended . The antimicrobial agent of choice for perioperative prophylaxis should not be widely used as a therapeutic agent, should be selectively active against micro-organisms most frequently isolated from surgical site infections, and should have a plasma-half-life that makes single-dosing possible for most operations . Therefore cefazoline is an agent that is widely used for perioperative prophylaxis.

J Clin Periodontol, 2000 Nov, 27(11), 806 - 9
A study to assess the plaque inhibitory activity of a new triclosan mouthrinse formulation; Moran J et al.; BACKGROUND/AIMS: Toothpastes and mouthrinses containing triclosan have been shown to be of some value at inhibiting both plaque and gingivitis . However much improved activity can be obtained by the addition of other chemicals which increase substantivity or antimicrobial activity . The present study was designed to determine whether a new mouthwash formulation containing a triglyceride oil was capable of reducing plaque reformation when compared to a control rinse containing neither triclosan or oil . METHODS: A total of 24 subjects took part in a double-blind, single-centre, cross-over study in which rinses were used as the only form of oral hygiene over a 4-day period . On the 1st day of each period, the subjects were given a prophylaxis to remove all plaque and calculus deposits . A single supervised rinse was taken and subsequent 2x daily rinses over the following 3 days . 24 and 96 h after the prophylaxis, the volunteers returned to the clinic, the plaque disclosed and assessed by plaque index and area . The test procedure and wash-out phase were repeated until all of the subjects had used both rinses . RESULTS: After 24 h, a 12% reduction in plaque score and a 25% reduction in plaque area was noted for the triclosan/oil rinse compared to the control rinse; however, these reductions were not significant (p>0.05) . After 96 h, the triclosan/ oil rinse failed to produce a numerical or statistical reduction in plaque whether measured by plaque score or area . CONCLUSIONS: These findings would suggest that the triclosan/oil rinse would be of little value at inhibiting dental plaque whether used alone or as an adjunct to conventional oral hygiene measures.

J Pept Sci, 2000 Oct, 6(10), 497 - 511
Antibacterial peptides isolated from insects; Otvos L Jr; Insects are amazingly resistant to bacterial infections . To combat pathogens, insects rely on cellular and humoral mechanisms, innate immunity being dominant in the latter category . Upon detection of bacteria, a complex genetic cascade is activated, which ultimately results in the synthesis of a battery of antibacterial peptides and their release into the haemolymph . The peptides are usually basic in character and are composed of 20-40 amino acid residues, although some smaller proteins are also included in the antimicrobial repertoire . While the proline-rich peptides and the glycine-rich peptides are predominantly active against Gram-negative strains, the defensins selectively kill Gram-positive bacteria and the cecropins are active against both types . The insect antibacterial peptides are very potent: their IC50 (50% of the bacterial growth inhibition) hovers in the submicromolar or low micromolar range . The majority of the peptides act through disintegrating the bacterial membrane or interfering with membrane assembly, with the exception of drosocin, apidaecin and pyrrhocoricin which appear to deactivate a bacterial protein in a stereospecific manner . In accordance with their biological function, the membrane-active peptides form ordered structures, e.g . alpha-helices or beta-pleated sheets and often cast permeable ion-pores . Their cytotoxic properties were exploited in in vivo studies targeting tumour progression . Although the native peptides degrade quickly in biological fluids other than insect haemolymph, structural modifications render the peptides resistant against proteases without sacrificing biological activity . Indeed, a pyrrhocoricin analogue shows lack of toxicity in vitro and in vivo and protects mice against experimental Escherichia coli infection . Careful selection of lead molecules based on the insect antibacterial peptides may extend their utility and produce viable alternatives to the conventional antimicrobial compounds for mammalian therapy.

Lett Appl Microbiol, 2000 Oct, 31(4), 299 - 302
A note: ortho-phthalaldehyde: proposed mechanism of action of a new antimicrobial agent; Simons C et al.; Ortho-phthalaldehyde (OPA) is a new aromatic dialdehyde antimicrobial agent, the mechanism of action of which has been little studied . The aims of this paper are to examine what is currently known about its mechanism of action, to compare the action with that of a widely investigated aliphatic dialdehyde, glutaraldehyde (GTA), and to put forward a hypothesis that would, in the light of current knowledge, explain how OPA inactivates micro-organisms, including GTA-resistant Mycobacterium chelonae.

Lett Appl Microbiol, 2000 Oct, 31(4), 265 - 9
Development and demonstration of RNA isolation and RT-PCR procedures to detect Escherichia coli O157:H7 gene expression on beef carcass surfaces; Berry ED; Preventing the development of pathogen resistance to processing and preservation techniques will require an understanding of the genetic mechanisms that pathogens use in situ to adapt and develop tolerance to stresses they encounter in the food environment . RNA isolation and reverse-transcription (RT)-PCR protocols were developed as tools to detect gene expression in bacteria on beef carcass surfaces . The utility of these procedures was demonstrated by detecting the expression of a selectively-inducible green fluorescent protein (GFP) gene in a plasmid-transformed strain of Escherichia coli O157:H7 inoculated onto beef carcass surface tissue . These procedures should serve as useful tools for studying the genetic responses of bacteria when exposed to antimicrobial interventions applied to food animal carcasses.

Rev Med Brux, 2000 Sep, 21(4), A375 - 80
{Bacterial resistance and implications for daily practice}; Sternon J; Present and future solutions to the problem of bacterial multiple resistance involve physicians, patients and veterinarians . Their behaviour should evolve to take into account the medical and economical issues of antibiotic prescription . The clinical diagnosis requires a more rigorous assessment, based on bacteriological and rapid antigenic tests . Vaccination in both young people and the elderly, is an essential prophylactic tool, which is too often neglected . When a bacterial infection is suspected or proven, priority should be given to a targeted antimicrobial therapy with a bactericidal activity, in order to quickly eradicate pathogens . Therapies should be shorter and questionable antibio-prophylaxis should also be avoided . A watch laboratory network should provide physicians with an adequate information on local bacterial resistance patterns on a regular basis, in order to allow them adjusting their prescription.

Arch Med Res, 2000 Jul-Aug, 31(4), 415 - 21
Comparison of invasive and noninvasive methods for the diagnosis and evaluation of eradication of Helicobacter pylori infection in children; Yanez P et al.; BACKGROUND: Acquisition of Helicobacter pylori infection occurs mainly during childhood . To study the events associated with H . pylori colonization in children it is important to have reliable diagnostic methods . Our objective was to validate invasive and noninvasive tests for diagnosis of H . pylori infection in children before and after antimicrobial treatment . METHODS: Before treatment, invasive rapid urease test (RUT) culture and histology, as well as the noninvasive carbon-13 urea breath test (13C-UBT) and serology were validated in 59 children . The gold standard for H . pylori infection was any of three positives of the five tests . After antimicrobial treatment culture, histology, and 13C-UBT were validated in 43 children to determine eradication . The gold standard for eradication was negative in all three tests . RESULTS: For primary diagnosis, RUT was the most sensitive and specific test, followed by 13C-UBT, which performed better than serology, culture, and histology . Concordance tests also showed that RUT and 13C-UBT performed better . For determination of eradication, 13C-UBT and histology were better than culture, which showed poor sensitivity . CONCLUSIONS: RUT performed better for primary diagnosis . However, as endoscopy might not be indicated in most children, 13C-UBT could be the test of choice for diagnosis of H . pylori infection both before and after eradication treatment.

J Immunol, 2000 Nov 15, 165(10), 5773 - 9
CTL-mediated killing of intracellular Mycobacterium tuberculosis is independent of target cell nuclear apoptosis; Thoma-Uszynski S et al.; Two subsets of human CTL have been defined based upon phenotype and function: CD4(-) CD8(-) double-negative (DN) CTL lyse susceptible targets via Fas-Fas ligand interaction and CD8(+) CTL via the granule exocytosis pathway . CD8(+) CTL, but not DN CTL, can mediate an antimicrobial activity against Mycobacterium tuberculosis-infected target cells that is dependent on cytotoxic granules that contain granulysin . We investigated the role of nuclear apoptosis for the antimicrobial effector function of CD1-restricted CTL using the caspase inhibitor N:-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone . We found that DN CTL-induced target cell lysis was completely dependent on caspase activation, whereas the cytolytic activity of CD8(+) CTL was caspase independent . However, both DN and CD8(+) CTL-induced nuclear apoptosis required caspase activation . More important, the antimicrobial effector function of CD8(+) CTL was not diminished by inhibition of caspase activity . These data indicate that target cell nuclear apoptosis is not a requirement for CTL-mediated killing of intracellular M . tuberculosis.

Manag Care Interface, 2000 Apr, 13(4), 83 - 8
The management of bacterial infections of the upper respiratory tract in children: pharyngitis and otitis media; Adam D; Despite changes in the activities of infectious microorganisms, particularly variations in their prevalences in different parts of the body, in clinically defined diseases, and in their susceptibilities to antibiotics, the established first-line agents for the empiric treatment of otitis media and pharyngitis are still valid . Nevertheless, a number of the newer antimicrobials have become valuable as second- and third-line medications when the first-choice drugs fail or are contraindicated . In terms of fundamental principles, the question of whether pharyngitis in children warrants routine antibiotic therapy remains unresolved; in practical terms, antibiotic treatment should be considered routinely.

J Antimicrob Chemother, 2000 Sep, 46 Suppl T2, 53 - 8
Surveillance studies: how can they help the management of infection?
Masterton RG.
The increase in antimicrobial resistance has led to predictions of doom in the international press and to depression in the medical community . It has focused attention upon measures for fighting resistance, foremost of which is susceptibility surveillance . Until recently, global efforts at surveillance have been largely uncoordinated and random . This scene is rapidly changing with the World Health Organization (WHO), among others, leading multidisciplinary, targeted initiatives . In terms of individual surveillance programmes, much has been learned about their design . The best of these, the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC), SENTRY and the Alexander Project, involve well-defined patient and organism groups against key denominators, and use standardized, internationally recognized methods that are quality-controlled, explore susceptibility quantitatively and include investigation of resistance mechanisms . Results are rapidly returned to the user . Evidence shows that surveillance, when used to guide policies on antibiotic use and infection control, can be helpful in the fight to control the development and spread of resistance . Further work is required to demonstrate these benefits and quantify them fully.

J Antimicrob Chemother, 2000 Sep, 46 Suppl T2, 39 - 52
MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from Europe: comparison of antibiotic susceptibilities between countries and centre types . MYSTIC Study Group (European centres only); Goossens H; The activity of meropenem and five comparators has been studied against 7886 isolates from 29 centres in 10 European countries from 1997 to 1999 as part of the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance study . Gram-positive and Gram-negative isolates from intensive care units (ICUs), neutropenia centres, cystic fibrosis (CF) centres and general wards were investigated in Belgium (1 year), Czech Republic (2 years), Germany (3 years), Italy (3 years), Poland (2 years), Russia (2 years), Sweden (2 years), Switzerland (1 year), Turkey (1 year) and UK (3 years) . Resistance to quinolones and aminoglycosides was observed, as was resistance to the cephalosporins and penicillins via extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases . Meropenem showed good activity against the pathogens tested, particularly in CF and neutropenia centres, over the 3 year period . The overall order of potency of the six antimicrobial agents tested was: meropenem > imipenem > piperacillin/tazobactam and ciprofloxacin > ceftazidime > gentamicin . No increase in resistance to the carbapenems, to date, has been detected in any of the European centres included in this study.

J Antimicrob Chemother, 2000 Sep, 46 Suppl T2, 25 - 37
MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from the Americas: resistance implications in the treatment of serious infections . MYSTIC Study Group (Americas); Pfaller MA et al.; The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme aims to provide in vitro surveillance data for geographically diverse institutions where meropenem is available for use . The in vitro activity of meropenem and eight comparator antimicrobial agents against 2340 significant pathogens obtained in 1999 was assessed and compared in 14 study centres in Brazil, Mexico and the USA . Isolates were further characterized for production of extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases and carbapenemases . Carbapenems demonstrated their broad spectrum and potency, inhibiting > or = 95% of all isolates irrespective of the geographical region or centre type . The overall order of activity of the nine agents tested against all pathogens in 1999 was meropenem (96%) > imipenem (95%) > cefepime (92%) > gentamicin (89%) > piperacillin/tazobactam (88%) > ceftazidime = tobramycin (86%) > cefotaxime (84%) > ciprofloxacin (83%) . Thus far, the results from the Americas indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for the treatment of seriously ill patients . In contrast, other ESBLs, fluoroquinolones and aminoglycosides have lost activity in many institutions as a result of the selection of strains producing ESBLs or having AmpC and other resistance determinants . Carbapenem resistance was observed rarely and at a prevalence similar to those reported in earlier studies . Carbapenems appear to be a continuing reliable option for the treatment of serious nosocomial infection.

J Antimicrob Chemother, 2000 Sep, 46 Suppl T2, 1 - 8
Detection of emerging resistance patterns within longitudinal surveillance systems: data sensitivity and microbial susceptibility . MYSTIC Advisory Board . Meropenem Yearly Susceptibility Test Information Collection; Jones RN; Communicating information from antimicrobial resistance surveillance study data to microbiologists and physicians can be challenging . Large amounts of data, commonly reaching millions of MICs or zone diameter endpoints, must be analysed and condensed to easily-read tables or figures . Furthermore, data must not be prejudged relative to susceptibility categories, because of the diverse nature of interpretive criteria available internationally . An attempt must be made to present results of all surveillance studies in a mode that can be reinterpreted for immediate use in different geographical areas, or used to compare future data with relative ease and high accuracy . Such data displays require peer-reviewed journals to permit greater numbers of more complex tables to present results . The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) study is a year-on-year global surveillance programme in medical centres where meropenem is available for use . We have developed a presentation strategy that expands the long-term clinical value of MYSTIC results . In addition to statistical parameters, tables of cumulative percentages or numbers of strains inhibited at each tested antimicrobial concentration will be presented . Alternative figures (Finland-o-grams) could also be used, but these generally lack precise extractable rates and require more journal space . Regardless of study design, promotion of this presentation philosophy enhances any surveillance study's value to each reader or user and facilitates application to locally appropriate interpretations . The widespread use of these analysis and presentation principles as benchmarks by various resistance studies and networks is strongly encouraged, particularly by investigations across international boundaries.

Int J Pharm, 2000 Nov 4, 208(1-2), 71 - 80
Colloidal carriers for benzathine penicillin G: nanoemulsions and nanocapsules; Santos-Magalhaes NS et al.; The main purpose of this work is to formulate benzathine penicillin G nanoemulsion and nanocapsules, to evaluate their physicochemical and stabilising characteristics, and to determine their antimicrobial activity and penicillin in vitro release kinetics . Nanoemulsions were produced by the spontaneous emulsification approach and nanocapsules of poly (D,L-lactic acid-co-glycolic acid) polymer (PLGA) were prepared by the method of interfacial deposition of a pre-formed polymer . A 207+/-8 nm mean diameter nanoemulsion formulation maintained stability for more than 5 months at 4 degrees C . Stable nanocapsules with 224+/-58 nm mean diameter were obtained, which remained stabilised over 120 days at 4 degrees C . The penicillin encapsulation ratio in the nanocapsules was 85% . The in vitro release profiles indicated that penicillin released from the nanoemulsion was similar to the one observed from nanocapsules . However it can be clearly deduced from the in vitro kinetic analysis that the antibiotic cannot be protected in colloidal delivery systems . Nevertheless, stable formulations obtained in this investigation supply a potential dosage form to encapsulate more easily soluble drugs.

J Anim Sci, 2000 Nov, 78(11), 2896 - 902
Growth-promoting efficacy in young pigs of two sources of zinc oxide having either a high or a low bioavailability of zinc; Mavromichalis I et al.; Commercial sources of zinc oxide (ZnO) differ widely in Zn relative bioavailability (RBV), but it is unknown whether growth-promoting efficacy in young pigs is influenced by RBV of the ZnO sources used . We compared a low-RBV (39%) ZnO manufactured by the Waelz process (W) to a high-RBV (93%) ZnO manufactured by the hydrosulfide process (HS) . Antibacterial agents were included in the diet in only one of the four trials (Exp . 4) . In Exp . 1, pigs (n = 36, 6.5 kg, 28 d of age) were randomly assigned in three replicates to receive 0, 1,500, or 3,000 mg Zn/kg from HS Zn in a 21-d growth assay . Growth rates and feed intake responded linearly (P < 0.01) to incremental doses of Zn . In Exp . 2, pigs (n = 60, 6.1 kg, 28 d of age) were randomly assigned in five replicates to receive either 0 or 1,500 mg W or HS Zn/kg during a 21-d feeding period . Growth performance was improved (P < 0.01) by the addition of ZnO . During wk 1, however, pigs receiving HS Zn grew faster (P < 0.03) than those receiving W Zn, but the difference diminished to a trend (P < 0.08) during wk 2 . Morphology of duodenal, jejunal, and ileal intestinal sections was examined at d 21 of the assay, but neither source of ZnO had an effect on crypt depth or on villus height or width . In Exp . 3, weaned pigs (n = 48, 5.4 kg, 21 d of age) were randomly assigned in four replicates to the same dietary treatments as in Exp . 2 for a 17-d growth assay . Growth performance was improved (P < 0.05) by the addition of ZnO, but no difference was detected between the two sources . In Exp . 4, pigs (n = 60, 6.2 kg, 28 d of age) were randomly assigned in five replicates to receive either 0 or 1,500 mg/kg W or HS Zn in an 11-d growth assay wherein antimicrobial agents were included in the basal diet . Growth rates during the first 6-d were improved (P < 0.06) by the addition of ZnO, with a trend (P < 0.10) for greater weight gain in pigs receiving HS than in those fed W Zn . During the entire 11-d, however, there was no difference in growth rates between pigs fed the two sources of ZnO . In conclusion, RBV of Zn in ZnO did not substantially affect the growth-promoting efficacy of ZnO in young pigs fed diets with or without antimicrobial agents.

Scand J Gastroenterol, 2000 Sep, 35(9), 929 - 34
Cure of Helicobacter pylori infection after failed primary treatment: one-center results from 120 patients; Seppala K et al.; BACKGROUND: Treatment with a proton pump inhibitor (PPI) and antimicrobials cures Helicobacter pylori infection in about 90% of patients . This is a retrospective overview of our studies aiming to cure the infection in all compliant patients with failed initial therapy . METHODS: We retreated 120 (19% of 644) H . pylori-infected patients whose initial therapy had failed . The retreatments included (i) triple therapy (TT): colloidal bismuth subcitrate, metronidazole, amoxicillin (or tetracycline); (ii) quadruple therapy (QT): TT and a PPI; or (iii) high doses of both a PPI and clarithromycin combined with a further 1-3 individually selected antimicrobials . The eradication results were determined after 6-12 months . RESULTS: The 1st retreatment was successful in 70 of 120 patients . The 2nd retreatment cured 25 of the remaining 42 patients, the 3rd 13 of 17, and the 4th the last 4 patients . The cumulative eradication rate (ITT) was 93% (95% CI: 88.9%-97.9%; 8 patients withdrew after a failed 1st retreatment) and the rate was 100% in the remaining 112 patients who accepted several retreatments . The 1st retreatment with TT cured 23% (95% CI: 12%-34%) of 57 patients and QT 85% (95% CI: 74%-96%) of 41 patients who had initially undergone a failed metronidazole-based treatment . All retreatments were well tolerated . CONCLUSIONS: In this study, high doses of a PPI and clarithromycin combined with 1-3 antimicrobials according to susceptibility data proved to be the best drug combination in the cure of H . pylori infection after failed primary treatment . Giving imidazole- and bismuth-based QT (without clarithromycin) as the first-line treatment of H . pylori infection ensures that the number of failures remains low.

Artif Cells Blood Substit Immobil Biotechnol, 2000 Nov, 28(6), 521 - 33
Iodinated natural rubber latex: preparation, characterisation & antibacterial activity assessment; Tyagi M et al.; Natural Rubber (NR) in both its latex and dried form was treated with iodine to make it antibacterial in nature . The NR latex was dried and washed, dissolved in toluene, iodinated and cast into films . In a different approach, NR in its latex form (emulsion) was blended with aqueous solution of povidone-iodine complex (PVP-I) and films were cast . Phase separation of PVP-I was observed in the films prepared using NR latex; whereas the film prepared using NR solution in toluene and molecular iodine were homogeneous, transparent light brown . Solubility assessment of the films revealed that unlike pure NR, the iodinated NR failed to go into solution completely . The films obtained from both the approaches were evaluated for release of iodide ions . On immersion in water, PVP-I blended latex did not retain iodine while sustained release of iodide ion was observed in case of dried NR dissolved in toluene and treated with iodine . The FT-IR spectra of the iodinated films revealed that iodine attaches covalently to the double bonds in the isoprene units of NR . The films were also evaluated for their antibacterial properties and it was observed that the films prepared from both the approaches, acquired antimicrobial properties.

Can Vet J, 2000 Oct, 41(10), 777 - 85
Etiology, forms, and prognosis of gastrointestinal dysfunction resembling vagal indigestion occurring after surgical correction of right abomasal displacement; Sattler N et al.; The objectives of this study were to determine the etiology and types of vagal indigestion (VI) occurring after right displacement of the abomasum or abomasal volvulus (RDA/AV), and the prognosis for each type . Data of cows presented for RDA/AV from a retrospective (n = 288) and a prospective (n = 132) study were used . Vagal indigestion occurred in 39 and 22 cows in each study, respectively . A necropsy was performed in 29 cases . Gastric compartment dilation compatible with VI type III or IV occurred in 23 cases . An abnormal gastric wall was detected in 22 cases . Peritonitis was present in 18 cows . Vagal nerve lesions were present in 5 out of 13 cases studied . Clinical, hematological, and necropsy results suggested a classification of VI with respect to presence or absence of peritonitis . Gastric wall damage, peritonitis and vagal nerve lesions appear important in the etiology . Considering peritonitis occurrence, antimicrobial therapy appears necessary in the treatment of RDA/AV.

Med J Aust, 2000 Oct 2, 173 Suppl, S48 - 50
Conjugate pneumococcal vaccines: an overview; Mulholland EK; A seven-valent conjugate pneumococcal vaccine has been shown to have dramatic efficacy against invasive pneumococcal disease and lesser efficacy against otitis media and pneumonia . This vaccine was licensed for use in infants in the United States in February 2000 and is recommended there for routine use in infants and catch-up vaccination in high-risk children . Specific regional pneumococcal vaccines are not needed; nine to 11 serotypes cover most pneumococcal disease in most parts of the world; nine- and 11-valent conjugate vaccines are currently being developed for the global market . There is evidence of serotype replacement in vaccine recipients (in both carriage and disease), which might reduce overall vaccine effectiveness . There is also evidence that vaccines may reduce rates of antimicrobial resistance in pneumococci . Studies of the burden of pneumococcal disease as well as program support are needed to assist developing countries to introduce these expensive vaccines.

Med J Aust, 2000 Oct 2, 173 Suppl, S41 - 4
Efficacy and effectiveness of pneumococcal polysaccharide vaccines and their use in industrialised countries; Lehmann D; Use of pneumococcal polysaccharide vaccines remains controversial, even though clinical trials have shown their efficacy in preventing invasive disease caused by vaccine serotypes in immunocompetent adults . Retrospective studies indicate these vaccines have about 50%-80% effectiveness for preventing invasive disease caused by vaccine serotypes, although effectiveness wanes over time and with age . The elderly, people living in institutions and those with chronic cardiac or respiratory disease, alcoholism or diabetes mellitus who are in relatively good health would benefit from vaccination; a polysaccharide vaccine program in the elderly has been shown to be cost-effective . In young children, polysaccharide vaccine should be evaluated as a booster to conjugate pneumococcal vaccines, which are likely to be available soon in industrialised countries . In view of the high rates of hospitalisation and of antimicrobial resistance in pneumococci, every effort should be made to increase coverage by pneumococcal polysaccharide vaccine in Australia, according to guidelines of the National Health and Medical Research Council.

Nat Biotechnol, 2000 Nov, 18(11), 1162 - 6
Transgenic plants expressing cationic peptide chimeras exhibit broad-spectrum resistance to phytopathogens; Osusky M et al.; Here we describe a strategy for engineering transgenic plants with broad-spectrum resistance to bacterial and fungal phytopathogens . We expressed a synthetic gene encoding a N terminus-modified, cecropin-melittin cationic peptide chimera (MsrA1), with broad-spectrum antimicrobial activity . The synthetic gene was introduced into two potato (Solanum tuberosum L.) cultivars, Desiree and Russet Burbank, stable incorporation was confirmed by PCR and DNA sequencing, and expression confirmed by reverse transcription (RT)-PCR and recovery of the biologically active peptide . The morphology and yield of transgenic Desiree plants and tubers was unaffected . Highly stringent challenges with bacterial or fungal phytopathogens demonstrated powerful resistance . Tubers retained their resistance to infectious challenge for more than a year, and did not appear to be harmful when fed to mice . Expression of msrA1 in the cultivar Russet Burbank caused a striking lesion-mimic phenotype during leaf and tuber development, indicating its utility may be cultivar specific . Given the ubiquity of antimicrobial cationic peptides as well as their inherent capacity for recombinant and combinatorial variants, this approach may potentially be used to engineer a range of disease-resistant plants.

Regul Pept, 2000 Nov 24, 95(1-3), 87 - 92
Recombinant granulocyte colony-stimulating factor induces production of human neutrophil peptides in lung cancer patients with neutropenia; Ashitani J et al.; Human neutrophil peptides (HNPs) 1, 2 and 3 are antimicrobial peptides localized in the azurophil granules of neutrophils . We investigated the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the biosynthesis of HNPs 1-3 using a sensitive radioimmunoassay and Northern blot analysis . Seven patients with lung cancer were first treated with various anticancer agents for 3 days (days 1-3) followed by treatment with rhG-CSF (2 microgram/kg weight/day) for 7 days (days 8-14) . Chemotherapy caused neutropenia but the neutrophil count increased biphasically between days 8 and 14 . Chemotherapy did not change the baseline plasma concentration of HNPs 1-3 (74.1+/-2.1 pmol/ml) but the concentration increased from day 12, 5 days after commencement of rhG-CSF therapy, to reach a peak value of 430.8+/-57.0 pmol/ml on day 15, 1 day after the last administration of rhG-CSF . Baseline HNPs 1-3 content per neutrophil was 0.59+/-0.02 fmol, decreased to 0.30+/-0.07 fmol on day 9, then increased to 0.78+/-0.07 fmol on day 15 . Analyses of peripheral blood neutrophils by Northern blot and reverse-phase high-performance liquid chromatography showed that the amounts of HNPs 1-3 mRNA and precursors of HNPs 1-3 markedly increased in response to rhG-CSF . Our results indicate that recombinant hG-CSF does not only increase neutrophil count but stimulates HNPs 1-3 biosynthesis in neutrophils, thus enhancing the host defense system of compromised hosts with neutropenia.

J Antimicrob Chemother, 2000 Nov, 46(5), 803 - 5
In vitro susceptibility of Helicobacter pylori to, and in vivo suppression by, antimicrobials used in selective decontamination of the digestive tract; van der Voort PH et al.; The incidence of bleeding related to stress ulcers is reduced in critically ill patients in whom gut decontamination has been performed; this may be a result of suppression of Helicobacter pylori infection . We determined the susceptibility of H . pylori to the applied antibiotics . In nine of 10 critically ill patients (using intravenous cefotaxime and topical polymyxin, tobramycin and amphotericin B (PTA) given by nasogastric tube) and all six volunteers (using PTA alone), H . pylori was suppressed as long as the topical antibiotics were ingested . The in vitro studies revealed that all strains were susceptible to cefotaxime and tobramycin . The strains were not susceptible to polymyxin or amphotericin B.

Biochem Biophys Res Commun, 2000 Nov 2, 277(3), 575 - 80
High-level expression of antimicrobial peptide mediated by a fusion partner reinforcing formation of inclusion bodies; Lee JH et al.; A gene expression system for antimicrobial peptides, which could be effectively used for various studies or applications of the antimicrobial peptides, has been developed . To avoid the harmful effects on an expression host, Escherichia coli, the antimicrobial peptides were expressed as fusion proteins with a polypeptide F4, which is a truncated PurF fragment that highly tends to form inclusion bodies . Seven different kinds of antimicrobial peptides have been successfully expressed by this expression system and the resulting expression level of fusion proteins reached up to 30% of total cell proteins . To confirm the identity of the recombinant peptide, MSI-344 was selected as a model peptide and purified to homogeneity, and we could obtain the recombinant MSI-344 of a high purity and with a good yield, which was identical to the authentic peptide in the aspects of the chemical and antimicrobial properties . These results show that the neutral fusion partner, which reinforces the formation of inclusion bodies, could mediate a high-level expression of the antimicrobial peptides .

Pulm Pharmacol Ther, 2000, 13(6), 249 - 56
Parenteral antibiotic therapy in the treatment of lower respiratory tract infections . Strategies to minimize the development of antibiotic resistance; Cazzola M et al.; Antibiotic use is often imputed for increases in the prevalence of infections due to antibiotic-resistant bacteria . Resistance depends on the variety of genotypes in the large bacterial population and also on the selective pressures that are produced along the antibiotic concentration gradients in the body . In effect, at certain selective concentrations the antibiotic eliminates the susceptible majority, leaving a selected remainder intact . Therefore, the choice of antibiotics for the treatment of lower respiratory tract infections should take into consideration not only their effectiveness but also the pharmacokinetics of each agent and its delivery schedule . In fact, the potential therapeutic efficacy of an antibiotic depends not only on its spectrum of action, but also on the concentration it reaches at the site of infection . Most infections occur in the tissues of the body rather than in the blood and that it is accepted that appropriate antibiotic therapy requires the maintenance of significant concentrations of antibiotics at the site of infection in the lung long enough to eliminate the invading pathogen . Thus, the development of dosing schedules for most antimicrobials has been based on the postulate that drug levels need to be above the minimal inhibitory concentration (MIC) at this site for most or all the dosing interval . The selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUIC(0-24)/MIC ratio of less than 100O125 . Antimicrobial regimens that do not achieve these values cannot prevent the selective pressure that leads to overgrowth of resistant bacterial subpopulations . It has been suggested that resistance can be avoided with attention to dosing, since dosing which provides an AUIC(0-24)/MIC ratio of at least 100 appears to reduce the rate of the development of bacterial resistance . Unfortunately, very different serum or lung concentration profiles can result in the same AUIC(0-24)/MIC . High doses administered sufficiently may often completely prevent any possibility of attaining a selective concentration . Alternatively, an antibiotic which has good bactericidal potency and maintains tissue and/or serum concentrations greater than the MIC or, better, minimal bactericidal concentration (MBC) throughout the dosing interval is equally effective in minimizing the development of antibiotic resistance .

Expert Opin Investig Drugs, 2000 Aug, 9(8), 1815 - 27
Artemisinin drugs: novel antimalarial agents; Price RN; Artemisinin and its derivatives, artesunate and artemether, represent a new class of antimicrobial drug with potent activity against Plasmodium falciparum . Although they show excellent efficacy in both severe and uncomplicated malaria, dosage regimens still need to be optimised and pharmacokinetic profiles defined . In the treatment of uncomplicated malaria, the artemisinin drugs should be used in combination with a long acting antimalarial to protect both drugs against the emergence of resistance . In the treatment of severe malaria, parenteral artemether is at least as effective as quinine and is simpler to use . The use of rectal preparations of artesunate and artemisinin at the rural health level will facilitate early initiation of the treatment of falciparum malaria and this may reduce the proportion of patients progressing to severe disease . All of the artemisinin drugs have comparable efficacy; the choice of derivative should be based upon availability, cost and quality of the preparation . Artemisinin, artesunate and artemether are well-tolerated in both adults and children, with no evidence to date of serious clinical toxicity.

Expert Opin Investig Drugs, 2000 Aug, 9(8), 1731 - 42
Protegrins: new antibiotics of mammalian origin; Bellm L et al.; Protegrins and their derivatives are a new class of peptide antibiotics based on mammalian antimicrobial peptides . Their pharmacological properties include an unusually broad spectrum of antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi and some enveloped viruses . Preclinical and clinical studies of the lead compound, IB-367, developed for topical applications, show promise for the prevention of chemotherapy- and radiation-induced oral mucositis.

Expert Opin Investig Drugs, 2000 Feb, 9(2), 263 - 72
Cholic acid derivatives: novel antimicrobials; Savage PB et al.; Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding new antimicrobial agents . The squalamine mimics include the polyamine and sulphate functionalities found in the parent antibiotic, however, the positions relative to the steroid nucleus have been exchanged . The PMB mimics include the conservation of functionality among the polymyxin family of antibiotics, the primary amine groups and a hydrophobic chain . Although the squalamine and PMB mimics are morphologically dissimilar, they display similar activities . Both are simple to prepare and demonstrate broad spectrum antimicrobial activity against Gram-negative and Gram-positive organisms . Specific examples may be inactive alone, yet effectively permeabilise the outer membranes of Gram-negative bacteria rendering them sensitive to hydrophobic antibiotics . Problems associated with some of the squalamine and PMB mimics stem from their haemolytic activity and interactions with serum proteins, however, examples exist without these side effects which can sensitise Gram-negative bacteria to hydrophobic antibiotics.

J Gastroenterol Hepatol, 2000 Sep, 15(9), 1007 - 17
Pooled analysis of Helicobacter pylori eradication regimes in Asia; Wang WH et al.; BACKGROUND AND AIMS: Differences in Helicobacter pylori strains and their resistance to antimicrobials between Asian and Western countries may affect the success in eradicating this bacterium . Our objective was to systematically review the regimens that have been tested in Asia . METHODS: Data on anti-H . pylori therapies reported from Asia in a large number of publications identified up to December 1998 were pooled into a few groups based on the combination of drugs used . A comparison of different groups was made by calculating the pooled eradication rates . RESULTS: Seventy-three studies with 134 treatment arms were reviewed . Pooled eradication rates of dual, triple and quadruple therapies were 61.0, 86.5 and 93.4%, respectively . Proton pump inhibitor (PPI)-based combinations were more widely used and effective, with overall eradication rates of 90.7% in triple therapy and 93.4% in quadruple therapy . Bismuth combined with tetracycline and metronidazole also showed a high eradication rate of 92.0% . CONCLUSIONS: Proton pump inhibitor-based triple therapy with either clarithromycin, amoxycillin or metronidazole was one of the most commonly used and effective anti-H . pylori triple therapy regimens in Asia . The classical triple therapy with a bismuth, tetracycline and metronidazole combination has a similar efficacy . The results of anti-H . pylori treatment in Asia are not different from those in Western countries.

Pediatr Int, 2000 Oct, 42(5), 461 - 3
Child health in the new millennium; Gracey M; In today's modern, industrialized and affluent countries, like Japan and Australia, better living conditions and hygiene, plentiful nutritious food and rapid advances in biology and medical technologies have helped to bring about dramatic improvements in child health . The previous heavy burdens of infections and undernutrition have been eliminated or can now be controlled or effectively treated . In these countries, child health standards are higher than ever and expectation of life at birth is much higher than in the past . Some of the technological advances that have helped bring about this transformation are immunization, antimicrobial therapy, successful treatment of childhood leukemias, transplantation of vital organs and implementation of genetic diagnosis and gene therapy . The use of genetically modified foods and the prospects for cloning of humans are areas of intense interest and controversy . However, these advances have their disadvantages (e.g . antibiotic-induced drug resistance) . Urbanization has encouraged the 'westernization' of dietary patterns and the long-term 'lifestyle diseases' that can follow in adults . Accidents, violence and drug abuse are major problems in many parts of the world . Changes in attitudes to sexuality and the spread of HIV/AIDS is another major problem, especially in Africa and Asia . Environmental pollution and the degradation of agricultural lands, rivers and seas are also important . Ironically, standards of child health and the prospects for long life in countries like Japan are better than ever before, but social and environmental changes are presenting children and their carers with new and unanswered challenges as we enter the 21 st century and the new millennium.

Biochim Biophys Acta, 2000 Oct 18, 1482(1-2), 284 - 97
Immunocalins: a lipocalin subfamily that modulates immune and inflammatory responses; Logdberg L et al.; A subset of the lipocalins, notably alpha(1)-acid glycoprotein, alpha(1)-microglobulin, and glycodelin, exert significant immunomodulatory effects in vitro . Interestingly, all three are encoded from the q32-34 region of human chromosome 9, together with at least four other lipocalins (neutrophil gelatinase-associated lipocalin, complement factor gamma-subunit, tear prealbumin, and prostaglandin D synthase) that also may have anti-inflammatory and/or antimicrobial activity . This review addresses important features of this genetically linked subfamily of lipocalins (involvement with the acute phase response, immunomodulatory and anti-inflammatory properties, the tissue localization, complex formation with other proteins and receptors, etc.) . It is likely that these proteins have evolved to be an integrated part of the body's defense system as part of the extended cytokine network . Its members exert a regulatory, dampening influence on the inflammatory cascade, thereby protecting against tissue damage from excessive inflammation . That most major mammalian allergens are lipocalins may reflect this connection of lipocalins with the immune system . We propose that this immunologically active lipocalin subset be named the 'immunocalins', signifying not only the structural homology and close genetic linkage of its members, but also their protective involvement with immunological and inflammatory processes . As immune mediators, immunocalins appear to use at least three interactive sites: the lipocalin 'pocket', binding sites for other plasma proteins, and binding sites for cell surface receptors.

Proc Natl Acad Sci U S A, 2000 Nov 7, 97(23), 12723 - 8
An essential amino acid induces epithelial beta -defensin expression; Fehlbaum P et al.; Antimicrobial peptides constitute an important component of the mammalian innate immune response . Several types of antimicrobial peptides, including the beta-defensins, are produced at epithelial surfaces in response to infectious threats . Here we show that a class of small molecules, including l-isoleucine and several of its analogs, can specifically induce epithelial beta-defensin expression . This induction is transcriptional in nature and involves activation of the NF-kappaB/rel family of trans-activating factors . We hypothesize that these substances represent unique markers for the presence of pathogens and are recognized by innate immune pattern recognition receptors . Isoleucine or its analogs ultimately may have clinical utility as novel immunostimulants that could bolster the barrier defenses of mucosal surfaces.

Crit Care Med, 2000 Oct, 28(10), 3456 - 64
Inadequate treatment of nosocomial infections is associated with certain empiric antibiotic choices; Kollef MH et al.; OBJECTIVE: The purpose of this study was to determine the impact of scheduled changes of antibiotic classes, used for the empirical treatment of suspected or documented Gram-negative bacterial infections, on the occurrence of inadequate antimicrobial treatment of nosocomial infections . DESIGN: Prospective observational study . SETTING: Medical (19-bed) and surgical (18-bed) intensive care units in an urban teaching hospital . PATIENTS: A total of 3,668 patients requiring intensive care unit admission were prospectively evaluated during three consecutive time periods . INTERVENTIONS: During each time period, one antibiotic class was selected for the empirical treatment of Gram-negative bacterial infections as follows: time period 1 (baseline period) (1,323 patients), ceftazidime; time period 2 (1,243 patients), ciprofloxacin; and time period 3 (1,102 patients), cefepime . MEASUREMENTS AND MAIN RESULTS: The overall administration of inadequate antimicrobial treatment for nosocomial infections decreased during the course of the study (6.1%, 4.7%, and 4.5%; p = .15) . This was primarily because of a statistically significant decrease in the administration of inadequate antibiotic treatment for Gram-negative bacterial infections (4.4%, 2.1%, and 1.6%; p < .001) . There were no statistically significant differences in the overall hospital mortality rate among the three time periods (15.6%, 16.4%, and 16.2%; p = .828) despite a significant increase in severity of illness as measured with Acute Physiology and Chronic Health Evaluation (APACHE) II scores (15.3 +/- 7.6, 15.7 +/- 8.0, and 20.7 +/- 8.6; p < .001) . The hospital mortality rate decreased significantly during time period 3 (20.6%) compared with time period 1 (28.4%; p < .001) and time period 2 (29.5%; p < .001) for patients with an APACHE II score > or = 15 . CONCLUSIONS: These data suggest that scheduled changes of antibiotic classes for the empirical treatment of Gram-negative bacterial infections can reduce the occurrence of inadequate antibiotic treatment for nosocomial infections . Reducing inadequate antibiotic administration may improve the outcomes of critically ill patients with APACHE II scores > or = 15.

Am J Health Syst Pharm, 2000 Oct 15, 57 Suppl 2, S25 - 7
Benchmarking in health-system pharmacy: experience at MeritCare Medical Center; Nelson RE; The experience of MeritCare Medical Center (MMC) with the Benchmarking Program coordinated by The Clinical Pharmacokinetics Laboratory at Millard Fillmore Hospital is described . MMC is a community-based teaching institution in Fargo, North Dakota, that serves patients in North Dakota, South Dakota, and Minnesota . MeritCare began participating in the Benchmarking Program in 1997 . Data from the individual hospital report raised concern about the high cost of antimicrobials at MMC relative to peer-group institutions . The staff conducted an evaluation of antimicrobial prophylaxis for noncardiovascular surgery, concluded that cefazolin use was suboptimal, and attempted to encourage more cost-effective utilization . MMC's participation in the Benchmarking Program also prompted more appropriate use of various other antimicrobial agents, including i.v . and oral ciprofloxacin . An i.v.-to-oral switching program was begun for various agents . Preliminary analysis after 15 months demonstrated direct cost savings for drug acquisition of $60,000 to $80,000 per year and a reduced length of stay . Initiatives undertaken by MeritCare on the basis of data obtained through the Benchmarking Program resulted in substantial estimated savings in drug acquisition costs.

Am J Health Syst Pharm, 2000 Oct 15, 57 Suppl 2, S21 - 4
Benchmarking in health-system pharmacy: experience at Glens Falls Hospital; Huntington N; The experience of Glens Falls Hospital (GFH) with the Benchmarking Program coordinated by The Clinical Pharmacokinetics Laboratory at Millard Fillmore Hospital is described . GFH, a community hospital in upstate New York with 442 licensed beds, serves a patient population drawn from a five-county area . In 1998, GFH developed a multidisciplinary pharmacy task force charged with generating strategic initiatives for curtailing drug costs . Proposals for various programs, including specific goals, were developed with the aid of trends reported in the individual hospital reports provided by the Benchmarking Program . The data obtained through these reports helped GFH's pharmacy staff establish goals for the appropriate use of many agents, including vancomycin, and allowed GFH to assess the impact of its initiatives through comparisons with similar hospitals across the United States . In 1995, vancomycin expenditures at GFH substantially exceeded those for benchmark hospitals of similar types, but, with the implementation of new vancomycin guidelines aimed at reducing inappropriate use in 1996, the difference was eliminated . The individual hospital reports generated by the Benchmarking Program provide valuable data that can be used to assess pharmacy performance, set drug expenditure goals, and design programs to reduce antimicrobial resistance.

Am J Health Syst Pharm, 2000 Oct 15, 57 Suppl 2, S13 - 20
Benchmarking in health-system pharmacy: current research and practical applications; Bhavnani SM; The application of benchmarking techniques to hospital pharmacy practice is discussed . Benchmarking is a process designed to discover best practices through a comparison of various competing methods aimed at achieving a particular goal . Benchmarking antimicrobial drug utilization and rates of bacterial resistance through comparison with a multitude of similar hospitals can be used by an institution both to identify potential problem areas in its pharmacy practice and to aid in establishing appropriate and attainable goals . The effectiveness of various activities targeted at reducing appropriate drug use can also be benchmarked . In 1993, the Benchmarking Program was established at Millard Fillmore Hospital . This program consists of a network of hospital pharmacists who supply data on antimicrobial use, antimicrobial management activities, and rates of antimicrobial resistance . The program was designed both to serve hospital pharmacies in optimizing antimicrobial management and to create a national database for evaluating relationships among antimicrobial use, management, and resistance . Hospitals participating in the Benchmarking Program receive an annual report that allows them to compare themselves with peer groups and with best-performing "benchmark hospitals." All data from U.S . hospitals contained in the Benchmarking Program database are pooled and analyzed to identify meaningful trends . However, information gained from the institutionwide data must be supplemented by studies at the patient level . Benchmarking antimicrobial drug use in an institutional setting can identify successes as well as potential problem areas in pharmacy practice and aid in establishing appropriate and attainable goals.

J Health Popul Nutr, 2000 Sep, 18(2), 97 - 102
Perceived causes and management of diarrhoea in young children by market women in Enugu State, Nigeria; Ene-Obong HN et al.; The aim of the study was to determine the perceptions of mothers regarding the causes and management of diarrhoea of their children aged 0-24 months . In Enugu State, Nigeria, 80 market women whose children had diarrhoea during last 6 months were interviewed fortnightly . When possible, the children were observed to determine the types of diarrhoea and treatments given . Fifty-three of the women brought their children to market, and 27 left their children at home . Seventy-one percent of the mothers perceived that diarrhoea was caused by teething . The most common types of diarrhoea occurring in these children were watery diarrhoea (59%) and the so-called teething diarrhoea (29%) . Dysentery (6%) and jedi jedi or frothy and mucoid stools (4%) occurred less frequently . In 68% of the cases, drugs were used alone or in conjunction with salt-sugar solution (SSS) or other forms of treatment . These drugs were prescribed by medical personnel (40%), patent medicine dealers (23%), or mothers themselves (30%) . About 26% and 39% of the mothers treated, respectively, watery and teething diarrhoeas with drugs only, while 23% used SSS alone . The drugs used were mainly antimicrobials (34%) and a combination of antimicrobial, antimalarial, antacid, analgesic, and some local herbal preparations (21%) . The results of the study showed the evidence of unnecessary use of drugs and ignorance about their potential adverse effects . These underscore the need for appropriate primary care education among the market women in Nigeria.

J Biochem (Tokyo), 2000 Nov, 128(5), 745 - 54
Functional mapping against Escherichia coli for the broad-spectrum antimicrobial peptide, thanatin, based on an in vivo monitoring assay system; Taguchi S et al.; Previously, we established for the first time an in vivo monitoring assay system conjugated with random mutagenesis in order to study the structure-function relationship of the antimicrobial peptide, apidaecin {Taguchi et al . (1996) Appl . Environ . Microbiol . 62, 4652-4655} . In the present study, this methodology was used to carry out the functional mapping of a second target, thanatin, a 21-residue peptide that exhibits the broadest antimicrobial spectrum so far observed among insect defense peptides {Fehlbaum et al . (1996) Proc . Natl . Acad . Sci . USA 93, 1221-1225} . First, a synthetic gene encoding thanatin was expressed in a fused form with Streptomyces protease inhibitor protein, SSI, under the control of tac promoter in Escherichia coli JM109 . Expression of the thanatin-fused protein was found to depend on the concentration of the transcriptional inducer, isopropyl-beta-D-thio-galactopyranoside (IPTG), and to parallel the degree of growth inhibition of the transformant cells . When a PCR random mutation was introduced into the structural gene for thanatin, diminished growth inhibition of the IPTG-induced transformed cells was mostly observed in variants as measured by colony size (plate assay) or optical density (liquid assay) in comparison with the wild-type peptide, possibly depending on the decreased antimicrobial activity of each variant . Next, wild-type thanatin and three variants screened by the in vivo assay, two singly mutated proteins (C11Y and M21R) and one doubly mutated protein (K17R/R20G), were stably overproduced with a fusion partner protein resulting in the efficient formation of inclusion bodies in E . coli BL21(DE3) . The products were isolated in large amounts (yield 30%) from the fused protein by successive chemical and enzymatic digestions at the protein fusion linker site . Anti-E . coli JM109 activities, judged by minimum inhibitory concentration, of the purified peptides were in good agreement with those estimated semi-quantitatively by the in vivo assay . Based on the NMR solution structure and molecular dynamics, the structure-function relationship of thanatin is discussed by comparing the functional mapping data obtained here with the previous biochemical data . The functional mapping newly suggests the importance of a hydrogen bonding network formed within the C-terminal loop joining the beta-strands arranged antiparallel to one another that are supposed to be crutial for exhibiting anti-E . coli activity.

Crit Care, 1997, 1(1), 45 - 50
Beneficial effect of carboxy-PTIO on hemodynamic and blood gas changes in septic shock dogs; Mitaka C et al.; BACKGROUND: Nitric oxide (NO) production following bacterial infection may play a physiological role in the host defense mechanism due to its antimicrobial activity . However, excess production of NO in severe infection such as sepsis has been implicated in the pathogenesis of septic shock . To determine whether a nitronyl nitroxide NO scavenger compound could prevent the hemodynamic and blood gas alterations in sepsis, bacterial lipopolysaccharide (LPS: 250ng/kg/min) was administered for 2 h in anesthetized dogs with or without infusion of carboxy-2-phenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO: 0.1 mg/kg/min) for 1 h . Control animals received isotonic saline instead of LPS with or without carboxy-PTIO . RESULTS: Infusion of LPS caused a marked decrease in mean arterial pressure (MAP), metabolic acidosis, and hypoxia . These effects were reversed by co-administration of carboxy-PTIO, without affecting other hemodynamic parameters . In control animals, neither hemodynamic nor blood gas parameters changed with or without carboxy-PTIO . CONCLUSION: These results indicate that carboxy-PTIO attenuates LPS-induced hypotension, metabolic acidosis, and hypoxia by scavenging excess NO from the circulation without affecting NO synthase (NOS) activity . An NO scavenger, carboxy-PTIO, may be preferable to non-selective NOS inhibitors for the treatment of human septic shock.

Appl Environ Microbiol, 2000 Nov, 66(11), 4798 - 802
Engineering increased stability in the antimicrobial peptide pediocin PA-1; Johnsen L et al.; Pediocin PA-1 is a food grade antimicrobial peptide that has been used as a food preservative . Upon storage at 4 degrees C or room temperature, pediocin PA-1 looses activity, and there is a concomitant 16-Da increase in the molecular mass . It is shown that the loss of activity follows first-order kinetics and that the instability can be prevented by replacing the single methionine residue (Met31) in pediocin PA-1 . Replacing Met by Ala, Ile, or Leu protected the peptide from oxidation and had only minor effects on bacteriocin activity (for most indicator strains 100% activity was maintained) . Replacement of Met by Asp was highly deleterious for bacteriocin activity.

Phytother Res, 2000 Nov, 14(7), 561 - 3
In vitro antimicrobial activity of extracts and isolated constituents of Geum rivale; Panizzi L et al.; The antimicrobial activity of extracts of Geum rivale (Rosaceae) and that of some isolated constituents, on bacteria and fungi, was evaluated . The activity was concentrated in the triterpenes fraction and, for gram+ and gram- bacteria, also in the flavonoids fraction .

Int J Antimicrob Agents, 2000 Oct, 16(2), 185 - 7
Multinational cooperation in trials and guidelines dealing with febrile neutropenia; Feld R; Multinational cooperation has lead to many of the advances in the therapy of cancer patients with febrile neutropenia over the last two decades and will likely continue to do so . Some of the groups and societies that have contributed to this success include the European Organization for Research and Treatment of Cancer (EORTC) Antimicrobial Group, The Immunocompromised Host Society (ICHS), the Multinational Association for Supportive Care in Cancer (MASCC) infection subcommittee and the International Disease Society of America (IDSA) . Some of these contributions are described in this manuscript . Without this approach the data from single institutions may not have been so well accepted in centers all over the world . Multinational cooperation in this field along with better antimicrobials have contributed significantly to the drop in mortality in 'high risk patients' from >50% in the 1950s and 1960s to 5-10% noted in most recently published studies.

Int J Antimicrob Agents, 2000 Oct, 16(2), 177 - 80
Febrile neutropenia in allogeneic transplantation; De Bock R et al.; Infections post allogeneic bone marrow transplant (BMT) are a major problem . Post BMT, three periods with infectious complications are discerned: pre-engraftment and early recovery, mid recovery and late recovery . In the first period mucosal damage and neutropenia are the major host defence deficits . Bacterial infections with Gram-positive and Gram-negative organisms, and fungal infections are seen in this period . In the mid recovery phase graft versus host and its treatment contribute to diminished host defences . Viral infections and fungal infections predominate . In the late recovery phase chronic graft versus host reaction impairs the monocyte macrophage function and CD4 counts are low . In this phase patients are at risk for infections with encapsulated bacteria, fungi, Pneumocystis carinii and Toxoplasma . Strategies for the management of febrile neutropenia are similar to those in 'high risk' neutropenic patients: immediate broad spectrum I.V . antibiotics (3rd or 4th generation cephalosporin+/-aminoglycoside or carbapenem) and early amphothericin B (lipid formulation) if fever persists beyond 5 days despite adequate I.V . antibiotics . Cytomegalovirus (CMV) prophylaxis or better preemptive therapy guided by viraemia is accepted practice . Prevention of infection measures, antimicrobial, antifungal and viral prophylaxis are generally accepted strategies but would differ from center to center . The post transplant infection history will change with different transplant techniques and evolving prophylactic and preemptive treatments.

Int J Antimicrob Agents, 2000 Oct, 16(2), 173 - 6
Febrile neutropenia in children; Crokaert F; Fever is frequent in neutropenic patients and often related to infection . Two major concepts, have contributed to the marked mortality decrease of those patients by the end of the 1960s: firstly, the duration and severity of neutropenia were the most important variables linked to infection and secondly, prompt administration of broad-spectrum antimicrobials empirically, was life-saving . At the same time it was universally admitted that a careful daily examination of all portals of entry for micro-organisms was mandatory and that laboratory and imaging investigations were needed at regular intervals, keeping constantly in mind the individual type and stage of immunosuppression . Through many studies, paediatricians contributed markedly in standardisation of management of febrile neutropenic patients . Neutropenic patients are not equally prone to infections, partly due to the underlying cancer, chemotherapy and co-morbidity factors . Neutropenic children are not only vulnerable to bacteria, fungi and viruses commonly encountered in adults, but also to common viruses and bacteria . Very few studies included a viral work-up . Epidemiological new trends are observed: Gram-positive bacteria and fungi are on the rise . Simplifying and shortening antibiotic regimens were made possible because new potent antibiotics were launched . Since the mid-1980s, many paediatric centres commonly discharge patients before complete bone marrow recovery, provided that patients meet certain low-risk criteria and do not exhibit any clinical or biological evidence of bacterial infection . However, a few prospective randomised studies have been conducted for assessing the safety of early antibiotics discontinuation and safe early discharge . The choice of oral agents up to now was complicated by the reluctance using fluoroquinolones in children . New challenges are numerous in terms of diagnostic tools, detection of epidemiological trends and emerging pathogens, identification and control of nosocomial threats including drug resistance, assessment of the real impact of prophylaxis, evaluation of new agents, the need for more accurate risk scoring systems, outpatient management and the necessity for an optimal use of resources.

Int J Antimicrob Agents, 2000 Oct, 16(2), 165 - 8
Intravenous access: related problems in oncology; Viot M; This article reviews the latest developments in the literature concerning two types of catheter widely used in oncology: Hickman central venous catheters (CVCs) and totally implanted venous ports . It now seems possible to diagnose catheter-related bloodstream infections (CRBI) without removing the device; recent studies showed that paired quantitative blood cultures are the most reliable and convenient method for diagnosis of CRBI . Can CRBI be cured and treated without device removal? A decision-tree/flow-chart resulting from analysis of international data by French International Experts is presented . Futures trends are reviewed: new techniques for prevention, including catheters impregnated with antimicrobials and, antiseptic hubs; flushing and antibiotic lock techniques that can be used both for prevention and treatment.

Int J Antimicrob Agents, 2000 Oct, 16(2), 139 - 41
Modifications of therapy; Kern WV; Rates of response to empirical therapy in the neutropenic patient with fever, range between 40 and 90% . Modifications of therapy are needed in patients who do not respond but may also be considered in patients who respond . In patients with unexplained fever and rapid defervescence, switch to oral therapy is an acceptable option and there is no need to continue the regimen until neutrophil recovery . Neutropenic patients with persistent undefined fever and those with progressive pneumonia benefit from the addition of antifungals while the empiric addition of a glycopeptide is unlikely to be effective . In patients with gram-negative bacterial infection initially treated with monotherapy, response may be increased after the addition of an aminoglycoside . In cases of a defined etiology, the institution of narrow-spectrum antimicrobials in a persistent neutropenic patient carries a substantial risk for superinfection and is not generally recommended . Improved diagnostic tools and sensitive clinical risk-assessment methods will allow selecting and targeting therapy modifications better.

Int J Antimicrob Agents, 2000 Oct, 16(2), 87 - 9
Laboratory diagnosis of infections in febrile neutropenic or immunocompromised patients; Bille J; Laboratory diagnosis of infections in febrile neutropenic or immunocompromised patients is particularly challenging, and covers the most frequent clinical presentations such as bloodstream infections, lung, CNS and skin infections, as well as invasive fungal infections . Classic methods such as direct examination, culture and tests for susceptibility are being more complemented by molecular detection of microorganisms (PCR in particular) and antigen detection in various body fluids or tissues; two promising methods which offer the advantage of speed and high sensitivity even after starting antimicrobial therapy.

Free Radic Biol Med, 2000 Oct 15, 29(8), 730 - 5
Cellular dissociation of NF-kappaB and inducible nitric oxide synthase in Helicobacter pylori infection; Zhang X et al.; The transcription factor nuclear factor kappaB (NF-kappaB) regulates the expression of inducible nitric oxide synthase (iNOS) . We hypothesized that induction of iNOS in Helicobacter pylori gastritis may be due to NF-kappaB activation . Antral biopsy specimens from Helicobacter pylori-infected gastritis patients were collected before (n = 30) and after antimicrobial therapy to clear the infection (n = 22) . Biopsies were assessed for NF-kappaB by immunohistochemistry (p65) . The mRNA and protein of iNOS were localized by in situ RT-PCR and immunohistochemistry . Both of iNOS protein and mRNA were evident in stromal inflammatory cells, but absent in epithelia . Antimicrobial therapy resulted in a 73% reduction in iNOS levels (protein, p <.002) . Nuclear staining for NF-kappaB p65 was evident in epithelial cells, especially in the neck region of gastric glands, and inflammatory cells . Treatment to clear H . pylori infection resulted in a 74% reduction in the epithelial staining for NF-kappaB p65 (p =.0001), whereas the lamina propria staining was unaltered . In conclusion, H . pylori infection activates NF-kappaB and iNOS expression . However, as the changes in NF-kappaB and iNOS with H . pylori clearance occurred in different cell types (epithelial vs . inflammatory), it appears that a NF-kappaB-dependent epithelial-derived mediator may be responsible for the induction of iNOS expression.

J Nutr, 2000 Nov, 130(11), 2797 - 801
Glucose is absorbed in a sodium-dependent manner from forestomach contents of sheep; Aschenbach JR et al.; Intraruminal glucose is thought to be completely converted to short-chain fatty acids (SCFA) by symbiotic microorganisms . Nevertheless, earlier in vitro studies evidenced the expression of the sodium glucose-linked transporter (SGLT)-1, in the ovine ruminal epithelium . The present study aimed to determine whether the ruminal SGLT-1 is functionally important in vivo . In a first experimental series using the emptied, washed, and isolated reticulorumen of sheep, 6.3% of glucose was absorbed from an intraruminal buffer solution (2 L, 128 mmol/L Na(+), 0.5 mmol/L glucose, 0 mmol/L galactose) within 30 min (P < 0.001) . Reducing Na(+) concentration to 10 mmol/L resulted in complete inhibition of glucose absorption, and the addition of 10 mmol/L galactose (at 128 mmol/L Na(+)) induced a small but insignificant inhibition . In a second experimental series, the addition of 12 mmol/L glucose to an initially glucose-free buffer led to an increase in the transruminal potential difference from 34.4 to 37.1 mV within 4 min (P < 0.001) . From the 12 mmol/L glucose-containing buffer, 11.0% of glucose was absorbed within 30 min (P < 0.05) . In all experiments, microbial glucose degradation in the reticulorumen was prevented by adding cefuroxime (100 mg/L) and colistin methanesulfonate (25 mg/L) to the buffer solution . The effectiveness of antimicrobial treatment was verified by ex vivo incubations of buffer samples drawn from the reticulorumen . We conclude that glucose is absorbed in a sodium-dependent manner from the reticulorumen at low and high glucose concentrations . Absorption at high glucose concentrations is of nutritional importance because it counteracts the genesis of ruminal lactic acidosis.

Am J Physiol Lung Cell Mol Physiol, 2000 Nov, 279(5), L799 - 805
Synergistic and additive killing by antimicrobial factors found in human airway surface liquid; Singh PK et al.; Airway surface liquid contains multiple factors thought to provide a first line of defense against bacteria deposited in the airways . Although the antimicrobial action of individual factors has been studied, less is known about how they work in combination . We examined the combined action of six antimicrobial peptides found in airway surface liquid . The paired combinations of lysozyme-lactoferrin, lysozyme-secretory leukocyte protease inhibitor (SLPI), and lactoferrin-SLPI were synergistic . The triple combination of lysozyme, lactoferrin, and SLPI showed even greater synergy . Other combinations involving the human beta-defensins, LL-37, and tobramycin (often administered to cystic fibrosis patients by inhalation) were additive . Because the airway surface liquid salt concentration may be elevated in cystic fibrosis patients, we examined the effect of salt on the synergistic combinations . As the ionic strength increased, synergistic interactions were lost . Our data suggest that the antibacterial potency of airway surface liquid may be significantly increased by synergistic and additive interactions between antimicrobial factors . These results also suggest that increased salt concentrations that may exist in cystic fibrosis could inhibit airway defenses by diminishing these synergistic interactions.

J Agric Food Chem, 2000 Oct, 48(10), 5030 - 4
Comparison of antioxidant and antimicrobial activities of tilia (Tilia argentea Desf ex DC), sage (Salvia triloba l.), and black tea (Camellia sinensis) extracts; Yildirim A et al.; The antioxidant activity of the water extract of Tilia argentea Desf ex DC was determined by the thiocyanate method . The antioxidant activity of the water extract increased with the increasing amount of lyophilized extract (50-400 microg) added into the linoleic acid emulsion . Statistically significant effect was determined in 100 microg and higher amounts . Antioxidant activities of water extracts of tilia (Tilia argentea Desf ex DC), sage (Salvia triloba L.), and two Turkish black teas commercially called Rize tea and young shoot tea (Camellia sinensis) were compared . For comparison studies, 100 microg portions of extracts were added into test samples . All samples were able to show statistically significant antioxidant effect . Both of the tea extracts showed highest antioxidant activities, nevertheless, differences between tilia and sage and tilia and tea were not statistically significant (for both cases p > 0.05) . Like antioxidant activity, the reducing power of water extract of Tilia argentea Desf ex DC was also concentration dependent . Even in the presence of 50 microg of extract, the reducing power was significantly higher than that of the control (p < 0.05) in which there was no extract . Unlike antioxidant activity, the highest reducing power activity was shown by sage extract . Among the tea extracts, young shoot extract was the most effective one, however, it had significantly lower activity than sage (p < 0.05) . Although tea flower had the lowest reducing power activity, it was higher than that of tilia . But this difference was not statistically significant (p > 0.05) . From these results, we could suggest that although the reducing power of a substance may be an indicator of its potential antioxidant activity, there may not always be a linear correlation between these two activities . In addition, antimicrobial activities of each of the above extracts were studied by disk diffusion methods on different test microorganisms . None of the extracts showed antibacterial activity on the studied microorganisms.

J Agric Food Chem, 2000 Oct, 48(10), 4984 - 90
Lactoferrin in infant formulas: effect on oxidation; Satue-Gracia MT et al.; Lactoferrin is an iron transport protein present in human milk at an average concentration of 1.4 mg/mL . Commercially modified infant formulas based on cow's milk contain much lower amounts of lactoferrin (0.1 mg/mL lactoferrin) and soy based formulas have none . In addition to its role in iron transport, lactoferrin has bacteriostatic and bactericidal activities . Infant formulas are supplemented with relatively large amounts of iron (up to 12 mg/L) . The effect of various concentrations of added lactoferrin and supplemental iron on lipid oxidation was tested in two different infant formulas . The extent of oxidation in the formulas as a function of time was determined by formation of hydroperoxides, production of hexanal, and fluorescence . On the basis of all three of these determinations, lactoferrin acted as an antioxidant in the absence and presence of different concentrations of supplemented iron . Lactoferrin inhibited oxidation in a concentration-dependent manner even at concentrations beyond its capacity to bind iron at its two high affinity binding sites . Lactoferrin can be used, therefore, as a dual purpose additive in infant formulas and similar food products for its antioxidant and its antimicrobial properties.

Semin Respir Infect, 2000 Sep, 15(3), 248 - 57
Treatment of hospital-acquired penumonia; Markewitz BA et al.; Hospital-acquired pneumonia (HAP) remains a significant cause of morbidity and attributable mortality, especially among patients undergoing mechanical ventilation . The clinical approach to this disorder continues to evolve . Although our understanding of the epidemiology, risk factors, and pathogenesis of this disorder are expanding, consensus on diagnostic, therapeutic, and preventive strategies is lacking . Although outcome is significantly improved by the rapid introduction of appropriate antimicrobial therapy, presently available diagnostic tests rarely are able to identify a specific pathogen when antimicrobial choices are made . Thus, most therapy is by necessity empirical . The American Thoracic Society (ATS) published guidelines for the empiric treatment of HAP in 1996, this article reviews the recommendations of these guidelines and, if new information is available, updates these recommendations.

Pediatr Infect Dis J, 2000 Oct, 19(10 Suppl), S114 - 6
Consumer and market use of antibacterials at home; Rosenberg S; In this increasingly complex, time-constrained world, consumers will continue to look for solutions that promise them peace of mind . A large component of this peace of mind is perceived as personal safety against infectious agents . Manufacturers have a responsibility to provide sound advice and to develop solutions to consumers' questions . Through working with leaders in the infection control field, as well as governmental organizations like the Centers for Disease Control and Prevention, the Food and Drug Administration and the Environmental Protection Agency, manufacturers can develop faster and more effective disinfectant and antimicrobial products . Targeted education programs are needed that clearly and effectively communicate proper infection control techniques and prudent use of antibacterial products to both the consumer and the health professional . Manufacturers should also work closely with the media to educate the public about the potential benefits and risks of their products . Finally manufacturers of household and personal cleaning products should help set guidelines for regulatory monitoring, including correct definition and use of common terms such as antibacterial, antimicrobial, antiviral and sanitization, as well as the extent of protection the consumer can expect from the product.

J Org Chem, 2000 Oct 6, 65(20), 6412 - 7
Ascosalipyrrolidinone A, an antimicrobial alkaloid, from the obligate marine fungus Ascochyta salicorniae; Osterhage C et al.; From the green alga Ulva sp., the endophytic and obligate marine fungus Ascochyta salicorniae was isolated . A . salicorniae was mass cultivated and found to produce the unprecedented and structurally unusual tetramic acid containing metabolites ascosalipyrrolidinones A (1) and B (2) . Additionally, the new natural product ascosalipyrone (3) and the known metabolites 4 and 5 were obtained . Ascosalipyrrolidinone A (1) has antiplasmodial activity toward Plasmodium falciparum strains K1 and NF 54, as well as showing antimicrobial activity and inhibiting tyrosine kinase p56lck.

J Antimicrob Chemother, 2000 Sep, 46 Suppl 1, 9 - 14; discussion 63-5
Comparative potency of mecillinam and other beta-lactam antibiotics against Escherichia coli strains producing different beta-lactamases; Sougakoff W et al.; The activity of mecillinam, a beta-lactam antibiotic with high affinity for gram-negative penicillin-binding protein 2 (PBP2), was assessed against ampicillin-resistant Escherichia coli strains producing beta-lactamases representing the three molecular classes, A (TEM-1 and -3, SHV-3 and IRT-5), C (AmpC) and D (OXA-3) . The antimicrobial activity of mecillinam and other beta-lactam antibiotics was evaluated by determining their MICs on Mueller-Hinton agar . The time course of hydrolysis in crude extracts prepared from the various beta-lactamase-producing strains was also measured and was used to determine the relative rate of hydrolysis and the apparent affinity for ampicillin, cephalothin and mecillinam . When compared with the other beta-lactam antibiotics, mecillinam demonstrated significantly greater antibacterial potency and higher stability to beta-lactamase hydrolysis in TEM-, IRT- and AmpC-producing isolates . These findings confirm that the antimicrobial potency of mecillinam compares favourably with those of the other penicillins included in the present study, suggesting that mecillinam use in the treatment of infections caused by gram-negative bacteria should be re-evaluated.

Am J Gastroenterol, 2000 Oct, 95(10), 2762 - 7
Influence of Helicobacter pylori eradication therapy on 13C aminopyrine breath test: comparison among omeprazole-, lansoprazole-, or pantoprazole-containing regimens; Giannini E et al.; OBJECTIVE: Proton pump inhibitors and antimicrobial agents are widely used to eradicate Helicobacter pylori (H . pylori) infection . In the general population the prevalence of infection and of polypharmacy increases the possibility of drug-drug interactions during H . pylori eradication therapy . The purpose of the present study was to assess the prevalence, degree, and clinical relevance of metabolic interference with the cytochrome P450 enzymatic system occurring during 1 wk of administration of omeprazole, lansoprazole, or pantoprazole followed by the association of clarithromycin and metronidazole for another week . The 13C aminopyrine breath test (ABT) was chosen to screen for possible interactions . METHODS: We studied 30 patients referred to our Unit for H . pylori eradication therapy . They were randomized to receive either omeprazole (20 mg b.i.d.), lansoprazole (30 mg b.i.d.), or pantoprazole (40 mg b.i.d.) for 2 wk . During the second week clarithromycin (250 mg b.i.d.) and metronidazole (500 mg b.i.d.) were added . ABT was performed before, and at the end of the first and second week of therapy . Percentage of the administered dose of 13C recovered per hour at the peak (percent 13C dose/h at the peak) and cumulative percentage of administered dose of 13C recovered over time at 120 min (percent 13C dose cum120) were the ABT evaluated parameters . RESULTS: At baseline all patients showed a normal liver function . In individual patients during treatment we observed various liver metabolic interactions both as inhibition and induction, as well as after the first and the second week of therapy . However, mean modifications of the ABT parameters during the 2 weeks of therapy were not statistically significant compared to baseline values . None of the patients who had ABT variations complained of side effects . CONCLUSIONS: H . pylori eradication therapy interferes with cytochrome P450-dependent liver metabolic activity . However, the clinical relevance of these metabolic interactions is not yet apparent, and further investigation is needed . H . pylori eradication therapy appears safe, but these interactions should be considered in the choice of proton pump inhibitor and antimicrobial agents.

J Am Acad Dermatol, 2000 Oct, 43(4 Suppl), S57 - 69
Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis; Bohn M et al.; Ciclopirox is a synthetic hydroxypyridone antifungal agent . In contrast to the azoles, glucuronidation is the main metabolic pathway of ciclopirox; therefore interactions with drugs metabolized via the cytochrome P450 system are unlikely Ciclopirox is also distinct from the common systemic agents, which interfere with sterol biosynthesis . In fact, ciclopirox chelates trivalent cations (such as Fe3+), inhibits metal-dependent enzymes that are responsible for degradation of toxic metabolites in the fungal cells, and targets diverse metabolic (eg, respiratory) and energy producing processes in microbial cells . Ciclopirox is a broad spectrum antimicrobial with activity against all the usual dermatophytes as well as yeast and nondermatophyte molds . It has demonstrated activity against gram positive and negative bacteria, including resistant strains of Staphlococcus aureus . Ciclopirox exhibits fungal inhibitory activity (minimum inhibitory concentration < 4 microg/mL for dermatophytes) as well as fungicidal activity; to date resistance to the drug has not been identified . Ciclopirox has been formulated in a nail lacquer delivery system . After evaporation of volatile solvents in the lacquer, the concentration of ciclopirox in the remaining lacquer film reaches approximately 35%, providing a high concentration gradient for penetration into the nail . Radiolabel data demonstrate penetration into infected nails after only 1 application of the lacquer . Ciclopirox nail lacquer is a topical product that provides an active fungicidal agent in a delivery system capable of promoting nail penetration . With repeated applications, the antifungal agent is homogeneously distributed through all layers of the toenail achieving concentrations of ciclopirox in excess of inhibitory and fungicidal concentrations for most pathogens . Although ciclopirox readily penetrates nails, very low levels of ciclopirox are recoverable systemically, even after chronic use . Ciclopirox nail lacquer 8% is a topical product that provides an active fungicidal agent in a delivery system capable of penetrating nails.

Rev Med Chil, 2000 Jul, 128(7), 758 - 65
{Prevalence of the Chlamydia trachomatis in neonatal conjunctivitis determination by indirect fluorescence and gene amplification}; Valencia C et al.; BACKGROUND: Chlamydia trachomatis is one of the most common identifiable infectious agents in neonatal conjunctivitis . It also causes pneumonitis, that is preceded by conjunctivitis in one third of cases . AIM: To asses the prevalence of Chlamydia trachomatis in newborns with conjunctivitis . PATIENTS AND METHODS: In 162 newborns, coming from 14 Primary Health Centers from Santiago de Chile, C . trachomatis was detected by indirect fluorescence and two polymerase chain reaction (PCR 1 and 2), which amplified different sequences from the common endogenous plasmid . Those patients with positive indirect fluorescence and PCR 2 were defined as infected: RESULTS: The prevalence of C . trachomatis was 8%, and the distribution of the positive cases was similar in the different Health Centers . Other isolates were: S . aureus (9.8%), S . pneumoniae (8%), S . viridans (6.2%) y H . influenzae (5.5%) . CONCLUSIONS: The prevalence of C . trachomatis in neonatal conjunctivitis in Chile is similar to that of developed countries . Therefore, C . trachomatis should be considered in the election of antimicrobials for the treatment of neonatal conjunctivitis, to avoid ocular and respiratory complications.

J Biol Chem, 2001 Feb 9, 276(6), 4085 - 92 Epub 2000 Oct 26.
Insect immunity . Constitutive expression of a cysteine-rich antifungal and a linear antibacterial peptide in a termite insect; Lamberty M et al.; Two novel antimicrobial peptides, which we propose to name termicin and spinigerin, have been isolated from the fungus-growing termite Pseudacanthotermes spiniger (heterometabole insect, Isoptera) . Termicin is a 36-amino acid residue antifungal peptide, with six cysteines arranged in a disulfide array similar to that of insect defensins . In contrast to most insect defensins, termicin is C-terminally amidated . Spinigerin consists of 25 amino acids and is devoid of cysteines . It is active against bacteria and fungi . Termicin and spinigerin show no obvious sequence similarities with other peptides . Termicin is constitutively present in hemocyte granules and in salivary glands . The presence of termicin and spinigerin in unchallenged termites contrasts with observations in evolutionary recent insects or insects undergoing complete metamorphosis, in which antimicrobial peptides are induced in the fat body and released into the hemolymph after septic injury.

Aliment Pharmacol Ther, 2000 Oct, 14 Suppl 3, 55 - 8
Review article: Helicobacter pylori: where are we and where are we going?
Tytgat GN.
This paper contains a personal view on what has been achieved in Helicobacter pylori research and what the expectations might be for further developments . Knowledge about the organism is already extensive . Particularly intriguing are the differences in genetic make-up in the various geographical regions . Sadly, detailed knowledge on how the organism spreads is still lacking . The clinical spectrum of the disease in man is largely known, but as H . pylori is disappearing worldwide, the relative frequency of H . pylori-negative ulcer disease is increasing . To what extent H . pylori disappearance and eradication is responsible for the decreasing incidence of gastric cancer remains uncertain . Antimicrobial therapy is dominated by proton pump inhibitor triple therapy as first line with quadruple therapy as second-line therapy . The long-term consequences of the rising resistance to the 'key' antimicrobials are so far unknown and speculative.

Curr Opin Microbiol, 2000 Oct, 3(5), 522 - 7
Will genomics revolutionize antimicrobial drug discovery?
Black T, Hare R.
Utilizing genome sequence data from bacterial and fungal pathogens for the discovery of new antimicrobial agents has received considerable attention, both practical and critical, from the pharmaceutical and biotechnological communities . Although no new drugs derived from genomics-based discovery have been reported to be in a development pipeline, the utilization of genomics has revolutionized many aspects of drug discovery . The application, utility, opportunity, and challenges afforded by many of these new approaches are discussed.

Curr Opin Microbiol, 2000 Oct, 3(5), 515 - 21
Pharmacodynamics in the study of drug resistance and establishing in vitro susceptibility breakpoints: ready for prime time; Dudley MN et al.; Considerable advancements have been made in providing informative, relevant interpretations of the results of antimicrobial susceptibility tests to clinicians, clinical microbiologists, epidemiologists, and researchers . At the same time, the science of pharmacokinetics has flourished, and the importance of drug exposure in vivo on outcome is now recognized by researchers and clinicians alike . More recently, pharmacokinetic and quantitative measures of antimicrobial susceptibility have been integrated using pharmacokinetic-pharmacodynamic (PK-PD) models to forecast clinical and microbiological outcomes . Stochastic methods utilizing patient population pharmacokinetics, target organism minimum inhibitory concentration (MIC) distributions, and PK-PD targets from non-clinical models of infection or clinical data have established a new paradigm for determining in vitro susceptibility breakpoints and selection of empirical therapy in clinical practice . Given the increasing problem of antimicrobial resistance, these new tools are valuable additions for clinicians, researchers, and regulatory authorities.

Curr Opin Microbiol, 2000 Oct, 3(5), 496 - 501
Antimicrobial use and bacterial resistance; Monroe S et al.; The current epidemic of bacterial resistance is attributed, in part, to the overuse of antibiotics . Recent studies have documented increases in resistance with over-use of particular antibiotics and improvements in susceptibility when antibiotic use is controlled . The most effective means of improving use of antibiotics is unknown . Comprehensive management programs directed by multi-disciplinary teams, computer-assisted decision-making, and antibiotic cycling have been beneficial in controlling antibiotic use, decreasing costs without impacting patient outcomes, and possibly decreasing resistance.

Eur J Pharmacol, 2000 Oct 27, 407(1-2), 197 - 204
Tryptanthrin inhibits nitric oxide and prostaglandin E(2) synthesis by murine macrophages; Ishihara T et al.; Nitric oxide (NO) and prostaglandins have been implicated in the pathogenesis of several inflammatory diseases . In this study, we investigated the effect of tryptanthrin (6,12-dihydro-6, 12-dioxoindolo-(2,1-b)-quinazoline), an antimicrobial and antitumoral plant compound isolated from Porigonum tinctorium, on NO and prostaglandin E(2) production by interferon-gamma and lipopolysaccharide-stimulated murine macrophage-like RAW 264.7 cells . Tryptanthrin markedly inhibited both NO and prostaglandin E(2) production in a dose-dependent manner . Tryptanthrin at 20 microM fully inhibited expression of inducible NO synthase, suggesting that the inhibitory effect on NO synthesis was mediated by inhibited expression of the enzyme . On the other hand, tryptanthrin had no effect on the levels of cyclooxygenase-2 protein, but inhibited cyclooxygenase enzyme activity with a ICM(50) value of 1.5 microM . Thus, tryptanthrin has the dual functions of inhibiting both NO and prostaglandin E(2) production by activated macrophages, suggesting that tryptanthrin exhibits anti-inflammatory properties.

Blood, 2000 Nov 1, 96(9), 3086 - 93
The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations; Agerberth B et al.; We identified antibacterial components in human T and natural killer (NK) cells by using freshly isolated lymphocytes enriched for T and NK cells as starting material . After growing these lymphocytes for 5 days in the presence of interleukin (IL)-2, we isolated and characterized several antibacterial peptides/proteins from the supernatant-alpha-defensins (HNP 1-3), LL-37, lysozyme, and a fragment of histone H2B-although other active components were also present . We then used reverse transcriptase-polymerase chain reaction to search for expression of the gene coding for LL-37 in several B-cell lines, gammadelta T-cell lines, NK clones, and one monocytic cell line, with positive results, but found no expression in several alphabeta T-cell lines . The alpha-defensins (HNP 1-3) were also found to be expressed in several of these cell lines . To confirm the presence of these antibacterial peptides in lymphocytes, we localized them to NK, gammadelta T cells, B cells, and monocytes/macrophages by using double-staining immunohistochemical analysis of freshly isolated lymphocytes . We also found that primary cultures of lymphocytes transcribe and secrete LL-37 and that these processes are affected by IL-6 and interferon-gamma . In addition, we demonstrated that LL-37 has chemotactic activity for polymorphonuclear leukocytes and CD4 T lymphocytes, whereas others have shown chemotactic activity for human alpha-defensins (HNP 1-2) . These findings suggest that microbicidal peptides are effector molecules of lymphocytes and that antibacterial activity previously shown to be derived from T and NK cells may be partly mediated by the antibacterial peptides LL-37 and HNP 1-3.

Clin Infect Dis, 2000 Oct, 31(4), 968 - 72 Epub 2000 Oct 25.
Nocardia infection in heart-lung transplant recipients at Alfred Hospital, Melbourne, Australia, 1989-1998; Roberts SA et al.; Nocardia infections are uncommon in recipients of heart, lung, or heart-lung transplants, but such infections are well described . Frequent episodes of rejection, high-dose prednisolone treatment, renal impairment, and prolonged respiratory support have all been shown to increase the risk of Nocardia infection in this group . In this retrospective review of 540 recipients of heart, lung, or heart-lung transplants, 10 patients developed Nocardia infection (frequency, 1.85%) . Infection occurred at a mean +/- standard deviation of 13+/-14.5 months after transplantation . All patients had pulmonary disease with no evidence of extrapulmonary disease . The Nocardia infection did not contribute directly to patient deaths . Coinfection with other pathogens was present in 6 patients, and 2 patients had sequential infections . Radiological findings varied . All isolates were susceptible to trimethoprim-sulfamethoxazole, amikacin, and imipenem . Treatment regimens varied . Two (30%) of 6 patients treated with trimethoprim-sulfamethoxazole developed adverse reactions, which necessitated a change in antibiotic therapy . The optimal treatment regimen, which comprises both the antimicrobial agent and the length of treatment, is unclear.

J Hosp Infect, 2000 Oct, 46(2), 83 - 8
Nosocomial infective endocarditis; Gilleece A et al.; Summary: Nosocomial infective endocarditis (NIE) is a rare complication of nosocomial bacteraemia; however, it is an infection of great importance because of its high mortality and because in many cases it is potentially preventable . Whilst many aspects of NIE are similar to community-acquired infective endocarditis (CIE), there are important differences between the two, most notably the predisposing factors, microbial aetiology and prognosis . The diagnosis of NIE is often difficult as many patients have severe underlying disease and coexistent infection elsewhere . Many of these infections could potentially be prevented by the identification of high risk patients, careful assessment of positive blood cultures and effective treatment of bacteraemia in high risk patients . The use of prophylactic antimicrobials in the prevention of infective endocarditis is unproven, however, it is recommended that prophylaxis be considered for certain invasive hospital-based procedures .

J Pediatr Gastroenterol Nutr, 2000 Oct, 31(4), 424 - 7
Helicobacter pylori infection in recurrent abdominal pain; Frank F et al.; BACKGROUND: Helicobacter pylori is associated with chronic gastritis and peptic ulcer in adults and in children . The purpose of the present study was to analyze the association of recurrent abdominal pain and H . pylori infection in children and to evaluate the efficacy of antimicrobial treatment in patients with evidence of infection . METHODS: The clinical and histopathologic findings in children who underwent diagnostic upper endoscopy for recurrent abdominal pain were analyzed retrospectively . Patients with evidence of infection with H . pylori were treated with a combination of omeprazole, amoxicillin, and clarithromycin . Efficacy of treatment was assessed using the 13C-urea-breath test . RESULTS: H . pylori was found in histopathologic sections of 29 (40%) of 73 patients undergoing diagnostic endoscopy for recurrent abdominal pain . Five children (17%) were of Swiss ethnic origin, and 24 (83%) were non-Swiss . All the infected patients had chronic gastritis and 4 (14%) had ulcerations in the duodenum . Treatment with omeprazole, amoxicillin, and clarithromycin resulted in eradication of the infection in all and in resolution of the clinical symptoms in 15 (80%) of 19 patients who had a follow-up examination . CONCLUSIONS: The presented data suggest that gastritis induced by H . pylori may be associated with recurrent abdominal pain and that in Switzerland infections with H . pylori primarily involve persons who are non-Swiss . A combined therapy results in eradication of the bacterium and in improvement of the clinical symptoms in a significant majority of the patients.

J Gene Med, 2000 Sep-Oct, 2(5), 317 - 25
Lentivirus-mediated gene transfer of gp91phox corrects chronic granulomatous disease (CGD) phenotype in human X-CGD cells; Saulnier SO et al.; BACKGROUND: Chronic granulomatous diseases (CGD) are caused by impaired antimicrobial activity in phagocytes, due to the absence or malfunction of the respiratory burst NADPH oxidase . Two-thirds of the patients have mutations in their X-linked CGD gene encoding gp91phox, the largest subunit of the NADPH oxidase . METHODS: Aimed at gene therapy of X-CGD already at the level of resting pluripotent hematopoietic stem cells, we generated an advanced HIV-1-based vector with self-inactivating (SIN2) features containing the therapeutic gp91phox gene . In this vector an internal cytomegalovirus (CMV) promoter exclusively drives transgene expression . The green fluorescent protein (GFP) served as reporter for evaluation of gene transfer and expression in the human myeloid PLB985 X-CGD cell line . RESULTS: The X-CGD cells were efficiently transduced by the VSV-G pseudotyped lentivirus constructs (up to 74% GFP+ cells at 3 days post-transduction) . CMV-driven GFP-expression was stable for at least 3 weeks after transduction and persisted after granulocytic differentiation of the target cells . Using the lentivector with the gp91phox transgene, 26% and 48% of the X-CGD cells expressed gp91phox at Days 2 and 20 after co-culture with 293T producer cells, respectively . Upon granulocytic differentiation of the transduced X-CGD cells with dimethylformamide (DMF), up to 63% (mean 49%, n = 7) of the cells were found to be functionally reconstituted with mean levels of superoxide production of 31% (n = 7) compared to wild-type PLB985 cells . CONCLUSION: Lentivirus vectors expressing gp91phox are able to at least partially correct human myeloid X-CGD cells.

Biochim Biophys Acta, 2000 Oct 18, 1523(2-3), 196 - 205
Ovotransferrin antimicrobial peptide (OTAP-92) kills bacteria through a membrane damage mechanism; Ibrahim HR et al.; Ovotransferrin antimicrobial peptide (OTAP-92) is a cationic fragment of hen ovotransferrin (OTf) . OTAP-92 consists of 92 amino acid residues located within the 109-200 sequence of the N-lobe of OTf . This study was aimed to delineate the antimicrobial mechanism of OTAP-92 and to identify its interaction with bacterial membranes . OTAP-92 caused permeation of Escherichia coli outer membrane (OM) to 1-N-phenylnaphthylamine fluorescent probe in a dose-dependent manner . These results suggested that OTAP-92 crossed the bacterial OM by a self-promoted uptake . Cytoplasmic membrane of E . coli was found to be the target for OTAP-92 bactericidal activity, as assayed by the unmasking of cytoplasmic beta-galactosidase due to membrane permeabilization in a kinetic manner . Pretreatment of bacteria with uncoupler, carbonyl cyanide m-chlorophenylhydrazone, markedly enhanced permeation of cytoplasmic membrane, suggesting that the membrane permeation due to OTAP-92 is independent of the transmembrane potential . In an E . coli phospholipid liposome model, it was demonstrated that OTAP-92 has the ability to dissipate the transmembrane electrochemical potential . Intrinsic fluorescence spectra of the two tryptophan residues in OTAP-92, using liposomal membrane, have identified the lipid-binding region as a helix-sheet motif, and suggested an adjacent Ca(2+)-sensitive site within OTAP-92 . These data indicated that OTAP-92 possesses a unique structural motif similar to the insect defensins . Further, this cationic antimicrobial peptide is capable of killing Gram-negative bacteria by crossing the OM by a self-promoted uptake and cause damage to the biological function of cytoplasmic membrane.

Arch Pharm (Weinheim), 2000 Sep, 333(9), 299 - 304
A new class of antifungal agents . Synthesis and antimycotic activity of disubstituted N-azolylamines; Castellano S et al.; In this study we extended our exploration of the N-azolylamine moiety for its antifungal activity . We prepared a number of N-azolylamino derivatives . The synthetic sequence includes the preparation of aminoazole Schiff bases, and the reduction and the alkylation of the corresponding secondary amines . The title compounds were evaluated in vitro against several pathogenic fungi responsible for human disease . The most potent antimicrobial compound was the N-(biphenyl-4-yl)methyl-N-(2,4-dichlorophenyl)methyl-1H-imidazol-l-yl amine (21), which was found to be active against yeasts and dermatophytes; its potency and selectivity were comparable to those of miconazole.

Arch Pharm (Weinheim), 2000 Sep, 333(9), 281 - 6
New tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as potential antimicrobial agents; el-Shorbagi AN; The deacylated chloramphenicol amine D-(-)-threo-2-amino-1-(4-nitrophenyl)-1,3-diol (D-amine, 1a), and its enantiomer, the L-(+)-threo-form (L-amine, 1b), were introduced into a tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) skeleton . They are incorporated in three ways (Chart 1, types I-III) at N3 (type I), N5 (type II) or both N3 and N5 (type III) of the THTT system . These selections were made in order to investigate the effect of combining the structural features of the THTT and the D-amine on the antimicrobial activity, if any.

Luminescence, 2000 Sep-Oct, 15(5), 291 - 7
Detection of tetracyclines with luminescent bacterial strains; Kurittu J et al.; The performance of two bioluminescent Escherichia coli K-12 strains for the specific detection of the tetracycline family of antimicrobial agents was compared, and the analytical applicability of one of the strains was preliminarily evaluated . One sensor plasmid contained the bacterial luciferase operon of Photorhabdus luminescens under the control of the tetracycline-responsive element from transposon Tn10 (15) . An analogous plasmid construction with firefly (Photinus pyralis) luciferase reporter gene was constructed, and these two divergent tetracycline-inducible light-emitting systems were compared for their suitability for the qualitative detection of tetracyclines . Both sensor strains behaved in a similar manner kinetically, and the most sensitive tetracycline response for both sensor strains was achieved in 90-120 min by performing the assay at 37 degrees C . The sensor strain containing the bacterial luciferase operon responded slightly more sensitively to different tetracyclines than the strain containing firefly luciferase gene . The sensor bacteria retained their inducibility in lyophilization, and freeze-dried cells detected tetracyclines as sensitively as freshly cultivated sensor cells . The preliminary results from the analysis of tetracycline-spiked pork serum samples indicated that these sensor bacteria could be used to screen veterinary samples for tetracycline residues in real-time .

Eur J Oral Sci, 2000 Oct, 108(5), 403 - 11
Microbiological aspects of an in situ model to study effects of antimicrobial agents on dental plaque ecology; Giertsen E et al.; This study validates an in situ model for ecological studies of dental plaque exposed to various antimicrobial agents with different modes of action on plaque bacteria . Eleven subjects wore two acrylic appliances, each containing two bovine enamel discs, during two 1-wk test periods . Using a split-mouth crossover design, the appliances were dipped twice daily for 1 min into water (control; treatment A), fluoride (26.3 mM NaF; B), zinc acetate (20.0 mM; C), or fluoride plus zinc acetate (D) . Four of the subjects used also chlorhexidine diacetate (2.2 mM; E) and chlorhexidine plus fluoride (F) . At the end of each period, plaque was collected from the discs, after which the microbiota were analyzed by culture, automated quantitative immunofluorescence, and a viability fluorescence stain . As compared to control, treatments B, C, and D resulted in a significant reduction of individual taxa as detected by immunofluorescence, whereas similar bacterial viability and total bacterial numbers were observed . In contrast, chlorhexidine significantly reduced bacterial viability, total cell numbers, and the abundance of most of the enumerated taxa . We conclude that this in situ model is well suited to study effects of antimicrobial agents on dental plaque ecology . Combined with viability testing, immunofluorescence is obviously superior to culture in detecting taxa-specific shifts caused by antimicrobial agents.

Adv Biochem Eng Biotechnol, 2000, 69, 1 - 39
The natural functions of secondary metabolites; Demain AL et al.; Secondary metabolites, including antibiotics, are produced in nature and serve survival functions for the organisms producing them . The antibiotics are a heterogeneous group, the functions of some being related to and others being unrelated to their antimicrobial activities . Secondary metabolites serve: (i) as competitive weapons used against other bacteria, fungi, amoebae, plants, insects, and large animals; (ii) as metal transporting agents; (iii) as agents of symbiosis between microbes and plants, nematodes, insects, and higher animals; (iv) as sexual hormones; and (v) as differentiation effectors . Although antibiotics are not obligatory for sporulation, some secondary metabolites (including antibiotics) stimulate spore formation and inhibit or stimulate germination . Formation of secondary metabolites and spores are regulated by similar factors . This similarity could insure secondary metabolite production during sporulation . Thus the secondary metabolite can: (i) slow down germination of spores until a less competitive environment and more favorable conditions for growth exist; (ii) protect the dormant or initiated spore from consumption by amoebae; or (iii) cleanse the immediate environment of competing microorganisms during germination.

Methods Enzymol, 2000, 326, 73 - 96
IVET and RIVET: use of gene fusions to identify bacterial virulence factors specifically induced in host tissues; Slauch JM et al.; IVET was designed to identify those bacterial genes that are induced when a pathogen infects its host . A subset of these induced genes encode virulence factors, products specifically required for the infection process . The paradigm IVET system is based on complementation of an attenuating auxotrophic mutation by gene fusion and is designed to be of use in a wide variety of pathogenic organisms . In S . typhimurium, we have used this system successfully to identify a number of genes that are induced in a BALB/c mouse and that, when mutated, confer a virulence defect . The RIVET system is based on recombinase gene fusions, which, on induction during infection, mediate a site-specific recombination, the product of which can be screened for after recovery of bacteria from host tissues . In V . cholerae, we have used this system successfully to identify genes that are induced transcriptionally during infection of the gastrointestinal tract of infant mice . RIVET is also uniquely designed for postidentification analysis of in vivo-induced genes: (1) it has been used to analyze the temporal and spatial patterns of virulence gene induction during infection and (2) it has been used to dissect the regulatory requirements of in vivo induction with respect to both bacterial regulatory factors and host-inducing environments . The IVET system has several applications in the area of vaccine and antimicrobial drug development . This technique was designed for the identification of virulence factors and thus may lead to the discovery of new antigens useful as vaccine components . The IVET system facilitates the isolation of mutations in genes involved in virulence and, therefore, should aid in the construction of live-attenuated vaccines . In addition, the identification of promoters that are expressed optimally in animal tissues provides a means of establishing in vivo-regulated expression of heterologous antigens in live vaccines, an area that has been problematic previously . Finally, we expect that our methodology will uncover many biosynthetic, catabolic, and regulatory genes that are required for growth of microbes in animal tissues . The elucidation of these gene products should provide new targets for antimicrobial drug development.

Antimicrob Agents Chemother, 2000 Nov, 44(11), 3217 - 9
Effect of ceftazidime on systemic cytokine concentrations in rats; Alkharfy KM et al.; The effect of a single dose of ceftazidime on circulating concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in a rat model of sepsis was studied . IL-6 concentrations were significantly elevated (100 to 200 times the baseline) 6 h after ceftazidime administration in both septic and nonseptic (control) rats . TNF-alpha concentrations increased significantly in nonseptic (approximately 40 times the baseline) rats but not septic (approximately 2 to 3 times the baseline) rats . Ceftazidime administration was not associated with an increase in endotoxin concentrations . These findings suggest that ceftazidime modulation of proinflammatory cytokine concentrations may be independent of its antimicrobial properties.

Proc Natl Acad Sci U S A, 2000 Oct 24, 97(22), 12210 - 5
Antimicrobial activity of MHC class I-restricted CD8+ T cells in human tuberculosis; Cho S et al.; Studies of mouse models of tuberculosis (TB) infection have indicated a central role for MHC class I-restricted CD8+ T cells in protective immunity . To define antigens and epitopes of Mycobacterium tuberculosis (MTB) proteins that are presented by infected cells to CD8+ T cells, we screened 40 MTB proteins for HLA class I A*0201-binding motifs . Peptides that bound with high affinity to purified HLA molecules were subsequently analyzed for recognition by CD8+ cytotoxic T lymphocytes . We identified three epitopes recognized by CD8+ T cells from patients recovering from TB infection . Those three epitopes were derived from three different antigens: thymidylate synthase (ThyA(30-38)), RNA polymerase beta-subunit (RpoB(127-135)), and a putative phosphate transport system permease protein A-1 (PstA1(75-83)) . In addition, CD8+ T cell lines specific for three peptides (ThyA(30-38), PstA1(75-83), and 85B(15-23)) were generated from peripheral blood mononuclear cells of normal HLA-A*0201 donors . These CD8+ T cell lines specifically recognized MTB-infected macrophages, as demonstrated by production of IFN-gamma and lysis of the infected target cells . Finally, CD8+ cytotoxic T lymphocytes reduced the viability of the intracellular MTB, providing evidence that CD8+ T cell recognition of MHC class I-restricted epitopes of these MTB antigens can contribute to effective immunity against the pathogen.

Bone Marrow Transplant, 2000 Sep, 26(6), 645 - 8
The spectrum of Malassezia infections in the bone marrow transplant population; Morrison VA et al.; A consecutive series of 3044 patients who underwent BMT at the University of Minnesota over a 25 year period were reviewed for the post-transplant occurrence of infection caused by the yeast Malassezia furfur . Six patients, ranging in age from 1 to 54 years, developed Malassezia infections at a median of 59 days post transplant . Five patients were allogeneic transplant recipients; the remaining patient had undergone autologous transplantation . A spectrum of clinical manifestations of Malassezia infection was seen in these patients, including infections of mucosal surfaces and the skin, in addition to catheter-related fungemia . Unlike many of the other more common opportunistic fungal infections in immunocompromised patients, neutropenia and the use of broad-spectrum antimicrobials do not appear to be significant risk factors for Malassezia infections in the BMT population . In addition, disseminated fungal infection despite the presence of fungemia is uncommon . Lastly, the outcome of Malassezia infections in these patients, whether folliculitis, mucosal infection, or fungemia, appears to be quite favorable, in contrast to the poorer outcome with many other fungal infections in BMT patients . Catheter removal and discontinuation of intravenous lipids are important for a successful outcome in fungemic cases.

Am J Obstet Gynecol, 2000 Oct, 183(4), 904 - 10
Lactoferrin in intrauterine infection, human parturition, and rupture of fetal membranes; Pacora P et al.; OBJECTIVE: Lactoferrin is an iron-binding protein with antimicrobial properties . This study was undertaken to determine whether amniotic fluid concentrations of this protein change with gestational age, infection, labor, and rupture of membranes . STUDY DESIGN: This cross-sectional study included women who underwent transabdominal amniocentesis (n = 268) in the following groups: (1) mid trimester of pregnancy; (2) preterm labor who delivered at term, preterm labor who delivered preterm with intra-amniotic infection, and preterm labor who delivered preterm without intra-amniotic infection; (3) preterm premature rupture of membranes in the presence or absence of intra-amniotic infection; (4) term with intact membranes not in labor, in labor, and in labor with intra-amniotic infection; and (5) premature rupture of membranes at term not in labor . In addition, lactoferrin concentrations were determined in maternal plasma and cord blood of patients at term not in labor . Lactoferrin concentration was measured with an immunoassay . RESULTS: (1) Lactoferrin was detectable in 85.4% (229/268) of amniotic fluid samples, not detectable in all fluid obtained in the mid trimester, and detectable in all maternal and cord plasma samples . (2) The concentration of lactoferrin increased with advancing gestational age (r = 0.68; P <.0001) . (3) Intra-amniotic infection was associated with significant increases in amniotic fluid lactoferrin concentrations in patients with preterm labor (no intra-amniotic infection median, 1641.2 ng/mL; range, <1.24-35,090.0 ng/mL; vs intra-amniotic infection median, 3833.6 ng/mL; range, 746.0-47,020.0 ng/mL; P <.001), term labor (no intra-amniotic infection median, 2085.8 ng/mL; range, 425.0-23,230.0 ng/mL; vs intra-amniotic infection median, 5627.0 ng/mL; range, <1.24-19,220.0 ng/mL; P < . 001), and preterm premature rupture of membranes (no intra-amniotic infection median, 2190 ng/mL; range, <1.24-7456.1 ng/mL; vs intra-amniotic infection median, 3449.3 ng/mL; range, <1.24-83,600 . 0; P <.01) . (4) Spontaneous labor at term but not preterm was associated with a significant decrease in amniotic fluid lactoferrin concentration (P <.05) . (5) Spontaneous term parturition was associated with a significant increase in umbilical cord plasma lactoferrin concentration (P <.005) . CONCLUSION: (1) Intra-amniotic infection was consistently associated with dramatically increased concentrations of lactoferrin in amniotic fluid . (2) Term parturition was associated with a significant increase in lactoferrin concentration in the fetal compartment (umbilical cord blood) and a decrease in the amniotic compartment . We propose that lactoferrin is part of the repertoire of host defense mechanisms against intra-amniotic infection.

Diagn Microbiol Infect Dis, 2000 Oct, 38(2), 83 - 6
Comparison of Mycobacterium tuberculosis susceptibility testing performed with BACTEC 460TB (Becton Dickinson) and MB/BacT (Organon Teknika) systems; Tortoli E et al.; The recently introduced automated culture systems MB/BacT (Organon Teknika, Belgium) was compared with radiometric BACTEC 460TB (Becton Dickinson, USA) to test antimicrobial susceptibility of Mycobacterium tuberculosis to first line drugs . On 113 strains 97.5% agreement was obtained, with the difference being not significant . Concordance was practically complete for the most important drugs, isoniazid and rifampin . The two methods however significantly differed for the time needed to complete the test; in fact MB/BacT required on the average five days more than BACTEC 460TB . Despite the delay in the completion of the test, the excellent reliability along with the elimination of radioactivity and full automation make MB/BacT an attractive alternative for susceptibility testing of M . tuberculosis.

Peptides, 2000 Aug, 21(8), 1155 - 60
Combination studies between polycationic peptides and clinically used antibiotics against Gram-positive and Gram-negative bacteria; Giacometti A et al.; The in vitro interaction between five polycationic peptides, buforin II, cecropin P1, indolicidin, magainin II, and ranalexin, and several clinically used antimicrobial agents was evaluated against several clinical isolates of Gram-positive and Gram-negative aerobic bacteria, using the microbroth dilution method . The combination studies showed synergy between ranalexin and polymyxin E, doxycycline and clarithromycin . In addition, magainin II was shown to be synergic with betalactam antibiotics.

Cochrane Database Syst Rev . 2000;(4):CD000219.
Antibiotics for acute otitis media in children; Glasziou PP et al.; BACKGROUND: Acute otitis media is one of the most common diseases in early infancy and childhood . Antibiotic use for acute otitis media varies from 31% in the Netherlands to 98% in the USA and Australia . OBJECTIVES: The objective of this review was to assess the effects of antibiotics for children with acute otitis media . SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, MEDLINE, Index Medicus (pre 1965), Current Contents and reference lists of articles from 1958 to January 2000 . SELECTION CRITERIA: Randomised trials comparing antimicrobial drugs with placebo in children with acute otitis media . DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed trial quality and extracted data . MAIN RESULTS: Ten trials were eligible but only seven trials, with a total of 2,202 children, included patient-relevant outcomes . The methodological quality of the included trials was generally high . All trials were from developed countries . The trials showed no reduction in pain at 24 hours, but a 28% relative reduction (95% confidence interval 15% to 38%) in pain at two to seven days . Since approximately 80% of patients will have settled spontaneously in this time, this means an absolute reduction of 5% or that about 17 children must be treated with antibiotics to prevent one child having some pain after two days . There was no effect of antibiotics on hearing problems of acute otitis media, as measured by subsequent tympanometry . However, audiometry was done in only two studies and incompletely reported . Nor did antibiotics influence other complications or recurrence . There were few serious complications seen in these trials: only one case of mastoiditis occurred in a penicillin treated group . REVIEWER'S CONCLUSIONS: Antibiotics provide a small benefit for acute otitis media in children . As most cases will resolve spontaneously, this benefit must be weighed against the possible adverse reactions . Antibiotic treatment may play an important role in reducing the risk of mastoiditis in populations where it is more common . {This abstract has been prepared centrally.}

J Immunol, 2000 Oct 1, 165(7), 3592 - 8
Prolonged exposure to lipopolysaccharide inhibits macrophage 5-lipoxygenase metabolism via induction of nitric oxide synthesis; Coffey MJ et al.; LPS from bacteria can result in the development of sepsis syndrome and acute lung injury . Although acute exposure to endotoxin primes leukocytes for enhanced synthesis of leukotrienes (LT), little is known about the effect of chronic exposure . Therefore, we determined the effect of prolonged LPS treatment on 5-lipoxygenase (5-LO) metabolism of arachidonic acid in alveolar macrophages (AM) and in peripheral blood monocytes . Pretreatment of AM with LPS caused time- and dose-dependent suppression of LT synthetic capacity . LPS pretreatment failed to inhibit arachidonic acid (AA) release . The fact that LPS inhibited LT synthesis from endogenous AA more than from exogenous AA suggested an effect on 5-LO-activating protein (FLAP) . In addition, an inhibitory effect of LPS treatment on AM 5-LO activity was suggested by cell-free 5-LO enzyme assay . No effect on the expression of either 5-LO or FLAP proteins was observed . New protein synthesis was necessary for LPS-induced reduction of 5-LO metabolism in AM, and immunoblotting demonstrated marked induction of NO synthase (NOS) . Inhibition by LPS was reproduced by an NO donor and was abrogated by inhibitors of constitutive and inducible NOS . Compared with AM, peripheral blood monocytes exhibited no suppression by LPS of 5-LO metabolism and no induction of inducible NOS . We conclude that prolonged exposure to LPS impairs AM 5-LO metabolism by NO-mediated suppression of both 5-LO and FLAP function . Because LT contribute to antimicrobial defense, this down-regulation of 5-LO metabolism may contribute to the increased susceptibility to pneumonia in patients following sepsis.

Acta Orthop Belg, 2000 Jun, 66(3), 242 - 7
Spinal instrumentation for primary pyogenic infection report of 31 patients; Faraj AA et al.; The role of spinal instrumentation in the presence of infection is still controversial . Radical debridements of infected vertebrae and disc material and bone grafting usually leaves the spine unstable without some surgical stabilisation . We reviewed 31 cases of primary pyogenic spinal infection treated by radical debridement, bone grafting and posterior (30) or anterior (1) spinal instrumentation . The indication for surgery was the failure of conservative treatment (8), progressive neurological deficit (19) or the lack of diagnosis (3) . The clinical, laboratory and radiological parameters were assessed pre and postoperatively . The mean period of follow-up was 3.8 years (1-12 years) . The neurological deficit was progressive in 19 patients, following surgery all these patients were improved . The neurological deficit was established in one patient; following surgery, his neurological deficit did not improve . The infection was eradicated in all our patients . The following complications were encountered: (1) three patients developed deep wound infection, which responded to repeated debridement; (2) one death resulted from nosocomial septicaemia, (3) reoperation was carried out on one patient for implant failure and on another for a dislodged anterior bone graft . We conclude that spinal instrumentation may be indicated when after radical debridement of infected vertebrae and disc material and bone grafting the stability of the spine is still compromised . According to the location of the infection and the availability of suitable implants, anterior or posterior instrumentation may be necessary . With appropriate antimicrobial agents, the outcome has been satisfactory in our patients.

Vet Clin North Am Small Anim Pract, 2000 Sep, 30(5), 1151 - 67
Canine and feline primary ocular bacterial infections; Whitley RD; Bacterial infections are frequently associated with diseases of the eyelids, cornea, and conjunctiva . Animals sustaining KCS commonly have bacterial infections of the external eye owing to a lack of antimicrobial properties present in the normal tearfilm . Infection can occur in the nasolacrimal duct or lacrimal sac, which is referred to as dacryocystitis . Severe corneal ulcers are frequently infected with bacteria, especially Pseudomonas sp . Three new topical ophthalmic antibiotics have recently become commercially available: ciprofloxacin, norfloxacin, and ofloxacin.

Vet Clin North Am Small Anim Pract, 2000 Sep, 30(5), 1135 - 49
Canine rickettsial infections; Stiles J; Dogs that live in tick-infested areas are at risk for contracting rickettsial infections . Clinical signs associated with ehrlichiosis or Rocky Mountain spotted fever may be dramatic or mild . Clinicians must consider the possibility of rickettsial diseases to request laboratory tests that will permit a proper diagnosis . Specific antimicrobial therapy usually brings about clinical improvement, although some dogs may not be cleared of rickettsial organisms, even with prolonged treatment . A small percentage of dogs die of rickettsial infections, either in the acute stage or owing to chronic bone marrow suppression and generalized debilitation . Ocular lesions are an important clinical sign in canine rickettsial infections and may aid the clinician in making a diagnosis and monitoring response to therapy.

Cochrane Database Syst Rev . 2000;(4):CD000022.
Antibiotics for preventing respiratory tract infections in adults receiving intensive care; Liberati A et al.; BACKGROUND: Pneumonia is an important cause of mortality in intensive care units . The incidence of pneumonia in such patients ranges between 7% and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50% . Although not all deaths in patients with this form of pneumonia are directly attributable to infections, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths . OBJECTIVES: The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care . SEARCH STRATEGY: We searched Medline, the Cochrane Acute Respiratory Infections Group trials register, proceedings of scientific meetings and reference lists of articles from January 1984 to December 1999 . We also contacted investigators in the field . SELECTION CRITERIA: Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients . DATA COLLECTION AND ANALYSIS: Investigators were contacted for additional information . At least two reviewers independently extracted data and assessed trial quality . MAIN RESULTS: Overall 33 trials involving 5727 people were included . There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups . In 16 trials (involving 3361 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 30% respectively . There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval 0.29 to 0.41) and total mortality (odds ratio 0.80, 95% confidence interval 0.69 to 0.93) in the treated group . On average 5 patients needed to be treated to prevent one infection and 23 patients to prevent one death . In 17 trials (involving 2366 patients) that tested topical antimicrobials the rates of respiratory tract infections and deaths in the control groups were 28% and 26% respectively . There was a significant reduction of respiratory tract infections (odds ratio 0.56, 95% confidence interval 0.46 to 0.68) but not in total mortality (odds ratio 1.01, 95% confidence interval 0.84 to 1.22) in the treated group . REVIEWER'S CONCLUSIONS: A combination of topical and systemic prophylactic antibiotics can reduce respiratory tract infections and overall mortality in adult patients receiving intensive care . The design of the trials included in this systematic review does not allow to assess whether or not the treatment leads to antimicrobial resistance . Trials with different design are warranted to reliably address this question.

Orv Hetil, 2000 Sep 3, 141(36), 1981 - 3
{The role of bacteriology in the treatment of tuberculosis; the Hungarian program}; Fodor T; A positive result of the bacteriological examination of Mycobacterium tuberculosis is signal to start treatment . The response to antituberculosis chemotherapy in patients with positive bacteriology is best evaluated by repeated examinations . The recommendation of the Hungarian National Tuberculosis Programme for the initial intensive phase of chemotherapy of previously untreated patients is based on the frequency of primoresistance determined by the National Reference Laboratory . The treatment of multidrug resistant tuberculosis can be supported by the result of previous susceptibility test and/or by the outcome of multicenter validated Bactec 460 susceptibility test of second-line antimicrobial drugs . The presence of a mutation within a gen is predictive of rifampicin resistance of M . tuberculosis . The results are available within 48 h . 92.4% of rifampicin resistant and nearly 100% of pyrazinamid resistant isolates in the Reference Laboratory were resistant to isoniazid . On the other hand streptomycin resistant strains were susceptible to amikacin in a rate of 38:1 . Some rifampicin resistant strains are susceptible to rifabutin . The Reference Laboratory observed among the first that some ofloxacin resistant strains are susceptible to ciprofloxacin . It was the first which demonstrated effectivity of amikacin in the treatment of pulmonary tuberculosis . It was drawn attention to the importance of the PAS infusion therapy of multidrug resistant tuberculosis cases by observing bacteriological conversion.

J Allergy Clin Immunol, 2000 Oct, 106(4), 752 - 62
Digestibility of allergens extracted from natural rubber latex and vegetable foods; Yagami T et al.; BACKGROUND: Several cross-reactive allergens are now known to be involved in the defense responses of higher plants . Such proteins are drawing the attention of plant breeders because of their antimicrobial or stress-alleviating activities . Plants genetically modified to express defense-related proteins are being developed . The current concern is focused on the allergenicity of these intentionally expressed proteins . OBJECTIVE: It is believed that food allergens are proteins resistant to digestion . Digestibility tests have been accepted as an appropriate method for evaluating the allergenicity of newly introduced proteins . In this study we investigated the usefulness of this method for detecting allergens from natural rubber latex and vegetable foods . METHODS: Proteins were extracted from rubber latex, potato, and 5 kinds of fruits . Simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were used for the digestibility test . An aliquot of each digest was periodically withdrawn and analyzed . Allergens were detected with pooled sera from individuals with latex allergy or patients given a diagnosis of oral allergy syndrome . RESULTS: Most latex and vegetable food proteins were digested by the SGF within 4 minutes . Numerous allergens were also decomposed by the SGF within 8 minutes . Although vegetable food allergens were relatively stable in the SIF, kiwi allergens were substantially degraded by the SIF within 16 hours . CONCLUSION: The pronounced lability of the plant-derived allergens was thought to reflect the discrete sensitization and elicitation processes of patients with latex-fruit syndrome or oral allergy syndrome . These results indicate that the allergenicity of a newly expressed protein should be carefully evaluated according to not only its digestibility but also other important properties.

J Biol Chem, 2001 Jan 26, 276(4), 2701 - 7 Epub 2000 Oct 12.
Tigerinins: novel antimicrobial peptides from the Indian frog Rana tigerina; Sai KP et al.; Four broad-spectrum, 11 and 12 residue, novel antimicrobial peptides have been isolated from the adrenaline-stimulated skin secretions of the Indian frog Rana tigerina . Sequences of these peptides have been determined by automated Edman degradation, by mass spectral analysis and confirmed by chemical synthesis . These peptides, which we have named as tigerinins, are characterized by an intramolecular disulfide bridge between two cysteine residues forming a nonapeptide ring . This feature is not found in other amphibian peptides . Conformational analysis indicate that the peptides tend to form beta-turn structures . The peptides are cationic and exert their activity by permeabilizing bacterial membranes . Tigerinins represent the smallest, nonhelical, cationic antimicrobial peptides from amphibians.

Baillieres Best Pract Res Clin Gastroenterol, 1999 Jul, 13(2), 317 - 30
Antimicrobial prophylaxis in acute pancreatitis: selective decontamination versus antibiotics; Luiten EJ et al.; The results of several controlled clinical trials, published during the last 5 years, provide evidence of a beneficial role for early antimicrobial prophylaxis in severe acute pancreatitis . Pancreatic infections, especially gram-negative, which are of major importance with regard to morbidity and mortality, are gut-derived . Early enteral administration of antibiotics therefore seems the most logical measure to nip the danger in the bud . Intravenous antibiotics should adequately penetrate (peri)pancreatic tissues, i.e . necrotic tissues, and should be effective against the prevalent flora in infected necrotic tissues . However, the optimal route of administration is still a matter of debate . In contrast to one clinical trial using selective decontamination (SD) (i.e . enteral antibiotics combined with short systemic prophylaxis until SD is established), no clinical trial using intravenous antibiotics has been reported in which both pancreatic infections as well as mortality were reduced . Although the evidence supporting enteral administration, i.e . SD, is not unimpressive, further controlled clinical trials, in which the different ways of administration are compared, are warranted.

Gastroenterol Clin North Am, 2000 Sep, 29(3), 671 - 85
Immunology of Helicobacter pylori and prospects for vaccine; Blanchard TG et al.; Since the initial discovery of H . pylori by Marshall and Warren 17 years ago, much progress has been made in treating this infection . However, as we enter the millennium, H . pylori infection continues to be one of the most common infections of mankind . In addition, eradication of H . pylori still requires multiple antimicrobial agents . A better understanding of the host immune response to H . pylori infection should allow investigators to develop immunotherapies to prevent the acquisition of infection and eradicate existing chronic H . pylori infection.

Baillieres Best Pract Res Clin Haematol, 2000 Sep, 13(3), 441 - 56
Management of infection in children with bone marrow failure; Hann IM; The development of new and often more successful regimens of treatment for childhood blood and malignant diseases has usually been associated with a parallel increase in infectious problems . This is because these successes have often, in the absence of new effective drugs, been achieved by increasing drug dose intensity to new limits . This chapter is not intended to deal with every possible infection, but rather to be a practical guide to the current management of infection . The last few years have seen major improvements in the development of haematopoietic growth factors, new antifungal agents, new antibiotics and new ways to use aminoglycosides . Attempts are being made to identify good and poor risk factors for the outcome of infection in order to facilitate shorter courses and possibly home or day care use of antimicrobial agents . In addition the different needs of children are being recognized in view of the restricted use of quinolones in this group and the different organisms and types of infection that they experience.

Cell Mol Life Sci, 2000 Aug, 57(8-9), 1260 - 71
Penaeidins, a family of antimicrobial peptides from penaeid shrimp (Crustacea, Decapoda); Destoumieux D et al.; The production of antimicrobial peptides represents a first-line host defense mechanism of innate immunity that is widespread in nature . Only recently such effectors were isolated in crustacean species, whereas numerous antimicrobial peptides have been characterized from other arthropods, both insects and chelicerates . This review presents findings on a family of antimicrobial peptides, named penaeidins, isolated from the shrimp Penaeus vannamei . Their structure and antimicrobial properties as well as their immune function will be discussed through analyses of penaeidin gene expression and peptide distribution upon microbial challenge.

Shock, 2000 Sep, 14(3), 314 - 8; discussion 318-9
Biobrane improves wound healing in burned children without increased risk of infection; Lal S et al.; A synthetic bilaminar membrane used as a skin substitute (Biobrane) has been shown to decrease pain and hospitalization in superficial second-degree burns . Despite these benefits, it has not been utilized universally, particularly in young children, due to a perceived increase in related infections . We propose that when this synthetic membrane is applied to superficial scald burns <25% of the total body surface area (TBSA), decreased healing times are expected without increased risk of infection . Between 1994-1999, 89 children treated within 48 h after receiving superficial partial thickness scald burns covering 5-25% TBSA with no indication of infection were seen at our hospital . Forty-one were assigned randomly to receive treatment with the skin substitute Biobrane and 48 to receive conservative treatment with topical antimicrobials and dressing changes . Comparisons of treatment were made between groups for length of hospitalization, wound healing times, and infectious complications . Children treated with Biobrane or topical antimicrobials were similar in age, race, sex, %TBSA burned, and location of burn . Those receiving Biobrane had shorter hospitalizations and healing times, which was significant for both infants and toddlers and older children . Treatment groups were not different in the use of systemic antibiotics or readmissions for infectious complications . Biobrane was removed in 5.9% of cases for non-adherence . The application of Biobrane within 48 h of superficial burns provides for shorter hospitalizations and faster healing times in children of all ages without increased risk of infection.

Med Klin (Munich), 2000 Sep 15, 95(9), 496 - 502
{Antimicrobial peptides and peptide antibiotics}; Bals R; Antimicrobial peptides are naturally occurring antibiotics . As part of the innate immune system of vertebrates they have direct antimicrobial function . Further, they can act as mediators of inflammation . Their antimicrobial spectrum covers gram-positive and -negative bacteria as well as fungi and certain viruses . Based on their structure, antimicrobial peptides can be divided into several families . Peptides of the defensin, cathelicidin, and histatin families have been isolated from humans, where they have been found in defense cells, such as macrophages or neutrophils, as well as in epithelial cells . Decreased production of antimicrobial peptides is associated with immune deficiencies . Further, lung disease in cystic fibrosis may be linked to the dysfunction of antimicrobial peptides . Based on naturally occurring antimicrobial peptides, derivates of these molecules were developed as innovative antibiotic drugs . The present review focuses on the biology of antimicrobial peptides as well as their potential as drugs.

J Clin Epidemiol, 2000 Oct, 53(10), 1069 - 75
A new method for identifying antibiotic-treated infections using automated pharmacy records; Leveille SG et al.; For research purposes, there are few alternatives to costly surveillance for ascertaining infections in community populations . We propose a new approach based on antibiotic prescription fills in automated pharmacy records of the Group Health Cooperative of Puget Sound, in Seattle, Washington, to identify treated infections in postmenopausal women . After excluding probable antimicrobial prophylaxis and chronic antibiotic use, four intervals between antibiotic fills (30, 45, 60, and 90 days) were tested for their ability to detect new infections . Concordance with outpatient medical record reviews was evaluated in 150 women . The sensitivity of the automated pharmacy records using the four cutpoints for detecting new infections ranged from 88 to 80%, from 30 to 90 days, respectively . Of the 81 women with no infection in the chart reviews, 75% also had no infection using the pharmacy method . Good agreement was found between the two methods for counts of infections per person over the 2-year follow-up, with the 60-day cutpoint showing the greatest overall agreement with chart reviews (kappa = 0.55) . The pharmacy method presented here offers a useful new approach for infection ascertainment for epidemiologic research.

Arch Intern Med, 2000 Oct 9, 160(18), 2819 - 22
The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance; Lee CE et al.; BACKGROUND: The development of antimicrobial guidelines is one way in which institutions attempt to control emerging resistance, but the real challenge falls on promoting and ensuring adherence to these guidelines . Investigating reasons for the prescribing of alternative antimicrobial agents outside of these guidelines is crucial for modifying practices that may adversely impact institutional antimicrobial goals . METHODS: Retrospective cross-referencing of computerized pharmacy printouts and concurrent manual medical record review . RESULTS: Approximately 25% (470/1893) of the patients requiring antimicrobial therapy reported an allergy to at least 1 antimicrobial agent . The most commonly reported antimicrobial allergy was penicillin (295/1893 {15.6%}) . Eighty-five patients (18.1%) reported having an allergy to 2 or more antimicrobial agents . Only 4% (27/601) of the reported antimicrobial allergies contained documentation as to the nature of the specific allergic reactions, while a manual medical record review revealed that 32% (23/73) of the antimicrobial allergies contained documentation of the specific allergic reaction . Ninety-eight (39 . 7%) of 247 patients reporting an allergy only to penicillin and/or cephalosporin received vancomycin in comparison with 247 (17.4%) of 1423 patients without any antimicrobial allergies (P<.001) . Similarly, 53 (21.5%) of 247 patients with reported penicillin and/or cephalosporin allergies received levofloxacin compared with 114 (8.0%) of 1423 patients without any antimicrobial allergy (P< . 001) . CONCLUSION: The incidence of penicillin allergy at our institution exceeds population averages . This finding, in combination with limited documentation of drug allergies, appears to lead to the prescribing of alternative antimicrobial agents that do not fit into institutional antimicrobial guidelines and, in some instances, may put the patient at risk for infection and/or colonization with resistant organisms . Use of these alternative agents may adversely impact the ability to manage emerging antimicrobial resistance.

J Ethnopharmacol, 2000 Nov, 73(1-2), 317 - 22
Antimicrobial activity of flavonoids in medicinal plants from Tafí del Valle (Tucumán, Argentina); Hernandez NE et al.; Preliminary studies of flavonoids have been realised in five native species from Tafi del Valle (Tucuman, Argentina) used in popular medicine . Most of compounds detected were flavonoids mono and dihydroxylated in B ring . Screening for antimicrobial activity against Gram positive and Gram negative microorganisms has been realised with Lippia turbinata, Satureja parvifolia, Sambucus peruviana, Verbena officinalis and Chenopodium graveolens . The total extracts of flavonoids of each plant were tested and four species studied showed antimicrobial activity.

J Ethnopharmacol, 2000 Nov, 73(1-2), 299 - 305
Antimicrobial activity of some coumarin containing herbal plants growing in Finland; Ojala T et al.; Antimicrobial screening against selected Gram-positive and Gram-negative bacteria, yeasts, mold, as well as plant pathogenic fungi, with emphasis on method optimization was carried out on methanol extracts prepared from seven plants grown in Finland . Sensitivity to the extracts was found to vary considerably among the micro-organisms, the extract from Petroselinum crispum and Ruta graveolens showing the highest toxicity against Rhizoctonia solani . The growth of Heterobasidium annosum was inhibited, whereas that of Phytophtora (cactorum) was promoted by all the extracts . The antibacterial and antifungal activities of six natural coumarin compounds were weak, except for the inhibitory effect against Fusarium culmorum.

J Ethnopharmacol, 2000 Nov, 73(1-2), 171 - 4
Isolation of an antibacterial sesquiterpenoid from Warburgia salutaris; Rabe T et al.; The bark of Warburgia salutaris is used in traditional medicine as an expectorant and smoked for coughs and colds, including a topical application for sores and inflammation . A previous screening of South African medicinal plants showed that this plant had promising antibacterial activity . Subsequently, this endangered tree species was selected for bioassay-guided fractionation in order to identify the active principles . Fractionation of the ethyl acetate extract of the stem bark by chromatographic techniques yielded a sesquiterpenoid which exhibited antimicrobial activity against Gram-positive bacteria . The compound, muzigadial, has previously been reported in two other Warburgia species, this being the first time it has been reported from W . salutaris . Muzigadial had minimum inhibitory concentration values ranging from 12.5 to 100 microg ml(-1).

Burns, 2000 Dec, 26(8), 724 - 6
Human beta defensin is absent in burn blister fluid; Ortega MR et al.; Defensins are a family of cationic antimicrobial peptides that participate in innate host defence . Human beta defensin-2 (HBD-2) is produced by human keratinocytes, and has a potent bactericidal activity against a wide spectrum of microorganisms . We have recently shown that expression of HBD-2 is present in normal skin and lost in the full-thickness burn wound . Defensins have been found in the blister fluid of chronic wounds . Our study was designed to examine blister fluid from partial-thickness burns for defensin content . Fluid from five patients was collected from partial-thickness burn blisters, and then analysed by sandwich Enzyme-Linked Immunosorbent Assay (ELISA) with a monoclonal antibody and rabbit polyclonal antibody to HBD-2 . The assay was validated against a Western blot assay for HBD-2 in samples of bronchoalveolar lavage fluid from patients with inflammatory lung disease . No HBD-2 was detectable in any of the burn blister fluids analysed . HBD-2 is lost in the full-thickness burn wound, and we have now demonstrated its absence in burn blister fluid . This finding represents evidence of a host defence defect within the burn wound and suggests a possible therapeutic role for antimicrobial peptides in the management of burn wounds.

Clin Microbiol Rev, 2000 Oct, 13(4), 523 - 33
Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function; Tzianabos AO; Polysaccharide immunomodulators were first discovered over 40 years ago . Although very few have been rigorously studied, recent reports have revealed the mechanism of action and structure-function attributes of some of these molecules . Certain polysaccharide immunomodulators have been identified that have profound effects in the regulation of immune responses during the progression of infectious diseases, and studies have begun to define structural aspects of these molecules that govern their function and interaction with cells of the host immune system . These polymers can influence innate and cell-mediated immunity through interactions with T cells, monocytes, macrophages, and polymorphonuclear lymphocytes . The ability to modulate the immune response in an appropriate way can enhance the host's immune response to certain infections . In addition, this strategy can be utilized to augment current treatment regimens such as antimicrobial therapy that are becoming less efficacious with the advent of antibiotic resistance . This review focuses on recent studies that illustrate the structural and biologic activities of specific polysaccharide immunomodulators and outlines their potential for clinical use.

Biophys J, 2000 Oct, 79(4), 2075 - 83
Polar angle as a determinant of amphipathic alpha-helix-lipid interactions: a model peptide study; Uematsu N et al.; Various physicochemical properties play important roles in the membrane activities of amphipathic antimicrobial peptides . To examine the effects of the polar angle, two model peptides, thetap100 and thetap180, with polar angles of 100 degrees and 180 degrees, respectively, were designed, and their interactions with membranes were investigated in detail . These peptides have almost identical physicochemical properties except for polar angle . Like naturally occurring peptides, these peptides selectively bind to acidic membranes, assuming amphipathic alpha-helices, and formed peptide-lipid supramolecular complex pores accompanied by lipid flip-flop and peptide translocation . Despite its somewhat lower membrane affinity, thetap100 exhibited higher membrane permeabilization activity, a greater flip-flop rate, as well as more antimicrobial activity due to a higher pore formation rate compared with thetap180 . Consistent with these results, the peptide translocation rate of thetap100 was higher . Furthermore, the number of peptides constituting thetap100 pores was less than that of thetap180, and thetap100 pores involved more lipid molecules, as reflected by its cation selectivity . The polar angle was found to be an important parameter determining peptide-lipid interactions.

Biophys J, 2000 Oct, 79(4), 2002 - 9
Crystallization of antimicrobial pores in membranes: magainin and protegrin; Yang L et al.; Membrane pores spontaneously formed by antimicrobial peptides in membranes were crystallized for the first time by manipulating the sample hydration and temperature . Neutron diffraction shows that magainins and protegrins form stable pores in fully hydrated fluid membranes . At lower hydration levels or low temperature, the membrane multilayers crystallize . In one crystalline phase, the pores in each bilayer arrange in a regular hexagonal array and the bilayers are stacked into a hexagonal ABC lattice, corresponding to the cubic close-packed structure of spheres . In another crystalline phase, the bilayers are modulated into the rippled multilamellae, corresponding to a 2D monoclinic lattice . The phase diagrams are described . Crystallization of the membrane pores provides possibilities for diffraction studies that might provide useful information on the pore structures.

J Infect, 2000 Sep, 41(2), 159 - 61
Presenting clinical features and C-reactive protein in the prediction of a positive stool culture in patients with diarrhoea; Cadwgan AM et al.; OBJECTIVES: To devise a scoring system by which clinical features and C-reactive protein (CRP) can be used to predict a positive stool culture in patients admitted with acute diarrhoea . METHODS: One hundred and thirty-two patients admitted to the Regional Infection Unit with diarrhoea thought to be due to bacterial gastroenteritis were included . Clinical features, CRP and outcome of stool culture were recorded, together with the final diagnosis . RESULTS: Forty-one patients had bacterial gastroenteritis characterized by the isolation of a bacterial enteropath (BGE) . Sixty-three patients had non-specific gastroenteritis, defined as more than three loose stools per day with no bacterial enteropath isolated (NSGE) . In 28 patients another diagnosis was made (Others) . More of the patients with BGE (91%) had abdominal pain as compared with those with NSGE (67%) and Others (61%) (P=0.01) . The mean duration of symptoms was longer in the Others group (6.14 days) as compared with patients with BGE (3.29) and NSGE (3.25) (P=0.01) . The mean CRP was significantly higher in those with BGE (113.9mg/l) and Others (116.9mg/l) as compared to the NSGE patients (38.9mg/l) (P=0.001) . A scoring system was devised which incorporated the presence or absence of abdominal pain (+10 or 0), the duration of symptoms (-10, for 5 or more days, 0 for less than 5 days of symptoms) and the CRP (CRP<50=0, CRP>50=5) . A score of 15 or more predicted 79% of patients with BGE, while a score of <15 predicted 87% of those with NSGE and 86% of those with another diagnosis . CONCLUSIONS: This simple scoring system may be useful in predicting the positivity of stool culture, and therefore may be helpful in targeting those small number of patients who require antimicrobial therapy after hospital admission . We would not, however, favour reliance on this scoring system alone to choose whom to treat with antimicrobials .

Blood, 2000 Oct 15, 96(8), 2664 - 72
Antimicrobial proteins and peptides of blood: templates for novel antimicrobial agents; Levy O; The innate immune system provides rapid and effective host defense against microbial invasion in a manner that is independent of prior exposure to a given pathogen . It has long been appreciated that the blood contains important elements that mediate rapid responses to infection . Thus, anatomic compartments with ample blood supply are less frequently infected and recover more readily once infected, whereas regions with poor perfusion are prone to severe infection and may require surgical debridement . Blood-borne innate immune mediators are either carried in circulating blood cells (ie, leukocytes and platelets) or in plasma after release from blood cells or on secretion by the liver . (Blood . 2000;96:2664-2672)

J Infect Dis, 2000 Nov, 182(5), 1545 - 8 Epub 2000 Oct 09.
Polymorphisms in candidate genes and risk of scarring trachoma in a Chlamydia trachomatis--endemic population; Mozzato-Chamay N et al.; Genes involved in regulating antimicrobial immunity and inflammation may modulate the risk of tissue scarring and fibrosis in chlamydial diseases such as trachoma . By use of a large case-control study of scarring trachoma in The Gambia, the importance of single-nucleotide polymorphisms in several candidate genes was investigated . Overall, no significant differences were found between patients and control subjects in genotype frequencies for polymorphisms in cytokine promoters interleukin (IL)-10 (positions -1082, -819, -592), IL-4 (-590), or tumor necrosis factor-alpha (-376) or for codon 57 of the mannose-binding protein . Among the ethnic groups in the study, Mandinkas had the highest frequency of the IL-10-1082G allele (0.36) . Within this ethnic group, the IL-10-1082G homozygote genotype was significantly more common among case patients than control subjects (odds ratio, 5.10; 95% confidence interval, 1.24-24.2; P=.009) . This single association is consistent with data indicating that the IL-10-1082G allele is associated with higher levels of IL-10 transcription and that Th2-type immune responses are associated with risk of chlamydial disease.

J Dent Res, 2000 Sep, 79(9), 1669 - 74
Expression of the antimicrobial peptide, human beta-defensin 1, in duct cells of minor salivary glands and detection in saliva; Sahasrabudhe KS et al.; The oral cavity is exposed to a variety of environmental insults . Salivary secretions play a critical role in maintaining oral health via innate host defense mechanisms and secretion of secretory IgA . Human beta-defensins (hBD) are antimicrobial peptides that are a component of the innate immune response; they are expressed in epithelia and are proposed to have a role in mucosal defense . hBD-1 mRNA is constitutively expressed in numerous mucosal tissues, including human gingiva and submandibular and parotid glands . Our objective was to detect the expression and localization of hBD-1 peptide in human salivary glands and in saliva . Minor salivary gland tissue was obtained from biopsies of patients with mucoceles (n = 20) . hBD-1 peptide was detected by immunohistochemistry; expression was localized to the ductal cells and not the acinar cells of these glands . The peptide was located apically, toward the lumen in the duct cells . Further evaluation showed stronger hBD-1 expression in ducts with periductal inflammation, as indicated by the immunostaining of serial sections with anti-CD45 specific for B- and T-lymphocytes . Statistical analysis showed a strong correlation of hBD-1 staining and inflammation . Results of immunolocalization suggest that hBD-1 functions to protect salivary glands from retrograde infection, that expression of the peptide is enhanced in inflamed sites, and that post-transcriptional regulatory mechanisms may be involved in hBD-1 peptide expression . Western immunoblot analysis also detected hBD-1 peptide in unstimulated, whole, acidified saliva from normal volunteers . However, hBD-1 peptide associated with salivary mucin resulted in loss of the detection in a dot-immunoblot assay . Association of hBD-1 with salivary mucin may facilitate peptide distribution and adherence to oral surfaces and aid its function within the oral cavity.

Paediatr Drugs, 2000 Sep-Oct, 2(5), 357 - 65
Helicobacter pylori infection and eradication in paediatric patients; Malaty HM; Helicobacter pylori is now recognised to be typically acquired during childhood . Studies also indicate that the infection is frequently lost in childhood; however, it is still unclear whether this is related to the use of antibacterials, the natural history of the infection, or both . H . pylori colonises gastric mucosa and is causally related to chronic gastritis and peptic ulcer disease in both children and adults . Successful eradication of H . pylori has resulted in the healing of duodenal ulcers and the lowering of the ulcer relapse rate in children . Therapy to cure the infection should be started in all children with peptic (duodenal or gastric) ulcer who are still infected . The ideal anti-H . pylori regimen should be safe, cheap, easy to comply with, well tolerated by children and able to achieve a high cure rate . Although US data are lacking, it is anticipated that the treatment regimen for children should be similar to that in adults (a triple therapy regimen that combines a proton pump inhibitor with 2 antimicrobial agents for 14 days) . It is inappropriate to prescribe anti-H . pylori therapy without a firm diagnosis . The use of multiple antibacterials in a paediatric patient with an ulcer but without H . pylori infection cannot provide any benefit to the patient or the community . Such an approach only provides the possibility for adverse effects, for example development of antibacterial resistance among bystander bacteria . It is very important to confirm the diagnosis of H . pylori infection . The {13C}urea breath test is the noninvasive method of choice to determine H . pylori status in children and the ideal test for post-therapy testing . There is a need for post-therapy confirmation because of the likelihood of poor outcome for some treatment regimens, which is why post-therapy testing should be the standard of care . There is weak and inconsistent evidence of an association between H . pylori infection and recurrent abdominal pain (RAP) in children, in part because of the unclear definition of RAP in the literature . Therefore, there is still considerable debate regarding the treatment of infected children with RAP.

J Periodontol, 2000 Sep, 71(9), 1472 - 83
Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility; Thomas J et al.; BACKGROUND: Adjunctive subantimicrobial dose doxycycline (SDD) with scaling and root planing leads to improved clinical parameters of adult periodontitis, but has raised questions about potential changes in antibiotic susceptibility of the host microflora . Our four studies assessed whether long-term SDD changes antibiotic susceptibility of the oral microflora in adults with periodontitis . METHODS: In studies 1 and 2, adult patients with periodontitis were randomized to receive SDD 10 mg qd, 20 mg qd, 20 mg bid, or placebo . In study 3, patients were randomized to receive SDD 20 mg bid or placebo . No medication was administered in study 4, a follow-up to study 3 . Subgingival plaque samples were collected at baseline (all studies) and at 12, 15 to 18, and 24 months (study 1); 12, 18, and 27 months (study 2); 3, 6, and 9 months (study 3); and 3 months post-study 3 (study 4) . Antimicrobial susceptibility of isolated bacteria was assessed by: 1) minimum inhibitory concentration (MIC) levels (studies 1 and 2); 2) cross-resistance to non-tetracycline antibiotics (studies 2 and 3); and 3) the proportion of doxycycline-resistant isolates (studies 3 and 4) . RESULTS: Organism MIC levels remained constant among all treatment groups at 18 and 24 months compared with baseline (study 1) . Observed changes in susceptibility at 12 and 18 months for the 20 mg groups were attributed to the limited number of isolates tested (study 1) . There were no statistically significant differences in the proportion of doxycycline-resistant isolates among treatment groups (studies 3 and 4), and no evidence of multi-antibiotic resistance (studies 3 and 4) or cross-resistance (studies 2 and 3) at any timepoint . CONCLUSION: Long-term SDD does not contribute to changes in antibiotic susceptibility.

J Periodontol, 2000 Sep, 71(9), 1465 - 71
Long-term treatment with subantimicrobial dose doxycycline exerts no antibacterial effect on the subgingival microflora associated with adult periodontitis; Walker C et al.; BACKGROUND: The purpose of this study was to determine whether treatment with subantimicrobial dose doxycycline (SDD), 20 mg bid, exerted an antimicrobial effect on the microflora associated with adult periodontitis . METHODS: Following the approval of the protocol and informed consent forms by the respective IRBs at the University of Florida and West Virginia University, 76 subjects with adult periodontitis were entered and randomly assigned to receive SDD or placebo . A split-mouth design was utilized, with each subject receiving subgingival scaling and root planing (SRP) in two quadrants immediately following baseline data collection, while the remaining two quadrants were left unscaled (non-SRP) . Microbial samples were collected prior to treatment, after 3, 6, and 9 months of treatment, and after 3 months of no treatment . The samples were examined by microscopy and by enumeration on selective and non-selective media . RESULTS: All treatments resulted in statistically significant decreases in the proportions of spirochetes and motile rods (P <0.05) and in an increase in the proportion of coccoid forms (P <0.0001) relative to baseline . No between-treatment differences were detected between the SDD and placebo treatments in either the SRP or non-SRP design, with the exception of the small and large spirochetal groups . The spirochetal proportions present in the SDD group were significantly lower (P<0.05) than the paired placebo group during the 9-month treatment and was preceded by a significant decrease (P<0.01) in the proportion of microbiologic sample sites that bled on probing . No between- treatment differences were detected in any of the other microbial parameters . CONCLUSION: The microbial differences observed were attributed to the anticollagenase and anti-inflammatory properties of SDD and not to an antimicrobial effect.

J Antimicrob Chemother, 2000 Oct, 46(4), 589 - 94
Evaluation of a human monocytic cell line THP-1 model for assay of the intracellular activities of antimicrobial agents against Legionella pneumophila; Takemura H et al.; We examined the intracellular activities of 11 antimicrobial agents against Legionella pneumophila using a human monocyte-derived cell line, THP-1 . Colony counting and microscopic examination of L . pneumophila co-incubated with THP-1 cells (5 x 105 cells/well) were performed . Both extra- and intra-cellular multiplication of L . pneumophila were observed and were dependent on the inoculum of L . pneumophila in the culture; L . pneumophila did not grow in the cell culture medium alone . Light microscopic examination confirmed that extracellular L . pneumophila originated from THP-1 cells disrupted by bacterial multiplication . L . pneumophila multiplied by 3-4 logs after 24 h incubation with THP-1 cells and their number remained stable at 106-107 cfu/mL until 72 h . The results of viability studies using four antimicrobial agents-ciprofloxacin, erythromycin, minocycline and rifampicin-demonstrated that our system was suitable for the intracellular activity assay . We used a concept of 'minimum extracellular concentration inhibiting intracellular multiplication' (MIEC) to evaluate the intracellular activity of antimicrobial agents . The MIECs of three beta-lactams were markedly higher than their conventional MICs while those of macrolides, quinolones, rifampicin and minocycline were similar to their MICs . Our results suggest that evaluation of the clinical efficacy of drugs against L . pneumophila should include determination of their intracellular activity against the bacteria, which could be measured using our assay system in THP-1 cells.

J Antimicrob Chemother, 2000 Oct, 46(4), 583 - 8
Clindamycin promotes phagocytosis and intracellular killing of periodontopathogenic bacteria by crevicular granulocytes: an in vitro study; Eick S et al.; Phagocytosis of periodontopathogenic bacteria by crevicular polymorphonuclear neutrophil granulocytes (PMNs) plays a key role in the aetiology of periodontitis . Antimicrobials such as clindamycin have been proven to be effective in treating progressive forms of this disease . Therefore, the purpose of this study was to determine the effect of clindamycin on the phagocytosing properties of gingival crevicular PMNs obtained from 16 patients with rapidly progressive periodontitis (RPP), eight with localized juvenile periodontitis (LJP), 12 with adult periodontitis (AP) and 13 periodontally healthy controls . The phagocytosis assay was performed with the two strains Porphyromonas gingivalis ATCC 33277 and Actinobacillus actinomycetemcomitans Tanner FDC 44 on a slide . Phagocytosis and intracellular killing were assessed by fluorescence microscopy after staining with acridine orange . The addition of clindamycin elevated the percentage of phagocytosing PMNs in periodontitis patients and controls regardless of whether P . gingivalis or A . actinomycetemcomitans was used as test strain . In granulocytes of healthy controls an enhancement of the intracellular killing of both strains was observed if clindamycin was added . Besides the antimicrobial effect, the enhancement of the phagocytosis might be an additional indication for treatment of periodontitis patients with clindamycin.

Clin Pharmacokinet, 2000 Sep, 39(3), 185 - 201
Comparative pharmacokinetics of the carbapenems: clinical implications; Mouton JW et al.; During the last few decades, several carbapenems have been developed . The major characteristic of the newer drugs, such as MK-826, is a prolonged half-life . Alternatively, some carbapenems have been developed that can be given orally, such as CS-834 and L-084 . Although imipenem and panipenem have to be administered with a co-drug to prevent degradation by the enzyme dehydropeptidase-1 and reduce nephrotoxicity, the newer drugs such as meropenem, biapenem and lenapenem are relatively stable towards that enzyme . Structural modifications have, besides changes in pharmacology, also led to varying antimicrobial properties . For instance, meropenem is relatively more active against Gram-negative organisms than most other carbapenems, but is slightly less active against Gram-positive organisms . Except for half-life and bioavailability, the pharmacokinetic properties of the carbapenems are relatively similar . Distribution is mainly in extracellular body-water, as observed both from the volumes of distribution and from blister studies . Some carbapenems have a better penetration in cerebrospinal fluid than others . In patients with renal dysfunction, doses have to be adjusted, and special care must be taken with imipenem/cilastatin and panipenem/betamipron to prevent accumulation of the co-drugs, as the pharmacokinetic properties of the co-drugs differ from those of the drugs themselves . However, toxicity of the co-drugs has not been shown . The carbapenems differ in proconvulsive activity . Imipenem shows relatively the highest proconvulsive activity, especially at higher concentrations . Pharmacodynamic studies have shown that the major surrogate parameter for antimicrobial efficacy is the percentage of time of the dosage interval above the minimum inhibitory concentration (MIC) . The minimum percentage percentage of time above the MIC (TaM) needed for optimal effect is known in animals (30 to 50%), but not in humans . It is probably less than 100%, but may be higher than 50% . Dosage regimens currently in use result in a TaM of about 50% at 4 mg/L, which is the current 'susceptible' breakpoint determined by the National Committee for Clinical Laboratory Standards (NCCLS) for most micro-organisms . Dosage regimens in patients with reduced renal clearance should be based on the TaM . The increased half-life of the newer carbapenems will probably lead to less frequent administration, although continuous infusion may still be the optimal mode of administration for these drugs . The availability of oral carbapenems will have a profound effect on the use of carbapenems in the community.

J Refract Surg, 2000 Sep-Oct, 16(5), 523 - 38
Postoperative inflammation, microbial complications, and wound healing following laser in situ keratomileusis; Alio JL et al.; Although the biology of corneal wound healing is only partly understood, healing after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) differs in many respects, and the mechanisms appear to be differently controlled . There is less of an inflammatory and healing response after LASIK, but a longer period of sensory denervation . The cellular, molecular, and neural regulatory phenomena associated with postoperative inflammation and wound healing are likely to be involved in the adverse effects after LASIK, such as flap melt, epithelial ingrowth, and regression . Interface opacities in the early postoperative period include diffuse lamellar keratitis (DLK), microbial keratitis, epithelial cells, and interface opacities . Diffuse lamellar keratitis (sands of the Sahara syndrome) describes an apparently noninfectious diffuse interface inflammation after lamellar corneal surgery probably caused by an allergic or a toxic inflammatory reaction . Noninfectious keratitis must be distinguished from microbial keratitis to avoid aggressive management and treatment with antimicrobial drugs . Microbial keratitis is a serious complication after LASIK, but a good visual outcome can be achieved following prompt and appropriate treatment.

Yakugaku Zasshi, 2000 Sep, 120(9), 795 - 9
{Determination of antimicrobial, 10,10'-oxybis-10H-phenoxarsine, in artificial leather used for the seat of chairs}; Ikarashi Y et al.; Recently, a case of patients with allergic contact dermatitis caused by the poly (vinyl chloride) (PVC) seat, containing 10,10'-oxybis-10H-phenoxarsine (OBPA), of a chair was reported . OBPA was developed as an antimicrobial for plastics such as PVC and polyurethane, and it has been widely used in artificial leather for the seats of chairs and sofas . To identify causative chemicals for allergic contact dermatitis, a combination of patch testing in the patients and chemical analysis of causative products is valuable . However, no analytical method and data of OBPA in commercial products was reported . In this study, a method for the determination of OBPA in the artificial leather (PVV base) was developed . OBPA was extracted from PVC samples with methanol . The extract was loaded on an aluminum oxide column, and washed with diethyl ether:hexane, and eluted with ethanol:hexane . The eluate was evaporated, dissolved in methanol and injected to a HPLC equipped an ODS column and an UV detector (detection wavelength 300 nm) . OBPA standard crystal was isolated from commercial agents containing OBPA . The calibration curve for OBPA was linear in the range of 0.1-100 micrograms/ml . The minimum detection and determination concentrations of OBPA in samples were 0.07 and 0.25 microgram/g . By this method, eight PVC sheets for the seat of a chair were analyzed . In two PVC sheets, 52.7 and 84.9 micrograms/g of OBPA were detected . In the PVC product that caused contact dermatitis, OBPA was not found.

Biochim Biophys Acta, 2000 Sep 29, 1468(1-2), 213 - 30
X-ray studies on the interaction of the antimicrobial peptide gramicidin S with microbial lipid extracts: evidence for cubic phase formation; Staudegger E et al.; We have investigated the effect of the interaction of the antimicrobial peptide gramicidin S (GS) on the thermotropic phase behavior of model lipid bilayer membranes generated from the total membrane lipids of Acholeplasma laidlawii B and Escherichia coli . The A . laidlawii B membrane lipids consist primarily of neutral glycolipids and anionic phospholipids, while the E . coli inner membrane lipids consist exclusively of zwitterionic and anionic phospholipids . We show that the addition of GS at a lipid-to-peptide molar ratio of 25 strongly promotes the formation of bicontinuous inverted cubic phases in both of these lipid model membranes, predominantly of space group Pn3m . In addition, the presence of GS causes a thinning of the liquid-crystalline bilayer and a reduction in the lattice spacing of the inverted cubic phase which can form in the GS-free membrane lipid extracts at sufficiently high temperatures . This latter finding implies that GS potentiates the formation of an inverted cubic phase by increasing the negative curvature stress in the host lipid bilayer . This effect may be an important aspect of the permeabilization and eventual disruption of the lipid bilayer phase of biological membranes, which appears to be the mechanism by which GS kills bacterial cells and lysis erythrocytes.

Control Clin Trials, 2000 Oct, 21(5), 488 - 97
Indirect comparison in evaluating relative efficacy illustrated by antimicrobial prophylaxis in colorectal surgery; Song F et al.; This paper aims to explore the potential usefulness and limitations of indirect comparisons in evaluating the relative efficacy of interventions . From a systematic review of antimicrobial prophylaxis in colorectal surgery, we identified 11 sets of randomized trials that can be used to compare antibiotics both directly and indirectly . The discrepancy between the direct and the indirect comparison is defined as the absolute value of difference in log odds ratio . The adjusted indirect comparison has the advantages that the prognostic factors of participants in different trials can be partially taken into account and more uncertainty be incorporated into its result by providing a wider confidence interval . However, considerable discrepancies exist between the direct and the adjusted indirect comparisons . When there is no direct comparison, the adjusted indirect method may be used to obtain some evidence about the relative efficacy of competing interventions, although such indirect results should be interpreted with great caution . Further empirical and methodologic research is needed to explore the validity and generalizability of the adjusted indirect comparison for evaluating different interventions.

Clin Infect Dis, 2000 Sep, 31 Suppl 4, S144 - 9
Emerging therapies for serious gram-positive bacterial infections: a focus on linezolid; Plouffe JF; Respiratory tract infections and skin and soft-tissue infections frequently are caused by gram-positive cocci, and treating these infections with standard antibiotics has recently become problematic . Many of the primary pathogens causing these infections are now resistant to current standard treatment regimens . In addition, the frequency of these infections is increasing, particularly among patients with complex medical conditions . Thus, new and effective antimicrobial agents are needed, and many are currently in various stages of development . Linezolid, the first approved oxazolidinone, has enhanced activity against gram-positive organisms . Recent results of 5 large, randomized, phase 3 trials evaluating linezolid for the treatment of community-acquired pneumonia, nosocomial pneumonia, and uncomplicated and complicated skin and soft-tissue infections are encouraging and indicate that linezolid is as effective as standard comparator agents as therapy for these infections . Thus, the recent availability of linezolid offers clinicians a promising new agent for the treatment of serious gram-positive bacterial infections.

Clin Infect Dis, 2000 Sep, 31 Suppl 4, S131 - 8
Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients; Kollef MH; Inadequate antimicrobial treatment, generally defined as microbiological documentation of an infection that is not being effectively treated, is an important factor in the emergence of infections due to antibiotic-resistant bacteria . Factors that contribute to inadequate antimicrobial treatment of hospitalized patients include prior antibiotic exposure, use of broad-spectrum antibiotics, prolonged length of stay, prolonged mechanical ventilation, and presence of invasive devices . Strategies to minimize inadequate treatment include consulting an infectious disease specialist, using antibiotic practice guidelines, and identifying quicker methods of microbiological identification . In addition, clinicians should determine the prevailing pathogens that account for the community-acquired and nosocomial infections identified in their hospitals . Clinicians can improve antimicrobial treatment by using empirical combination antibiotic therapy based on individual patient characteristics and the predominant bacterial flora and their antibiotic susceptibility profiles . This broad-spectrum therapy can then be narrowed when initial culture results are received . Further study evaluating the use of antibiotic practice guidelines and strategies to reduce inadequate treatment is necessary to determine their impact on patient outcomes.

Clin Infect Dis, 2000 Sep, 31 Suppl 4, S124 - 30
The impact of changing pathogens of serious infections in hospitalized patients; McGowan JE; New epidemiological patterns are being observed for multidrug-resistant nosocomial organisms . Current problems include the appearance of resistance determinants in organisms that are virulent enough to cause infection in patients with normal host defenses . In addition, multidrug-resistant organisms are spreading from health care to community settings, and organisms from the community are spreading to health care settings . The appearance and spread of resistance can be examined both at a molecular level and on a larger scale involving several pathways . Potential pathways within institutions include the following: introduction of new strains from outside sources (e.g., patients or health care workers from other institutions); exchange of resistance determinants via genetic mutation or transfer of genetic material; emergence or selection of resistant strains following exposure to antimicrobials; and clonal dissemination . Strategies such as multidisciplinary management of infections, appropriate infection control measures, and surveillance of resistance patterns are necessary to address the problem of resistance.

Clin Infect Dis, 2000 Sep, 31(3), 762 - 9 Epub 2000 Oct 04.
Bacterial monopolists: the bundling and dissemination of antimicrobial resistance genes in gram-positive bacteria; Rice LB; Antibiotic resistance is the unavoidable result of our placing selective pressure on the microbial community . Advances in molecular biology techniques in the past 2 decades have allowed us to greatly improve our understanding of the mechanisms by which resistance emerges and disseminates among human pathogenic bacteria . Gram-positive bacteria employ a diverse array of elements, including plasmids, transposons, insertion sequences, and bacteriophages, to disseminate resistance . An understanding of these mechanisms and their prevalence can improve our ability to treat clinical infections in hospitalized patients, as well as to predict and control the spread of resistant bacteria in the nosocomial environment.

Viral Immunol, 2000, 13(3), 383 - 97
Immune components in porcine mammary secretions; Wagstrom EA et al.; Immune components present in mammary secretions are reviewed . In swine, the histological structure of the placenta prevents in utero transfer of immunoglobulins and mammary secretions are the sole source of maternal antibody for the neonate . In addition to immunoglobulins, porcine mammary secretions contain significant numbers of maternal cells of various types that may contribute to neonatal immunity, including phagocytes (neutrophils and macrophages), lymphocytes (B and T cells), and epithelial cells . Immunomodulating and/or antimicrobial substances, including lactoferrin, lysozyme, lactoperoxidase, and cytokines, are also present in mammary secretions and may contribute to the protection of the neonate . While the role of immunoglobulins in mammary secretions is well understood, the contribution of cellular components and non-specific immune factors to neonatal immunity remains to be defined.

J Exp Med, 2000 Oct 2, 192(7), 1069 - 74
LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells; De Yang et al.; We have previously shown that antimicrobial peptides like defensins have the capacity to mobilize leukocytes in host defense . LL-37 is the cleaved antimicrobial 37-residue, COOH-terminal peptide of hCAP18 (human cationic antimicrobial protein with a molecular size of 18 kD), the only identified member in humans of a family of proteins called cathelicidins . LL-37/hCAP18 is produced by neutrophils and various epithelial cells . Here we report that LL-37 is chemotactic for, and can induce Ca(2+) mobilization in, human monocytes and formyl peptide receptor-like 1 (FPRL1)-transfected human embryonic kidney 293 cells . LL-37-induced Ca(2+) mobilization in monocytes can also be cross-desensitized by an FPRL1-specific agonist . Furthermore, LL-37 is also chemotactic for human neutrophils and T lymphocytes that are known to express FPRL1 . Our results suggest that, in addition to its microbicidal activity, LL-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and T cells to sites of microbial invasion by interacting with FPRL1.

Community Dent Oral Epidemiol, 2000 Oct, 28(5), 373 - 81
Salivary alterations in type 2 (non-insulin-dependent) diabetes mellitus and hypertension; Dodds MW et al.; OBJECTIVES: The aim of this study was to determine whether saliva output and composition are altered in type 2 diabetes mellitus by comparison with a healthy, non-medicated control group, and also a group of hypertensives . METHODS: From a community-dwelling cohort of Mexican American and European American subjects enrolled in the OH:SALSA oral aging study, we identified 233 subjects with type 2 diabetes mellitus, 227 with hypertension, and 240 healthy control subjects . We collected unstimulated whole (UW) and submandibular/ sublingual (US) saliva, as well as stimulated parotid (SP) and submandibular/ sublingual (SS) saliva . Flow rates were determined, yeast carriage was assayed in UW saliva, and SP and SS saliva samples were analyzed for protein composition . ELISA was used to determine concentrations of an array of specific protein components, with both antimicrobial and other activities . RESULTS: Both diabetic and hypertensive subjects had reduced output of both stimulated and unstimulated submandibular/sublingual saliva . 30% of the diabetic subjects had high oral yeast counts (> or =1000 cfu/mL) compared with 17% of the healthy subjects and 20% of the hypertensives . Significant increases in the concentrations of a number of the protein components were found in the diabetic subjects, specifically, SP lactoferrin, myeloperoxidase (MPO), and salivary peroxidase (SPO), as well as SS total protein, albumin, lactoferrin and secretory IgA . CONCLUSIONS: The pattern of decreased flow rates and increased protein concentrations were similar, but consistently greater in diabetics than hypertensives, suggesting that disease-specific mechanisms may be responsible . Diabetics may be more prone to oral dryness and infections than non-diabetics.

Aliment Pharmacol Ther, 2000 Oct, 14(10), 1329 - 34
Helicobacter pylori-positive duodenal ulcer: three-day antibiotic eradication regimen; Catalano F et al.; BACKGROUND: The most widely used treatments for ulcer healing and Helicobacter pylori eradication consist of a 1-2 week regimen of a proton pump inhibitor plus two or three antimicrobials . AIMS: To evaluate the efficacy, safety, cost, and tolerance of a three-day regimen with three antibiotics vs . a 10-day treatment with a proton pump inhibitor or vs . a ranitidine bismuth citrate triple therapy . METHODS: Two hundred and twenty-one patients with endoscopically-proven H . pylori-positive duodenal ulcers were recruited to the study . Recruited patients were assigned to one of the following four regimens: (I) omeprazole 40 mg o.m . plus amoxycillin 1 g b.d . and clarithromycin 500 mg b.d . for 10 days (OAC: 55 patients); (ii) omeprazole 40 mg o.m . on days 1-5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d . and metronidazole 500 mg b.d . on days 3-5 (OACM: 56 patients); (iii) ranitidine bismuth citrate 400 mg b.d . plus amoxycillin 1 g b.d . and clarithromycin 500 mg b.d . for 10 days (RAC: 54 patients); (iv) ranitidine bismuth citrate 400 mg b.d . on days 1-5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d . and metronidazole 500 mg b.d . on days 3-5 (RACM: 56 patients) . Fisher's exact test was used to compare data regarding healing and eradication in the four groups . RESULTS: The intention-to-treat eradication and ulcer healing rates for the RACM regimen were 95% and 98%, respectively . Statistically significant differences were observed, relating to the eradication and healing of ulcers, between RACM and either the RAC or OAC regimens . CONCLUSION: The three-day antibiotic therapy with amoxycillin, clarithromycin and metronidazole in addition to ranitidine bismuth citrate is a very effective anti-H . pylori regimen.

J Biol Chem, 2000 Dec 22, 275(51), 40478 - 82
Germ-free and colonized mice generate the same products from enteric prodefensins; Putsep K et al.; The use of germ-free mice offers the possibility to study antibacterial components in a gut uncolonized by bacteria . We have developed a method to extract and high pressure liquid chromatography-fractionate the antibacterial factors present in the small intestine of a single mouse . By mass spectrometry and sequence analyses of fractions exhibiting antimicrobial activity, we identified and characterized the defensin region in germ-free mice as well as in colonized mice . Defensins made up around 15% of the total antibacterial activity both in germ-free and colonized mice . The intestine of germ-free mice exhibited the same set of mature enteric defensins (defensins 1, 2, 3, 4, and 6) as mice colonized by a normal microflora . Mature defensins are generated through processing of larger precursors by enzymatic removal of a signal peptide and a propiece . We found that all prodefensins were cleaved at a Ser/Ala-Leu bond, giving 34-residue propiece peptides and only trace amounts of the predicted 39-residue peptide . This first step must be followed by the removal of a residual peptide to render the mature defensins, indicating that the processing is more complex than previously anticipated . The same propieces were found in both germ-free and colonized mice, suggesting that the same processing operates independent of bacterial presence in the intestine.

Biochemistry, 2000 Oct 3, 39(39), 11907 - 12
Comparison of the membrane interaction and permeabilization by the designed peptide Ac-MB21-NH2 and truncated dermaseptin S3; Moll GN et al.; Ac-MB21-NH(2) (Ac-FASLLGKALKALAKQ-NH(2)) and dermaseptin S3(1-16)-NH(2) (ALWKNMLKGIGKLAGK-NH(2)) are cationic amphipathic peptides with antimicrobial activity against a broad spectrum of microorganisms including various fungi . The interaction of the peptides with liposomes was studied by exploiting the tryptophan fluorescence of F1W-Ac-MB21-NH(2) and dermaseptin S3(1-16)-NH(2) . Spectral analysis and the use of quenchers indicate that the tryptophans of both peptides insert more deeply in anionic than in zwitterionic liposomes . Membrane insertion correlates with the formation of an alpha-helical peptide structure . Both peptides permeabilize liposomes composed of anionic, cylindric phospholipids more efficiently than liposomes formed of zwitterionic, conic (phospho)lipids.

Biochemistry, 2000 Oct 3, 39(39), 11855 - 64
Role of the hinge region and the tryptophan residue in the synthetic antimicrobial peptides, cecropin A(1-8)-magainin 2(1-12) and its analogues, on their antibiotic activities and structures; Oh D et al.; A 20-residue hybrid peptide CA(1-8)-MA(1-12) (CA-MA), incorporating residues 1-8 of cecropin A (CA) and residues 1-12 of magainin 2 (MA), has potent antimicrobial activity without toxicity against human erythrocytes . To investigate the effects of the Gly-Ile-Gly hinge sequence of CA-MA on the antibacterial and antitumor activities, two analogues in which the Gly-Ile-Gly sequence of CA-MA is either deleted (P1) or substituted with Pro (P2) were synthesized . The role of the tryptophan residue at position 2 of CA-MA on its antibiotic activity was also investigated using two analogues, in which the Trp2 residue of CA-MA is replaced with either Ala (P3) or Leu (P4) . The tertiary structures of CA-MA, P2, and P4 in DPC micelles, as determined by NMR spectroscopy, have a short amphiphilic helix in the N-terminus and about three turns of alpha-helix in the C-terminus, with the flexible hinge region between them . The P1 analogue has an alpha-helix from Leu4 to Ala14 without any hinge structure . P1 has significantly decreased lytic activities against bacterial and tumor cells and PC/PS vesicles (3:1, w/w), and reduced pore-forming activity on lipid bilayers, while P2 retained effective lytic activities and pore-forming activity . The N-terminal region of P3 has a flexible structure without any specific secondary structure . The P3 modification caused a drastic decrease in the antibiotic activities, whereas P4, with the hydrophobic Leu side chain at position 2, retained its activities . On the basis of the tertiary structures, antibiotic activities, vesicle-disrupting activities, and pore-forming activities, the structure-function relationships can be summarized as follows . The partial insertion of the Trp2 of CA-MA into the membrane, as well as the electrostatic interactions between the positively charged Lys residues at the N-terminus of the CA-MA and the anionic phospholipid headgroups, leads to the primary binding to the cell membrane . Then, the flexibility or bending potential induced by the Gly-Ile-Gly hinge sequence or the Pro residue in the central part of the peptides may allow the alpha-helix in the C-terminus to span the lipid bilayer . These structural features are crucial for the potent antibiotic activities of CA-MA.

Biochemistry, 2000 Oct 3, 39(39), 11837 - 44
The functional association of polymyxin B with bacterial lipopolysaccharide is stereospecific: studies on polymyxin B nonapeptide; Tsubery H et al.; The Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is a major inducer of sepsis . The natural cyclic peptide polymyxin B (PMB) is a potent antimicrobial agent, albeit highly toxic, by virtue of its capacity to neutralize the devastating effects of LPS . However, the exact mode of association between PMB and LPS is not clear . In this study, we have synthesized polymyxin B nonapeptide, the LPS-binding cyclic domain of PMB, and its enantiomeric analogue and studied several parameters related to their interaction with LPS and their capacity to sensitize Gram-negative bacteria toward hydrophobic antibiotics . The results suggest that whereas the binding of the two enantiomeric peptides to E . coli and to E . coli LPS is rather similar, functional association with the bacterial cell is stereospecific . Thus, the L-enantiomer is capable of synergism with the hydrophobic antimicrobial drugs novobiocin and erythromycin, whereas the D-enantiomer is devoid of such activity . The potential of understanding and consequently utilizing the PMB-LPS association for novel, nontoxic PMB-derived drugs is discussed.

Cornea, 2000 Sep, 19(5), 644 - 9
The diagnosis and management of dry eye: a twenty-five-year review; Pflugfelder SC et al.; PURPOSE: To review the advances in the diagnosis, pathogenesis, and management of dry eye disease in the past 25 years . METHODS: Literature review . RESULTS: The preocular tear film is a hydrated mucus gel that contains soluble antimicrobial proteins and growth factors that protect and support the ocular surface . The final common pathway in dry eye is a perturbation of the integrated ocular surface/lacrimal gland reflex unit . Diagnostic tests evaluating tear composition and clearance appear to show stronger correlation with the severity of ocular irritation symptoms and keratoconjunctivitis sicca (KCS) than the conventional Schirmer tests . KCS is a condition of abnormal differentiation and mucus production by the ocular surface epithelium that results in a poorly lubricated, abnormally permeable ocular surface that has increased susceptibility to environmental insults . Chronic subclinical ocular surface inflammation appears to play a key role in the pathogenesis of KCS . New therapeutic strategies are aimed at reducing the ocular surface inflammation of dry eye disease . CONCLUSIONS: There has been a tremendous increase in knowledge regarding dry eye disease in the past 25 years that has resulted in improved diagnostic classification and new targeted therapies.

Crit Care Med, 2000 Sep, 28(9), 3332 - 8
Prevention of nosocomial bloodstream infections: effectiveness of antimicrobial-impregnated and heparin-bonded central venous catheters; Marin MG et al.; OBJECTIVES: To examine the effectiveness of antimicrobial-impregnated and heparin-bonded catheters relative to standard central venous catheters in lessening catheter-related bloodstream infections . DATA SOURCES: Articles were identified by computer-assisted searching . STUDY SELECTION: Studies were eliminated from further consideration if they did not contain original data relevant to lessening catheter-related bloodstream infections, were nonrandomized or uncontrolled, described subjects <17 yrs of age, or used animal subjects . DATA ABSTRACTION: From each eligible article, we abstracted the following: a) citation; b) type of control; c) study setting; d) type of experimental catheter; e) catheter-specific complications; f) total numbers of patients and catheters; g) number of experimental catheters used that resulted in a catheter-related bloodstream infection; h) number of control catheters used that resulted in a catheter-related bloodstream infection; i) number of experimental catheters used without catheter-related bloodstream infections; and j) number of control catheters used without infections . We also recorded the duration of catheter use and the types of microbes cultured in association with the catheters and with catheter-related bloodstream infections . DATA SYNTHESIS: Eleven eligible studies were identified . Using meta-analysis, we showed that antimicrobial-impregnated and heparin-bonded central venous catheters significantly decreased catheter-related bloodstream infections by 2.32% (95% confidence interval, 1.04% to 3.61%) . CONCLUSIONS: The modest additional cost for the use of these catheters relative to the considerable cost of treating even a single bloodstream infection makes their use cost-effective.

Braz J Infect Dis, 2000 Aug, 4(4), 161 - 7
Epidemiology of nosocomial candidiasis: the importance of molecular typing; Pfaller MA; Modern epidemiology studies now require that nosocomial pathogens be characterized to the subspecies level whenever possible to better define infectious processes and modes of transmission . In general, if isolates are classified as different by at least one molecular typing method, they may be assumed to represent different strains and to reflect independent infections . If the isolates are the same, it may be assumed that cross infection has occurred or that the patients were infected by exposure to a common source . Typing methods may also be used to address clinical problems related to distinguishing reinfection versus relapse of an infection, and to examine the development of antifungal resistance among fungal pathogens during the course of antifungal therapy . Determining DNA fingerprints of sequential isolates from patients undergoing antifungal therapy has been useful in demonstrating the potential for the development of antifungal resistance in previously susceptible strains and for detecting the substitution of a more resistant strain for a more susceptible strain in the face of intense antimicrobial pressure . In order to be useful as an epidemiological typing method, a DNA fingerprinting system must effectively distinguish between genetically unrelated strains, identify the same strain in separate samples, and reflect genetic relatedness or unrelatedness (genetic distance) among strains.

Biochem Pharmacol, 2000 Oct 15, 60(8), 1109 - 14
Nuclear factor-kappa B activation and innate immune response in microbial pathogen infection; Naumann M; Human pathogenic microorganisms have developed a variety of strategies to infect the host organism successfully, whereas the host has evolved a series of defense mechanisms . In most cases, the epithelial cell layer represents the first barrier for the bacterial pathogen and triggers the innate and inflammatory responses in the host . Epithelial cells release proinflammatory mediators including cytokines and chemokines, leading to the subsequent attraction of monocytes/macrophages . Therefore, epithelial cells represent an immediate-early warning system in the host organism . Subsequent to the colonization of the epithelial layer, invasive microbial pathogens often induce an acute inflammatory response, which functions to activate residential macrophages and recruits blood leukocytes to the site of infection . Distinct receptors of the Toll family on the cell surface of immune cells mediate antibacterial responses in mammals as well as in Drosophila . One of the most important cellular factors involved in the regulation of the host innate antimicrobial response is the immediate-early response transcription factor nuclear factor (NF)-kappa B . Microbial pathogens activate cellular signal transduction pathways that induce NF-kappa B activation, but pathogens also find ways to overcome the innate immune response through active manipulation of the NF-kappa B signal transduction pathways . Exploration of the mechanisms that influence NF-kappa B activity could contribute to a better understanding of the molecular pathogenesis of microbial infections and could be important for potential therapeutic intervention that may be relevant in a wide variety of inflammatory diseases.

Rapid Commun Mass Spectrom, 2000, 14(19), 1736 - 45
Evaluation of the metal binding properties of the histidine-rich antimicrobial peptides histatin 3 and 5 by electrospray ionization mass spectrometry; Brewer D et al.; Electrospray ionization mass spectrometry (ESI-MS) was used to investigate metal ion interactions with salivary peptides histatin 3 (H3) and histatin 5 (H5) . Conformational changes of these peptides in the presence of metal ions were studied using circular dichroism spectroscopy . H3 and H5 formed high affinity complexes with Cu(2+) and Ni(2+) and, to a lesser extent, with Zn(2+) . Both peptides show the potential for multiple binding sites for Cu(2+) and Ni(2+) and only a single strong binding site for Zn(2+) . The binding of a third Cu(2+) ion to H3 seems to enable the binding of a fourth ion to H3 . The binding of a second and third Ni(2+) ion to H5 has a similar effect in enabling the binding of a fourth ion . None of the metal ions examined stabilized a regular secondary structure for either peptide . Subtle changes in overall conformation are seen with the addition of Cu(2+) to both H3 and H5 .

South Med J, 2000 Sep, 93(9), 842 - 8
Confronting the problem of increasing antibiotic resistance; Hellinger WC; Significant increases in prevalence of resistance to antibiotics have been observed in common pathogens of humans in the United States and worldwide . The consequences of the appearance and spread of antibiotic resistance have included increasing morbidity, mortality, and cost of health care . The fundamental cause for the appearance and spread of antimicrobial resistance has been increasing antimicrobial use . However, other factors contribute in both inpatient and outpatient settings . Recognizing the important causes of increasing antibiotic resistance in these settings has led to practical recommendations, which health care facilities and outpatient practitioners will need to review, adapt, and apply for maximum local effectiveness for progress to be made in addressing one of the most challenging problems facing modern medicine.

Pneumonol Alergol Pol, 2000, 68(5-6), 261 - 4
{Chronic Chlamydia pneumonia infection in patients with chronic obstructive pulmonary disease}; Mazur E et al.; The aim of our study was to evaluate the frequency of Chlamydia pneumoniae infection (especially chronic infection) in COPD patients . Microimmunofluorescence method has been applied Chlamydia pneumoniae Micro-IF test (Labsystems) has been used . The levels of specific IgG, IgA and IgM have been estimated in patients' serum . According to serologic criteria, 64.1% of COPD patients and 20.5% of healthy controls appeared to be chronically infected with Chlamydia pneumoniae (p < 0.001) . Taking in account COPD severity, persistent Chlamydia pneumoniae infection has been present in 68.2%, 57.1%, and 50% of patients with severe, moderate and mild COPD, respectively . Our study has revealed that chronic Chlamydia pneumoniae infection occurs more frequently in COPD patients than in healthy controls and in patients with severe COPD than in ones with mild and moderate disease . It is possible that persistent Chlamydia pneumoniae infection can initiate or amplify inflammatory reactions in the respiratory tract . The results suggest a need to diagnose chronic Chlamydia pneumoniae infection in COPD patients and, if confirmed, to take an attempt of antimicrobial therapy.

Biochim Biophys Acta, 2000 Jun 21, 1492(1), 185 - 90
Structural organization and expression of the gaegurin 4 gene of Rana rugosa; Kwon SY et al.; Gaegurin 4 (GGN4) is a member of the antimicrobial peptide subfamily isolated from the skin of Rana rugosa . We cloned gDNA encoding GGN4 to study its gene organization and regulation of expression . The GGN4 gene occurs in single copy in the R . rugosa genome and contains a single intron of about 3.4 kb . The transcription start site is located 68 bases upstream of the translation initiation codon . The GGN4 gene was expressed both in Xenopus kidney epithelial cells (A6) and in Xenopus oocytes using the chloramphenicol acetyltransferase reporter gene system . The 5' flanking region of the GGN4 gene contains a dl binding site that is known to regulate acute phase immune response related gene expression in mammals and insects . The dl protein bound specifically to the GGN4 gene promoter region . Mutants that serially delete the 5' flanking region show that removal of the dl binding site inhibited GGN4 gene expression in both A6 cells and Xenopus oocytes . From these results, we propose that expression of the GGN4 gene may be regulated by the region containing the dl element which plays a key role in the regulation of antimicrobial peptide genes in Drosophila and mammals.

Obstet Gynecol, 2000 Oct, 96(4), 504 - 6
Wet smear compared with gram stain diagnosis of bacterial vaginosis in asymptomatic pregnant women; Mastrobattista JM et al.; OBJECTIVE: To compare wet smear and Gram stain diagnoses of bacterial vaginosis among asymptomatic pregnant women . METHODS: Between November 1, 1996 and December 31, 1997, asymptomatic women who initiated prenatal care in our obstetric clinics were invited to participate . Exclusion criteria included antimicrobial use within 2 weeks, cervical cerclage, vaginal bleeding, placenta previa, spermicide use, douching, or intercourse within 8 hours . Clinical diagnosis that required two of three positive criteria for bacterial vaginosis (vaginal pH, whiff test, and clue cells on wet smear) was compared with Gram stain diagnosis (Bacterial vaginosis score 7-10 by Nugent criteria) . RESULTS: Population characteristics (n = 69) included an average (+/- standard deviation {SD}) maternal age of 27 . 3 +/- 6.6 years, 26 nulliparas (38%), 28 black women (41%), 23 white women (38%), 15 Hispanic women (22%), and three Asian women (4%) . The mean (+/-SD) gestational age at entry was 15.6 +/- 7.6 weeks . Twenty-seven percent (18 of 67) of the study population was diagnosed with bacterial vaginosis by definitive Gram stain . Two slides were lost or were of poor quality and not included . Using Gram stain diagnosis of bacterial vaginosis as the standard, clinical diagnosis had sensitivity of 56% (95% confidence interval {CI} 32%, 78%), a specificity of 96% (95% CI 90%, 100%), a positive predictive value of 83%, and a negative predictive value of 85% . CONCLUSION: In asymptomatic pregnant women, bacterial vaginosis can be diagnosed reliably by Gram stain.

Bioorg Med Chem, 2000 Aug, 8(8), 2059 - 65
Synthesis and antimicrobial activity of squalamine analogue; Kim HS et al.; Synthesis and antimicrobial activity of squalamine analogue 2 are reported . The synthesis of 2 was accomplished from bisnoralcohol 3 . The spermidine moiety was introduced via reductive amination of an appropriately functionalized 3beta-aminosterol with spermidinyl aldehyde 17 utilizing sodium triacetoxyborohydride as the reducing agent . Compound 2 shows weaker antimicrobial activity than squalamine.

J Otolaryngol, 2000 Aug, 29(4), 211 - 7
Practice variations in the management of sinusitis; Trinh N et al.; OBJECTIVE: It has been shown that controlling inappropriate practice variations decreases cost, increases efficiency, and improves quality of health care . The objective of this study was to identify practice variations in the management of acute sinusitis in primary care practice and to explore possible influential factors . DESIGN: A cross-sectional study by mail survey was conducted . SUBJECTS: Practicing primary care physicians in the province of Quebec were selected for the study . METHODS: A questionnaire was sent to a random sample of 500 physician members of the Quebec College of Physicians . RESULTS: Three hundred and twenty-seven questionnaires were returned (total response rate = 65.4%), of which 53 were excluded . Two hundred and seventy-four completed surveys were then analyzed . Practice variations in the management of acute sinusitis were observed with respect to diagnostic indicators, the use of diagnostic tools and imagery, prescription of therapeutic agents, factors influencing the choice of antimicrobial agents, and the indications for referral to a specialist . Factors affecting such variations included age, gender, practice region (urban vs . rural), volume of practice, and university affiliation . CONCLUSIONS: This survey confirms that confusion exists among primary care physicians about the recommended management of acute sinusitis, despite the recent advent of a multitude of clinical practice guidelines . These variations highlight the need for further research to clarify these issues, as well as better methods and more specific objectives for continuing medical education.

J Perinatol, 2000 Sep, 20(6), 346 - 50
Early discharge with home antibiotic therapy in the treatment of neonatal infection; Wagner CL et al.; OBJECTIVE: To determine the feasibility and cost of home antibiotic therapy for a select group of neonates . METHODS: A cohort of neonates at a university hospital who met criteria for home antibiotic therapy at discharge were prospectively followed (November 1995 to October 1997) for type and duration of antibiotic therapy as well as for hospital readmission . RESULTS: During the study period, 95 infants diagnosed with sepsis, presumed sepsis, pneumonia, or uncomplicated meningitis (having received > 10 days of in-hospital therapy) met prior, established, criteria for home antibiotic therapy . The mean +/- SD birth weight of the cohort was 3160 +/- 526 gm, with a mean gestational age of 38.4 +/- 2.1 weeks . A total of 59 infants (62%) received antimicrobial therapy for a clinical presentation consistent with sepsis or presumed sepsis, and 24 infants (25%) were treated for pneumonia . Ampicillin and gentamicin were prescribed for 56% of the cohort, and ceftriaxone was prescribed for 21% of the cohort . Four of those infants were switched from intravascular ampicillin/gentamicin therapy to intramuscular ceftriaxone after discharge due to loss of intravascular access . With a bilirubin level of > 8, four additional infants were changed from ceftriaxone back to ampicillin and gentamicin to complete coverage . The mean age at discharge was 5.2 days, with a mean hospitalization cost of $6121 for that period . There were no rehospitalizations or emergency department visits secondary to a worsening clinical course . CONCLUSION: In this cohort of neonates who met early discharge and defined home antibiotic therapy criteria, there were no serious complications or treatment failures reported; in addition, there were fewer costs compared with continued inpatient treatment.

Infect Control Hosp Epidemiol, 2000 Sep, 21(9), 608 - 10
Physician preferences for educational media; Smith TL et al.; BACKGROUND: Although educational media have expanded in variety, information on physicians' preferences for types of educational media remains limited . METHOD: An assessment form was distributed to 14 medical societies evaluating their members' medical education media preferences and society antimicrobial-resistance educational offerings . RESULTS: These 14 medical societies represent 349,685 physicians . All supported educational offerings, most frequently as professional meetings, followed by audiotapes, computer programs, Internet sites, or print-based self-study materials . Only 5 (36%) societies had measured how many members used their educational offerings . Eight (57%) societies had made antimicrobial resistance an educational priority for their medical societies . Antimicrobial treatment was the most commonly offered educational topic on antimicrobial resistance . CONCLUSIONS: These 14 medical societies help to educate over one half the practicing US physicians . However, less than one half of the societies knew how many of their members used the educational materials they offered, or how their members would prefer to obtain medical education . Understanding how physicians want to obtain medical information potentially could improve the delivery of medical knowledge to physicians.

Pediatr Infect Dis J, 2000 Sep, 19(9), 871 - 4
Doxycycline use for rickettsial disease in pediatric patients; Purvis JJ et al.; BACKGROUND: Recent evidence suggests that despite potential side effects, doxycycline should be considered the drug of choice for children of all ages in whom a rickettsial disease is considered in the differential diagnosis of the illness . We hypothesized that doxycycline would be used infrequently for the treatment of suspected rickettsial disease . The objective of the investigation was to determine the initial antibiotic administered to children for whom rickettsial infection was considered likely . METHODS: The study population consisted of 35 children evaluated at Texas Children's Hospital between 1987 and 1999 in whom rickettsial disease was a diagnostic consideration . Demographic information and clinical manifestations were assessed through a retrospective chart review . RESULTS: Thirty children (86%) presented with fever, 21 (60%) with rash and 14 (40%) with headache, which are typical presenting symptoms for rickettsial diseases . Only 1 of 35 children (3%) was prescribed a tetracycline class antibiotic as initial empiric therapy . Eleven (31%) children received doxycycline during the hospital course . A total of 19 patients, or 54%, received an antimicrobial known to have efficacy in the treatment of rickettsial infection, usually at the suggestion of an infectious diseases consultant . CONCLUSIONS: Even among children for whom rickettsial infection is a diagnostic consideration, doxycycline is not prescribed with the frequency that is indicated . Pediatric caregivers should have heightened awareness regarding the appropriate indications for doxycycline use in childhood.

J Formos Med Assoc, 2000 Sep, 99(9), 704 - 9
Impact of Helicobacter pylori antimicrobial resistance on the outcome of 1-week lansoprazole-based triple therapy; Huang AH et al.; PURPOSE: To determine the effect of Helicobacter pylori antimicrobial resistance on the efficacy of different proton pump inhibitor (PPI)-based triple therapies . METHODS: One-hundred and twelve dyspeptic patients with H . pylori infection, as demonstrated by positive histology and culture, were randomized to receive one of the three PPI-based triple therapies . The regimens included lansoprazole (L) plus any two of the following three antibiotics: amoxicillin (A), metronidazole (M), and clarithromycin (C); patients were allocated to ALC, MLC, and ALM subgroups . Six weeks after the start of triple therapy, the 13C-urea breath test (UBT) was performed to evaluate the success of H . pylori eradication . Patients with positive UBT results underwent endoscopy for H . pylori culture . The pre- and post-treatment H . pylori isolates were analyzed for initial and acquired resistance using the E-test . RESULTS: One hundred patients completed the study . The H . pylori eradication rates were 70% (21/30) in the ALM subgroups, 79% (26/33) in the MLC subgroup, and 89% (33/37) in the ALC subgroup . The frequencies of pretreatment H . pylori antimicrobial resistance were 0% for amoxicillin resistance (AR), 32% for metronidazole resistance (MR), and 6% for clarithromycin resistance (CR) . For H . pylori isolates with initial MR, the eradication rates in the ALM (40%) and MLC (67%) subgroups were apparently lower than that in the ALC (92%) subgroup . In the ALM and MLC subgroups (i.e., patients who received metronidazole), the eradication failure rate was significantly higher for patients with MR isolates than for patients with metronidazole-susceptible isolates (47% vs 16%, p < 0.05) . In the ALC and MLC subgroups (i.e., patients who received clarithromycin), the eradication failure rate was significantly higher for patients with CR isolates than for those with clarithromycin-susceptible isolates (100% vs 11%, p < 0.05) . CONCLUSIONS: The results indicate that H . pylori antimicrobial resistance is relevant to the success of eradication . The high MR but low CR and AR prevalence among H . pylori isolates in this study suggests that PPI-based triple therapy including amoxicillin and clarithromycin may achieve the most favorable eradication rate.

J Microbiol Methods, 2000 Sep, 42(1), 3 - 16
Microbial analysis at the single-cell level: tasks and techniques; Shapiro HM; The heterogeneity of microorganisms themselves is orders of magnitude greater than the heterogeneity of perspectives from which they are contemplated by human observers . Even closely related species may exhibit marked differences in biochemistry and behavior, and, under many conditions, similar, striking heterogeneity may exist within a clonal population of organisms which, in the aggregate, occupy too small a region of space to be visible to the unaided human eye . Using methods of microscopy, microspectrophotometry, and cytometry developed and refined since the 1960s, it is now possible to characterize the physiology and pharmacology of individual microorganisms, and, in many cases, to isolate organisms with selected characteristics for culture and/or further analysis . These methods include fluorescent and confocal microscopy, scanning and image cytometry, and flow cytometry . Fluorescence measurements are particularly important in single-cell analysis; they allow demonstration and quantification of cells' nucleic acid content and sequence, of the presence of specific antigens, and of physiologic characteristics such as enzyme activity and membrane potential . Multiparameter cytometry, combined with cell sorting, provides insight into population heterogeneity and allows selected cells to be separated for further analysis and culture . The technology is applicable to a wide range of problems in contemporary microbiology, including strain selection and the development of antimicrobial agents.

Ann Intern Med, 2000 Sep 19, 133(6), 447 - 54
Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy; DeSimone JA et al.; PURPOSE: To review reported inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) in persons infected with HIV-1 and to explore the mechanisms leading to these reactions . DATA SOURCES: MEDLINE search of biomedical literature reporting inflammatory reactions after HAART . Bibliographies of retrieved reports were also reviewed . STUDY SELECTION: Articles describing patients infected with HIV-1 who had immunologic and virologic responses to HAART and subsequently developed inflammatory reactions . DATA EXTRACTION: Data on the immune status, clinical characteristics, and therapeutic management of patients who were seropositive for HIV-1 and had inflammatory reactions after HAART . DATA SYNTHESIS: Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1 . These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts . Clinical presentation was often atypical of that in patients with untreated HIV-1 infection, probably because of restored immunity . Most cases improved despite continuation of HAART, although some patients required anti-inflammatory drugs or specific antimicrobial agents . CONCLUSIONS: Clinicians caring for patients who are infected with HIV-1 and receiving HAART must be aware of this new and diverse clinical syndrome . As more HAART recipients are studied, new presentations will probably be observed.

Vet Surg, 2000 Sep-Oct, 29(5), 398 - 406
Determination of synovial fluid and serum concentrations, and morphologic effects of intraarticular ceftiofur sodium in horses; Mills ML et al.; OBJECTIVES: To determine the serum and synovial fluid concentrations of ceftiofur sodium after intraarticular (IA) and intravenous (IV) administration and to evaluate the morphologic changes after intraarticular ceftiofur sodium administration . STUDY DESIGN: Strip plot design for the ceftiofur sodium serum and synovial fluid concentrations and a split plot design for the cytologic and histopathologic evaluation . ANIMALS: Six healthy adult horses without lameness . METHODS: Stage 1: Ceftiofur sodium (2.2 mg/kg) was administered IV . Stage 2: 150 mg (3 mL) of ceftiofur sodium (pHavg 6.57) was administered IA into 1 antebrachiocarpal joint . The ceftiofur sodium was reconstituted with sterile sodium chloride solution (pH 6.35) . The contralateral joint was injected with 3 mL of 0.9% sterile sodium chloride solution (pH 6.35) . Serum and synovial fluid samples were obtained from each horse during each stage . For a given stage, each type of sample (serum or synovial fluid) was collected once before injection and 12 times after injection over a 24-hour period . All horses were killed at 24 hours, and microscopic evaluation of the cartilage and synovium was performed . Serum and synovial fluid concentrations of ceftiofur sodium were measured by using a microbiologic assay, and pharmacokinetic variables were calculated . Synovial fluid was collected from the active joints treated during stage 2 at preinjection and postinjection hours (PIH) 0 (taken immediately after injection of either the ceftiofur sodium or sodium chloride), 12, and 24, and evaluated for differential cellular counts, pH, total protein concentration, and mucin precipitate quality . RESULTS: Concentrations of ceftiofur in synovial fluid after IA administration were significantly higher (P = .0001) than synovial fluid concentrations obtained after IV administration . Mean peak synovial fluid concentrations of ceftiofur after IA and IV administration were 5825.08 microg/mL at PIH .25 and 7.31 microg/mL at PIH 4, respectively . Mean synovial fluid ceftiofur concentrations at PIH 24 after IA and IV administration were 4.94 microg/mL and .12 microg/mL, respectively . Cytologic characteristics of synovial fluid after IA administration did not differ from cytologic characteristics after IA saline solution administration . White blood cell counts after IA ceftiofur administration were < or =3,400 cells/ML . The mean synovial pH of ceftiofur treated and control joints was 7.32 (range, 7.08-7.5) and 7.37 (range, 7.31-7.42), respectively . Grossly, there were minimal changes in synovium or cartilage, and no microscopic differences were detected (P = .5147) between ceftiofur-treated joints and saline-treated joints . The synovial half-life of ceftiofur sodium after IA administration joint was 5.1 hours . CONCLUSIONS: Synovial concentrations after intraarticular administration of 150 mg of ceftiofur sodium remained elevated above minimal inhibitory concentration (MIC90) over 24 hours . After 2.2 mg/kg IV, the synovial fluid ceftiofur concentration remained above MIC no longer than 8 hours . CLINICAL RELEVANCE: Ceftiofur sodium may be an acceptable broad spectrum antimicrobial to administer IA in septic arthritic equine joints.

Emerg Infect Dis, 2000 Sep-Oct, 6(5), 458 - 65
Toxin gene expression by shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response; Kimmitt PT et al.; Toxin synthesis by Shiga toxin-producing Escherichia coli (STEC) appears to be coregulated through induction of the integrated bacteriophage that encodes the toxin gene . Phage production is linked to induction of the bacterial SOS response, a ubiquitous response to DNA damage . SOS-inducing antimicrobial agents, particularly the quinolones, trimethoprim, and furazolidone, were shown to induce toxin gene expression in studies of their effects on a reporter STEC strain carrying a chromosome-based stx2::lacZ transcriptional fusion . At antimicrobial levels above those required to inhibit bacterial replication, these agents are potent inducers (up to 140-fold) of the transcription of type 2 Shiga toxin genes (stx2); therefore, they should be avoided in treating patients with potential or confirmed STEC infections . Other agents (20 studied) and incubation conditions produced significant but less striking effects on stx2 transcription; positive and negative influences were observed . SOS-mediated induction of toxin synthesis also provides a mechanism that could exacerbate STEC infections and increase dissemination of stx genes . These features and the use of SOS-inducing antibiotics in clinical practice and animal husbandry may account for the recent emergence of STEC disease.

Mem Inst Oswaldo Cruz, 2000 Sep-Oct, 95(5), 729 - 32
Multiple isolates from aids patients: aspects of an analysis by a genotypic marker and antimicrobial susceptibilities variations; Saad MH et al.; Twenty-one Mycobacterium avium multisolates, from ten human immunodeficiency virus-infected patients, were typed by restriction fragment length polymorphism using as marker the IS1245 and characterized by minimum inhibitory concentration for nine different antibiotics . Two out of four patients harboring multisolates with different fingerprint profile, were therefore considered as having a polyclonal infection, since their isolates were taken from sterile site . This result confirms that polyclonal infection caused by M . avium occurs with a nonnegligenciable frequency . Analyzing the multisolates susceptibility profile of each patient it was observed that most of them were infected with strains having appreciably different antimicrobial susceptibility patterns, no matter what the genotypic pattern of the strains was . These results have strong implication for the treatment of the patients.

J Antimicrob Chemother, 2000 Jul, 46 Suppl T1, 33 - 7
Gemifloxacin: survival of the fittest; Mandell L; The incidence of penicillin resistance in pneumococci is increasing in the USA, having risen from <5% before 1989 to >35% in 1997 . There has also been a shift in the ratio of intermediate to high-level resistance from 3 or 4:1 to 2 or 1:1 . Multidrug resistance and resistance to macrolides and fluoroquinolones in pneumococci is also a matter of concern . The implications for empirical treatment of respiratory tract infections are considerable . The potential of quinolones with activity against respiratory pathogens including pneumococci must be preserved by careful antimicrobial prescribing.

J Antimicrob Chemother, 2000 Jul, 46 Suppl T1, 17 - 24
Quinolone generations: natural history or natural selection?
Ball P.
The quinolones have evolved from antibacterial agents with a limited spectrum of predominantly anti-gram-negative antimicrobial activity and a restricted number of indications to a class of widely used oral (and, in some cases, intravenous) antibiotics with extensive indications for infections caused by many bacterial pathogens in most body tissues and fluids . This evolutionary pattern has arisen through the development of new core and side-chain structures, with associated improvements in activity, pharmacokinetics and tolerability, and through the selection of molecules that remain useful and well tolerated . This review describes the progress of the quinolones from the first to the third (IIIa and IIIb) generations . Special attention is given to gemifloxacin, currently the most developmentally advanced third-generation quinolone, which has enhanced in vitro gram-positive antimicrobial activity and no troublesome adverse drug reactions . Preliminary data indicate that gemifloxacin should prove to be an important addition to the fluoroquinolone class . Further clinical trial data are awaited with interest.

Int J STD AIDS, 2000 Sep, 11(9), 599 - 602
Genital mycoplasmas among pregnant women in Cóte d'Ivoire, West Africa: prevalence and risk factors; Faye-Kette H et al.; A cross-sectional study was conducted among pregnant women in Cote d'Ivoire to assess the prevalence and the factors associated with mycoplasma colonization . A positive culture was found in 400 of 551 women (73%); Ureaplasma urealyticum was identified in 22%, Mycoplasma hominis in 20% and both microorganisms in 31% . Mycoplasma colonization was not associated with genital symptoms or signs . Young age, low educational level, antimicrobial chemotherapy before consultation and presence of bacterial vaginosis were factors independently associated with M . hominis colonization . Among women colonized with M . hominis, HIV seroprevalence was 21% in women with high amounts of M . hominis (> or = 10(4) colour-changing units per ml) versus 7% in women with lower amounts (P=0.01) . U . urealyticum was found more often in unmarried women and when pregnancy was less than 20 weeks . Mycoplasma colonization is frequent among pregnant women in Abidjan, but their pathogenicity requires further study.

Acta Microbiol Pol, 2000, 49(1), 63 - 74
Antimicrobial effect of crude extracts of Nigella sativa on multiple antibiotics-resistant bacteria; Morsi NM; Different crude extracts of Nigella sativa were tested for antimicrobial effectiveness against different bacterial isolates . These isolates comprised 16 gramnegative and 6 grampositive representatives . They showed multiple resistance against antibiotics, specially the gramnegative ones . Crude extracts of Nigella saliva showed a promising effect against some of the test organisms . The most effective extracts were the crude alkaloid and water extracts . Gramnegative isolates were affected more than the grampositive ones.

EXS, 2000, 89, 29 - 53
New trends in antimicrobial development; Setti EL et al.; So far, two strategies have been applied to develop new anti-infective agents: (a) the synthesis of analogs of classical antibiotics with enhanced activity against resistant pathogens and (b) the screening of naturally occurring substances and libraries of synthetic compounds for antimicrobial activity in whole-cell assays . Today, the same principles are being used; however, the search for antimicrobial compounds with novel modes of action is based on targeting specific resistance and virulence factors . Novel targets for anti-infective agents are currently being discovered as a consequence of a better understanding of cell biology, the molecular basis of bacterial resistance, the gene-pathogenicity relationship and the mechanism of the infection process.

Curr Biol, 2000 Sep 21, 10(18), R678 - 81
Translocases: a bacterial tunnel for drugs and proteins; Lewis K; Unrelated translocases extrude proteins or antimicrobial agents across both membranes of the cell envelope in Gram-negative bacteria . The TolC protein links the translocases to the external environment . The recently determined crystal structure of TolC shows how this universal tunnel operates.

Trends Endocrinol Metab, 2000 Oct, 11(8), 304 - 8
Alpha-melanocyte-stimulating hormone in normal human physiology and disease states; Catania A et al.; Over the past two decades, research in animal models has indicated that alpha-melanocyte-stimulating hormone (alpha-MSH) has potent anti-inflammatory properties . Furthermore, recent data show that the peptide has antimicrobial effects and probably contributes to innate immunity . alpha-MSH, which is produced by many extrapituitary human cells, should no longer be considered solely a pituitary hormone; rather, it should be viewed as a ubiquitous modulatory peptide.

J Ethnopharmacol, 2000 Oct, 72(3), 459 - 64
Variation of the antimicrobial activity of Pseudognaphalium vira vira (Asteraceae): isolation and X-ray structure of ent-3beta-hydroxy-16-kauren-19-oic acid; Rezende MC et al.; The antimicrobial properties of the resinous exudate from twigs and leaves of a population of Pseudognaphalium vira vira were re-examined against five Gram positive bacteria . The observed decrease in the antimicrobial activity might reflect a change in the diterpenoid composition of the exudate . The title compound 2 was isolated in substantial amount, together with ent-16-kauren-19-oic acid (1), and its structure determined by X-ray diffraction analysis.

J Ethnopharmacol, 2000 Oct, 72(3), 403 - 10
Screening of Zingiberaceae extracts for antimicrobial and antioxidant activities; Habsah M et al.; Dichloromethane and methanol extracts of 13 Zingiberaceae species from the Alpinia, Costus and Zingiber genera were screened for antimicrobial and antioxidant activities . The antimicrobial activity of most of the extracts was antibacterial with only the methanol extract of Costus discolor showing very potent antifungal activity against only Aspergillus ochraceous (MID, 15.6 microg per disc) . All the extracts showed strong antioxidant activity comparable with or higher that of alpha-tocopherol.

J Ethnopharmacol, 2000 Oct, 72(3), 395 - 402
Antimicrobial, antioxidant, antitumour-promoting and cytotoxic activities of different plant part extracts of Garcinia atroviridis griff . ex T . anders; Mackeen MM et al.; Crude extracts (methanol) of various parts, viz . the leaves, fruits, roots, stem and trunk bark, of Garcinia atroviridis were screened for antimicrobial, cytotoxic, brine shrimp toxic, antitumour-promoting and antioxidant activities . The crude extracts exhibited predominantly antibacterial activity with the root extract showing the strongest inhibition against the test bacteria at a minimum inhibitory dose (MID) of 15.6 microg/disc . Although all the extracts failed to inhibit the growth of most of the test fungi, significant antifungal activity against Cladosporium herbarum was exhibited by most notably the fruit (MID: 100 microg), and the leaf (MID: 400 microg) extracts . None of the extracts were significantly cytotoxic, and lethal towards brine shrimps . The root, leaf, trunk and stem bark extracts (except for the fruits) showed strong antioxidant activity exceeding that of the standard antioxidant, alpha-tocopherol . Antitumour-promoting activity (>95% inhibition) was shown by the fruit, leaf, stem and trunk bark extracts.

Fish Shellfish Immunol, 2000 Jul, 10(5), 395 - 404
The influence of in vitro and in vivo exposure to antibiotics on mitogen-induced proliferation of lymphoid cells in rainbow trout (Oncorhynchus mykiss); Lunden T et al.; The influence of five different antimicrobial drugs on mitogen-induced lymphoid cell proliferation in vitro and after oral administration of the drugs was studied in rainbow trout (Oncorhynchus mykiss) . The drugs tested were: oxolinic acid, oxytetracycline, florfenicol and trimethoprim in combination with sulfadiazine in ratio 1:5 . In the in vitro tests, trimethoprim:sulfadiazine increased the 3H-thymidine incorporation into the DNA of phytohaemagglutinin and lipopolysaccharide-stimulated lymphoid cells while all the other drugs tested interfered negatively with the incorporation in a dose dependent manner . In the experiment with oral drug administration, the fish were fed 10 days with a therapeutic dose of the drugs . After the drug treatment, lymphoid cells were isolated from the head kidney of the fish and tested for proliferating capacity . All drugs except trimethoprim+sulfadiazine, suppressed the mitogenic response of the head kidney cells . The suppression of the response was more severe in phytohaemagglutinin-stimulated than in lipopolysaccharide-stimulated cells indicating that the T-cells were more vulnerable to the toxic effects of the drugs than B-cells.

Berl Munch Tierarztl Wochenschr, 2000 Jul-Aug, 113(7-8), 299 - 305
{Guidelines for planning studies to determine the resistance of infectious agents of veterinary relevance}; Bottner A et al.; This paper describes the most important criteria for the planning of statistically sound and representative studies on the prevalence of antimicrobial resistance among pathogenic bacteria from animals . The statistical design of the study is of particular importance and therefore described in some detail . The existing published data about antimicrobial resistance are mostly retrospective summaries of results and do not give a true picture of the resistance situation . The authors propose to conduct a pilot study initially because many basic elements for a sound study design are still not known . The systematic recording and assessment of the target variables including the necessary quality assurance are an important prerequisite . Moreover, potential cause variables can be further narrowed down and conclusively identified . To ensure the representativity of the cross-sectional study and avoid potential bias, it is important to achieve the highest possible response rate . This will form the basis of a scientifically sound resistance monitoring programme which should be the joint responsibility of regulatory authorities, industry and academia.

Prikl Biokhim Mikrobiol, 2000 Jul-Aug, 36(4), 492 - 6
{Factors, determining the activity of a new antimicrobial substance from fish oils from various species}; Rybin VG et al.; The induction of antimicrobial activity of a new preparation, an aqueous fraction of water-oil emulsion oxidized by air oxygen, was studied . The effect of various factors (the degree of unsaturation of the initial oil and the content of oil oxidation products in obtained preparation) on the antimicrobial activity was determined . The antimicrobial activity of the preparation was induced by oil oxidation . The preparation produced from sardine Sardinops melanostica oil (33.95% of polyunsaturated fatty acids) displayed the highest antimicrobial activity . The antimicrobial activity was shown in water-soluble oil oxidation products.

Arzneimittelforschung, 2000 Aug, 50(8), 747 - 51
Study of the relationship between chemical structure and antimicrobial activity in a series of hydrazine-based coordination compounds; Dobrova BN et al.; The dependence of antimicrobial activity on the structure of compounds is studied in a series of compounds based on hydrazine coordinated with ions of Cu(II), Ni(II) and Pd(II) . The study has been carried out by means of the original electron-topological method developed earlier . A molecular fragment has been found that is only characteristic of biologically active compounds . Its spatial and electron parameters have been used for the quantitative assessment of the activity in view . The results obtained can be used for the antimicrobial activity prediction in a series of compounds with similar structures.

Biol Pharm Bull, 2000 Sep, 23(9), 1077 - 83
Physiologically-based pharmacokinetic analysis of grepafloxacin; Nakajima Y et al.; Grepafloxacin (GPFX) is a synthetic new quinolone antimicrobial agent that possesses an extensive tissue distribution and exhibits a strong antibacterial activity in vivo . In this study, the tissue distribution characteristics of GPFX were examined using tissue concentration-time profiles following intravenous administration to rats . Subsequently, the pharmacokinetics of GPFX were analyzed based on the physiological pharmacokinetic model . The tissue-to-plasma partition coefficients (Kp) of GPFX in rats were high in all tissues except brain . A pharmacokinetic model for rabbits, monkeys and dogs was constructed using the tissue-to-plasma free concentration ratio (Kp,f) of GPFX in rats to simulate the GPFX concentration-time profile in plasma following intravenous administration of GPFX to each animal . The calculation-derived concentrations correlated well with the experimentally-derived data, suggesting that there are no interspecies differences in the high tissue distribution characteristics of GPFX . The clearance rates of GPFX in humans were predicted from the pharmacokinetic parameters of rats, rabbits, monkeys and dogs by an animal scale-up method and a pharmacokinetic model for humans was constructed . The GPFX concentration-time profiles in plasma, following oral administration of GPFX to humans, were predicted within 0.5-1.0 h of mean absorption time and the calculation-derived results were in good agreement with the experimental data . Thus, it is suggested that the concentration-time profile in plasma and all human organs can be predicted from the pharmacokinetic data of animals.

Yonsei Med J, 2000 Aug, 41(4), 497 - 506
Korean Nationwide Surveillance of Antimicrobial Resistance of Bacteria in 1998; Lee K et al.; Antimicrobial resistance surveillance can provide information needed for empirical therapy of antimicrobial agents and for control of resistance . To determine the trend of antimicrobial resistance in Korea, in vitro susceptibility data in 1998 were collected from 25 hospitals participating to a program of Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR) . The data were analyzed based upon hospital location and bed capacity . The results showed that cefoxitin-resistant E . coli and K . pneumoniae and 3rd-generation cephalosporin-resistant K . pneumoniae were prevalent, that 3rd-generation cephalosporin-resistant E . cloacae, S . marcesens and A . baumannii had increased, and ampicillin-resistant S . enterica were not rare . Oxacillin-resistant S . aureus, penicillin-non-susceptible pneumococci and beta-lactamase-producing H . influenzae were prevalent even smaller hospitals surveyed, and an increase of imipenem-resistant P . aeruginosa and vancomycin-resistant E . faecium is a new obvious threat . In general, resistance rates to some old antimicrobial agents, i.e., E . coli to ampicillin and S . aureus to oxacillin were high and did not vary greatly between the different levels of hospitals, while the rates to some of the newer ones, i.e., P . aeruginosa to imipenem, was quite variable and depended on the hospitals, probably reflecting difference in selective pressure.

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2895 - 6
Activity of ABT-773 against Mycobacterium avium complex in the beige mouse model; Cynamon MH et al.; ABT-773, a new ketolide antimicrobial agent, was evaluated in comparison to clarithromycin (CLA) in vitro against Mycobacterium avium complex (MAC) and in a beige mouse model of disseminated MAC infection . The MICs at which 50 and 90% of the isolates tested were inhibited were 2 and 4 microg/ml, respectively, for CLA and 8 and 16 microg/ml, respectively, for ABT-773 . Eight CLA-resistant isolates were found to be resistant to ABT-773 (MICs > 64 microg/ml) . In the in vivo study mice were treated with ABT-773 (50, 100, and 200 mg/kg of body weight) or CLA (200 mg/kg) . Both ABT-773 (100 and 200 mg/kg) and CLA significantly decreased the viable cell counts in spleens and lungs . ABT-773 (200 mg/kg) and CLA had similar activities in lungs, but the former was more active in spleens.

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2824 - 35
Effects of antiviral usage on transmission dynamics of herpes simplex virus type 1 and on antiviral resistance: predictions of mathematical models; Lipsitch M et al.; Herpes simplex virus type 1 (HSV-1) causes recurrent herpes labialis (RHL), a common disease afflicting up to 40% of adults worldwide . Mathematical models are used to analyze the effect of antiviral treatment on the transmission of, and the prevalence of drug resistance in, HSV-1 in the United States . Three scenarios are analyzed: no antiviral use, the current level of use, and a substantial increase in nucleoside analogue use, such as might occur if topical penciclovir were available over-the-counter for the treatment of RHL . A basic model predicts that present level of nucleoside analogue use has a negligible effect on HSV-1 transmission and that even if use of topical penciclovir for (RHL) increased substantially, the overall prevalence of infectious HSV-1 is unlikely to be reduced by more than 5% . An expanded model, which allows for acquired resistance and includes immunocompromised hosts and other more realistic features, predicts that current antiviral use is unlikely to lead to any noticeable increase in resistance . If antiviral use increases, the resulting rise in resistance in the population will depend primarily on the probability that immunocompetent hosts will acquire permanent resistance upon treatment . This probability is known to be small, but its exact value remains uncertain . If acquired resistance occurs less than once per 2,500 treated episodes, then in the community at large, the frequency of HSV-1 resistance is predicted to increase slowly, if at all (remaining below 0.5% for >50 years), even with extensive nucleoside analogue use . If acquired resistance emerges in 1 of 625 treated episodes (the maximum of an approximate 95% confidence interval derived from the results of several studies of resistance in treated hosts), then the prevalence of infection with resistant HSV-1 could rise from about 0.2% to 1.5 to 3% within 50 years . The limitations of existing data on acquired resistance and the potential impact of acquired resistance if it occurs are discussed, and strategies are suggested for enhancing information on acquired resistance . The predictions of this model contrast with the more rapid increases in antimicrobial resistance anticipated by models and observed for other pathogenic bacteria and viruses . The reasons for these contrasting predictions are discussed.

Biomed Pharmacother, 2000 Aug, 54(7), 410 - 4
Effect of cefotaxime on cytokine production in newborns and adults in vitro; Bessler H et al.; The in vitro effect of cefotaxime on the production of interleukin (IL)-1beta, IL-2, IL-6 and tumor necrosis factor alpha (TNFalpha) was studied in term neonates and was compared with that of adults . The addition of cefotaxime caused a significant enhancement of IL-2 production by cells of both adults and neonates, and increased the secretion of TNFalpha by peripheral blood mononuclear cells (PBMC) of adults, whereas the synthesis of this cytokine by cord blood mononuclear cells (CBMC) of the newborns was not affected . In contrast with the described stimulatory effects of cefotaxime, this drug induced dose-dependent inhibition of the spontaneous and lipopolysaccharide (LPS)-induced IL-1beta production by cells of the two groups, but had no effect on the in vitro production of IL-6 . These data suggest that cefotaxime, apart from its known antimicrobial activity, may modify the host immune response of both newborns and adults, via the alteration of cytokine production.

Pharmazie, 2000 Aug, 55(8), 577 - 83
Synthesis, reactions and antimicrobial activity of new cyclopenta{e}thieno{2,3-b}pyridines and related heterocyclic systems; Bakhite EA et al.; Reaction of the arylidene cyanothioacetamides 1a, b with cyclopentanone was proved to give a mixture of 4-aryl-3-cyanocyclopenta{b}pyridine-2(1H)-thiones 2a, b and the corresponding 7-arylidene derivatives 3a, b . Compounds 2a, b were reacted with ethyl chloroacetate or chloroacetamide to give the promising S-substituted thiopyridines 6a-d . On treatment of the latter compounds with sodium ethoxide in boiling ethanol, they underwent intramolecular Thorpe-Ziegler cyclization to yield the corresponding 3-amino-4-aryl-2-functionalized-cyclopenta{e}thieno{2,3-b}pyridines (7a-d) . Most of these thienopyridines were reacted with a variety of reagents to produce other new cyclopentathienopyridines as well as numerous of their condensed heterocyclic derivatives . Some of the compounds synthesized were tested in vitro for their antibacterial and antifungal activity.

Oncology (Huntingt), 2000 Aug, 14(8 Suppl 6), 17 - 22
Ambulatory antimicrobial therapy for hematologic malignancies; Rolston KV et al.; Risk prediction in patients with neutropenia and fever in a reliable and timely manner has only become possible in the last decade . Patients have been categorized as high risk or low risk based on certain presenting characteristics . Low-risk patients may be defined as hemodynamically stable, with responsive or controlled malignancies, brief (< or = 7-day) periods of neutropenia, and no significant comorbidities or serious documented infections . Such patients may be suitable for alternative treatment strategies, such as outpatient parenteral, sequential, or oral therapy . These approaches still need to be definitively evaluated, with safety being the primary concern . Substantial advantages may be gained from such strategies, including reduced exposure to resistant nosocomial pathogens, greater cost effectiveness, and enhanced quality of life.

Trends Microbiol, 2000 Sep, 8(9), 402 - 10
The role of cationic antimicrobial peptides in innate host defences; Hancock RE et al.; Cationic antimicrobial peptides are found in all living species . A single animal can contain >24 different antimicrobial peptides, which fall into four structural classes . These peptides are produced in large quantities at sites of infection and/or inflammation and can have broad-spectrum antibacterial, antifungal, antiviral, antiprotozoan and antisepsis properties . In addition, they interact directly with host cells to modulate the inflammatory process and innate defences.

Chest, 2000 Sep, 118(3), 767 - 74
Predisposing factors for nosocomial pneumonia in patients receiving mechanical ventilation and requiring tracheotomy; Georges H et al.; STUDY OBJECTIVES: To assess the incidence of nosocomial pneumonia (NP) after tracheotomy in an ICU population and to determine NP risk factors during the ICU stay, particularly on the day of tracheotomy . DESIGN: A retrospective study using prospectively collected data . SETTING: A 16-bed multidisciplinary ICU . PATIENTS: One hundred thirty-five patients requiring tracheotomy for mechanical ventilation (MV) weaning . RESULTS: The mean (+/- SD) duration of MV before tracheotomy was 17.8 +/-13.4 days . Thirty-seven cases of NP occurred in 35 patients (25.9%), 8.7+/-7.3 days after the tracheotomy procedure . NP cases were classified as early NP (n = 19) if they occurred within 5 days after the procedure (mean, 2.7+/-1.1 days), and as late NP (n = 18) if they occurred beyond the fifth day (mean, 14.4+/-6.1 days) . Multivariate analysis identified the following three independent factors associated with early NP: the presence of positive endotracheal aspirates (EAs) with pathogen levels of > or =10(5) cfu/mL (p = 0.0001); hyperthermia (temperature, > or =38.3 degrees C; p = 0.002) on the day of tracheotomy; and the continuation of sedation beyond 24 h after the tracheotomy (p = 0 . 0001) . Accountable pathogens of early NP were present in EA on the day of tracheotomy (p = 0.001) . Cases of late NP were significantly associated with the duration of sedation before the procedure (p = 0 . 002) and with hyperthermia (temperature, > or =38.3 degrees C) on the day of tracheotomy (p = 0.0005) . The ICU admitting diagnosis, previous NP, duration of administration of antimicrobial agents and MV before tracheotomy, indication for tracheotomy, PO(2)/fraction of inspired oxygen ratio, and use of steroids on the day of the procedure were not associated with the occurrence of NP . The mortality rate of our population was 33.3%, and NP increased this percentage to 54.3% . CONCLUSIONS: Our results could suggest that tracheotomy should be delayed in mechanically ventilated patients with bronchial colonization and hyperthermia, when sedation cannot be discontinued after the procedure, to prevent occurrence of early NP.

Clin Infect Dis, 2000 Aug, 31(2), 597 - 601 Epub 2000 Sep 14.
Prophylaxis for opportunistic infections in an era of effective antiretroviral therapy; Powderly WG; Potent antiretroviral treatment is associated with dramatic improvements in immune function in many human immunodeficiency virus-infected patients . This has led to new US Public Health Service/Infectious Diseases Society of America guidelines that suggest that in certain circumstances (primary prophylaxis for Pneumocystis carinii pneumonia and disseminated Mycobacterium avium complex infection, and secondary prophylaxis for cytomegalovirus retinitis), antimicrobial prophylaxis can be discontinued for patients whose CD4 T-cell counts rise above threshold levels for at least 3-6 months . The new guidelines are probably too conservative, and effective antiretroviral treatment almost certainly provides protection against all major opportunistic pathogens . Therefore, in the future, specific prophylaxis will be needed only for those patients who do not benefit from or fail to adhere to the current more effective treatment of human immunodeficiency virus infection.

MMWR Morb Mortal Wkly Rep, 2000 Sep 1, 49(34), 780 - 2
Recall of isoniazid used for antimicrobial susceptibility testing for tuberculosis; Pyogenic liver abscesses; Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, USAPyogenic liver abscess is a classic clinical entity whose presentation and management have evolved significantly with the advent of potent antimicrobials and the availability of improved diagnostic imaging . The classic triad of fever, upper right quadrant pain or fullness, and jaundice resulting from advanced pylephlebitis is now seldom seen . Despite these changes, pyogenic liver abscess remains an important clinical entity for which prompt recognition and treatment are essential to achieve a favorable outcome . This article discusses the presentation and diagnosis of and current therapy for liver abscesses.

Infect Dis Clin North Am, 2000 Sep, 14(3), 521 - 46
Acute (ascending) cholangitis; Hanau LH et al.; Cholangitis is an infection of an obstructed biliary system, most commonly due to common bile duct stones . Bacteria reach the biliary system either by ascent from the intestine or by the portal venous system . Once the biliary system is colonized, biliary stasis allows bacterial multiplication, and increased biliary pressures enable the bacteria to penetrate cellular barriers and enter the bloodstream . Patients with cholangitis are febrile, often have abdominal pain, and are jaundiced . A minority of patients present in shock with hypotension and altered mentation . There is usually a leukocytosis, and the alkaline phosphatase and bilirubin levels are generally elevated . Noninvasive diagnostic techniques include sonography, which is the recommended initial imaging modality . Standard CT, helical CT cholangiography, and magnetic resonance cholangiography often add important information regarding the type and level of obstruction . Endoscopic sonography is a more invasive means of obtaining high-quality imaging, and endoscopic or percutaneous cholangiography offers the opportunity to perform a therapeutic procedure at the time of diagnostic imaging . Endoscopic modalities currently are favored over percutaneous procedures because of a lower risk of complication . Treatment includes fluid resuscitation and antimicrobial agents that cover enteric flora . Biliary decompression is required when patients do not rapidly respond to conservative therapy . Definitive therapy can be performed by a surgical, percutaneous, or endoscopic route; the last is favored because it is the least invasive and has the lowest complication rate . Overall prognosis depends on the severity of the illness at the time of presentation and the cause of the biliary obstruction.

J Am Dent Assoc, 2000 Sep, 131(9), 1293 - 304
Efficient antimicrobial treatment in periodontal maintenance care; Slots J et al.; BACKGROUND: The goal of follow-up care after periodontal therapy is to preserve the function of individual teeth and the dentition, ameliorate symptoms and simplify future surgery or make it unnecessary . Effective follow-up periodontal care depends on early diagnosis and treatment, as well as patient education . RESULTS: The main determinants of successful periodontal maintenance therapy are dental professionals' ability to combat periodontal infections and patients' compliance with prescribed follow-up care . Mechanical and chemical antimicrobial intervention is the mainstay of preventive periodontal therapy . Chemotherapeutics alone are unlikely to be effective in the presence of subgingival calculus, underscoring the importance of subgingival mechanical debridement . Also, because toothbrushing and rinsing alone do not reach pathogens residing in periodontal pockets of increased depths, oral hygiene procedures should include subgingival treatment with home irrigators or other appropriate self-care remedies . CLINICAL IMPLICATIONS: When considering possible preventive therapies, dental professionals must weigh the risk of patients' acquiring destructive periodontal disease against potentially adverse effects, financial costs and inconvenience of the preventive treatment . The authors discuss theoretical and practical aspects of follow-up care for patients with periodontal disease . In addition, because it can be both difficult and expensive to control periodontal disease via conventional preventive measures alone, they present a new, simple and more cost-effective antimicrobial protocol for supportive periodontal therapy.

Clin Perinatol, 2000 Sep, 27(3), 577 - 601
A practical approach to evaluating and treating neutropenia in the neonatal intensive care unit; Christensen RD et al.; Neutropenia is a relatively common problem in the NICU, recognized in as many as 8% of patients at some time during their hospital stay . In most instances, neutropenia among NICU patients is of short duration and has little influence on outcome . In other cases it is prolonged and severe, and constitutes a serious antimicrobial defense deficiency . When a neonatologist discovers a low blood neutrophil count, choices must be made regarding further evaluation and treatment . The authors hope that the information provided in this article is useful in making these choices.

Planta Med, 2000 Aug, 66(6), 560 - 3
Chemical analysis and antimicrobial studies on three species of Ferulago from Greece; Demetzos C et al.; The chemical composition of the essential oils of the flowering parts and of the hexane extracts of the leaves, of three species of the genus Ferulago (Apiaceae) from Greece, i.e., F . thyrsiflora, F . sylvatica and F . nodosa, was analysed by GC and GC-MS . Manoyl oxide isomers and lupanine, were identified in the hexane extracts of F . thyrsiflora . Dillapiole, was identified in all hexane extracts . Ent-3 beta-hydroxy-13-epi-manoyl oxide was identified and isolated from the essential oil of F . thyrsiflora . All these compounds are new reports for the genus Ferulago and are useful chemotaxonomic markers . Chemical data of F . thyrsiflora is presented for the first time . The essential oils and the extracts were investigated for their antimicrobial activity against Gram-positive and Gram-negative microorganisms.

Planta Med, 2000 Aug, 66(6), 556 - 60
A comparative study of the in vitro antimicrobial activity of tea tree oils s.l . with special reference to the activity of beta-triketones; Christoph F et al.; The in vitro antibacterial and antifungal activities of Australian tea tree oil, cajuput oil, niaouli oil, kanuka oil and manuka oil as well as of a beta-triketone complex isolated from manuka oil were investigated in a constituent-oriented study . The compositions of the oils were analysed by capillary GLC and GLC-MS . The MICs for sixteen different microorganisms were determined applying the broth dilution method . Australian tea tree oil showed the best overall antimicrobial effect . The best inhibitory effects on Gram-positive bacteria and dermatophytes were achieved with manuka oil due to its beta-triketone content.

Planta Med, 2000 Aug, 66(6), 495 - 505
Bioavailability and pharmacokinetics of natural volatile terpenes in animals and humans; Kohlert C et al.; Herbal medicinal products containing natural volatiles are used in the treatment of gastrointestinal diseases, pain, colds and bronchitis . Many pharmacological studies report a wide variety of in vitro effects, with anti-inflammatory and antimicrobial activities investigated most frequently . In comparison, relatively few studies on the bioavailability and pharmacokinetics have been carried out . Thus, the relevance of the in vitro activity to the therapeutic effects found in individual studies or documented in textbooks of phytotherapy is still not established . Further studies with essential oils and their single compounds providing supporting evidence of efficacy and demonstrating systemic availability are necessary . Such data could also be important in the context of safety.

J Cell Sci, 2000 Oct, 113 (Pt 19), 3355 - 6
Phagocytosis, a cell biology view
Sansonetti PJ.
Advances in Cell and Molecular Biology of Membranes and Organelles Volume 5 - Phagocytosis: the Host edited by Alan M . Tartakoff; volume editor, Siamon Gordon JAI Press Inc./Ablex Publishing Corp . (1999) pp . 521 . ISBN 1-55938-999-0 $147.50 Over the last few years, cell biology has become a dominant approach in several disciplines of the life sciences, including the study of phagocytic cells! Before, with exceptions, the science of phagocytosis had often remained descriptive, with microbiologists providing detailed descriptions of the various types and stages of internalization and killing or survival of the pathogenic microorganisms, and immunologists providing an exhaustive description of the complex processes of microbe degradation, antigen processing and presentation following the phagocytic process per se . Phagocytosis: the Host excellently reflects the revolution that has occurred in this field . In other words, the science of phagocytosis is now dominated by an analytical approach based on deciphering the signals that carry out each of the critical steps of the process . Edited by a master of the discipline, in 21 chapters, this book - with great justice dedicated to the late Zanvil A . Cohn - covers the molecular and cellular aspects of phagocytic processes in a logical progression . The best specialists in the field have risen to the challenge . Four chapters are devoted to receptors, certainly representing one of the best and most exhaustive current reviews of this field . Of particular interest are the recent developments on scavenging receptors with regard to phagocytosis of both microbes and apoptotic bodies . In the next three chapters, signalling makes a spectacular entry: our knowledge of the molecular mechanisms that regulate the cytoskeleton is exponentially increasing and finds here its perfect niche . To this section might have been added the chapter entitled 'The Phagocytic Actin Cytoskeleton', which appears in the next section of four chapters devoted to 'the pathway', in other words, the maturation of phagosomes . Here again, progress has been tremendous in understanding the logics of maturation pathways and we are very much looking forward to the next volume Phagocytosis: the Microbes, which will show how these microbes can perturb, to their profit, phagosomal maturation in order to 'carve' a niche which permits their survival . A splendid example of coevolution . The last five chapters form a section (Responses) that encompasses most of the effector mechanisms that link the phagocytic event to the immune response, a domain that dictates the subtle transition between the innate and the adaptative immune response . The antimicrobial mechanisms of phagocytic cells are largely described here, including antimicrobial peptides, in often overlapping chapters . This does not matter at all because, again, the best specialists have gathered to produce a single chapter and the science presented is of the highest quality . So, altogether, this is a splendid contribution that will represent a keystone in the fast moving field of phagocytosis . If this reader had one criticism, it would be the illustrations . For a field that is extremely prone to rich illustrations, figures are generally scarce and grey, and the reproduction of the electron microscopy images is generally poor in definition, brightness and contrast . This should not deter anyone interested in the field from acquiring this volume and its brother volume on interactions with microbes . No doubt this, for the years to come, will be a reference text for phagocytosis . Microbiologists, immunologists and cell biologists, both students and senior scientists will find here updated information and all the relevant and most recent references (up to 2500).

Clin Infect Dis, 2000 Aug, 31 Suppl 2, S35 - 9
Importance of atypical pathogens of community-acquired pneumonia; Plouffe JF; The atypical clinical presentation of patients with community-acquired pneumonia (CAP) was first recognized and reported by astute clinicians 50 years ago . The cause of pneumonia in this group eventually was shown to be Mycoplasma pneumoniae . More recently, Chlamydia pneumoniae also has been recognized as a cause of CAP . Legionella has been lumped together with M . pneumoniae and C . pneumoniae because of its antimicrobial susceptibility pattern . This group of organisms is susceptible to the macrolides, tetracycline, and the newer fluoroquinolones . However, Legionnaires' disease frequently presents a more acute clinical picture than either mycoplasmal or chlamydial infections . Recent data suggest that in the Medicare population hospitalized with pneumonia, morbidity and mortality can be decreased if initial therapy includes coverage for atypical pathogens (i.e., macrolides or fluoroquinolones) . Unfortunately, few studies use culture methodology for atypical pathogens . Future studies of the efficacy of macrolide or fluoroquinolone therapy for CAP should include aggressive diagnostic studies for M . pneumoniae, C . pneumoniae, and Legionella species.

Semin Respir Infect, 2000 Jun, 15(2), 119 - 31
Laboratory diagnosis of nosocomial pneumonia; Mayer J; The second most common nosocomial infection in the United States is pneumonia, with the highest rates seen in patients requiring mechanical ventilation . Nosocomial pneumonia is a serious disease associated with significant morbidity and mortality; crude mortality rates have been estimated at 20% to 50% . The rapid institution of appropriate antimicrobial therapy has been shown to improve mortality in patients with ventilator associated nosocomial pneumonia . Thus, the identification of nosocomial pneumonia with a timely microbiologic diagnosis is important for the management of these patients . However, the accurate diagnosis of nosocomial pneumonia, along with identification of the responsible organism(s), can be challenging . This task becomes even more difficult in patients who are mechanically ventilated . The presence of new pulmonary infiltrates along with clinical criteria including fever, cough, and purulent secretions are neither sensitive nor specific for the diagnosis of nosocomial pneumonia . The laboratory can enhance the accuracy of pneumonia diagnosis, as well as provide the identification of an etiologic organism(s) . There are, however, many challenges which confront the laboratory including: the ability to identify organisms from an extensive microbiologic spectrum; distinguishing colonization from infection of predominately gram-negative oropharyngeal flora; and providing timely results . This article reviews the various diagnostic tests available for nosocomial lung infections, and in particular, ventilator associated pneumonia including: blood cultures; pleural fluid; expectorated sputum; endotracheal aspirates; and respiratory specimens obtained by more invasive techniques using bronchoscopy and transthoracic needle aspiration . Emphasis is placed on optimal specimen collection, the processing of samples in the laboratory, and on the evaluation of potential risks and benefits associated with the varying techniques.

Semin Respir Infect, 2000 Jun, 15(2), 95 - 100
Community-acquired bacterial pneumonias; Reimer LG; Community-acquired bacterial pneumonias are among the most common of infectious diseases . The diagnosis of the etiological agent is becoming more challenging and more critical as new organisms are recognized as pathogens, and as well established agents become increasingly resistant to antimicrobial agents . The value of clinical microbiology laboratory data in the management of pneumonia is controversial . A well recognized, published guideline suggests that no laboratory studies be performed . Yet common practice and a more recent guideline advocate routine collection of sputum for Gram's stain and culture, along with traditional blood work . Given the increasing need to distinguish among a long list of possible pathogens and the need to recognize antibiotic resistance, it seems most prudent to include microbiological studies.This information can be used to guide initial therapy, and perhaps limit the overutilization of broad-spectrum antimicrobials . However, a prerequisite for the use of all cunently available test methods is their deployment in patients for whom there is clinical and radiographic evidence of pneumonia because recovery of a microorganism, especially from sputum, will occur with or without this clinical condition.

Farmaco, 2000 May, 55(5), 406 - 9
1,5-benzodiazepine derivatives of 3-arylsydnones: synthesis and antimicrobial activity of 3-aryl-4-{2'-aryl-2',4',6',7'-tetrahydro-(1'H)-1',5'-benzodiazepine-4' -yl}sydnones; Kavali JR et al.; The alpha-beta-unsaturated ketones of 3-arylsydnones (Ia-y) were treated with 1,2-phenylenediamine to obtain the 3-aryl-4-{2'-aryl- 2',4',6',7'-tetrahydro-(1'H)-1',5'-benzodiazepine-4'-yl}sydnones (IIa-y) in high yield . All the new compounds synthesised were screened for antibacterial and antifungal activities.

Farmaco, 2000 May, 55(5), 331 - 7
Synthesis and antimicrobial activity of 1-aryl-2-amino-3-(4-arylthiazol-2-yl)/(benzothiazol-2-yl)guanidines; Lakhan R et al.; The synthesis of fifteen new 1-aryl-2-amino-3-(4-arylthiazol-2-yl)/(benzothiazol-2-yl)gua nidines is described . They were screened for their antimicrobial susceptibility by the standard disc diffusion method of the World Health Organization (WHO) and the activities compared with that of standard strain of Escherichia coli NCTC 10418 . The sensitive aminoguanidines were further subjected to the minimum inhibitory concentration (MIC) test.

Haematologica, 2000 Sep, 85(9), 961 - 6
Bronchoscopy guided by high-resolution computed tomography for the diagnosis of pulmonary infections in patients with hematologic malignancies and normal plain chest X-ray; Ramila E et al.; BACKGROUND AND OBJECTIVES: High-resolution computed tomography (HRCT) of the chest is able to demonstrate the presence of pulmonary infiltrates in febrile neutropenic patients with normal chest X-rays . Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is a safe procedure for the etiological diagnosis of pulmonary infiltrates in oncohematologic patients . The objective of this study was to determine the diagnostic yield and subsequent therapeutic changes of a protected BAL (p-BAL) guided by HRCT in febrile oncohematologic patients unresponsive to broad-spectrum antibiotics with a normal chest X-ray . DESIGN AND METHODS: Twenty-two episodes from 20 oncohematologic patients were included: group A, 9 episodes (8 patients) with no respiratory symptoms and group B, 13 episodes (12 patients) with signs or symptoms of pulmonary infection . HRCT and p-BAL were performed in all episodes within the first 24 hours . RESULTS: HRCT showed abnormalities in all 22 episodes (bilateral abnormalities in 14 of the 22 episodes {64%}) and the most frequent pattern was ground-glass infiltrate (7 out of 22 episodes) . An infectious agent was isolated in 12 of the 22 episodes, 5 in group A and 7 in group B with a diagnostic yield of 54% . Antimicrobial therapy was modified in 12 of the 22 episodes (54%): 5 in group A and 7 in group B . In 6 episodes, treatment was changed according to HRCT results and in the remaining 6 due to positive microbiologic results . Modifications in empirical therapy were associated with a favorable response in 44% episodes of group A and in 31% of group B . INTERPRETATION AND CONCLUSIONS: Oncohematologic patients with fever of unknown origin unresponsive to empirical antibiotics and with a normal chest X-ray can be candidates to undergo a HRCT . This subgroup of high-risk patients can benefit from a combined strategy consisting of BAL guided by a previous HRCT.

J Antimicrob Chemother, 2000 Sep, 46(3), 501 - 8
Appropriate use of restricted antimicrobial agents in hospitals: the importance of empirical therapy and assisted re-evaluation; Thuong M et al.; We evaluated the appropriateness of use of restricted antimicrobial agents in the context of a newly implemented order form and delivery system for restricted antimicrobial agents, using sequential prospective audits of prescriptions . Four antimicrobial agents were selected: glycopeptides (61 prescriptions), ciprofloxacin (42), piperacillin-tazobactam (42) and imipenem- cilastatin (47) . The justification and adequacy of the antibiotic or combination used, reassessment of therapy and duration of treatment were appraised with reference to the clinical situation and hospital's guidelines . Of the 192 prescriptions, 30 (16%) were empirical therapy, 95 (49%) empirical and secondarily documented and 67 (35%) initially documented therapy . Overall, 73% of prescriptions conformed to guidelines, but the adequacy varied from 93% for vancomycin to only 38% for ciprofloxacin . Of 83/157 initially inadequate prescriptions, 42 (51%) were switched according to guidelines, but only 14% of ciprofloxacin prescriptions were adapted later . An intervention audit with counselling on ciprofloxacin usage increased this rate to 75% . Although implementation of the guidelines resulted in a marked reduction in overall antimicrobial costs, inappropriate antibiotic usage may persist for some drugs despite restricted access . These results emphasize the need for combined interventions using education and expert counselling, targeted to classes of antibiotic for which inappropriate usage is most common.

J Antimicrob Chemother, 2000 Sep, 46(3), 493 - 9
Primary care workshops can reduce and rationalize antibiotic prescribing; McNulty CA et al.; We describe a controlled study comparing the effects on primary care prescribing in west Gloucestershire, UK, where antibiotic workshops were offered, with those in east Gloucestershire, where microbiology tutorials were given . The year-on-year changes in quantity and costs of antibiotics dispensed following general practice prescriptions were measured . There was no significant difference in the number of antibiotic items prescribed across the county, but the number of prescriptions for broad-spectrum agents (quinolones, cephalosporins and co-amoxiclav) declined by 15.4% in west Gloucestershire, compared with a 6.5% increase in east Gloucestershire (P: = 0.002) . Use of narrow-spectrum antibiotics (penicillin V, trimethoprim and nitrofurantoin), whose use was encouraged, did not change in west Gloucestershire practices, but decreased by 12% in east Gloucestershire practices (P: = 0.003) . There was increased use of clarithromycin and azithromycin in both groups of practices . Antibiotic workshops held in the primary care setting can rationalize antibiotic prescribing . This can reduce prescribing costs and selection pressure by broad-spectrum antimicrobial agents and, perhaps, go some way to reducing the development of resistance.

J Antimicrob Chemother, 2000 Sep, 46(3), 461 - 4
In vitro activities of parenteral beta-lactam antimicrobials against TEM-10-, TEM-26- and SHV-5-derived extended-spectrum beta-lactamases expressed in an isogenic Escherichia coli host; Rebuck JA et al.; The in vitro activities were determined and time-kill studies of cefepime, imipenem-cilastatin, meropenem and piperacillin-tazobactam were performed against SHVand TEM-derived extended-spectrum beta-lactamases (ESBLs) . Sequence-confirmed SHV-5, TEM-10 and TEM-26 beta-lactamases were transferred into Escherichia coli C600N by conjugation . Imipenem and meropenem were more active (MIC range 0 . 0625-0.25 mg/L) than cefepime (MIC range 2-8 mg/L) and piperacillin-tazobactam (MIC range 8-32 mg/L) . Regrowth of strains expressing TEM-10 and TEM-26 was noted at all cefepime and piperacillin-tazobactam concentrations studied . Imipenem-cilastatin and meropenem demonstrated rapid, sustained bactericidal activity uninfluenced by the type of ESBL expressed.

J Antimicrob Chemother, 2000 Sep, 46(3), 385 - 90
The effect of azithromycin on intracellular Legionella pneumophila in the Mono Mac 6 cell line at serum concentrations attainable in vivo; Jonas D et al.; We investigated the antimicrobial efficacy of clinically meaningful, low concentrations of azithromycin against intracellular growth of two clinical isolates of Legionella pneumophila . The mature monocytic cell line Mono Mac 6 was used as a model to investigate the effects of antimicrobial agents on L . pneumophila . Extracellular susceptibility was determined by microdilution susceptibility testing in BYEalpha broth after 48 h of incubation . Mono Mac 6 cells infected with L . pneumophila were incubated with various concentrations of azithromycin . After 2 days of incubation, intracellular bacteria were released from the phagocytes and plated on to BCYEalpha agar . Addition of the intracellular-acting antibiotics azithromycin or ciprofloxacin at their MICs (0.5 and 0 . 015 mg/L, respectively) resulted in a significant decrease in cfu, of up to approximately 1 log(10) after 48 h of incubation . In contrast, incubation of intraphagocytic L . pneumophila in the presence of antibiotics without intracellular activity (ceftizoxime, imipenem or amoxycillin-clavulanic acid) did not have any effect . Azithromycin inhibited intracellular replication at concentrations as low as 0.125 mg/L, approximately one-quarter of the extracellular MIC . The Mono Mac 6 cell line is a useful infection model for investigating the intracellular activity of antimicrobial agents in vitro . In accordance with clinical data and animal experiments, azithromycin and ciprofloxacin inhibited the intraphagocytic replication of L . pneumophila . In particular, azithromycin killed ingested legionellae in vitro at concentrations below the peak serum concentrations and below the MIC.

Aust Vet J, 2000 Aug, 78(8), 533 - 7
In vitro antimicrobial susceptibilities of three Porphyromonas spp and in vivo responses in the oral cavity of cats to selected antimicrobial agents; Norris JM et al.; OBJECTIVES: To determine in vitro susceptibility of Porphyromonas gingivalis, P salivosa and P circumdentaria to seven antimicrobial agents by agar dilution and Epsilometer test methods and to assess the effectiveness of these antimicrobial agents in reducing the numbers of each Porphyromonas spp in the oral cavity of 16 domestic cats . DESIGN: A two-part prospective study involving in vitro antimicro-bial studies using Porphyromonas spp obtained from naturally occurring feline infections and in vivo antimicrobial response studies using client-owned cats with naturally occurring periodontal disease . PROCEDURE: Isolates (n = 25) of three feline Porphyromonas spp from the oral cavity and oral-associated disease were tested for their in vitro susceptibility to amoxycillin, amoxycillin-clavulanate, benzylpenicillin, clindamycin, doxycycline, erythromycin and metronidazole, using agar dilution and Epsilometer test methods . Digoxigenin-labelled whole chromosomal DNA probes directed against P gingivalis VPB 3492, P circumdentaria NCTC 12469T and P salivosa VPB 3313 were used to quantify organisms taken from two sample sites at the gingival margins of these cats prior to, and 5 days after, treatment with one of four commonly used antimicrobial products (amoxycillin-clavulanate, clindamycin, doxycycline or spiramycin-metronidazole) . The response to treatment was assessed clinically for each cat . RESULTS: All isolates were susceptible in vitro to all seven antimicrobial agents using both methods . The numbers of P gingivalis were not reduced at the gingival sample sites by administration of amoxycillin-clavulanate for 5 days, although this treatment reduced the numbers of P salivosa and P circumdentaria to below detection levels in six of eight and two of three of sample sites, respectively; clinical improvement was not observed in cats treated with amoxycillin-clavulanate . Treatment with clindamycin, doxycycline or spiramycin-metronidazole resulted in clinical improvement and a marked reduction of all Porphyromonas isolates at the sample sites . CONCLUSION: The Epsilometer test is a simple and accurate method for determining the minimum inhibitory concentration for P gingivalis, P salivosa and P circumdentaria . All strains were susceptible in vitro to all the antimicrobial agents tested although clinical improvement of gingival disease was not noted with amoxycillin-clavulanate when given for 5 days at usual doses . This appears to be the first report of the disparity between the in vivo and in vitro susceptibility of oral bacterial strains to amoxycillin-clavulanate in the veterinary dental literature . This also appears to be the first report in which clinical and microbiological responses to commonly used antimicrobial agents for periodontal disease in cats has been documented and quantified . It was shown that treatment with clindamycin, spiramycin-metronidazole or doxycycline not only produced a substantial reduction in the number of Porphyromonas spp (in the majority of cases to below detection levels), but also resulted in substantial clinical improvement . This would indicate that these antimicrobial agents are useful adjunctive therapy to mechanical debridement in domestic cats.

Nihon Hansenbyo Gakkai Zasshi, 2000 Jul, 69(2), 77 - 82
{The cytokine network and development of immune-based intervention in mycobacterial infection}; Kobayashi K et al.; Cell-mediated immunity, which is activated through the macrophage-cytokine-CD4 helper T cell axis, plays a key role in host defense against mycobacterial infection . In the process, protection in the host is a local event focused on granulomatous lesions that may lead to tissue damage including caseous necrosis, cavity formation, fibrosis, and consequently respiratory failure and marked deformity . The immune response to tuberculosis is a double-edged sword that may contribute to both clearance of infection and tissue damage . In experimental mouse models, immune-based intervention by interleukin (IL) 12 replacement therapy showed antimycobacterial activity in established infection but simultaneously induced both local and systemic toxicities, such as augmentation of granulomatous inflammation and damage to muscles, liver, and blood . Intermittent combination therapy including antimicrobial chemotherapy (rifamycins) and cytokine (IL-12) immune therapy resulted in maximal defense and minimal inflammation without toxicities . Although observations in mice cannot necessarily be extrapolated directly to humans, there has been a continuing hope that immune-based intervention and combination therapy, available in potentially unlimited quantities by biotechnology, albeit at considerable expense, would have a major impact on treatment of infectious diseases caused by drug-resistant microorganisms . In addition, the understanding of host defense mechanisms facilitates development of new vaccines for mycobacterial diseases.

J Biol Chem, 2000 Dec 8, 275(49), 38417 - 26
Styelin D, an extensively modified antimicrobial peptide from ascidian hemocytes; Taylor SW et al.; We isolated styelin D, a 32-residue, C-terminally amidated antimicrobial peptide, from the blood cells (hemocytes) of the solitary ascidian, Styela clava . Styelin D had remarkably extensive post-translational modifications, containing two novel amino acids, dihydroxyarginine and dihydroxylysine, and two distinctly unusual ones, 6-bromotryptophan and 3,4-dihydroxyphenylalanine . In addition, the peptide exhibited microheterogeneity because of differential mono- and dihydroxylation of several lysine residues . The primary sequence of one variant was: GW(*)LR(**)K(**)AAK(**)SVGK(**)FY(*)Y(*)K(**)HK(*)Y(*) Y(*)IK(*)AAWQIG KHAL-NH(2), where W(*) is 6-bromotryptophan, R(**) is dihydroxyarginine, Y(*) is 3,4-dihydroxyphenylalanine, K(*) is 5-hydroxylysine, and K(**) is dihydroxylysine . Styelin D exhibited activity against Gram-negative and Gram-positive bacteria, and this activity was retained in 200 mm NaCl . The role of the extensive modifications may be to preserve activity at low pH and/or high salinity because, under these conditions, the native peptide was considerably more active against the Gram-positive bacterial strains than its unmodified synthetic analogue . The peptide was also hemolytic and quite cytotoxic to eukaryotic cells . These broad ranging activities, combined with its relative abundance in ascidian hemocytes, suggest that styelin D plays a significant role in the innate immune mechanisms of S . clava.

J Med Chem, 2000 Sep 7, 43(18), 3448 - 52
QSAR based on biological microcalorimetry; Montanari ML et al.; In this paper we describe a QSAR based on biological microcalorimetry for a set of antimicrobial hydrazides acting against Saccharomyces cerivisiae and Escherichia coli . Results show that an extrathermodynamic relationship exists based upon partitioning (log P(TA)) and microcalorimetrically measured biopotencies using the same cell systems . Moreover, the extrathermodynamic relationship between drug potencies for these two cell systems shows that both cellular systems appear to behave in the same way with respect to the importance of partitioning . This means that the same set of congeneric compounds experience a similar environment in the two systems . This represents a lateral validation of the method and discloses the validity of the QSAR model.

Am J Manag Care, 2000 May, 6(8 Suppl), S427 - 36
The role of infection in acute exacerbations of chronic obstructive pulmonary disease; Hillberg RE; Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the second leading cause of work disability . Extensive data indicate that bacterial infection has an important role in acute exacerbations of COPD . Antibiotic therapy has been shown to benefit patients with exacerbations of COPD by improving clinical outcomes and hastening clinical and physiologic recovery . Antibiotics also provide long-term benefits such as preventing the progression of disease, minimizing secondary colonization with resistant organisms, and prolonging the time between exacerbations . Classifying an episode of COPD as uncomplicated, complicated, or at risk for Pseudomonas is useful in determining antibiotic therapy for patients with an acute exacerbation . Although patients with less severe uncomplicated disease can be treated with older antimicrobial agents, those with serious comorbid conditions or advanced structural lung disease require treatment with new more potent agents . Knowing the patterns of antimicrobial resistance in the respiratory pathogens, antibiotic pharmacokinetics, and factors influencing patient compliance is necessary to prevent treatment failures.

Am J Manag Care, 2000 May, 6(8 Suppl), S419 - 26
The challenge of prescribing treatment for respiratory tract infections; Nicolau DP; In the treatment of respiratory infections, good clinical and economic outcomes depend on the patient, the pathogen, and the therapeutic protocol . Of these, treatment is the only area in which a clinician can exert control, but selecting the optimal therapy can be very challenging . When choosing a therapy, clinicians should consider the pharmacodynamics of each antibiotic . This may be helpful as calculations of optimal drug exposure based on ratio of pharmacodynamic variables appear to correlate with clinical outcome . Although many current therapies are effective in the treatment of respiratory infections, several factors, such as the development of more severe illnesses, increasing antimicrobial resistance, and a growing awareness of the role of atypical pathogens, are leading many clinicians to prescribe new, more potent antibiotic therapy.

Orv Hetil, 2000 Jul 30, 141(31), 1711 - 4
{Lansoprazole versus ranitidine bismuth citrate containing triple regimens for Helicobacter pylori eradication in patients with duodenal ulcer}; Buzas Gyorgy M et al.; The aim of this study was to compare in an open, controlled and prospective trial the efficacy of one-week regimen using either lansoprazole (2 x 30 mg) + 2 x 500 mg metronidazole + 2 x 250 mg clarithromycin (group I, 60 cases) or ranitidine bismuth citrate (2 x 400 mg) + 2 x 500 mg metronidazole + 2 x 250 mg clarithromycin (group II, 61 cases) on the eradication of Hp infection in duodenal ulcer patients . The diagnosis was stated endoscopically . Hp infection was confirmed from 2 antral + 2 corporeal biopsies by the modified Giemsa stain and rapid urease test . After eradication the patients were given on-demand treatment with 30 mg lansoprazole (group I) or 2 x 150 mg ranitidine (group II) . Control 13C-urea breath test was performed 4-6 weeks after eradication . On intention to treat basis, Hp was eradicated in 78.3% (confidence interval, CI: 67.6-89.1%) in group I and 78.7% (CI: 68.1-89.2%) in group II (p > 0.05) . Per protocol eradication rates were 92.1% (CI: 84.5-99.7%) in group I and 90.5 (CI: 82.4-98.6%) in group II (p > 0.05) . Side effects were recorded in 13.5% in group I and 18.3% of cases in group II . Short term triple therapies using either lansoprazole or ranitidine bismuth citrate + 2 antimicrobials were effective and safe in the eradication of Hp in duodenal ulcer patients.

J Immunol, 2000 Sep 15, 165(6), 3358 - 65
An alpha-helical cationic antimicrobial peptide selectively modulates macrophage responses to lipopolysaccharide and directly alters macrophage gene expression; Scott MG et al.; Certain cationic antimicrobial peptides block the binding of LPS to LPS-binding protein and reduce the ability of LPS to induce the production of inflammatory mediators by macrophages . To gain a more complete understanding of how LPS activates macrophages and how cationic peptides influence this process, we have used gene array technology to profile gene expression patterns in macrophages treated with LPS in the presence or the absence of the insect-derived cationic antimicrobial peptide CEMA (cecropin-melittin hybrid) . We found that CEMA selectively blocked LPS-induced gene expression in the RAW 264.7 macrophage cell line . The ability of LPS to induce the expression of >40 genes was strongly inhibited by CEMA, while LPS-induced expression of another 16 genes was relatively unaffected . In addition, CEMA itself induced the expression of a distinct set of 35 genes, including genes involved in cell adhesion and apoptosis . Thus, CEMA, a synthetic alpha-helical peptide, selectively modulates the transcriptional response of macrophages to LPS and can alter gene expression in macrophages.

J Immunol, 2000 Sep 15, 165(6), 3268 - 74
Pepsin-mediated processing of the cytoplasmic histone H2A to strong antimicrobial peptide buforin I; Kim HS et al.; The intestinal epithelium forms a first line of innate host defense by secretion of proteins with antimicrobial activity against microbial infection . Despite the extensive studies on the antimicrobial host defense in many gastrointestinal tracts, little is known about the antimicrobial defense system of the stomach . The potent antimicrobial peptide buforin I, consisting of 39 aa, was isolated recently from the stomach tissue of an Asian toad, Bufo bufo gargarizans . In this study we examined the mechanism of buforin I production in toad stomach tissue . Buforin I is produced by the action of pepsin isozymes, named pepsin Ca and Cb, cleaving the Tyr39-Ala40 bond of histone H2A . Immunohistochemical analysis revealed that buforin I is present extracellularly on the mucosal surface, and unacetylated histone H2A, a precursor of buforin I, is localized in the cytoplasm of gastric gland cells . Furthermore, Western blot analysis showed that buforin I is also present in the gastric fluids, and immunoelectron microscopy detected localization of the unacetylated histone H2A in the cytoplasmic granules of gastric gland cells . The distinct subcellular distribution of the unacetylated histone H2A and the detection of the unacetylated buforin I both on the mucosal surface and in the lumen suggest that buforin I is produced from the cytoplasmic unacetylated histone H2A secreted into the gastric lumen and subsequently processed by pepsins . Our results indicate that buforin I along with pepsins in the vertebrate stomach may contribute to the innate host defense of the stomach against invading microorganisms.

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