Bactericidal

Epidemiol Infect, 2001 Oct, 127(2), 221 - 7
An outbreak of diarrhoea due to multiple antimicrobial-resistant Shiga toxin-producing Escherichia coli O26:H11 in a nursery; Hiruta N et al.; An outbreak due to Shiga toxin-producing Escherichia coli O26:H11 (STEC) occurred at a nursery in southeastern Japan in 1997 . Thirty-two children had watery or bloody diarrhoea but none of them suffered from haemolytic-uremic syndrome . All of the STEC O26 were isolated during the period from 23 July to 22 August from 24 children, 3 nurses, and 2 food samples . These organisms had stx1 and eae genes but none of the other genes for which we tested (stx2, bfp, and EAF plasmid) . They also possessed multiple antimicrobial resistances, which were encoded by a transmissible plasmid, and showed mostly identical genomic pulsed-field gel electrophoretic patterns . The results of this investigation suggested that contaminated food was the main contributing factor to this multiple antimicrobial-resistant STEC O26 infection, and person-to-person transmission also contributed to the spread of this outbreak.

Drugs, 2001, 61(12), 1801 - 33
Lansoprazole: an update of its place in the management of acid-related disorders; Matheson AJ et al.; Lansoprazole is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against Helicobacter pylori in vitro . Current therapy for peptic ulcer disease focuses on the eradication of H . pylori infection with maintenance therapy indicated in those patients who are not cured of H . pylori and those with ulcers resistant to healing . Lansoprazole 30 mg combined with amoxicillin 1g, clarithromycin 250 or 500mg, or metronidazole 400 mg twice daily was associated with eradication rates ranging from 71 to 94%, and ulcer healing rates were generally >80% in well designed studies . In addition, it was as effective as omeprazole- or rabeprazole-based regimens which included these antimicrobial agents . Maintenance therapy with lansoprazole 30 mg/day was significantly more effective than either placebo or ranitidine in preventing ulcer relapse . Importantly, preliminary data suggest that lansoprazole-based eradication therapy is effective in children and the elderly . In the short-term treatment of patients with gastro-oesophageal reflux disease (GORD), lansoprazole 15, 30 or 60 mg/day was significantly more effective than placebo, ranitidine 300 mg/day or cisapride 40 mg/day and similar in efficacy to pantoprazole 40 mg/day in terms of healing of oesophagitis . Lansoprazole 30 mg/day, omeprazole 20 mg/day and pantoprazole 40 mg/day all provided similar symptom relief in these patients . In patients with healed oesophagitis . 12-month maintenance therapy with lansoprazole 15 or 30 mg/day prevented recurrence and was similar to or more effective than omeprazole 10 or 20 mg/day . Available data in patients with NSAID-related disorders or acid-related dyspepsia suggest that lansoprazole is effective in these patients in terms of the prevention of NSAID-related gastrointestinal complications, ulcer healing and symptom relief . Meta-analytic data and postmarketing surveillance in >30,000 patients indicate that lansoprazole is well tolerated both as monotherapy and in combination with antimicrobial agents . After lansoprazole monotherapy commonly reported adverse events included dose-dependent diarrhoea, nausea/vomiting, headache and abdominal pain . After short-term treatment in patients with peptic ulcer, GORD, dyspepsia and gastritis the incidence of adverse events associated with lansoprazole was generally < or = 5% . Similar adverse events were seen in long-term trials, although the incidence was generally higher (< or = 10%) . When lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole adverse events included diarrhoea, headache and taste disturbance . In conclusion, lansoprazole-based triple therapy is an effective treatment option for the eradication of H . pylori infection in patients with peptic ulcer disease . Preliminary data suggest it may have an important role in the management of this infection in children and the elderly . In the short-term management of GORD, lansoprazole monotherapy offers a more effective alternative to histamine H2-receptor antagonists and initial data indicate that it is an effective short-term treatment option in children and adolescents . In adults lansoprazole maintenance therapy is also an established treatment option for the long-term management of this chronic disease . Lansoprazole has a role in the treatment and prevention of NSAID-related ulcers and the treatment of acid-related dyspepsia; however, further studies are needed to confirm its place in these indications . Lansoprazole has emerged as a useful and well tolerated treatment option in the management of acid-related disorders.

ASDC J Dent Child, 2001 May-Jun, 68(3), 183 - 8, 152
Antimicrobial and buffer capacity of crude extracts of chewing sticks (Miswaki) from Kenya; Kemoli AM et al.; The use of Chewing sticks (Miswaki) in the third world for control of dental plaque is very popular . Some of the studies that have been conducted on this subject have reported marked decrease in the incidences of dental caries and periodontal diseases in the users of Miswaki, when compared to the users of the conventional toothbrush living under similar conditions . Various mechanisms by which the Miswaki contributes to this phenomenon have been suggested . The purpose of the present study was to investigate in vitro, the anti-microbial action, the potential acid buffer capacity and fluoride content of crude aqueous extracts of eight commonly used chewing sticks from three regions in Kenya . The results obtained in the study, showed that one of the Miswaki had remarkable antibiotic activity against three stains of oral bacteria . Three of the Miswaki had significant acid buffer capacity . None of the eight Miswaki showed any significant fluoride release.

Vet Clin North Am Food Anim Pract, 2001 Nov, 17(3), 517 - 34
Immunology of inflammatory diseases of the bowel; Waters WR; During the past century, research on animal diseases has focused on the characterization of specific etiologies and disease control strategies . Many diseases affecting domestic animals have been successfully controlled using various methods, including vaccination, management, vector control, or antimicrobial agents . A number of microorganisms have proven resistant to these efforts . Control of these organisms requires the development of new strategies . As practitioners and researchers, we need to consider approaches that encompass the entire realm of disease expression from molecular to immune responses and interactions with other functional systems (e.g., endocrine, neurologic, and vascular systems) . We need a basic understanding of effective immune responses enabling the tailoring of vaccines to produce the desired response . This tailoring of host responses is augmented by the use of vaccines that use host growth factors, cytokines, or costimulatory molecules to bias the ensuing response . Intestinal microbial flora of food-producing animals can be managed to optimize health and minimize colonization by pathogenic organisms, especially zoonotic agents . New systems for the delivery of cytokines and other factors that favor optimal intestinal health and homeostasis need to be researched and evaluated . With time, it is likely that our clients and the consumers will be less tolerant of antibiotic usage . They will be more aware of the zoonotic potential of many microbes that colonize food animals . Food safety issues will be a continuing concern, as will the protection of our water supply from contamination from feedlots and pasture runoff . We are in the dawn of a new century, and, it is hoped, a new era of discovery of enteric disease pathogenesis and control.

Clin Infect Dis, 2001 Dec 1, 33(11), 1938 - 43 Epub 2001 Oct 24.
Disseminated Mycobacterium avium complex disease among patients infected with human immunodeficiency virus, 1985-2000; Horsburgh CR Jr et al.; Disseminated Mycobacterium avium complex disease remains a substantial cause of morbidity and mortality among patients with acquired immunodeficiency syndrome . From 1985 through 2000, we studied 1458 consecutive patients at Grady Memorial Hospital, Atlanta, with disseminated M . avium complex disease . There was a peak of 198 patients in the 1995, which decreased to 66 patients in 2000 . In 1997, significantly more patients than in 1991 or 1994 were female (P<.001) or black (P<.001) and significantly fewer had acquired human immunodeficiency virus through homosexual contact (P<.001) . In 1997, 50 (51%) of 99 of patients acquired M . avium complex disease despite receiving antimicrobial prophylaxis, but 32 (89%) of 36 patients did not adhere to the prophylaxis regimen . The median duration of survival of patients in 1991 was 110 days, whereas in 1994 it was 185 days, and in 1997 it was 339 days (P<.001) . Prolonged survival was associated with receiving therapy that included clarithromycin and receiving combination antiretroviral therapy that included a protease inhibitor.

Eur J Gastroenterol Hepatol, 2001 Nov, 13(11), 1281 - 4
Should anti-Helicobacter therapy be different in patients with dyspepsia compared with patients with peptic ulcer diathesis?
de Boer WA, Tytgat GN.
Physicians should try to reach an optimal cure rate with initial anti-Helicobacter therapy . Helicobacter pylori infection in patients with peptic ulcer disease (PUD) is more likely to be cured then in patients with 'functional' dyspepsia (FD) . Differences in cure rates of 5-15% are usually reported, which is considered to be clinically relevant . Different strains (virulent v . non-virulent) in PUD and FD may induce different alterations in the gastric mucosa, and thereby either facilitate or impair antimicrobial efficacy . A study in this journal showed that triple therapy with ranitidine bismuth citrate (RBC) was superior to triple therapy with a proton pump inhibitor (PPI), but only in the more-difficult-to-cure FD patients . Clinicians should be aware that most published treatment studies have included only PUD patients . This means that in clinical practice the cure rates obtained in patients with FD or even uninvestigated dyspepsia will usually be lower then those reported in the literature . One way to deal with this is to consider prolonging the duration of an initial anti-Helicobacter therapy from 7 to 10 or 14 days in patients without ulcers.

Cancer Res, 2001 Nov 1, 61(21), 7709 - 12
A proapoptotic peptide for the treatment of solid tumors; Mai JC et al.; We have designed a novel peptide, DP1, which is able to mediate significant induction of apoptosis in solid tumors by local injection . This peptide, comprised of a protein transduction domain (PTD), PTD-5, fused to an antimicrobial peptide, (KLAKLAK)2, was able to trigger rapid apoptosis in a variety of cell lines in vitro, including MCA205 murine fibrosarcomas and human head and neck tumors . Furthermore, direct injection of DP1 into day 7 established MCA205 tumors in C57BL/6 mice resulted in the induction of tumor apoptosis and subsequent reduction in tumor volume . These results suggest that DP1 may be used clinically to treat accessible solid tumors or as an adjuvant therapy in conjunction with radiotherapy, standard chemotherapy, immunotherapy, or surgical debulking.

Int J Antimicrob Agents, 2001 Oct, 18(4), 329 - 33
Optimising antibiotic prescribing in primary care; McNulty CA; Prudent antimicrobial prescribing in the community may help to prevent the relentless increase in resistance, highlighted worldwide by numerous parliamentary documents . Antibiotic guidance, developed by primary care professionals and disseminated locally with outreach workshops, helps to reduce the use of broad-spectrum antimicrobials . Computerised guidance, audit of antibiotic use and restricted laboratory sensitivity reporting moves the prescriber towards the selection of recommended drugs . Educational campaigns and patient leaflets given at the consultation help to modify patients' expectations . Primary care physicians need to consider how much pharmaceutical representatives and free samples influence their prescribing . This multi-faceted approach needs to be backed up with a research programme developing the evidence base for management guidance of antimicrobial use in primary care.

Clin Microbiol Infect, 2001, 7 Suppl 4, 83 - 90
Role of antibiotic prophylaxis for the prevention of intravascular catheter-related infection; Carratala J; Intravascular catheters have become essential tools for the management of patients in modern medical practice, but there are complications . In particular, catheter-related infection remains a major cause of nosocomial infection and primary septicemia . The development of preventive strategies to reduce the incidence of catheter-related infection is an important goal for all health providers . Over recent years, significant advances in prophylactic measures for the prevention of catheter-related infection have been made . This paper reviews strategies based on antibiotic prophylaxis such as systemic administration of antibiotics, application of antibiotic ointments to the skin insertion site as well as catheter flushing with antibiotics, the antibiotic-lock technique and the use of antimicrobial impregnated catheters.

Clin Diagn Lab Immunol, 2001 Nov, 8(6), 1204 - 12
Modulation of Mycobacterium bovis-specific responses of bovine peripheral blood mononuclear cells by 1,25-dihydroxyvitamin D(3); Waters WR et al.; Historically, administration of vitamin D has been considered beneficial in the treatment of tuberculosis . The interaction of this vitamin {i.e., 1,25-dihdroxyvitamin D(3) {1,25(OH)(2)D(3)}} with the antitubercular immune response, however, is not clear . In the present study, in vitro recall responses of peripheral blood mononuclear cells (PBMC) from cattle infected with Mycobacterium bovis were used to study the immune-modulatory effects of 1,25(OH)(2)D(3) on M . bovis-specific responses in vitro . Addition of 1 or 10 nM 1,25(OH)(2)D(3) inhibited M . bovis-specific proliferative responses of PBMC from M . bovis-infected cattle, affecting predominantly the CD4(+) cell subset . In addition, 1,25(OH)(2)D(3) inhibited M . bovis-specific gamma interferon (IFN-gamma) production yet enhanced M . bovis-specific nitric oxide (NO) production . Lymphocyte apoptosis, measured by flow cytometry using annexin-V staining, was diminished by addition of 1,25(OH)(2)D(3) to PBMC cultures . These findings support the current hypothesis that 1,25(OH)(2)D(3) enhances mycobacterial killing by increasing NO production, a potent antimicrobial mechanism of activated macrophages, and suggest that 1,25(OH)(2)D(3) limits host damage by decreasing M . bovis-induced IFN-gamma production.

Diagn Microbiol Infect Dis, 2001 Sep-Oct, 41(1-2), 71 - 8
In vitro susceptibility of Stenotrophomonas maltophilia to various antimicrobial combinations; Krueger TS et al.; Stenotrophomonas maltophilia has emerged as a significant pathogen in compromised patients, causing infections which are difficult to treat . Clinical isolates from patients in the Tucson area were tested against single and combination antibiotics using three testing methods . Ticarcillin/clavulanate, trimethoprim/sulfamethoxazole and trovafloxacin provided comparable inhibitory activity, in vitro . Ciprofloxacin, imipenem and ticarcillin were active less often . Agreements between disk diffusion and broth microdilution results were poor for ciprofloxacin and trimethoprim/sulfamethoxazole; however, agreement was > or = 90% for the other drugs tested . Major or very major errors were observed with ticarcillin, ticarcillin/clavulanate, and trovafloxacin . The addition of aztreonam to ticarcillin/clavulanate enhanced the activity compared to ticarcillin/clavulanate alone using the double-disk diffusion, broth microdilution (checkerboard), and time-kill testing methods . Trovafloxacin exhibited good activity by all three methods, with bactericidal activity at > or = 2x MIC . These results indicate that the newer fluoroquinolones or the triple combination of ticarcillin/clavulanate plus aztreonam may be potential options for treatment of infection caused by S . maltophilia in patients who are intolerant to or fail trimethoprim/sulfamethoxazole therapy.

Cochrane Database Syst Rev . 2001;(3):CD001439.
Antibiotics versus placebo for prevention of postoperative infection after appendectomy; Andersen BR et al.; BACKGROUND: Appendicitis is the most common cause of acute abdominal pain requiring surgical intervention . The cause of appendicitis is unclear and the mechanism of pathogenesis continues to be debated . Despite improved asepsis and surgical techniques, postoperative complications, such as wound infection and intraabdominal abscess, still account for a significant morbidity . Several studies implicate that postoperative infections are reduced by administration of antimicrobial regimes . OBJECTIVES: The objective of this review is to compare the use of antibiotics with placebo or no treatment in patients undergoing appendectomy . Will these patients benefit from antimicrobial prophylaxis? The outcomes are described according to the nature of the appendix, as either simple appendicitis (including the non-infectious stage) and complicated appendicitis . This review do not attempt to compare the effect of different regimens, a clinical question that is addressed in another review undertaken by this Group (CCCG) . SEARCH STRATEGY: We searched The Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4), Medline (January 1966 to September 2000), Embase and the Cochrane Colorectal Cancer Group specialised register (September 2000) . In addition we manually searched the reference lists of the primary identified trials . SELECTION CRITERIA: Randomised Controlled Trials (RCT) and Controlled Clinical Trials (CCT) in which any antibiotic regime were compared to placebo in patients suspected of having appendicitis undergoing appendectomy were evaluated . Both studies on children and adults were reviewed . The outcome measures of the studies were either wound infection, intraabdominal abscess, length of stay in hospital or mortality . DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed, recorded and cross-checked by to reviewers . MAIN RESULTS: Forty-four studies including 9298 patients were included in this review . The overall result is that use of antibiotics is superior to placebo for the outcome wound infection and intraabdominal abscess, with no apparant difference in the nature of the removed appendix . Studies exclusively on children and studies examining topical application reported results in favour to the above although the results were not significant . REVIEWER'S CONCLUSIONS: Antibiotic prophylaxis is effective in the prevention of postoperative complications in appendectomised patients, whether the administration are given pre-, per- and post-operatively and could be considered for routine in emergency appendectomies.

Environ Sci Technol, 2001 Oct 15, 35(20), 4103 - 10
Microbial inhibitors for U.S . EPA drinking water methods for the determination of organic compounds; Winslow SD et al.; Preservation of chemical analytes in drinking water samples is necessary to obtain accurate information concerning contaminant occurrence . Sample preservation to prevent biodegradation is important for most samples and analytes . With the unique demands of environmental methods, it is not always possible to kill all microorganisms without having undesirable effects . To find a suitable preservative, the sample, analysis, and preservation needs should be considered . During method development of U.S . Environmental Protection Agency (EPA) Methods 526 (for unstable semivolatile compounds) and 532 (for phenylurea pesticides), a number of studies were conducted to identify compatible microbial inhibitors . Copper sulfate was successfully used in Method 532 and is an excellent first-choice antimicrobial agent for many applications . Copper sulfate can catalyze hydrolysis reactions for some pesticides such as those analyzed in Method 526 . Under these conditions, a nonmetal compound of antimicrobial activity must be considered . During the development of Method 526, a survey of alternate organic based antimicrobial compounds found that diazolidinyl urea worked well in the method . Several other candidate microbial inhibitors were identified that could have application to other environmental methods . A general approach to selecting antimicrobial compounds in future environmental methods in water matrixes is discussed.

Aliment Pharmacol Ther, 2001 Jun, 15(6), 831 - 41
Anti-inflammatory and tissue-protectant drug effects: results from a randomized placebo-controlled trial of gastritis patients at high risk for gastric cancer; Fischbach LA et al.; BACKGROUND: The inflammatory process involving Helicobacter pylori-associated gastritis is thought to lead to epithelial damage and contribute to the development of gastric cancer . Evidence exists from animal and in vitro studies suggesting that tetracyclines have both anti-inflammatory and tissue-protectant effects unrelated to their antimicrobial activity . We attempted to modulate components of H . pylori's inflammatory process by: (i) eliminating the infection; (ii) using tetracycline to alter the host's reaction to the infection without reducing the bacterial load; and (iii) using calcium to counteract the effect of excessive dietary salt . METHODS: We conducted a 16-week placebo-controlled clinical trial with 374 H . pylori-associated gastritis patients randomly assigned to one of five groups: (1) triple therapy consisting of metronidazole, amoxicillin and bismuth subsalicylate for 2 weeks, followed by bismuth alone for 14 weeks; (2) calcium carbonate; (3) triple therapy and calcium carbonate; (4) tetracycline; or (5) placebo . RESULTS: Subjects in the tetracycline and triple therapy groups, but not the calcium carbonate only group, showed a reduction in inflammation and epithelial damage vs . those in the placebo group, independent of a change in H . pylori density and other factors . Our results also indicate that epithelial damage may be affected by mechanisms independent of H . pylori density or inflammation . CONCLUSION: The results are consistent with the hypothesis that tetracycline can decrease inflammation independent of a reduction in the bacterial load . More research is needed to investigate mechanisms leading to epithelial damage which are independent of H . pylori density and inflammation.

Aliment Pharmacol Ther, 2001 Jun, 15(6), 773 - 82
Guidelines for adults on self-medication for the treatment of acute diarrhoea; Wingate D et al.; Acute uncomplicated diarrhoea is commonly treated by self-medication . Guidelines for treatment exist, but are inconsistent, sometimes contradictory, and often owe more to dogma than evidence . An ad hoc multidisciplinary group has reviewed the literature to determine best practice . In general it is recognized that treatment of acute episodes relieves discomfort and social dysfunction . There is no evidence that it prolongs the illness . Self-medication in otherwise healthy adults is safe . Oral loperamide is the treatment of choice . Older anti-diarrhoeal drugs are also effective in the relief of symptoms but carry the risk of unwanted adverse effects . Oral rehydration solutions do not relieve diarrhoea, and confer no added benefit for adults who can maintain their fluid intake . Probiotic agents are, at present, limited in efficacy and availability . Antimicrobial drugs, available without prescription in some countries, are not generally appropriate for self-medication, except for travellers on the basis of medical advice prior to departure . Medical intervention is recommended for the management of acute diarrhoea in the frail, the elderly (> 75 years), persons with concurrent chronic disease, and children . Medical intervention is also required when there is no abatement of the symptoms after 48 h, or when there is evidence of deterioration such as dehydration, abdominal distension, or the onset of dysentery (pyrexia > 38.5 degrees C and/or bloody stools).

Mol Cell, 2001 Oct, 8(4), 921 - 30
A plant defense response effector induces microbial apoptosis; Narasimhan ML et al.; Osmotin is a tobacco PR-5 protein that has antifungal activity and is implicated in host-plant defense . We show here that osmotin induces apoptosis in Saccharomyces cerevisiae . Induction of apoptosis was correlated with intracellular accumulation of reactive oxygen species and was mediated by RAS2, but not RAS1 . Osmotin treatment resulted in suppression of transcription of stress-responsive genes via the RAS2/cAMP pathway . It was therefore concluded that osmotin induced proapoptotic signaling in yeast . The results indicate that the ability of antimicrobial proteins to induce microbial apoptosis could be an important factor in determining a pathogen's virulence and could therefore be targeted for the design of new antifungal drugs.

Eur J Biochem, 2001 Nov, 268(21), 5589 - 600
Amphipathic alpha helical antimicrobial peptides; Giangaspero A et al.; Antimicrobial peptides (AMPs) that assume an amphipathic alpha helical structure are widespread in nature . Their activity depends on several parameters including the sequence, size, degree of structure formation, cationicity, hydrophobicity and amphipathicity . The analysis of numerous natural AMPs provided representative values for these parameters and led to a sequence template with which to generate potent artificial lead AMPs . Sequences were then varied in a rational manner, using both natural and nonproteinogenic amino acids, to probe the individual roles of each parameter in modulating biological activity . A high cationicity combined with a stabilized amphipathic alpha helical structure conferred enhanced cidal activity towards all the cell types considered, and was a requirement for Gram-positive bacteria and fungi . An elevated helicity also correlated with increased hemolytic activity . The structural requirements for activity against several Gram-negative bacteria were instead considerably less stringent, so that it persisted in peptides in which formation of a helical structure and/or amphipathicity were impeded . Either a reduced charge or a reduced hydrophobicity resulted in generally inactive peptides . These observations, combined with the kinetics of bacterial membrane permeabilization and time-killing are discussed in terms of currently accepted models of action for this type of peptide . The simple guidelines obtained in this study allowed the design of highly active shortened AMPs and may be generally useful in the development of this type of peptides as anti-infective agents.

Biochemistry, 2001 Nov 6, 40(44), 13281 - 7
Interactions of bismuth with human lactoferrin and recognition of the Bi(III)-lactoferrin complex by intestinal cells; Zhang L et al.; Several bismuth compounds are currently used as antiulcer drugs, but the mechanism of action still remains unclear . The antimicrobial activity of Bi(III) complexes toward Gram-negative bacteria is reported to be dependent on the iron uptake system {Domenico, P., et al . (1996) J . Antimicrob . Chemother . 38, 1031-1040} . Electronic absorption and 13C NMR spectroscopic data show that Bi(III) binds to human lactoferrin at the specific Fe(III) sites along with either carbonate or oxalate as the synergistic anion . The uptake of Bi(III) by apo-hLF was rapid {minutes in 10 mM Hepes buffer and 5 mM bicarbonate (pH 7.4)}, and almost equal in both lobes . The presence of ATP facilitates the release of Bi(III) from the Bi2-hLF complex when the pH is lowered . The Bi2-hLF complex blocked the uptake of the radiolabeled 59Fe-hLF complex into rat IEC-6 cells . Surprisingly, apo-hLF (but not apotransferrin) was almost as effective in blocking 59Fe uptake as bismuth-loaded lactoferrin . These results suggest that Bi(III)-loaded hLF might be recognized by the lactoferrin receptor and be taken up into cells.

Pharm Res, 2001 Sep, 18(9), 1315 - 9
Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model; Suarez S et al.; PURPOSE: Targeted delivery of rifampicin loaded microspheres to the alveolar macrophage, the host cell for Mycobacterium tuberculosis (MTB), may be an effective targeted approach to pulmonary tuberculosis therapy . A guinea pig infection model has been adopted as a post-treatment screening method for antimicrobial effect . Insufflation and nebulization methods of drug delivery were evaluated . METHODS: Rifampicin alone (RIF, 1.03-1.72 mg/kg), within poly(lactide-co-glycolide) microspheres (R-PLGA, equivalent to 1.03-1.72 mg/kg) or polymer microparticles alone (PLGA) were administered by insufflation or nebulization, 24 h before bacterial aerosol exposure . Animals were infected with an aerosol containing a small number (2 x 10(5) cfu/mL) of virulent H37Rv strain of MTB . Lung and spleen tissue samples were collected 28 days after infection for quantitative bacteriology and histopathological analysis . RESULTS: There was a dose-effect relationship between insufflated R-PLGA and burden of bacteria in the lungs . In addition, guinea pigs treated with R-PLGA had a significantly smaller number of viable bacteria (P < 0.05), reduced inflammation and lung damage than lactose or saline control, PLGA or RIF treated animals . CONCLUSIONS: These studies indicate the potential of R-PLGA, delivered by insufflation or nebulization directly to the lungs, to affect the early development of pulmonary TB.

Euro Surveill, 2001 Jan, 6(1), 5 - 14
National policies for preventing antimicrobial resistance - the situation in 17 European countries in late 2000; Therre H; A survey carried out within Member States of the European Union and Norway shows that in all but two countries national surveillance of microorganisms resistant to antibiotics existed in December 2000 . In Italy, Ireland and Scotland, the systems were set up very recently (respectively in 1998, 1999 and 1999) . Moreover, excepting of Ireland and Scotland, all countries have a national system for data collection on the consumption of antibiotics, namely since 2000 in Austria, Italy and Luxembourg . Several of these systems were set up after 1998 when the recommendations of the European conference 'The Microbial Threat' held in Copenhague were published . In addition, a certain number of other measures have been undertaken since then: education campaigns to the population in England and Wales, in Ireland or in France, creation of committees specifically in charge of consumption surveillance in Italy or of the prevention of resistance in Belgium or in Ireland, publications of recommendations on the good use of antibiotics in Austria and in Finland, etc.

J Biol Chem, 2002 Jan 4, 277(1), 67 - 74 Epub 2001 Oct 26.
Optimization of microbial specificity in cyclic peptides by modulation of hydrophobicity within a defined structural framework; Kondejewski LH et al.; In the present study we have utilized the structural framework of the analog GS14K4 (cyclo(VKLd-KVd-YPL KVKLd-YP, where d denotes a d-amino acid)), to examine the role of hydrophobicity in microbial activity and specificity . The hydrophobicity of GS14K4 was systematically altered by residue replacements in the hydrophobic sites of the molecule to produce a series of analogs that were either less or more hydrophobic than the parent compound . Circular dichroism spectroscopy and reversed-phase high performance liquid chromatography analysis showed that the molecules were structurally similar and only differed in overall hydrophobicity . The hydrophobicity of GS14K4 was found to be the midpoint for hemolytic activity, with more hydrophobic analogs exhibiting increased hemolytic activity and less hydrophobic analogs showing decreased hemolytic activity . For antimicrobial activity there were differences between the hydrophobicity requirements against Gram-positive and Gram-negative microorganisms . The hydrophobicity of GS14K4 was sufficient for maximum activity against Gram-negative microorganisms and yeast, with no further increases in activity occurring with increasing hydrophobicity . With Gram-positive microorganisms significant increases in activity with increasing hydrophobicity were seen in three of the six microorganisms tested . A therapeutic index (calculated as a measure of specificity of the peptides for the microorganisms over human erythrocytes) served to define the boundaries of a therapeutic window within which lay the optimum peptide hydrophobicity for each microorganism . The therapeutic window was found to be at a lower hydrophobicity level for Gram-negative microorganisms than for Gram-positive microorganisms, although the limits were more variable for the latter . Our results show that the balance between activity and specificity in the present cyclic peptides can be optimized for each microorganism by systematic modulation of hydrophobicity.

FEBS Lett, 2001 Oct 19, 507(1), 95 - 100
Structural study of novel antimicrobial peptides, nigrocins, isolated from Rana nigromaculata; Park S et al.; Novel cationic antimicrobial peptides, named nigrocin 1 and 2, were isolated from the skin of Rana nigromaculata and their amino acid sequences were determined . These peptides manifested a broad spectrum of antimicrobial activity against various microorganisms with different specificity . By primary structural analysis, it was revealed that nigrocin 1 has high sequence homology with brevinin 2 but nigrocin 2 has low sequence homology with any other known antimicrobial peptides . To investigate the structure-activity relationship of nigrocin 2, which has a unique primary structure, circular dichroism (CD) and homonuclear nuclear magnetic resonance spectroscopy (NMR) studies were performed . CD investigation revealed that nigrocin 2 adopts mainly an alpha-helical structure in trifluoroethanol (TFE)/H(2)O solution, sodium dodecyl sulfate (SDS) micelles, and dodecylphosphocholine micelles . The solution structures of nigrocin 2 in TFE/H(2)O (1:1, v/v) solution and in SDS micelles were determined by homonuclear NMR . Nigrocin 2 consists of a typical amphipathic alpha-helix spanning residues 3-18 in both 50% TFE solution and SDS micelles . From the structural comparison of nigrocin 2 with other known antimicrobial peptides, nigrocin 2 could be classified into the family of antimicrobial peptides containing a single linear amphipathic alpha-helix that potentially disrupts membrane integrity, which would result in cell death.

Farmaco, 2001 Sep, 56(9), 689 - 93
Synthesis and microbiological activity of some 4-butyl-2H-benzo{1,4}thiazin-3-one derivatives; Guarda VL et al.; The synthesis and physicochemical properties of 4-butyl-2H-benzo{1,4}thiazin-3-one derivatives are described . These new compounds were synthesised by alkylation in 4-N position and acylation and/or alkylation of 6-NH2 by phase transfer catalysis . Acid hydrolysis of 6-alkylacylamino group yielded 6-alkylamino-4-butyl-2H-benzo{1,4}thiazin-3-ones . The antimicrobial in vitro activity was determined on five compounds.

Farmaco, 2001 Sep, 56(9), 641 - 6
Synthesis and biological evaluation of some new 3 ,4-dihydropyrimidin-4-ones; Modha J et al.; Condensation of 5-cyano-2-hydrazino-3-N-methyl-6-phenyl/p-chlorophenyl-3,4-dihydropyrimidin-4-one (3a and 3b) with 2,4-bisalkyl/arylamino-6-chloro-s-triazine (4) gave the corresponding 2,4-bisalkyl/arylamino-6-{5'-cyano-3'-N-methyl}-6'-phenyl/pchlorophenyl-3',4'-dihydropyrimidin-4'-one-2'-yl-hydrazino-s-triazines (5a-n and 6a-n) . The compounds 4 have been prepared by the condensation of cyanuric chloride and different alkyl/aryl amines . The reaction between 5-cyano-3-N-methyl-2-methylthio-6-phenyl/p-chlorophenyl-3,4-dihydropyrimidin-4-one (2a and 2b) with hydrazine hydrate furnished 3a and 3b, respectively . The condensation of 6-phenyl/p-chlorophenyl/5-cyano-2-mercapto-3,4-dihydropyrimidin-4-one (1a and 1b) with methyl iodide yielded 2a and 2b, respectively . All the products have been evaluated in vitro for their antimicrobial activity against several microbes and antitubercular activity against Mycobacterium tuberculosis H37 Rv.

Lakartidningen, 2001 Sep 26, 98(39), 4202 - 5
{Clinical guidelines developed by the STRAMA group in the county of Stockholm: skin and soft tissue infections}; Lundbergh P; In 1999 the County Medical Officer in Stockholm County established the third regional STRAMA-group (Swedish Strategic Programme for The Rational Use of Antimicrobial Agents and Surveillance of Resistance) to deal with skin and soft tissue infections . The group decided to publish guidelines for physicians in the county, and this third book was distributed among the 7,000 physicians in Stockholm County.

Med Clin North Am, 2001 Nov, 85(6), 1583 - 94
Therapy of nosocomial pneumonia; Cross JT Jr et al.; HAP remains a major cause of morbidity and mortality among hospitalized patients . Although early appropriate therapy results in improved outcomes, the cause of HAP frequently is not known at the time antimicrobial therapy is initiated . Most cases of HAP result from microaspiration of oropharyngeal secretions previously colonized with pathogenic bacteria, and the spectrum of potential pathogens is broad . Taking several factors into account can narrow this spectrum, including severity of illness, length of stay before the onset of pneumonia, and presence of risk factors for specific pathogens . When therapy has been initiated, follow-up of microbial studies and careful monitoring of the patient's course is important . The clinical improvement, even when therapy is appropriate, frequently takes days; therapy should not be changed for the first 2 to 3 days unless frank deterioration is noted . Patients who fail to respond or experience clinical deterioration should be re-examined carefully, and thought should be given to the possibility of other noninfectious processes.

Med Clin North Am, 2001 Nov, 85(6), 1381 - 96
What diagnostic tests are needed for community-acquired pneumonia?
Smith PR.
Diagnostic tests play an important part in the evaluation and management of patients with CAP . Tests have key roles in diagnosing the presence of CAP and in assessing severity . An ideal test for microbiologic diagnosis in CAP is not yet available, and initial antimicrobial therapy usually is empiric . Nonetheless, when appropriately applied and correctly performed, tests for the identification of pathogens in CAP are useful and cost-effective.

Spine, 2001 Nov 1, 26(21), 2397 - 9
Pneumococcal vertebral osteomyelitis: a unique case with atypical clinical course; Poyanli A et al.; STUDY DESIGN: A case report . OBJECTIVES: To report and discuss a case of pneumococcal vertebral osteomyelitis with meningitis in a previously healthy 51-year-old immunocompetent woman who presented with acute onset lower back pain . SUMMARY OF BACKGROUND DATA: To the authors' knowledge, pneumococcal vertebral osteomyelitis with meningitis in an immunocompetent person with no other predisposing factor has not been reported previously . METHODS: The patient was diagnosed to have pneumococcal meningitis 10 days after the onset of acute and severe lower back pain . Significant improvement of clinical symptoms from meningitis was achieved with appropriate antimicrobial treatment . Lumbar CT and MRI scans were performed on persistence of fever and lower back pain . Loss of height and peridiscal inflammation at L3-L4 and epidural and bilateral psoas abscesses were detected . RESULTS: Diagnosis of pneumococcal vertebral osteomyelitis was established after evaluation of the material obtained from CT-guided aspiration of the psoas abscess and biopsy of the L3 body . With appropriate antimicrobial treatment, the patient's complaints resolved completely . CONCLUSION: To the authors' knowledge, this is the first reported case of pneumococcal vertebral osteomyelitis with meningitis.

Med Wieku Rozwoj, 2001 Apr-Jun, 5(2), 149 - 55
{Is therapeutic drug monitoring (TDM) in paediatric patients necessary?}; Prokopczyk J et al.; There is increasing discussion about the clinical usefulness of routine TDM of selected drugs in paediatrics . Routine TDM is performed as a way to individualize dosing requirements so as to achieve "therapeutic" concentrations in all patients, independently of age and individual drug response . The therapeutic ranges established for most drugs are based upon studies performed in adults . Extrapolation of these ranges to paediatric patients, especially to neonates, is questionable because drugs disposition and pharmacodynamics differ in this population compared to adults . The scepticism of the value of routine TDM in paediatric patients concerns antiepileptic drugs and digoxin . Recently also the value of vancomycin TDM in neonates has been the subject of discussion, resulting in new recommendation for dosing schedule in this age group . Therapeutic monitoring of methotrexate, especially administered in high doses in anticancer therapy is not questioned . Aminoglycosides have an extremely important role in paediatric antimicrobial therapy . They are still frequently used in the neonatal period . The rationale for monitoring of aminoglycosides is a narrow therapeutic range resulting in risk of oto- and nephrotoxicity, and large inter- and intra-subject variation in pharmacokinetics . Routine TDM is not recommended for paediatric patients (other than neonates) with normal renal function and without chronic illnesses associated with changes in pharmacokinetics of aminoglycosides . In these patients the peak and trough concentrations are within the therapeutic range using standard dosing regimes . Therapeutic monitoring of aminoglycosides is still obligatory in neonates, especially in premature and low birthweight neonates because of particularly wide inter-patient and intra-patient pharmacokinetic variability and risk of oto- and nephrotoxicity.

J Antimicrob Chemother, 2001 Nov, 48(5), 667 - 75
BMS-284756 (T-3811ME) a new fluoroquinolone: in vitro activity against Legionella, efficacy in a guinea pig model of L . pneumophila pneumonia and pharmacokinetics in guinea pigs; Edelstein PH et al.; The activity of BMS-284756 was studied against extracellular Legionella spp . and intracellular Legionella pneumophila, and for the treatment of guinea pigs with L . pneumophila pneumonia . The BMS-284756 MIC(50) of 22 different Legionella spp . strains was 0.008 mg/L, compared with 0.016 and 0.125 mg/L for levofloxacin and azithromycin, respectively . BMS-284756 (1 mg/L) reduced the intracellular concentrations of two L . pneumophila strains grown in guinea pig alveolar macrophages by c . 1.5 log(10 )cfu/mL, and was more active than erythromycin, but less active than azithromycin or levofloxacin at the same drug concentrations . Efficacy studies of BMS-284756, levofloxacin and azithromycin were performed in guinea pigs with L . pneumophila pneumonia . In infected guinea pigs given BMS-284756 10 mg/kg ip, mean peak plasma levels were 1.8 mg/L at 0.5 h and 0.7 mg/L at 1 h post-dose . The elimination half-life in plasma was 0.5 h, and the AUC(0-24 )was 1.7 mg*h/L, about 2% of the AUC(0-24 )for a single 400 mg oral dose in man . Sixteen of 18 L . pneumophila-infected guinea pigs treated with BMS-284756 10 mg/kg ip once daily for 5 days survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin 15 mg/kg ip once daily for 2 days . All 12 animals that were treated with levofloxacin 10 mg/kg ip once daily for 5 days survived . None of 12 control animals treated with saline survived . Animals treated with BMS-284756 had significantly higher residual lung counts of L . pneumophila at the end of therapy than did animals treated with levofloxacin or azithromycin, which may be attributable to the very low drug concentrations that were obtained . BMS-284756 was more active than erythromycin against L . pneumophila in infected macrophages, and effectively treated animals with experimental L . pneumophila pneumonia . These data support further studies of BMS-284756 for the treatment of Legionnaires' disease.

Hum Reprod, 2001 Nov, 16(11), 2338 - 42
Effects of treatment with carnitines in infertile patients with prostato-vesiculo-epididymitis; Vicari E et al.; BACKGROUND: We have recently shown that patients with prostato-vesiculo-epididymitis (PVE) have a greater reactive oxygen species (ROS) overproduction than patients with prostatitis or prostato-vesiculitis . Since this biochemical stress persists even after treatment with antimicrobials, it may relate to an imbalance between pro- and anti-oxidant factors at the epididymal level . METHODS: To evaluate the effects of antioxidant treatment of patients with PVE, whether in the presence or absence of pro-oxidant factors, abacterial PVE infertile patients with normal (<1x10(6)/ml, group A, n = 34) or abnormal (>1x10(6)/ml, group B, n = 20) seminal white blood cell (WBC) concentrations received carnitines (L-carnitine 1 g and acetyl-carnitine 0.5 g twice/day) for 3 months followed by a wash-out period of 3 months . Semen parameters, ROS production and pregnancy outcome were evaluated before, during and following carnitine treatment . RESULTS: Carnitines increased sperm forward motility and viability in group A patients . This was associated with a significant reduction in ROS production which persisted during wash-out . Carnitines increased only the percentage of viable spermatozoa in group B patients . Within 3 months after the discontinuation of carnitines, the rate of spontaneous pregnancy in group A patients was significantly higher than that of group B patients, being 11.7% (4/34) compared with 0% . CONCLUSION: These results indicate that carnitines are only an effective treatment in patients with abacterial PVE and elevated ROS production when seminal WBC concentration is normal.

Am J Med Sci, 2001 Oct, 322(4), 209 - 12
Long-term suppressive antimicrobial therapy for intravascular device-related infections; Baddour LM; Infectious Diseases Society of America's Emerging Infections Network; BACKGROUND: Long-term suppressive antimicrobial therapy is an alternative treatment choice in patients with medical device-related infection who are not eligible for surgical device removal for attempted cure . There is a paucity of data published that examines this treatment option . METHODS: Members of the Infectious Diseases Society of America's Emerging Infections Network were polled to identify patients with intravascular device-related infections who were not candidates for surgery and were given long-term antimicrobial therapy to suppress clinical manifestations of infection . RESULTS: Clinical and microbiologic data were collected retrospectively for 51 patients . Sixty-nine percent of patients were men; vascular grafts were the most common type of medical device infected {30 (58.8%) patients} . Sixty-three percent (32 of 51) of cases involved gram-positive cocci . A variety of antimicrobials were administered as chronic suppressive therapy, with beta-lactams used most frequently (39.2%) . Therapy ranged from 3 months to 10 years . Three (7.32%) of 41 patients in whom follow-up data were available developed relapsing infection while on long-term suppressive therapy . Three other patients suffered drug adverse events . CONCLUSIONS: Overall, long-term suppressive therapy was well-tolerated and efficacious in preventing signs of infection relapse.

West Indian Med J, 2001 Jun, 50(2), 105 - 8
Non-antimicrobial properties of tetracyclines--dental and medical implications; Rawal SY et al.; The tetracyclines are a group of broad-spectrum antimicrobial agents . The first of these compounds, chlortetracycline was isolated from Streptomyces aureofaciens by Benjamin Duggar and introduced into the market in 1948 . In 1952, tetracycline was derived semisynthetically from chlortetracycline by removal of its chlorine atom by catalytic hydrogenation . Methacycline, doxycycline and minocycline are all semi-synthetic derivatives . The tetracyclines are closely congeneric derivatives of the polycyclic napthacenecarboxamide . The tetracyclines possess a wide range of antimicrobial activity against gram-positive and gram-negative bacteria . In vitro, these drugs are primarily bacteriostatic . Tetracyclines have been used extensively as antimicrobial agents for the treatment of various types of periodontal diseases until light was shed on their equally important non-antimicrobial properties by Golub . The tetracyclines and their non-antimicrobial, chemically modified analogues have properties that appear to modulate host response by inhibiting the activity of the matrix metalloproteinases that cause collagen destruction . They also inhibit osteoclast function, stimulate osteoblastic bone formation, and regulate angiogenesis.

Fitoterapia, 2001 Nov, 72(7), 825 - 8
Antimicrobial activity of Symplocos cochinensis; Khan MR et al.; The methanol extracts of leaves, root and stem barks of Symplocos cochinchinensis and their fractions obtained by partition (petrol, dichloromethane, ethyl acetate) were screened for antimicrobial activity . All the crude extracts and fractions showed a broad spectrum of antibacterial activity, that was enhanced on fractionation . None of them showed activity against the tested moulds.

Fitoterapia, 2001 Nov, 72(7), 822 - 4
Antimicrobial activity of Boswellia dalziellii stem bark; Adelakun EA et al.; The methanol and aqueous extracts of Boswellia dalziellii stem bark showed broad spectrum inhibiting activity against bacteria, both Gram-positive and Gram-negative, and fungi.

Fitoterapia, 2001 Nov, 72(7), 818 - 21
Antimicrobial activity of Psychotria microlabastra; Khan MR et al.; The methanol extracts of leaves, root and stem barks of Psychotria microlabastra showed a broad spectrum of antibacterial activity, that was increased on fractionation (petrol, dichloromethane, ethyl acetate), particularly in the ethyl acetate fractions . None of the extractives showed activity against the tested moulds.

Res Vet Sci, 2001 Jun, 70(3), 287 - 93
The effect of organic acids on the control of porcine post-weaning diarrhoea; Tsiloyiannis VK et al.; Post-weaning diarrhoea syndrome (PWDS) of piglets is caused mainly by Enterotoxigenic Escherichia coli (ETEC) strains . Six organic acids were tested for their efficacy in the control of PWDS, using a total of 384 weaned piglets, in eight groups, during a 28-day period . One group (negative control) was offered a diet free of antimicrobials, one group (positive control) was offered the same diet medicated with 44 p.p.m . of lincomycin and 44 p.p.m . spectinomycin (Lincospectin 22 premix, Upjohn), and six groups were offered feed supplemented with either 1.0 per cent propionic acid, 1.6 per cent lactic acid, 1.2 per cent formic acid, 1.2 per cent malic acid, 1.5 per cent citric acid or 1.5 per cent fumaric acid . Groups were compared with regard to the appearance of clinical signs, mortality, weight gain and feed conversion . All groups supplemented with organic acids had reduced incidence and severity of diarrhoea, and performed significantly better than the negative control group (P<0.05) . At the end of the trial, ETEC strains were detected in the control group not receiving antibiotics but not in the treated group . Organic acids and especially lactic acid are a useful tool in controlling PWDS.

Res Vet Sci, 2001 Jun, 70(3), 281 - 5
The effect of organic acids on the control of post-weaning oedema disease of piglets; Tsiloyiannis VK et al.; Oedema disease usually occurs after weaning and is due to infection with Enterotoxaemic Escherichia coli strains . A total of 240 weaned piglets were used in five groups during a 28-day period . One group (a negative control) was offered feed free of antimicrobials ad libitum, three groups were offered the same diet ad libitum supplemented with either 1.6 per cent lactic acid, 1.5 per cent citric acid or 50 p.p.m . of enrotloxacin (ENR/Baytril I.E.R . 2 5 per cent, Bayer), respectively . Finally, one group was offered the same diet but the amount offered was restricted during the first 12 days post-weaning . Groups receiving acid or ENR additions to the diet had lower mortality than the negative control group (P<0.05) . The three groups on treated feed also showed significantly better growth performance and food conversion ratio than the control group (P<0.05) . Both organic acids and medication with 50 p.p.m . of ENR for a 10-day period are useful in controlling and/or preventing post-weaning oedema disease.

Ann Pharmacother, 2001 Oct, 35(10), 1255 - 63
Antimicrobial-coated/bonded and -impregnated intravascular catheters; Pai MP et al.; OBJECTIVE: To review the literature regarding the prevention of catheter colonization and catheter-related bloodstream infections (CRBIs) with the use of antimicrobial-coated/bonded and -impregnated intravascular catheters . DATA SOURCES: Primary and review English-language literature were identified using MEDLINE (1966-September 2000) pertaining to the key terms antibiotic, antimicrobial, antiseptic, silver, and bonded, coated, Impregnated catheters . In addition, textbooks and relevant reference lists were reviewed . DATA EXTRACTION: All articles identified through the data sources were evaluated . Information deemed relevant to the objectives of the review was included . DATA SYNTHESIS: Significant morbidity and mortality are associated with the development of CRBIs . Preventative measures such as modification of these catheters with antimicrobial coating/bonding have produced varying results . Trials evaluating cefazolin, teicoplanin, vancomycin, silver, and chlorhexidine-silver sulfadiazine (C-SS) used for coated/bonded intravascular catheters have not demonstrated a consistent decrease in the incidence of CRBIs . However, a meta-analysis of trials evaluating C-SS intravascular catheters demonstrated a statistically significant reduction in CRBIs . A larger reduction in CRBIs has been reported with minocycline-rifampin (M-R) versus C-SS intravascular catheters . Use of the M-R and C-SS catheters may result in a cost savings of $100 million and reduce as many as 12,000 CRBI-related deaths annually when used short term (<7 d) . CONCLUSIONS: When used for short-term catheterization, M-R catheters appear to be superior to the currently available C-SS catheters at preventing CRBIs . Significant cost savings and reduction in mortality can be anticipated with the use of M-R catheters.

Ann Pharmacother, 2001 Oct, 35(10), 1224 - 32
Antimicrobial cycling: the future or a fad?
Hodges BM, White RL.
OBJECTIVE: To assess the current evidence of the value of cycling of antimicrobials to control the emergence of resistance or to reverse existing resistance to antimicrobials . DATA SOURCES: Articles were obtained through a MEDLiNE search of the English-language literature from 1966 to January 2000 . Additionally, references from retrieved publications were reviewed to identify further articles . STUDY SELECTION AND DATA EXTRACTION: All investigations of switching between or cycling among antimicrobials were evaluated . Studies switching between or cycling among specific drugs or classes of drugs within institutional settings were included in this review . DATA SYNTHESIS: Studies involving cycling among different aminoglycosides suggest that, although temporary decreases in resistance can be documented, resistance usually rebounds rapidly on completion of the cycle and return to the original agent . Switching between classes of antimicrobials has produced inconsistent results and has been shown to replace resistance to one agent with resistance to another . Mathematical models using both in vitro and clinical data have suggested that, due to residual resistance in the population, cycling among drug classes is unlikely to yield long-term reductions in antimicrobial resistance, especially if a high level of antimicrobial resistance exists . CONCLUSIONS: Cycling among different antimicrobials to reverse resistance trends is currently not supported by published literature . Cycling to prevent the emergence of resistance may ultimately be more useful; however, no studies have evaluated this concept . Well-designed prospective studies are needed to evaluate the potential clinical value of antimicrobialcycling.

J Biol Chem, 2002 Jan 4, 277(1), 416 - 23 Epub 2001 Oct 23.
Lipoxygenase H1 gene silencing reveals a specific role in supplying fatty acid hydroperoxides for aliphatic aldehyde production; Leon J et al.; Lipoxygenases catalyze the formation of fatty acid hydroperoxide precursors of an array of compounds involved in the regulation of plant development and responses to stress . To elucidate the function of the potato 13-lipoxygenase H1 (LOX H1), we have generated transgenic potato plants with reduced expression of the LOX H1 gene as a consequence of co-suppression-mediated gene silencing . Three independent LOX H1-silenced transgenic lines were obtained, having less than 1% of the LOX H1 protein present in wild-type plants . This depletion of LOX H1 has no effect on the basal or wound-induced levels of jasmonates derived from 13-hydroperoxylinolenic acid . However, LOX H1 depletion results in a marked reduction in the production of volatile aliphatic C6 aldehydes . These compounds are involved in plant defense responses, acting as either signaling molecules for wound-induced gene expression or as antimicrobial substances . LOX H1 protein was localized to the chloroplast and the protein, expressed in Escherichia coli, showed activity toward unesterified linoleic and linolenic acids and plastidic phosphatidylglycerol . The results demonstrate that LOX H1 is a specific isoform involved in the generation of volatile defense and signaling compounds through the HPL branch of the octadecanoid pathway.

J Biol Chem, 2002 Jan 4, 277(1), 148 - 54 Epub 2001 Oct 23.
Escherichia coli produces phosphoantigens activating human gamma delta T cells; Feurle J et al.; Human Vgamma9delta2 T lymphocytes are suggested to play an important role in the immune response to various microbial pathogens . In contrast to alphabeta T cells, gammadelta T lymphocytes recognize small, non-protein, phosphate-bearing antigens (phosphoantigens) in a major histocompatibility complex-independent manner . Four different phosphoantigens termed TUBag1 to TUBag4 with a common 3-formyl-1-butyl-pyrophosphate moiety and isopentenyl-pyrophosphate have been isolated and identified from mycobacteria . However, natural occurring gammadelta T cell ligands from other bacterial species were not characterized so far . Here, we describe the structural identification of the two compounds responsible for the gammadelta T cell-stimulating capacity of Escherichia coli as similar to the mycobacterial phosphoantigens 3-formyl-1-butyl-pyrophosphate and its M(r) 275 homologue TUBag2 . In addition, E . coli phosphoantigens exert bioactivities on gammadelta T cells with similar potencies to the mycobacterial phosphoantigens at 5-15 nm concentration . Furthermore, our results clearly prove that the deoxyxylulose 5-phophate pathway (also referred to as Rohmer metabolic route of isoprenoid biosynthesis) is essential for the biosynthesis of the phosphoantigens in E . coli . Because this pathway is absent from human cells, it proves an ideal target for focusing efficiently the antimicrobial selectivity of human gammadelta T lymphocytes.

Antiviral Res, 2001 Dec, 52(3), 225 - 39
Antiviral activities of lactoferrin; van der Strate BW et al.; Lactoferrin (LF) is an iron binding glycoprotein that is present in several mucosal secretions . Many biological functions have been ascribed to LF . One of the functions of LF is the transport of metals, but LF is also an important component of the non-specific immune system, since LF has antimicrobial properties against bacteria, fungi and several viruses . This review gives an overview of the present knowledge about the antiviral activities and, when possible, the antiviral modes of action of this protein . Lactoferrin displays antiviral activity against both DNA- and RNA-viruses, including rotavirus, respiratory syncytial virus, herpes viruses and HIV . The antiviral effect of LF lies in the early phase of infection . Lactoferrin prevents entry of virus in the host cell, either by blocking cellular receptors, or by direct binding to the virus particles.

J Org Chem, 1999 Sep 3, 64(18), 6861 - 6869
DNA Binding by 4-Methoxypyrrolic Natural Products . Preference for Intercalation at AT Sites by Tambjamine E and Prodigiosin; Melvin MS et al.; The 4-methoxypyrrolic natural products contain a common 4-methoxy-2,2'-bipyrrole chromophore and exhibit promising anticancer, antimicrobial, and immunosuppressive activities . Herein, the ability of two representative members, tambjamine E (1) and prodigiosin (2), to bind calf thymus DNA (CT-DNA), polyd{G-C}(2), and polyd{A-T}(2) has been characterized using absorption and fluorescence spectroscopy . Scatchard plots showed that 1 occupies a site size (n) of ca . three base pairs and possesses affinity constants (K) ranging from 1 to 0.1 x 10(5) M(-)(1) . Prodigiosin (2) binds DNA by mixed modes, as isobestic points were not evident in titration experiments . The neutral aldehyde precursor 4 was found to possess no measurable DNA binding affinity, indicating that the enamine structure of 1 and the pyrromethene of 2 are essential elements for DNA binding affinity . The enamine of 1 was found to undergo hydrolysis to 4 with a half-life (t(1/2)) of 14.5 h at pH 7.4 and 37.5 degrees C . For the B-ring nitrogen atom of 1, a pK(a) value of 10.06 was also established . From fluorescence spectroscopy it was found that 1, 2, and 4 possess weak emission spectra in water that is increased in nonaqueous solvents . For 1 and 2, DNA binding also increased the emission yield . Energy-transfer measurements suggested an intercalative binding mode, with preference for AT sites . The ability of distamycin to displace 1 and 2 from the helix also suggested that they intercalate from the minor-groove . This specificity differs from other unfused aromatic cations that bind by a minor-groove mode at AT sequences and intercalate at GC sites . Reasons for the specificity displayed by 1 and 2, as well as the implications of our findings to their biological properties are discussed.

J Org Chem, 1999 Jan 8, 64(1), 70 - 80
Vancomycin CD and DE Macrocyclization and Atropisomerism Studies; Boger DL et al.; Continued studies on the synthesis and atropisomerism of the vancomycin CD and DE ring systems based on aromatic nucleophilic substitution macrocyclization reactions for formation of the biaryl ethers are detailed in efforts that further define substituent effects, explore the impact of protecting groups, and establish the stereochemical integrity of peripheral substituents . These have led to the identification of a previously unrecognized site of epimerization within our original approach to the DE ring system and the introduction of significant improvements in the approach that will find utilization in syntheses of the vancomycin CDE ring system and of the natural product itself . The preparation of a complete set of DE ring system isomers bearing the unnatural stereochemistry at the labile C8, C11, and C14 sites was accomplished for comparison and established that C8 is prone to epimerization to the more stable, unnatural S versus R absolute stereochemistry if it bears an ester, but not a carboxamide, substituent . Additionally, an improved synthesis of the CD ring system, enlisting a C14 carboxamide versus ester substituent, is disclosed and establishes the stereochemical integrity of our prior approach which incorporated a C14 ester . A set of fully functionalized CD and DE ring systems were prepared and include the development of conditions for the final deprotections required for incorporation into efforts on the natural product . The examination of the antimicrobial activity of these key substructures of vancomycin is detailed.

Br J Ophthalmol, 2001 Nov, 85(11), 1336 - 40
Detection of galectin-3 in tear fluid at disease states and immunohistochemical and lectin histochemical analysis in human corneal and conjunctival epithelium; Hrdlickova-Cela E et al.; BACKGROUND/AIM: Components of the tear fluid contribute to the biochemical defence system of the eye . To reveal whether the immune mediator and lipopolysaccharide binding galectin-3 is present in tears, tear samples were collected from eyes in healthy and pathological states . Investigation of expression of galectin-3 and galectin-3 reactive glycoligands in normal human conjunctival and corneal epithelia was also initiated as a step to understand the role of galectin-3 in ocular surface pathology . METHODS: Immunoblot analysis using either a rabbit polyclonal or a mouse monoclonal antibody against galectin-3 was employed to detect galectin-3 in tear fluid . Galectin-3 expression in tissue specimens was detected by immunocytochemistry employing A1D6 mouse monoclonal antibody, and galectin-3 reactive glycoligands were visualised by lectin histochemistry using labelled galectin-3 . RESULTS: Galectin-3 was found only in tears from patients with ocular surface disorders . It was expressed in normal corneal and conjunctival epithelia but not in lacrimal glands . Inflammatory leucocytes and goblet cells found in galectin-3 containing tear fluid also expressed galectin-3 . Galectin-3 binding sites were detected on the surface of conjunctival and corneal epithelial cells co-localising with desmoglein . CONCLUSIONS: This study revealed expression of galectin-3 in tear fluid obtained from patients with eye diseases . The role of this endogenous lectin (produced by inflammatory as well as epithelial cells) in antimicrobial action and inflammation modulation could be expected.

Mutat Res, 2001 Nov 15, 498(1-2), 193 - 205
Ciprofloxacin: in vivo genotoxicity studies; Herbold BA et al.; The fluoroquinolone ciprofloxacin is widely used in antimicrobial therapy . It inhibits the bacterial gyrase and in high concentrations in vitro also the functionally related eukaryotic topoisomerase-II, which resulted in genotoxic effects in several in vitro tests . In order to evaluate the relevance of these findings, ciprofloxacin was tested in vivo for genotoxic activity using the following test systems: micronucleus test in bone marrow of mice, cytogenetic chromosome analysis in Chinese hamster, dominant lethal assay in male mice and UDS tests in primary rat and mouse hepatocytes in vivo . These results are compared with already published in vitro and in vivo studies with ciprofloxacin . All in vivo genotoxicity revealed no genotoxic effect for ciprofloxacin . In addition, ciprofloxacin was found to be non-carcinogenic in two rodent long-term bioassays . Therefore, ciprofloxacin is considered to be safe for therapeutic use.

Int J Antimicrob Agents, 2001 Sep, 18(3), 283 - 6
The usage of antibiotics in Russia and some countries in Eastern Europe; Stratchounski L et al.; The patterns of antibiotic use in 1998 in Russia and some other countries in Eastern Europe (Belarus, Poland, Slovakia, Hungary) were studied . Poland, Slovakia and Hungary were "more modern" users of antibiotics, consuming new and expensive drugs . Russia and Belarus were "conservative" having a lower level of total consumption and using lesser quantities of penicillins, cephalosporins, macrolides, quinolones, carbapenems but greater amounts of aminoglycosides and chloramphenicol . It is essential for "conservative" countries to establish a national surveillance system of antibiotic consumption to monitor the development of bacterial resistance to antimicrobial agents and to monitor individual antibiotic use.

Int J Antimicrob Agents, 2001 Sep, 18(3), 279 - 82
Antibiotic usage in Nordic countries; Bergan T; The consumption of antibacterials has remained relatively stable in Scandinavia and is low compared with most other countries . Measured as "Defined Daily Doses" (DDD), the highest consumption is found in Iceland and Finland, and the lowest in Denmark and Norway . The consumption in Iceland, Finland and Sweden is about twice that in Norway . The distribution of different classes of antimicrobials shows striking differences . Phenoxymethyl and benzylpenicillin make up about 55% of the DDDs in Sweden and 40% of the DDDs in Denmark and Norway, whereas the narrow-spectrum penicillins represent 20% of the DDDs in Iceland . Fluoroquinolones are little used except in Sweden where they account for about 10% of DDDs . The use of cephalosporins ranges from 1% (in Denmark) to 15% (in Finland) and between 3 and 5% in the other countries . The policy that narrow-spectrum penicillins may be used when necessary but broad-spectrum compounds should be avoided has the positive effect that there is greater susceptibility in the Nordic countries to these antibiotics than elsewhere.

Eur J Med Chem, 2001 Sep, 36(9), 743 - 6
Synthesis and antitubercular activity of imidazo{2,1-b}thiazoles; Andreani A et al.; A number of selected imidazo{2,1-b}thiazoles entered the screening at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) and one of these compounds, 2-chloro-6-phenylimidazo{2,1-b}thiazole, showed antitubercular activity . On this basis we planned the synthesis of new analogues bearing a substituted ring at the 6 position . For one compound only (2-chloro-6-p-chlorophenylimidazo{2,1-b}thiazole) the 5-nitroso derivative was also prepared . The antitubercular activity of these compounds was compared with the known analogues lacking the chlorine at the 2 position . 5-Nitroso-6-p-chlorophenylimidazo{2,1-b}thiazole showed potent antitubercular activity.

Immunol Lett, 2001 Sep 3, 78(2), 103 - 11
Dendritic cell discoveries provide new insight into the cellular immunobiology of DNA vaccines; Coombes BK et al.; The evolution of increasingly virulent human pathogens, together with the rapid onset of antimicrobial resistance has created a need for new vaccination strategies . Nucleic acid vaccines, based on recombinant DNA technology are a promising new vaccine formulation capable of eliciting both humoral and cellular immune responses . This technology has been experimentally validated in animal models of pathogen challenge and tumor protection following administration of a DNA vaccine and has led to extensive research into the mechanisms of protective immunity . We focus here on the cellular and molecular mechanisms leading to cell-mediated immune responses to DNA vaccines and discuss these mechanisms in light of recent advances in the field of dendritic cell immunobiology . In particular, the potential involvement of: (i) the CpG pattern-recognition receptor, toll-like receptor-9; (ii) the dendritic cell-specific surface adhesion molecule, DC-SIGN; and (iii) the molecular interactions between CD40 and CD154 in the evolution of protective cell-mediated immunity to DNA vaccines are discussed . An improved understanding of the precise mechanisms leading to protective cellular immunity following DNA vaccination may help in the design of novel DNA constructs containing immunostimulatory features that target one or more of these mechanisms, with the aim of increasing the immunogenic potential and protective efficacy of DNA vaccines.

Int J Environ Health Res, 2001 Sep, 11(3), 257 - 66
Thermal inactivation of antimicrobial-resistant Gram-positive cocci in chicken meat: D and Z value determinations; Bertolatti D et al.; Antimicrobial-resistance in Gram-positive bacteria is reported with increasing frequency in strains isolated from food animals . Their isolation from commercial poultry carcasses and meat products constitute a potential risk that resistant strains or resistance genes might spread to humans via the food chain . As bacterial inactivation by thermal process is a critical control point in the safe preparation of many ready-to-eat foods, it is important to determine the thermal resistance of these organisms . The present study was undertaken to investigate the thermal tolerance (D and Z values) of antimicrobial-resistant, Gram-positive cocci in ground chicken meat . The antimicrobial-resistant, Gram-positive cocci for this study were isolated from two poultry processing plants in Western Australia . D and Z value data indicate that these isolates do not exhibit enhanced thermal resistant characteristics . The estimated lethal effect of the cooking process for chicken meat indicates that an internal temperature of 70 degrees C for 2.1 min would provide a 7-log reduction of all cell suspensions tested.

In Vitro Cell Dev Biol Anim, 2001 Sep, 37(8), 480 - 9
Isolation and culture of airway epithelial cells from chronically infected human lungs; Randell SH et al.; We describe procedures for isolating and culturing airway epithelial cells from chronically infected human lungs . Experience in our laboratory demonstrated the need to balance pathogen eradication against antibiotic toxicity to epithelial cells . To provide a logical basis for antibiotic selection and dose, we systematically analyzed the cytotoxicity of antibiotics useful against typical pathogens . Alone, colistin, ciprofloxacin, doxycycline, and tobramycin were moderately toxic at concentrations close to those used in cell culture, whereas amphotericin, ceftazidime, chloramphenicol, imipenem, meropenem, piperacillin, sulfamethoxazole/trimethoprim, and vancomycin were nontoxic even at concentrations many times the antimicrobial level . Epithelial cytotoxicity of combined antibiotics was additive, with no evidence of competition or synergism . Antibiotics had little effect on initial cell attachment and did not acutely lyse cells, but inhibited subsequent growth . Interestingly, cytotoxicity decreased markedly with increasing epithelial cell density . Cystic fibrosis (CF) and non-CF epithelial cells showed no differences in sensitivity to the antibiotics tested and initial exposure to antibiotics did not affect the electrophysiologic properties of resistance or short circuit current in well-differentiated cells . Tailored combinations of antibiotics at appropriate doses killed even multidrug-resistant bacteria . Thus, epithelial cells can usually be cultured from chronically infected CF airways.

Respir Res, 2000, 1(3), 141 - 50 Epub 2000 Oct 20.
Epithelial antimicrobial peptides in host defense against infection; Bals R; One component of host defense at mucosal surfaces seems to be epithelium-derived antimicrobial peptides . Antimicrobial peptides are classified on the basis of their structure and amino acid motifs . Peptides of the defensin, cathelicidin, and histatin classes are found in humans . In the airways, alpha-defensins and the cathelicidin LL-37/hCAP-18 originate from neutrophils . beta-Defensins and LL-37/hCAP-18 are produced by the respiratory epithelium and the alveolar macrophage and secreted into the airway surface fluid . Beside their direct antimicrobial function, antimicrobial peptides have multiple roles as mediators of inflammation with effects on epithelial and inflammatory cells, influencing such diverse processes as proliferation, immune induction, wound healing, cytokine release, chemotaxis, protease-antiprotease balance, and redox homeostasis . Further, antimicrobial peptides qualify as prototypes of innovative drugs that might be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation.

Respir Res, 2000, 1(2), 87 - 92 Epub 2000 Aug 23.
The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease; Sallenave JM; Secretory leukocyte proteinase inhibitor and elafin are two low-molecular-mass elastase inhibitors that are mainly synthesized locally at mucosal sites . It is thought that their physicochemical properties allow them to efficiently inhibit target enzymes, such as neutrophil elastase, released into the interstitium . Historically, in the lung, these inhibitors were first purified from secretions of patients with chronic obstructive pulmonary disease and cystic fibrosis . This suggested that they might be important in controlling excessive neutrophil elastase release in these pathologies . They are upregulated by 'alarm signals' such as bacterial lipopolysaccharides, and cytokines such as interleukin-1 and tumor necrosis factor and have been shown to be active against Gram-positive and Gram-negative bacteria, so that they have joined the growing list of antimicrobial 'defensin-like' peptides produced by the lung . Their site of synthesis and presumed functions make them very attractive candidates as potential therapeutic agents under conditions in which the excessive release of elastase by neutrophils might be detrimental . Because of its natural tropism for the lung, the use of adenovirus-mediated gene transfer is extremely promising in such applications.

J Org Chem, 1996 Nov 1, 61(22), 7764 - 7776
Role of the C(5)-C(5a) Exomethylene Group in Bicyclomycin: Synthesis, Structure, and Biochemical and Biological Properties; Park Hg H et al.; Thirty-two C(5)-C(5a) exomethylene-modified bicyclomycin derivatives were prepared to determine the effect of structural modification of this unit on bicyclomycin (1) function . The compounds were grouped into three categories: the C(5)-unsaturated bicyclomycins, the C(5a)-substituted C(5)-C(5a)-dihydrobicyclomycin derivatives, and the C(5)-modified norbicyclomycins . An efficient three-step procedure was developed to synthesize C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins . Bicyclomycin was converted to bicyclomycin C(2'),C(3')-acetonide (36) and then treated with a nucleophile in 50% aqueous methanol ("pH" 10.5) to give the C(5a)-substituted C(5),C(5a)-dihydrobicyclomycin C(2'),C(3')-acetonide . Removal of the acetonide group (trifluoroacetic acid in 50% aqueous methanol) in the final step provided the desired bicyclomycin derivative . All the compounds were evaluated using the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay . Most of the compounds were also tested in the transcription termination assay . We observed that many of the C(5)-unsaturated bicyclomycins effectively inhibited ATP hydrolysis at 400 &mgr;M and inhibited the production of rho-dependent transcripts at 100 &mgr;M . The biochemical activities of C(5a)-bicyclomycincarboxylic acid (5), methyl C(5a)-bicyclomycincarboxylate (6), ethyl C(5a)-bicyclomycincarboxylate (7), and bicyclomycin C(5)-norketone O-methyloxime (11) were all similar to 1 . Compounds 6, 7, and 11 exhibited diminished antibiotic activity compared to 1, and 5 displayed no detectable activity . Several C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins showed significant inhibition of rho-dependent ATPase and transcription termination activities . The inhibitory properties of C(5),C(5a)-dihydrobicyclomycin C(5a)-methyl sulfide (18), C(5),C(5a)-dihydrobicyclomycin C(5a)-phenyl sulfide (23), and C(5)-C(5a)-dihydrobicyclomycin-5,5a-diol (31) approached those of 1 . Compounds 18, 23, and 31 did not exhibit antibiotic activity . Two of the four C(5)-modified norbicyclomycin adducts showed moderate inhibitory activities in the ATPase assay, and none showed significant antibiotic activity . Our findings showed that the C(5)-C(5a) exomethylene unit retention in 1 was not essential for inhibition of in vitro rho activity . The structure-activity relationship data indicated that bicyclomycins that contained a small unsaturated C(5) unit or C(5),C(5a)-dihydrobicyclomycins that possessed a small, nonpolar C(5a) substituent effectively inhibited rho function in in vitro biochemical assays . We concluded that the C(5)-C(5a) unit in 1 was not a critical structural element necessary for drug binding to rho and that irreversible, inactivating units placed at this site would permit the bicyclomycin derivative to bind efficiently to rho.

J Org Chem, 1996 Nov 1, 61(22), 7756 - 7763
Role of the {4.2.2} Bicyclic Unit in Bicyclomycin: Synthesis, Structure, Chemical, Biochemical, and Biological Properties; Santillan A Jr et al.; Twelve bicyclomycin derivatives were synthesized to determine the effect of modification of the {4.2.2} bicyclic unit in bicyclomycin (1) on drug function . Few bicyclomycin derivatives have been described in which the {4.2.2} ring system has been modified . The compounds evaluated were divided into two categories: the two N-methyl-modified bicyclomycins (2, 3) and the ten C(6)-substituted bicyclomycins (4-13) . Substituents introduced at the C(6) site included alkoxy, thioalkoxy, thiophenoxy, anilino, and hydrogen . A procedure was developed to synthesize select C(6)-substituted bicyclomycins . Bicyclomycin was first converted to bicyclomycin C(2'),C(3')-acetonide (16) and then treated with methanesulfonyl chloride to give in situ the corresponding C(6) mesylate 17 . Treatment of 17 with the appropriate nucleophile followed by removal of the C(2'),C(3')-acetonide group gave the desired C(6)-substituted bicyclomycin . The chemical properties of C(6) O-methylbicyclomycin (4) were examined . Treatment of THF-H(2)O mixtures of 4 with excess EtSH maintained at "pH" 8.0-9.0 led to no detectable reaction, while at more basic "pH" values 4 underwent stereospecific conversion to the bis-spiro derivative 33 and no appreciable EtSH addition to the C(5)-C(5a) exomethylene unit . These results were compared to the reactivity of 1 with EtSH . The stability (pH 7.4, 37 degrees C) of C(6)-substituted bicyclomycins 4, 6, and 10-13 in aqueous solutions were examined . We observed that most of these compounds (4, 6, 10-12) underwent near complete change (>75%) within 200 h . The {4.2.2} bicyclic-modified bicyclomycins were evaluated in the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay . Most of the compounds were also tested in the transcription termination assay . We observed that all structural modifications conducted within the {4.2.2} bicyclic unit led to a loss of rho-dependent ATPase (I(50) > 400 &mgr;M) and to transcription termination (I(50) > 100 &mgr;M) inhibitory activities, as well as a loss of antimicrobial activity (MIC > 32 mg/mL) . Only N(10)-methylbicyclomycin (2) displayed moderate inhibitory activities in these assays . These findings indicated that the {4.2.2} bicyclic unit played an important role in the antibiotic-rho recognition process . Potential factors that govern this interaction are briefly discussed . We concluded that placement of an irreversible inactivating unit at the N- and O-sites within the {4.2.2} bicyclic unit in 1 would likely prohibit the bicyclomycin derivative from efficiently binding to rho.

J Org Chem, 1996 Nov 1, 61(22), 7750 - 7755
Role of the C(1) Triol Group in Bicyclomycin: Synthesis and Biochemical and Biological Properties; Park Hg H et al.; Bicyclomycin (1) is a commercial antibiotic whose primary site of action in Escherichia coli is the essential cellular protein transcription termination factor rho . The bicyclomycin binding domain in rho is unknown; however, enzyme irreversible inactivators that modify rho upon activation may identify the site . In this study, we investigated the importance for rho binding of the C(1) triol group in 1 . Twelve bicyclomycin derivatives were prepared, and the C(1) triol group was modified at the C(1'), the C(2'), and the C(3') sites . The compounds were evaluated by rho-dependent ATPase and transcription termination assays and their antimicrobial activities assessed using a filter disc assay . Bicyclomycin inhibited both rho-dependent ATPase (I(50) = 60 &mgr;M) and rho-dependent transcription termination (I(50) approximately 5 &mgr;M) processes and had a minimum inhibitory concentration value of 0.25 mg/mL against E . coli W3350 cells . None of the 12 C(1) triol bicyclomycin derivatives significantly inhibited rho-dependent ATPase (I(50) > 400 &mgr;M) and transcription termination (I(50) > 100 &mgr;M) activities or exhibited antibiotic activity at a 32 mg/mL concentration . These results indicated that there was a strong molecular complement between the C(1) triol group and its rho binding site . We concluded that the C(1) triol group in 1 is a critical structural element necessary for drug binding to rho and that an enzyme irreversible inactivating unit placed at this site would prohibit the bicyclomycin derivative from efficiently binding to rho.

J Org Chem, 1996 Jun 14, 61(12), 4120 - 4124
Framework-Reactive Siderophore Analogs as Potential Cell-Selective Drugs . Design and Syntheses of Trimelamol-Based Iron Chelators; Ramurthy S et al.; Currently, the role of DNA-directed alkylating agents as potential anticancer/ antimicrobial drugs is of wide interest . Most of the alkylating agents used clinically as drugs damage DNA in cells without specificity, and this can lead to undesired toxicity problems . Minimizing serum residence time by targeting the drug to select pathogens or organs might diminish the effects of nonselective reactivity . This paper describes the syntheses and preliminary studies of analogs of siderophores (microbial iron chelators) 2 and 20 that incorporate centers within the siderophore framework capable of generating potent electrophiles (iminium ions), hopefully after directed cellular recognition and uptake . Formation of N-aminals from trimelamol (3) and substituted hydroxamic acid 4 or 5was critical for the design and synthesis of the targets . In preliminary biological testing, compound 2, a trimelamol-based siderophore analog, was active against Escherichia coli X580, illustrating the therapeutic potential of this new type of siderophore-mediated drug design and delivery.

Arch Immunol Ther Exp (Warsz), 2001, 49 Suppl 2, S83 - 7
Effect of granulocyte-macrophage colony-stimulating growth factor on interferon and tumor necrosis factor production in whole blood cell cultures of patients with acute myelogenous leukemia; Kaminska T et al.; The effect of recombinat human granulocyte-macrophage colony-stimulating growth factor (rHuGM-CSF) treatment on in vitro interferon (IFN) and tumor necrosis factor (TNF) production in peripheral blood cells of 46 patients with acute myelogenous leukemia (AML) was examined . GM-CSF significantly enhanced virus-induced IFN-alpha production in blood cells (containing 68% of blasts) of 28 patients with M4-M5 AML according to the French-American-British (FAB) classification and also phytohemagglutinin (PHA)-induced IFN-gamma production in blood cells (containing 70% of blasts) of 18 patients with AML MO-M3 type . In control blood cells (25 healthy persons) GM-CSF enhanced PHA-induced IFN-gamma but did not influence IFN-alpha production . In the presence of GM-CSF, TNF-alpha titers induced with lipopolysaccharide were also higher in control blood cells but not in cells of patients with M0-M3 or M4-M5 type of AML . The significance of GM-CSF-enhanced IFN-alpha and IFN-gamma production in antimicrobial and anti-leukemic immune reactions which can develop during GM-CSF therapy is discussed.

Pharmacotherapy, 2001 Oct, 21(10 Pt 2), 273S - 283S
Integrating fluoroquinolones into the hospital formulary; Bertino JS Jr; With the increasing availability of new agents, selection of fluoroquinolones for formulary inclusion can be difficult . Appropriate evaluation of the important characteristics (pharmacokinetic and pharmacodynamic properties, antimicrobial activity, efficacy, tolerability, cost) of these agents should allow selection of the most cost-effective ones . Evidence from in vitro studies and clinical trials indicates differences exist among fluoroquinolones, especially in terms of activity against gram-positive, aerobic organisms . For selected clinical situations, it may be important to choose an agent that is available in both intravenous and oral formulations . Comparative drug costs, as well as costs associated with potential clinical failure and adverse events, should be evaluated carefully . Dosage regimens should be considered, as shorter durations of therapy and less frequent dose administration may lead to reduced labor costs and increased patient compliance, thereby improving effectiveness and economic efficiency.

Pharmacotherapy, 2001 Oct, 21(10 Pt 2), 253S - 272S
Fluoroquinolone adverse effects and drug interactions; Fish DN; Extensive pharmacologic and clinical development of quinolone antimicrobial agents has resulted in improved antimicrobial activity, pharmacokinetic features, toxicity, and drug-drug interaction profiles . Nalidixic acid and other early quinolones had limited use due to poor pharmacokinetics, relatively narrow antimicrobial spectrum of activity, and frequent adverse effects . Beginning with the development of fluoroquinolones, such as norfloxacin and ciprofloxacin, in the 1980s, the agents assumed a greatly expanded clinical role because of their broad antimicrobial spectrum of action, improved pharmacokinetic properties, and more acceptable safety profile . Although the pharmacokinetics and efficacy of the drugs have improved significantly, a major area of continued emphasis is to further reduce the frequency and severity of adverse events and drug-drug interactions . Older agents such as ciprofloxacin and ofloxacin are still extensively prescribed, but the focus of this article is on the newer fluoroquinolones (levofloxacin and other drugs that have been approved or have been under investigation since approximately 1997).

An R Acad Nac Med (Madr), 2001, 118(2), 343 - 57; discussion 357-61
{The active efflux pump in antimicrobial resistance}; Piedrola Angulo G; Active efflux of antibiotics is one of the different resistance mechanisms of bacteria against antimicrobial agents . The rapid exit of the antibiotic from the bacteria prevents its interaction with target point . This mechanism, also known as active efflux pump, is very important since it can explain the simultaneous resistance to several antibiotic families . There are four main active efflux systems: MFS, RND, Smr and ABC . This review includes all of them, together with their transporting proteins, the bacteria that have those proteins and the phenotype of the antibiotics affected . The complex genotype regulation systems, including codifying genes, positive and negative regulators, chromosomal or plasmidic localization is also studied . Finally, the causes of marked resistance to antimicrobial agents of isolated strains in the clinic, especially in hospital areas are revised . The role of the European Antimicrobial Resistance Surveillance System (EARSS) in the evaluation of those resistances is discussed.

Clin Infect Dis, 2001 Nov 15, 33(10), 1692 - 6 Epub 2001 Oct 12.
Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices; Singh N; In the past decade, the frequency of opportunistic fungal infections has increased, and the spectrum of fungal pathogens has changed . The increasing number of susceptible hosts, the introduction of newer modalities for hematopoietic stem cell transplantation, the evolution of organ transplantation practices, the use of novel immunosuppressive agents, and current antimicrobial prophylactic strategies have likely contributed to the changing epidemiology of invasive mycoses . The introduction of azoles more than a decade ago has had a profound impact on curtailing candidal infections . However, a dramatic increase in azole-resistant Candida species and mold infections has been documented . The trends in time of onset, spectrum, and frequency of infections due to invasive molds and opportunistic yeasts are unique for different fungi and vary between subsets of immunocompromised hosts . This review discusses the implications of these trends for guiding judicious use of antimicrobial prophylactics and for unraveling the pathophysiological basis of fungal infections.

Proc Natl Acad Sci U S A, 1994 Mar 15, 91(6), 2329 - 33
Lipid-derived signals that discriminate wound- and pathogen-responsive isoprenoid pathways in plants: methyl jasmonate and the fungal elicitor arachidonic acid induce different 3-hydroxy-3-methylglutaryl-coenzyme A reductase genes and antimicrobial isoprenoids in Solanum tuberosum L; Choi D et al.; Induction of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR; EC 1.1.1.34) is essential for the synthesis of steroid derivatives and sesquiterpenoid phytoalexins in solanaceous plants following mechanical injury or pathogen infection . Gene-specific probes corresponding to different HMGR genes (hmg1 and hmg2) were used to study HMGR expression in potato tissue following treatment with methyl jasmonate, a lipoxygenase product of linolenic acid, or arachidonic acid, an elicitor present in the lipids of the potato late blight fungus Phytophthora infestans . Treatment of potato discs (2.2 cm in diameter) with low concentrations (0.45-45 nmol per disc surface) of methyl jasmonate nearly doubled the wound-induced accumulation of hmg1 transcripts and steroid-glycoalkaloid (SGA) accumulation, reduced the abundance of hmg2 transcripts, and did not induce phytoalexins . High concentrations of methyl jasmonate (2-4.5 mol per disc surface) suppressed hmg1 mRNA and SGA accumulation but did not affect hmg2 mRNA abundance or induce phytoalexins . In contrast, arachidonate treatment strongly suppressed hmg1 and strongly induced hmg2 mRNA in a concentration-dependent manner . There was a corresponding suppression of SGA accumulation and an induction of sesquiterpene phytoalexin accumulation by this elicitor . Lipoxygenase inhibitors reduced the wound-induced accumulation of hmg1 transcripts and suppressed SGA levels, effects that were overcome by exogenous methyl jasmonate (45 nmol per disc surface) . The results (i) suggest that methyl jasmonate can function as a signal for hmg1 expression and SGA induction following wounding and (ii) indicate that the arachidonate- and jasmonate-response pathways are distinct in relation to HMGR gene expression and isoprenoid product accumulation . The results also are consistent with placement of the HMGR activities encoded by hmg1 and hmg2 within discrete steroid and sesquiterpenoid biosynthetic channels.

Cardiovasc Drug Rev, 2001 Fall, 19(3), 234 - 44
Cardiovascular actions of berberine; Lau CW et al.; Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants . It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea . This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine . Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties . Both derivatives of berberine have antiarrhythmic activity . Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K(ATP)) and stimulation of Na+ -Ca(2+) exchanger . Berberine has been shown to prolong the duration of ventricular action potential . Its vasodilator activity has been attributed to multiple cellular mechanisms . The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.

Nature, 2001 Oct 18, 413(6857), 732 - 8
Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3; Alexopoulou L et al.; Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses . Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication . Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs) . TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines . MyD88 is an adaptor protein that is shared by all the known TLRs . When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88 . Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.

Proc Natl Acad Sci U S A, 2001 Nov 6, 98(23), 13431 - 6 Epub 2001 Oct 23.
A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots; Haralampidis K et al.; Many plants synthesize antimicrobial secondary metabolites as part of their normal program of growth and development, often sequestering them in tissues where they may protect against microbial attack . These include glycosylated triterpenoids (saponins), natural products that are exploited by man for a variety of purposes including use as drugs {Hostettmann, K . & Marston, A . (1995) Saponins (Cambridge Univ . Press, Cambridge, U.K.)} . Very little is known about the genes required for the synthesis of this important family of secondary metabolites in plants . Here we show the novel oxidosqualene cyclase AsbAS1 catalyzes the first committed step in the synthesis of antifungal triterpenoid saponins that accumulate in oat roots . We also demonstrate that two sodium azide-generated saponin-deficient mutants of oat, which define the Sad1 genetic complementation group, are defective in the gene encoding this enzyme and provide molecular genetic evidence indicating a direct link between AsbAS1, triterpenoid saponin biosynthesis, and disease resistance . Orthologs of AsbAS1 are absent from modern cereals and may have been lost during selection, raising the possibility that this gene could be exploited to enhance disease resistance in crop plants.

Proc Natl Acad Sci U S A, 2001 Oct 23, 98(22), 12630 - 5 Epub 2001 Oct 16.
Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae; Vizioli J et al.; A novel mosquito antimicrobial peptide, gambicin, and the corresponding gene were isolated in parallel through differential display-PCR, an expressed sequence tag (EST) project, and characterization of an antimicrobial activity in a mosquito cell line by reverse-phase chromatography . The 616-bp gambicin ORF encodes an 81-residue protein that is processed and secreted as a 61-aa mature peptide containing eight cysteines engaged in four disulfide bridges . Gambicin lacks sequence homology with other known proteins . Like other Anopheles gambiae antimicrobial peptide genes, gambicin is induced by natural or experimental infection in the midgut, fatbody, and hemocyte-like cell lines . Within the midgut, gambicin is predominantly expressed in the anterior part . Both local and systemic gambicin expression is induced during early and late stages of natural malaria infection . In vitro experiments showed that the 6.8-kDa mature peptide can kill both Gram-positive and Gram-negative bacteria, has a morphogenic effect on a filamentous fungus, and is marginally lethal to Plasmodium berghei ookinetes . An oxidized form of gambicin isolated from the cell line medium was more active against bacteria than the nonoxidized form from the same medium.

Proc Natl Acad Sci U S A, 2001 Oct 23, 98(22), 12590 - 5 Epub 2001 Oct 16.
Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays; De Gregorio E et al.; To identify new Drosophila genes involved in the immune response, we monitored the gene expression profile of adult flies in response to microbial infection by using high-density oligonucleotide microarrays encompassing nearly the full Drosophila genome . Of 13,197 genes tested, we have characterized 230 induced and 170 repressed by microbial infection, most of which had not previously been associated with the immune response . Many of these genes can be assigned to specific aspects of the immune response, including recognition, phagocytosis, coagulation, melanization, activation of NF-kappaB transcription factors, synthesis of antimicrobial peptides, production of reactive oxygen species, and regulation of iron metabolism . Additionally, we found a large number of genes with unknown function that may be involved in control and execution of the immune response . Determining the function of these genes represents an important challenge for improving our knowledge of innate immunity . Complete results may be found at http://www.fruitfly.org/expression/immunity/.

Biophys J, 2001 Nov, 81(5), 2979 - 91
Comparison of the membrane association of two antimicrobial peptides, magainin 2 and indolicidin; Zhao H et al.; Interactions of two antimicrobial peptides, magainin 2 and indolicidin, with three different model biomembranes, namely, monolayers, large unilamellar vesicles (LUVs), and giant liposomes, were studied . Insertion of both peptides into lipid monolayers was progressively enhanced when the content of an acidic phospholipid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) in a film of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) was increased . Indolicidin and magainin 2 penetrated also into lipid monolayers containing cholesterol (mole fraction, X = 0.1) . Membrane association of magainin 2 attenuated lipid lateral diffusion in POPG-containing LUVs as revealed by the decrease in the excimer/monomer fluorescence ratio I(e)/I(m) for the pyrene fatty-acid-containing phospholipid derivative 1-palmitoyl-2-{10-(pyren-1-yl) decanoyl}-sn-glycero-3-phospho-rac-glycerol (PPDPG) . Likewise, an increase in steady-state fluorescence anisotropy of the membrane-incorporated diphenylhexatriene (DPH) was observed, revealing magainin 2 to increase acyl chain order and induce segregation of acidic phospholipids . Similar effects were observed for indolicidin . The topological effects of magainin 2 and indolicidin on phospholipid membranes were investigated using optical microscopy of giant vesicles . Magainin 2 had essentially no influence on either SOPC or SOPC:cholesterol (X = 0.1) giant liposomes . However, effective vesiculation was observed when acidic phospholipid (X(PG) = 0.1) was included in the giant vesicles . Indolicidin caused only a minor shrinkage of giant SOPC vesicles whereas the formation of endocytotic vesicles was observed when the giant liposome contained POPG (X(PG) = 0.1) . Interestingly, for indolicidin, vesiculation was also observed for giant vesicles composed of SOPC/cholesterol (X(chol) = 0.1) . Possible mechanisms of membrane transformation induced by these two peptides are discussed.

J Pept Res, 2001 Oct, 58(4), 293 - 306
Conformation and other biophysical properties of cyclic antimicrobial peptides in aqueous solutions; Jelokhani-Niaraki M et al.; As a step towards understanding the mechanism of the biological activity of cyclic antimicrobial peptides, the biophysical properties and conformations of four membrane-active cyclic peptide antibiotics, based on gramicidin S (GS), were examined in aqueous environments . These cyclic peptides, GS10 {cyclo(VKLdYP)2}, GS12 {cyclo(VKLKdYPKVKLdYP)}, GS14 {cyclo(VKLKVdYPLKVKLdYP)} and {d-Lys}4GS14 {cyclo(VKLdKVdYPLKVKLdYP)} (d-amino acid residues are denoted by d and are underlined) had different ring sizes of 10, 12 and 14 residues, were different in structure and amphipathicity, and covered a broad spectrum of hemolytic and antimicrobial activities . GS10, GS12 and {d-Lys}4GS14 were shown to be monomeric in buffer systems with ionic strength biological environments . GS14 was also monomeric at low concentrations, but aggregated at concentrations > 50 microm . The affinity of peptides for self-assembly and interaction with hydrophobic surfaces was related to their free energy of intermolecular interaction . The effects of variations in salt and organic solvent (trifluoroethanol) concentration and temperature on peptide conformation were also examined . Similar to GS, GS10 proved to have a stable and rather rigid conformation in different environments and over a broad range of temperatures, whereas GS12, GS14 and {d-Lys}4GS14 had more flexible conformations . Despite its conformational similarity to GS10, GS14 had unique physicochemical properties due to its tendency to aggregate at relatively low concentrations . The biophysical data explain the direct relation between structure, amphipathicity and hydrophobicity of the cyclic peptides and their hemolytic activity . However, this relation with the antimicrobial activity of the peptides is of a more complex nature due to the diversity in membrane structures of microorganisms.

Mol Plant Microbe Interact, 2001 Oct, 14(10), 1255 - 60
Wheat puroindolines enhance fungal disease resistance in transgenic rice; Krishnamurthy K et al.; Antimicrobial peptides play a role in the immune systems of animals and plants by limiting pathogen infection and growth . The puroindolines, endosperm-specific proteins involved in wheat seed hardness, are small proteins reported to have in vitro antimicrobial properties . Rice, the most widely used cereal crop worldwide, normally does not contain puroindolines . Transgenic rice plants that constitutively express the puroindoline genes pinA and/or pinB throughout the plants were produced . PIN extracts of leaves from the transgenic plants reduced in vitro growth of Magnaporthe grisea and Rhizoctonia solani, two major fungal pathogens of rice, by 35 to 50% . Transgenic rice expressing pinA and/or pinB showed significantly increased tolerance to M . grisea (rice blast), with a 29 to 54% reduction in symptoms, and R . solani (sheath blight), with an 11 to 22% reduction in symptoms . Puroindolines are effective in vivo in antifungal proteins and could be valuable new tools in the control of a wide range of fungal pathogens of crop plants.

Anal Chem, 2001 Oct 1, 73(19), 4640 - 6
Analysis of trace levels of sulfonamide and tetracycline antimicrobials in groundwater and surface water using solid-phase extraction and liquid chromatography/mass spectrometry; Lindsey ME et al.; A method has been developed for the trace analysis of two classes of antimicrobials consisting of six sulfonamides (SAs) and five tetracyclines (TCs), which commonly are used for veterinary purposes and agricultural feed additives and are suspected to leach into ground and surface water . The method used solid-phase extraction and liquid chromatography/mass spectrometry (LC/MS) with positive ion electrospray . The unique combination of a metal chelation agent (Na2EDTA) with a macroporous copolymer resulted in quantitative recoveries by solid-phase extraction (mean recovery, 98 +/- 12%) at submicrogramper-liter concentrations . An ammonium formate/formic acid buffer with a methanol/water gradient was used to separate the antimicrobials and to optimize the signal intensity . Mass spectral fragmentation and ionization characteristics were determined for each class of compounds for unequivocal identification . For all SAs, a characteristic m/z 156 ion representing the sulfanilyl fragment was identified . TCs exhibited neutral losses of 17 amu resulting from the loss of ammonia and 35 amu from the subsequent loss of water . Unusual matrix effects were seen only for TCs in this first survey of groundwater and surface water samples from sites around the United States, requiring that TCs be quantitated using the method of standard additions.

PDA J Pharm Sci Technol, 2001 Sep-Oct, 55(5), 278 - 85
Rapid methods for the microbiological surveillance of pharmaceuticals; Jimenez L; The use of rapid microbiological methods in pharmaceutical laboratories has improved the quality control analysis of water, products, raw materials, and enhanced the antimicrobial effectiveness testing of pharmaceutical finished products . Rapid release of samples has resulted in the optimization of manufacturing, product testing, and release allowing high throughput and simultaneous analysis of pharmaceutical formulations . ATP Bioluminescence, Impedance, Direct Viable Counts, and Flow Cytometry determine the total microbial content in a given pharmaceutical sample while PCR and Immunoassays detect the presence or absence of specific microbial species . Rapid methods provide reliable and cost effective analysis for the microbiological evaluation of pharmaceutical environments . The dramatic reduction in detection times and analysis, e.g., from 30 hours to 90 minutes, by using rapid methods will ultimately lead the pharmaceutical industry closer to real time monitoring of processes and samples.

Eur J Obstet Gynecol Reprod Biol, 2001 Nov, 99(1), 85 - 9
Delayed interval delivery in multiple pregnancies; Van der Straeten FM et al.; Preterm delivery remains the most important complication of multiple pregnancies . We describe six cases of successful delay of the subsequent child(ren) after very preterm birth of the first-born, with intervals ranging between 14 and 117 days.Based on our findings and on the available literature, we propose a set of guidelines for the management of early preterm multiple birth deliveries, including tocolysis, antimicrobial therapy and corticosteroids.

J Am Coll Nutr, 2001 Oct, 20(5 Suppl), 464S - 472S; discussion 473S-475S
The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population; Salganik RI; Cellular oxidants, called reactive oxygen species (ROS), are constantly produced in animal and human cells . Excessive ROS can induce oxidative damage in cell constituents and promote a number of degenerative diseases and aging . Cellular antioxidants protect against the damaging effects of ROS . However, in moderate concentrations, ROS are necessary for a number of protective reactions . Thus, ROS are essential mediators of antimicrobial phagocytosis, detoxification reactions carried out by the cytochrome P-450 complex, and apoptosis which eliminates cancerous and other life-threatening cells . Excessive antioxidants could dangerously interfere with these protective functions, while temporary depletion of antioxidants can enhance anti-cancer effects of apoptosis . Experimental data are presented supporting these notions . The human population is heterogeneous regarding ROS levels . Intake of exogenous antioxidants (vitamins E, C, beta-carotene and others) could protect against cancer and other degenerative diseases in people with innate or acquired high levels of ROS . However, abundant antioxidants might suppress these protective functions, particularly in people with a low innate baseline level of ROS . Screening human populations for ROS levels could help identify groups with a high level of ROS that are at a risk of developing cancer and other degenerative diseases . It also could identify groups with a low level of ROS that are at a risk of down-regulating ROS-dependent anti-cancer and other protective reactions . Screening populations could provide a scientifically grounded application of antioxidant supplements, which could significantly contribute to the nation's health.

Am Surg, 2001 Oct, 67(10), 974 - 8
Octylcyanoacrylate tissue adhesive as an alternative to mechanical fixation of expanded polytetrafluoroethylene prosthesis; Birch DW et al.; In minimally invasive incisional hernia repair positioning and fixation of the expanded polytetrafluoroethylene (ePTFE) mesh prosthesis on the deep surface of the abdominal wall may be facilitated using tissue adhesives . Octylcyanoacrylate (OCTYL), a new adhesive, forms a strong flexible bond with antimicrobial properties . In a rabbit model for incisional hernia we investigated characteristics of the bond created by OCTYL between ePTFE and abdominal wall musculature . We studied initial bond strength and the postoperative host response to the adhesive over a 6-week period . We compared sutured, stapled, and glued mesh prostheses and examined the tissue-prosthesis interface . The ePTFE mesh was fixed successfully to the abdominal wall with OCTYL and remained tightly attached at 6 weeks . Prostheses fixed with OCTYL and spiral tacks induced few intra-abdominal adhesions compared with sutured mesh . All prostheses were completely reperitonealized at 2 weeks . The force required to displace mesh fixed with sutures and staples was greater than mesh fixed with OCTYL . Analysis of the ePTFE/tissue interface by light and scanning electron microscopy showed host cellular migration into the interstices of the mesh with fixation by tacks and suture, whereas an inflammatory infiltrate was seen on the muscular surface with OCTYL fixation of the mesh.

J Dent Hyg, 2001 Summer, 75(3), 233 - 9
Antimicrobials in periodontal maintenance; Jorgensen MG et al.; Mechanical and chemical antimicrobial intervention is the mainstay of preventive periodontal therapy . Successful periodontal maintenance care depends upon the ability of oral health care professionals to combat periodontal infections, and patient compliance with prescribed follow-up care . Since tooth brushing, flossing, and oral rinsing do not reach pathogens present in furcations and at the depths of deep periodontal pockets, adequate oral hygiene should include subgingival treatment with home irrigators or other appropriate self-care remedies in patients with these conditions . Povidone-iodine for professional use and diluted bleach for self-care are inexpensive and valuable antimicrobial agents in periodontal maintenance . The present article outlines the prudent use of antimicrobial therapy in periodontal maintenance.

J Exp Med, 2001 Oct 15, 194(8), 1123 - 40
Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase; Ehrt S et al.; Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb) . Interferon-gamma (IFN-gamma) activates macrophages by driving Janus tyrosine kinase (JAK)/signal transducer and activator of transcription-dependent induction of transcription and PKR-dependent suppression of translation . Microarray-based experiments reported here enlarge this picture . Exposure to IFN-gamma and/or Mtb led to altered expression of 25% of the monitored genome in macrophages . The number of genes suppressed by IFN-gamma exceeded the number of genes induced, and much of the suppression was transcriptional . Five times as many genes related to immunity and inflammation were induced than suppressed . Mtb mimicked or synergized with IFN-gamma more than antagonized its actions . Phagocytosis of nonviable Mtb or polystyrene beads affected many genes, but the transcriptional signature of macrophages infected with viable Mtb was distinct . Studies involving macrophages deficient in inducible nitric oxide synthase and/or phagocyte oxidase revealed that these two antimicrobial enzymes help orchestrate the profound transcriptional remodeling that underlies macrophage activation.

Dev Comp Immunol, 2001 Oct-Dec, 25(8-9), 807 - 25
Antimicrobial mechanisms of fish phagocytes and their role in host defense; Neumann NF et al.; Phagocytosis is a primitive defense mechanism in all multicellular animals . Phagocytes such as macrophages and neutrophils play an important role in limiting the dissemination of infectious agents, and are responsible for the eventual destruction of phagocytosed pathogens . These cells have evolved elaborate killing mechanisms for destroying pathogens . In addition to their repertoire of degradative enzymes and antimicrobial peptides, macrophages and neutrophils can be activated to produce a number of highly toxic molecules . Production of reactive oxygen and nitrogen intermediates by these cells are potent cytotoxic mechanisms against bacteria and protozoan pathogens . Studies in fish suggest that the biological basis of these inducible killing mechanisms is similar to those described in mammals . More recent work suggest novel roles for regulating these killing responses in fish . In this review, we describe the biological basis of these killing mechanisms and how they are regulated in fish.

Biochemistry, 2001 Oct 23, 40(42), 12591 - 603
Effect of multiple aliphatic amino acids substitutions on the structure, function, and mode of action of diastereomeric membrane active peptides; Avrahami D et al.; The initial stages leading to the binding and functioning of membrane-active polypeptides including hormones, signal sequences, and lytic peptides are mainly governed by electrostatic attraction and hydrophobic partitioning between water and lipid bilayers . Antimicrobial peptides serve as an important model for studying the details of these initial steps . However, a systematic analysis of the contribution of multiple hydrophobic amino acids to these steps have been hindered by the propensity of many peptides to aggregate and become inactivated in solution . To this end, we synthesized a series of model amphipathic all L-amino acid peptides and their diastereomers with the sequence KX(3)KWX(2)KX(2)K, where X = Gly, Ala, Val, Ile, or Leu . The effect of the aliphatic amino acids on the biological activity, binding, structure, membrane localization, and mode of action of these peptides was investigated . Most of the L-amino acid peptides oligomerized and adopted distinct structures in solution and in a membrane mimetic environment . Among this group only the Leu containing peptide was hemolytic and highly active on most bacteria tested . The Val- and Leu-containing peptides were hemolytic but inactive toward most bacteria tested . In contrast, the diastereomeric peptides were monomeric and unstructured in solution, but they adopted distinct structures upon membrane binding . While hemolytic activity was drastically reduced, the spectrum of antibacterial activity was preserved or increased . Importantly, we found a direct correlation with the diastereomers between hydrophobicity and propensity to form a helical/distorted-helix and activity (induced membrane leakage and antibacterial activity), despite the fact that they contained 30% D-amino acids . Furthermore, efficient increase in membrane permeability can proceed through different mechanisms . Specifically, the Leu-containing diastereomeric peptide micellized vesicles and possibly bacterial membranes while the Ile-containing diastereomeric peptide fused model membranes and irregularly disrupted bacterial membranes.

Virology, 2001 Sep 30, 288(2), 351 - 7
Inactivation of frog virus 3 and channel catfish virus by esculentin-2P and ranatuerin-2P, two antimicrobial peptides isolated from frog skin; Chinchar VG et al.; While it is clear that some amphibian populations have recently experienced precipitous declines, the causes of those die-offs are complex and likely involve multiple variables . One theory suggests that environmental factors may trigger events that result in depressed immune function and increased susceptibility to infectious disease . Here we examine one aspect of innate immunity in amphibians and show that esculentin-2P (E2P) and ranatuerin-2P (R2P), two antimicrobial peptides isolated from Rana pipiens, inactivate frog virus 3, a potentially pathogenic iridovirus infecting anurans, and channel catfish herpesvirus . In contrast to mammalian antimicrobial peptides, E2P and R2P act within minutes, at temperatures as low as 0 degrees C, to inhibit viral infectivity . Moreover, these compounds appear to inactivate the virus directly and do not act by inhibiting replication in infected cells . This is the first report linking amphibian antimicrobial peptides with protection from an amphibian viral pathogen and suggests that these compounds may play a role in maintaining amphibian health .

J AOAC Int, 2001 Sep-Oct, 84(5), 1313 - 31
Supercritical fluid extraction of halogenated monoterpenes from the red alga Plocamium cartilagineum; Gao D et al.; Supercritical fluid extraction (SFE) of the marine red alga Plocamium cartilagineum, which is known to contain complex mixtures of halogenated monoterpenes, was investigated . P . cartilagineum samples were extracted by SFE with carbon dioxide and modified carbon dioxide containing up to 10% methanol at different pressure and temperature conditions to establish the optimum conditions for extraction . These conditions were then used in the extraction of halogenated monoterpenes from 2 different samples of P . cartilagineum: one from Davenport, CA, and the other from Casa Beach (San Diego, CA) . Several halogenated monoterpenes isolated by conventional solvent extraction with methanol and purified by column chromatography were used as the reference compounds for the determination of the extraction efficiency in the SFE experients . Plocamium cartilagineum belongs to the red alga family--Plocamiaceae, and has been found to contain a large number of halogenated monoterpenes, whose structures typically contain 1-6 bromine and/or chlorine atoms . P . cartilagineum grows along the Pacific coast from Washington to Chile, the British Isles, Australia, and Spain . Interestingly, P . cartilagineum collected from different geographical areas in the world are all reported to produce halogenated monoterpenes, but of different structural types and halogen substitution patterns . Most of these halogenated monoterpenes have been found to exhibit varied biological activities, including antifungal, antimicrobial, and molluscicidal activity.

Antimicrob Agents Chemother, 2001 Nov, 45(11), 3175 - 81
Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modelling; Gavigan CS et al.; The pathway of hemoglobin degradation by erythrocytic stages of the human malarial parasite Plasmodium falciparum involves initial cleavages of globin chains, catalyzed by several endoproteases, followed by liberation of amino acids from the resulting peptides, probably by aminopeptidases . This pathway is considered a promising chemotherapeutic target, especially in view of the antimalarial synergy observed between inhibitors of aspartyl and cysteine endoproteases . We have applied response-surface modelling to assess antimalarial interactions between endoprotease and aminopeptidase inhibitors using cultured P . falciparum parasites . The synergies observed were consistent with a combined role of endoproteases and aminopeptidases in hemoglobin catabolism in this organism . As synergies between antimicrobial agents are often inferred without proper statistical analysis, the model used may be widely applied in studies of antimicrobial drug interactions.

J Ind Microbiol Biotechnol, 2001 Jul, 27(1), 62 - 6
Isolation and biological activity of frankiamide; Haansuu JP et al.; An antibiotic produced by the symbiotic actinomycete Frankia strain AiPs1 was isolated from culture broth using optimized thin-layer chromatography and high-performance liquid chromatography (HPLC) methods . The novel compound that was isolated, dubbed frankiamide, displayed antimicrobial activity against all 14 Gram-positive bacterial strains and six pathogenic fungal strains tested . The pathogenic actinomycete Clavibacter michiganensis and the oomycete Phytophthora were especially susceptible . In addition to displaying antimicrobial activity, frankiamide also strongly inhibited 45Ca(2+) fluxes in clonal rat pituitary GH4C1 tumor cells and was comparable to a frequently used calcium antagonist, verapamil hydrochloride . The results of HPLC analysis, supported by both nuclear magnetic resonance and mass spectroscopy studies, showed that frankiamide has a high affinity for Na(+) ions.

Bioorg Med Chem, 2001 Nov, 9(11), 2871 - 84
Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents; Iwasa K et al.; Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities . Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents . These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV) . A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities . In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

Yao Xue Xue Bao, 1997 Sep, 32(9), 669 - 74
{Use of monoclonal antibody-pinyangmycin conjugate in experimental regional targeting therapy of tumor}; Wang WG et al.; McAb 3A5, a rat monoclonal antibody, was linked to pingyangmycin (PYM), an antitumor antibiotic identical to bleomycin A5 currently in clinical use, employing Dextran T-40 as an intermediate agent . The 3A5-PYM conjugate retained complete immunoreactivity of McAb 3A5 . Determined by clonogenic assay with colon cancer HT-29 cells, the IC50 values for 3A5-PYM conjugate and free PYM were 0.6 mumol.L-1 and 10.2 mumol.L-1, respectively . Hepatoma H22 ascites was transplanted into the peritoneal or thoracic cavity of mice . On the next day, 3A5-PYM or PYM, were injected into the cavity . Therapeutic effect was evaluated on the survival time of mice . For intraperitoneal tumor, the ILS(%) values were 238% for 3A5-PYM and 40% for PYM . For intrapleural tumor, the ILS(%) values were 384% for 3A5-PYM and 66% for PYM . Murine hepatoma H22 was transplanted s.c . into mice and 3A5-PYM conjugate or free PYM were injected peritumorally . As determined by antimicrobial assay, the administration of 3A5-PYM showed higher concentration and longer retention time in the tumor than that of free PYM . Tumor fragments of human colon cancer HT-29 were transplanted s.c . into nude mice . Then 3A5-PYM or PYM was injected i.v., i.p . or pt (peritumorally) 3 days after inoculation, twice a week, with a total of 7 injections . Tumor growth inhibition was evaluated 4 weeks later . The inhibition rates on the growth of colon cancer xenografts were as follows: (1) for i.v . route, 58% by PYM, 79% by 3A5-PYM; (2) for i.p . route, 52% by PYM, 61% by 3A5-PYM; and (3) for pt route, 73% by PYM, 96% by 3A5-PYM . These results indicate that 3A5-PYM conjugate is highly effective against targeted human cancer xenograft and mouse tumor when administered peritumorlly or intracavitarily.

Pediatr Pulmonol, 2001 Nov, 32(5), 356 - 66
Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis; Rosenfeld M et al.; A thorough understanding of the early natural history of cystic fibrosis (CF) lung disease is critical for the development of effective interventions in the youngest patients . We assessed the evolution of pulmonary infection, inflammation, and clinical course among 40 infants over a 2-year period through annual bronchoalveolar lavage (BAL) for culture and measurements of pro- and anti-inflammatory cytokines, semiannual infant pulmonary function testing, and quarterly clinical evaluations . Both the prevalence of CF pathogens and their density in BAL fluid increased with age . Infants had neutrophilic lower airway inflammation and elevated IL-8 concentrations independent of whether CF pathogens were recovered . Total leukocyte and neutrophil densities and IL-8 concentrations increased with density of CF pathogens in BAL fluid, whether the isolated organism was P . aeruginosa or another pathogen . IL-10 concentrations were similar in CF subjects and non-CF historical controls . Infants generally had suboptimal growth (low weight and height percentiles) and obstructive lung disease (decreased expiratory flows and air trapping) . Subjects from whom CF pathogens were isolated at > 10(5) cfu/mL had the worst air trapping and lowest Brasfield chest X-ray scores . Our findings provide a foundation for future studies of early intervention in CF lung disease, including antimicrobial and anti-inflammatory therapy .

Clin Infect Dis, 2001 Nov 15, 33(10), 1739 - 46 Epub 2001 Oct 10.
Understanding the spread of antibiotic resistant pathogens in hospitals: mathematical models as tools for control; Bonten MJ et al.; As microorganisms become more resistant to antimicrobial agents, effective infection control measures will become increasingly important . However, despite multiple studies on infection prevention, few data exist on the quantitative effects of the individual aspects of infection control strategies . The combination of epidemiologic surveillance, molecular genotyping, observational studies on compliance, and mathematical modeling may improve our ability to determine the quantitative effects of individual infection control measures . This may help to design more effective infection control programs . In this study, we review several of the models that have been published and speculate on the usefulness of mathematical modeling for improving the prevention of infection.

Clin Infect Dis, 2001 Nov 15, 33(10), 1661 - 7 Epub 2001 Oct 10.
Whither infectious diseases consultations? Analysis of 14,005 consultations from a 5-year period; Yinnon AM; During a 5-year period, data from all infectious disease (ID) consultations were recorded in a computerized database, which included 9068 new and 4937 additional consultations . The purpose of these 14,005 consultations was therapy (for 58%), diagnosis (for 13%), both (for 24%), and prophylaxis (for 4%); 51% were performed at the bedside, and the remainder were by discussion (19%) or telephone (30%) . Recommendations included the following: initiation, change, or discontinuation of antibiotics (in 46%); performance of diagnostic tests (in 20%) or surgical procedures (in 1%); prophylaxis (in 3%); or no change (in 29%) . Analysis of new versus additional consultations revealed significant differences . A new ID consultation was given at a rate of 6.0 consultations per 100 hospitalized patients; the rate per department correlated with the expenditure on antimicrobials per patient admission . During the study period, expenditure on antimicrobials per admission steadily decreased, from $44 in 1995 to $30 in 1999, a 35% reduction . In conclusion, analysis of data from ID consultations enables the ID service to evaluate its activity and to direct efforts to departments with high rates of nosocomial infections, antimicrobial resistance, and/or antimicrobial use.

Clin Infect Dis, 2001 Nov 15, 33(10), 1697 - 705 Epub 2001 Oct 05.
Ethical issues relating to the use of antimicrobial therapy in older adults; Marcus EL et al.; This article aims to review the literature relating to the ethics of antibiotic prescription decisions in older adults and to offer some suggestions as to how one might approach these difficult problems . According to many studies, most patients and their family members wish to receive antibiotics even when they are terminally ill or suffering from advanced dementia . Health care professionals are also frequently reluctant to deny the use of antibiotics in such situations . We suggest that the difficult decisions regarding whether one should withhold treatment can be based on consideration of the ethical principles of autonomy, beneficence, nonmaleficence, and justice . From the public health point of view, one should also take into account the need to avoid the emergence of antimicrobial resistance, keeping in mind the balance between the benefit to the specific patient and the cost to future patients . Infectious diseases consultants should actively participate in these ethical dilemmas.

Curr Probl Pediatr Adolesc Health Care, 2001 Sep, 31(8), 247 - 66
Helicobacter pylori infection in children; Gold BD; A number of scientific breakthroughs since H pylori first became recognized as a human pathogen have increased our understanding of the pathogenesis of gastroduodenal disease . In particular, advances in molecular bacteriology and the complete sequencing of the H pylori genome in 1999, and soon thereafter the human genome, provide tools allowing better delineation of the pathogenesis of disease . These molecular tools for both bacteria and host should now be applied to multicenter pediatric studies that evaluate disease outcome . More recent developments indicate that a better understanding of the microbial-host interaction is critical to furthering knowledge with respect to H pylori-induced diseases . Studies are needed to evaluate either DNA-based or more traditional protein-based vaccines, to evaluate more specific antimicrobials that confer minimal resistance, and to evaluate probiotics for the management of H pylori infection . Multicenter multinational studies of H pylori infection in the pediatric population, which include specific, randomized controlled eradication trials, are essential to extend current knowledge and develop better predictors of disease outcome.

Semin Cutan Med Surg, 2001 Sep, 20(3), 184 - 9
Acne therapy: clinical pearls; Stein RH et al.; Several classes of medications successfully treat acne . Systemic and topical retinoids, systemic and topical antimicrobials, and systemic hormonal therapy are the major categories . Failure of therapy may result from drug interactions, antibiotic resistance, or coexisting conditions; therefore, a detailed history including these points should be used to decide which therapy is appropriate for each patient . Furthermore, one must consider the potential side effects of each treatment and make sure that (1) the benefits outweigh the risks of the treatment, (2) the side effects can be avoided by adding another agent, or (3) the side effects can be safely treated.

Int J Syst Evol Microbiol, 2001 Sep, 51(Pt 5), 1751 - 64
Mycobacterium immunogenum sp . nov., a novel species related to Mycobacterium abscessus and associated with clinical disease, pseudo-outbreaks and contaminated metalworking fluids: an international cooperative study on mycobacterial taxonomy; Wilson RW et al.; PCR-restriction enzyme pattern analysis of a 439 bp hsp65 gene segment identified 113 unique isolates among non-pigmented rapidly growing mycobacteria (RGM) from clinical and environmental sources that failed to match currently recognized species patterns . This group represented 40% of isolates recovered from bronchoscope contamination pseudo-outbreaks, 0% of disease-associated nosocomial outbreaks and 4% of routine clinical isolates of the Mycobacterium abscessus/Mycobacterium chelonae group submitted to the Mycobacteria/Nocardia laboratory for identification . It is grouped within the Mycobacterium fortuitum complex, with growth in less than 7 d, absence of pigmentation, positive 3-d arylsulfatase reaction and growth on MacConkey agar without crystal violet . It exhibited overlapping biochemical, antimicrobial susceptibility and HPLC characteristics of M . abscessus and M . chelonae . By 16S rRNA gene sequencing, these isolates comprised a homogeneous group with a unique hypervariable region A sequence and differed by 8 and 10 bp, respectively, from M . abscessus and M . chelonae . Surprisingly, this taxon contained two copies of the ribosomal operon, compared with single copies in the two related species . By DNA-DNA hybridization, this new group exhibited <30% homology with recognized RGM species . The name Mycobacterium immunogenum sp . nov . is proposed for this new taxon.

Int J Hematol, 2001 Aug, 74(2), 125 - 33
Contributions of myeloperoxidase to proinflammatory events: more than an antimicrobial system; Nauseef WM; Optimal oxygen-dependent antimicrobial activity of circulating polymorphonuclear leukocytes reflects the synergistic effects of the myeloperoxidase (MPO)-hydrogen peroxide-halide system . Delivered from its storage compartment to the phagolysosome during fusion of the azurophilic granules, MPO catalyzes the oxidation of chloride in the presence of H2O2, chemistry unique to MPO, and thereby generates an array of highly reactive oxidants . Recent investigations of a wide range of inflammatory disorders have identified biochemical markers of MPO-dependent reactions, thus indirectly implicating MPO in their pathogenesis, progression, or perpetuation . The implied involvement of MPO-dependent events in diseases such as atherosclerosis forces reexamination of several fundamental tenets about MPO that are derived from studies of myeloid cells, most notably factors important in the regulated expression of MPO gene transcription . The evidence supporting a role for MPO in the pathogenesis of atherosclerosis, demyelinating diseases of the central nervous system, and specific cancers is reviewed and some of the new questions raised by these studies are discussed . Lastly, an appreciation for the existence of a broad family of proteins structurally related to MPO and the functional diversity implied by the corresponding structures may provide insights into novel ways in which MPO can function as more than an important antimicrobial component.

Int J Clin Pract, 2001 Sep, 55(7), 437 - 41
The efficacy of moxifloxacin in acute exacerbations of chronic bronchitis: a Spanish physician and patient experience; Miravitlles M et al.; Chronic bronchitis is a debilitating disease affecting many millions of patients globally . They suffer multiple acute exacerbations each year, often requiring many courses of antimicrobials to enable them to return to normal . The impact of the condition on both the individual patient and society as a whole is considerable and growing; thus antimicrobial therapy should induce rapid and effective outcomes as soon as possible . This open, community-based study of 5737 patients enrolled by over 2000 primary care physicians from across Spain examined the clinical effect of oral moxifloxacin on patients' signs and symptoms of acute exacerbations of chronic bronchitis (AECB) over a 45-day period . The symptoms were assessed using daily diary cards in addition to physician evaluations . Clinical assessment at day 7 showed 93.0% of patients were cured . The patient diary card showed that two-thirds of patients felt better by day 3 or 4 . Adverse events were reported in 3.5% of patients in this study, the most common being diarrhoea, nausea and dizziness, and epigastric pain . These reactions were mild to moderate in intensity . There were no patient deaths due to infection during the study . Physicians and patients reported that once-daily moxifloxacin gave fast relief of symptoms of acute exacerbations of chronic bronchitis.

Pharmazie, 2001 Sep, 56(9), 691 - 5
Synthesis and antibacterial activity of 5- and 6-hydroxy substituted 4-aminoquinolines and derivatives; Meyer T et al.; The synthesis and antimicrobial activity of 4-amino-8-methylquinolines 8, 11 substituted with a hydroxy- or methoxy-group at 5- and at 6-position have been investigated . The title compounds could be prepared by a six-step procedure according to the literature starting from commercially available anilines 1 . The novel 4-aminoquinolines 8,11 exhibited slight antibacterial activity against Gram-positive and Gram-negative bacteria.

Proc Natl Acad Sci U S A, 2001 Oct 9, 98(21), 11961 - 6 Epub 2001 Oct 02.
Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis; Gaut JP et al.; The myeloperoxidase system of neutrophils uses hydrogen peroxide and chloride to generate hypochlorous acid, a potent bactericidal oxidant in vitro . In a mouse model of polymicrobial sepsis, we observed that mice deficient in myeloperoxidase were more likely than wild-type mice to die from infection . Mass spectrometric analysis of peritoneal inflammatory fluid from septic wild-type mice detected elevated concentrations of 3-chlorotyrosine, a characteristic end product of the myeloperoxidase system . Levels of 3-chlorotyrosine did not rise in the septic myeloperoxidase-deficient mice . Thus, myeloperoxidase seems to protect against sepsis in vivo by producing halogenating species . Surprisingly, levels of 3-bromotyrosine also were elevated in peritoneal fluid from septic wild-type mice and were markedly reduced in peritoneal fluid from septic myeloperoxidase-deficient mice . Furthermore, physiologic concentrations of bromide modulated the bactericidal effects of myeloperoxidase in vitro . It seems, therefore, that myeloperoxidase can use bromide as well as chloride to produce oxidants in vivo, even though the extracellular concentration of bromide is at least 1,000-fold lower than that of chloride . Thus, myeloperoxidase plays an important role in host defense against bacterial pathogens, and bromide might be a previously unsuspected component of this system.

Proc Natl Acad Sci U S A, 2001 Oct 23, 98(22), 12648 - 53 Epub 2001 Oct 09.
Tsetse immune responses and trypanosome transmission: implications for the development of tsetse-based strategies to reduce trypanosomiasis; Hao Z et al.; Tsetse flies are the medically and agriculturally important vectors of African trypanosomes . Information on the molecular and biochemical nature of the tsetse/trypanosome interaction is lacking . Here we describe three antimicrobial peptide genes, attacin, defensin, and diptericin, from tsetse fat body tissue obtained by subtractive cloning after immune stimulation with Escherichia coli and trypanosomes . Differential regulation of these genes shows the tsetse immune system can discriminate not only between molecular signals specific for bacteria and trypanosome infections but also between different life stages of trypanosomes . The presence of trypanosomes either in the hemolymph or in the gut early in the infection process does not induce transcription of attacin and defensin significantly . After parasite establishment in the gut, however, both antimicrobial genes are expressed at high levels in the fat body, apparently not affecting the viability of parasites in the midgut . Unlike other insect immune systems, the antimicrobial peptide gene diptericin is constitutively expressed in both fat body and gut tissue of normal and immune stimulated flies, possibly reflecting tsetse immune responses to the multiple Gram-negative symbionts it naturally harbors . When flies were immune stimulated with bacteria before receiving a trypanosome containing bloodmeal, their ability to establish infections was severely blocked, indicating that up-regulation of some immune responsive genes early in infection can act to block parasite transmission . The results are discussed in relation to transgenic approaches proposed for modulating vector competence in tsetse.

J Surg Res, 2001 Oct, 100(2), 183 - 8
Therapeutic efficacy of the polymyxin-like peptide ranalexin in an experimental model of endotoxemia; Ghiselli R et al.; BACKGROUND: A rat model was used to investigate the efficacy of a polycationic peptide, the polymyxin-like ranalexin, in the prevention of lethality in a rat model of septic shock . The effect of ranalexin was compared with those of polymyxin B and imipenem . METHODS: Adult male Wistar rats (weight range: 250-300 g) were used for all the experiments . The study included five groups: an uninfected control group C(0), an untreated control group C(1), and three drug-treated groups that received 1 mg/kg ranalexin (group 2), 20 mg/kg imipenem (group 3), and 3 mg/kg polymyxin B (group 4) . Rats, with the exception of the uninfected control group (C(0)), were given an intraperitoneal injection of 2 x 10(10) colony-forming units of Escherichia coli . Each group included 15 animals . Bacterial growth in abdominal exudate and plasma; endotoxin and tumor necrosis factor alpha (TNF-alpha) concentrations in plasma, and mortality were evaluated . RESULTS: Results were evaluated 48 h after inoculation . Ranalexin, imipenem, and polymyxin B significantly reduced the lethality (survival was 93.3, 80.0, and 93.3%, respectively) and the growth of E . coli both in abdominal fluid and plasma compared with saline treatment . Ranalexin showed higher antimicrobial activity than polymyxin B and imipenem and, at the same time, exhibited an antiendotoxin activity similar to that of polymyxin B (< or =0.015 EU/mL) . Finally, ranalexin and polymyxin B significantly reduced plasma TNF-alpha levels (< or =4 pg/mL) . CONCLUSION: Monodose ranalexin treatment prevents bacterial growth, endotoxemia, and mortality in rats with septic shock .

J Antibiot (Tokyo), 2001 Aug, 54(8), 615 - 21
SW-163C and E, novel antitumor depsipeptides produced by Streptomyces sp . I . Taxonomy, fermentation, isolation and biological activities; Kurosawa K et al.; Novel depsipeptides, SW-163C and E were isolated from the culture broth of an actinomycete strain . The producing organism, designated as SNA15896, was identified as a member of Streptomyces from its morphological and cultural characteristics . SW-163C and E exhibited potent antitumor activities against various tumor cell lines in vitro and against murine leukemia P388 in vivo . The compounds also showed antimicrobial activities.

Chest, 2001 Oct, 120(4), 1094 - 100
Fiberoptic bronchoscopy in allogeneic bone marrow transplantation: findings in the era of serum cytomegalovirus antigen surveillance; Feinstein MB et al.; STUDY OBJECTIVES: Pulmonary complications occur in half of allogeneic bone marrow transplantation (BMT) patients . The incidence of these complications has been reduced by prophylaxis against Pneumocystis carinii pneumonia, preemptive therapy in patients at high risk for cytomegalovirus (CMV) reactivation, and, more recently, screening for serum CMV antigen . Since fiberoptic bronchoscopy (FOB) has historically been the primary diagnostic test to evaluate BMT patients with pulmonary disease, a review was performed to determine the impact, if any, that current prophylaxis and screening policies may have had on FOB utility . DESIGN: The records of 174 adult patients undergoing BMT between January 1997 and December 1999 were reviewed to determine the diagnostic yield of FOB and the frequency by which FOB altered management . RESULTS: Sixty-one patients underwent 76 bronchoscopies . FOB was diagnostic in 32 patients (42.1% of cases) and directly changed management in 24 patients (31.6% of cases) . Half of these changes included the withdrawal of an antimicrobial agent . The most common findings were infection (32 cases) and diffuse alveolar hemorrhage (6 cases) . CMV was the most prevalent infection identified, but FOB resulted in the addition of antiviral therapy to only two patients . P carinii pneumonia was not diagnosed in any patient studied . CONCLUSIONS: These data suggest a changing spectrum of pulmonary disease in BMT patients . FOB has limited impact on the diagnoses of CMV disease or P carinii pneumonia with current prophylaxis and screening strategies . It may be useful in identifying other infectious etiologies and in eliminating unnecessary antimicrobials.

Prog Lipid Res, 2001 Nov, 40(6), 467 - 97
Lipid biosynthesis as a target for antibacterial agents; Heath RJ et al.; Fatty acid biosynthesis, the first stage in membrane lipid biogenesis, is catalyzed in most bacteria by a series of small, soluble proteins that are each encoded by a discrete gene (Fig . 1; Table 1) . This arrangement is termed the type II fatty acid synthase (FAS) system and contrasts sharply with the type I FAS of eukaryotes which is a dimer of a single large, multifunctional polypeptide . Thus, the bacterial pathway offers several unique sites for selective inhibition by chemotherapeutic agents . The site of action of isoniazid, used in the treatment of tuberculosis for 50 years, and the consumer antimicrobial agent triclosan were revealed recently to be the enoyl-ACP reductase of the type II FAS . The fungal metabolites, cerulenin and thiolactomycin, target the condensing enzymes of the bacterial pathway while the dehydratase/isomerase is inhibited by a synthetic acetylenic substrate analogue . Transfer of fatty acids to the membrane has also been inhibited via interference with the first acyltransferase step, while a new class of drugs targets lipid A synthesis . This review will summarize the data generated on these inhibitors to date, and examine where additional efforts will be required to develop new chemotherapeutics to help combat microbial infections.

Altern Med Rev, 2001 Sep, 6 Suppl, S62 - 6
Curcuma longa (turmeric) . Monograph; Renal disease in small animals: a review of conditions and potential nutrient and botanical interventions; Coleman Animal Healing Center, 631 W . Clark St., Pasco, Washington 99301, USANutritional and botanical approaches that may benefit small animals diagnosed with renal disease are considered with regard to their effects on renal physiology and ability to ameliorate specific pathologies . Suggestions are made for water- and fat-soluble vitamins, mushrooms, quercetin, and Western and Chinese herbs, based on their activities as free-radical scavengers, immune modulators, antimicrobials, anti-emetics, and erythrocyte production stimulators . Attention is focused on omega-3 fatty acids from fish and flaxseed, in addition to several other nutrients and botanicals . Renal anatomy and physiology is reviewed, as well as the etiology of chronic renal disease in small animals, its symptomatic presentation, and progression.

Biochemistry, 2001 Oct 16, 40(41), 12395 - 9
Heterodimer formation between the antimicrobial peptides magainin 2 and PGLa in lipid bilayers: a cross-linking study; Hara T et al.; The antimicrobial peptides magainin 2 and PGLa, isolated from the skin of the African clawed frog Xenopus laevis, show marked synergism {Westerhoff, H . V., Zasloff, M., Rosner, J . L., Hendler, R . W., de Waal, A., Vaz Gomes, A., Jongsma, A . P . M., Riethorst, A., and Juretic, D . (1995) Eur . J . Biochem . 228, 257-264} . We suggested previously that these peptides form a potent heterodimer composed of either parallel or antiparallel helices in membranes {Matsuzaki, K., Mitani, Y., Akada, K., Murase, O., Yoneyama, S., Zasloff, M., and Miyajima, K . (1998) Biochemistry 37, 15144-15153} . To detect the putative heterodimer by chemical cross-linking, analogues of magainin 2 and PGLa with a Cys residue at either terminus were synthesized . These cross-linking experiments suggested that both peptides form a parallel heterodimer in membranes composed of phosphatidylglycerol/phosphatidylcholine but not in either buffer or a helix-promoting 2,2,2-trifluoroethanol/buffer mixture . The isolated parallel heterodimers exhibited an order of magnitude higher membrane permeabilization activity compared with the monomeric species, indicating that the observed synergism is due to heterodimer formation.

An Med Interna, 2001 Aug, 18(8), 415 - 20
{Prognostic factors of bacteremia: prospective study}; Pazos Anon R et al.; BACKGROUND: To identify the epidemiology and risk factors with influence in the outcome and mortality of a series of bacteriemic patients . MATERIAL AND METHODS: A prospective study of bloodstream infections with clinical significance detected in a secondary hospital of 650 beds over period from May 1998 to May 1999 . The true bacteriemia was defined in basis to the criteria both the physician and microbiologist . A total of 16 variables were defined and categorized such as clinical-epidemiologic, intrinsic risk factor, extrinsic risk factor, outcome and survival . We used SPSS statistical package: For cuantitative variables we carried out with the mean with confidence interval of 95%, for cualitative variables: number and % . Univariate analysis of the results was carried out with the X2 test and t Student, the survival was expressed with Kaplan Meyer graphics and the logistic regression model . RESULTS: A total of 320 positive blood cultures were studied but only 272 blood cultures were considered true bacteriemia in 259 patients . The calculated incidence of significant episodes of bacteriemia per 1000 admissions/year was 13 . The overall mortality was 22% whereas death attributable to bacteriemia was 16% . The mean age was 66.9 years (IC 95% 65-69), 59% episodes occurred in men . The 78% episodes occurred in patients hospitalized in medical services . 52% episodes were of nosocomial infection and 48% of community acquired infection . According to the severity of the underlying disease, 15% had fatal diseases and 35% episodes occurred in patients without underlying disease . According to the univariant analysis, the variables which where significantly associated with greater risk death were: etiology (fungus), septic shock, the inadequate antibiotic therapy, presence of extrinsic factors (central intravenous catheter, performance of invasive procedures, previous antimicrobial therapy) and the hospital stay of less than 10 days . According to the multivariable analysis showed that the factors remaining independent predictors of mortality were: septic shock (p < 0.0001, OR: 8), inadequate antimicrobial therapy (p < 0.005, OR: 6.7), existence of two or more extrinsic risk factors (p < 0.04) . CONCLUSIONS: The presence of septic shock was the most important variable which influenced in the mortality in our serie, together with inappropriate antimicrobian therapy and the association of various extrinsic risk factors . These variables could be modified partly, for this reason the aggressive hemodynamic control and the early and appropriate antibiotic therapy would be the support of the successful bacteriemia management.

Clin Infect Dis, 2001 Nov 1, 33(9), 1495 - 501 Epub 2001 Oct 04.
National shortages of antimicrobial agents: results of 2 surveys from the Infectious Diseases Society of America Emerging Infections Network; Strausbaugh LJ et al.; In November 1999 and August 2000, the Infectious Diseases Society of America Emerging Infections Network (EIN) surveyed its members about shortages of antimicrobial agents in their hospitals and medical centers . Almost 90% of the members had encountered shortages of 1 or more agents in 1999 . Of 496 respondents, 382 (77%) reported diminished supplies of penicillin G . Other agents in short supply included meropenem (38%), ticarcillin with or without clavulanate (24%), cefazolin (20%), gentamicin (50%), and nafcillin-oxacillin (13%) . In 2000, 291 (60%) of 485 respondents reported shortages of penicillin G, but significantly fewer members had experienced a lack of other agents . In both surveys, members indicated that shortages had affected numerous therapeutic indications . In 1999, members estimated that shortages had affected thousands of patients . In 2000, they estimated that fewer patients were affected . The results of these 2 EIN surveys raise questions about the forces that govern the availability of these valuable therapeutic resources.

Curr Opin Microbiol, 2001 Oct, 4(5), 526 - 34
Combinatorial biosynthesis of antimicrobials and other natural products; Rodriguez E et al.; Combinatorial biosynthesis utilizes the enzymes from antibiotic (and other natural product) biosynthetic pathways to create novel chemical structures . The manipulation of modular polyketide synthases (PKSs) has been the major focus of this effort and has led to the production of, for example, several erythromycin analogs . Many new tools for manipulating and studying these multifunctional enzymes have been developed . These include multiple hosts and expression systems, enzymology tools for in vitro study, and ways to engineer pre-PKS and post-PKS pathways . The result is more rational and faster methods of engineering new compounds for the development of chemotherapeutic agents from natural products . The most significant recent advances in combinatorial biosynthesis are outlined.

Curr Opin Microbiol, 2001 Oct, 4(5), 515 - 9
Discovering essential and infection-related genes; Lehoux DE et al.; Transposon-based approaches are very powerful for identification of essential and infection-related genes in bacteria, particularly in the context of microbial genomics . We describe recent progress in several of these approaches, and their underlying principles . The essential gene test (EGT) is a transposon-based technique that can rapidly identify a nucleotide sequence from a database as essential or dispensable . Also, variations of in vitro transposon mutagenesis applications, such as genomic analysis and mapping by in vitro transposition (GAMBIT), are described . The development of techniques including PCR-based signature-tagged mutagenesis is now used to find essential virulence genes in different bacterial hosts . These approaches form the basis for the identification of microbial targets in development of novel antimicrobials and vaccines by the biotechnology and pharmaceutical industry.

Curr Opin Microbiol, 2001 Oct, 4(5), 500 - 8
Multidrug resistance in Gram-negative bacteria; Poole K; Broadly specific, so-called multidrug, efflux mechanisms are now known to contribute significantly to intrinsic and acquired multidrug resistance in a number of Gram-negative bacteria, and the boom in bacterial genomics has confirmed the distribution of these systems in all bacteria . This broad distribution of multidrug transporters lends a certain credibility to suggestions that they play a housekeeping role in the cell, beyond any contributions they may make to antimicrobial efflux and resistance . In many instances, these transporters are dispensable, arguing against their carrying out essential cellular functions; nevertheless, the multiplicity of these broadly specific export systems within a given microorganism, often with overlapping substrate specificity, may explain the dispensability of individual exporters . Whatever their intended function, however, their conservation in so many organisms highlights their probable general importance in antimicrobial resistance, particularly in Gram-negative bacteria whose outer membranes work synergistically with many of these export systems to promote drug exclusion.

Curr Opin Microbiol, 2001 Oct, 4(5), 493 - 9
Veterinary use and antibiotic resistance; Teuber M; Globally, an estimated 50% of all antimicrobials serve veterinary purposes . Bacteria that inevitably develop antibiotic resistance in animals comprise food-borne pathogens, opportunistic pathogens and commensal bacteria . The same antibiotic resistance genes and gene transfer mechanisms can be found in the microfloras of animals and humans . Direct contact, food and water link animal and human habitats . The accumulation of resistant bacteria by the use of antibiotics in agriculture and veterinary medicine and the spread of such bacteria via agriculture and direct contamination are documented.

Peptides, 2001 Oct, 22(10), 1683 - 90
Affinity driven molecular transfer from erythrocyte membrane to target cells; Feder R et al.; A wide variety of antimicrobial peptides are known to bind to - and disrupt microbial plasma membranes . Recently, derivatives of the antimicrobial peptide dermaseptin S4 were shown to selectively disrupt the plasma membrane of the intracellular parasite Plasmodium falciparum without harming that of the mammalian host cell . The resulting antimalarial activity is allegedly exerted after the harmless peptide binding to the membrane of the host cell, followed by peptide translocation across a number of intracellular membrane systems and interaction with that of the intraerythrocyte parasite . In this study, we present evidence in support of the ability of a membrane-bound peptide, the dermaseptin S4 derivative K(4)-S4(1-13)a, to transfer from red blood cells (RBCs) to another distant membrane . Binding of K(4)-S4(1-13)a to the plasma membrane of RBCs was assessed in vitro and in vivo, and found to be rapid, spontaneous and receptor independent, as was the transfer of the RBC-bound peptide to the plasma membrane of microorganisms . The present study further provides a basis for the possible use of RBCs as a transport vehicle to deliver drugs to distant targets . This drug delivery system involves the transient "loading" of RBCs with a lipophilic "hook" peptide . Such a peptide has enough affinity for the RBC's plasma membrane to bind to the membrane, but given the opportunity, the peptide will exit its position and transfer to another (target) cell for which it has a greater affinity . The efficacy of such an affinity driven transfer system was demonstrated experimentally by the transfer of K(4)-S4(1-13)a from pre-loaded RBCs to bacteria, yeast and protozoan target cells.

Peptides, 2001 Oct, 22(10), 1643 - 50
Processing site and gene structure for the murine antimicrobial peptide CRAMP; Pestonjamasp VK et al.; Cathelicidins are a mammalian gene family notable for the presence of an antibiotic peptide encoded at the carboxy-terminal domain of the nascent pre-pro-protein . Following proteolytic release, this peptide has direct antimicrobial activity . To understand the function and regulation of cathelicidin we investigated the peptide processing site and gene structure of the mouse cathelicidin CRAMP . Amino acid sequencing of the purified native 5 kDa peptide identified the functionally critical amino terminal sequence of mature CRAMP . Characterization of the CRAMP gene (Cnlp) showed homology in structure and sequence identity in several potential transcription factors binding sites found in the human cathelicidin LL-37 . Overall, CRAMP shows striking similarities with LL-37, making it a useful model for study of human cathelicidin function and regulation.

Peptides, 2001 Oct, 22(10), 1629 - 41
From "carpet" mechanism to de-novo designed diastereomeric cell-selective antimicrobial peptides; Shai Y et al.; Living organisms of all types produce a large repertoire of gene-encoded, net positively charged, antimicrobial peptides as part of their innate immunity to microbial invasion . Despite significant variations in composition, length and secondary structure most antimicrobial peptides are active in micromolar concentrations, suggesting a common general mechanism for their mode of action . Many antimicrobial peptides bind bacterial phospholipid membranes up to a threshold concentration, followed by membrane permeation/disintegration (the "carpet" mechanism) . Recent data suggest that the details of the permeation pathways may vary for different peptides and are assigned to different modes of action . Accumulating data reveal that the molecular basis for cell selectivity is the ability of peptides to specifically bind the negatively charged bacterial membrane, as well as their oligomeric state in solution and in the membrane . Based on the "carpet" mechanism and the role of the peptide oligomeric state, a novel group of diastereomeric (containing D- and L-amino acids) antimicrobial peptides were developed . These peptides may serve as promising templates for the future designs of antimicrobial peptides.

AIDS Patient Care STDS, 2001 Sep, 15(9), 453 - 8
Burkitt's/Burkitt's-like lymphoma presenting as bacterial sinusitis in two HIV-infected children; Robinson MR et al.; Two children (ages 12 and 13 years) with transfusion-acquired human immunodeficiency virus (HIV) infection presented with facial pain and rhinorrhea . Radiographic imaging showed extensive paranasal sinus disease, presumed to be bacterial sinusitis, and the patients were treated with broad-spectrum oral antibiotics . Both patients were unresponsive to oral agents and were switched to intravenous antibiotics . Despite aggressive antimicrobial therapy, one patient (case 1) developed increased periorbital swelling and proptosis, and the other patient (case 2) developed symptoms of nasopharyngeal obstruction . Repeat imaging showed progression of the infiltrative process extending from the paranasal sinuses into the orbit (case 1), and nasopharynx (case 2) . Surgical exploration and tissue biopsies were performed on both patients and the histopathology was consistent with Burkitt's/Burkitt's-like lymphoma . Combination systemic and intrathecal chemotherapy resulted in a complete remission in both patients . These reports illustrate the fact that Burkitt's/Burkitt's-like lymphoma in the paranasal sinuses may initially masquerade as an acute bacterial sinusitis . The ability of the tumor to extend rapidly from the sinuses into the orbit and nasopharynx reinforces the importance of early diagnosis and treatment . Burkitt's/Burkitt's-like lymphoma in the paranasal sinuses has not been previously described in HIV-infected children.

Chemotherapy, 2001, 47 Suppl 4, 11 - 8; discussion 26-7
Optimal treatment strategies for community-acquired pneumonia: non-responders to conventional regimens; File TM Jr; When patients with community-acquired pneumonia (CAP) fail to respond after initiation of empirical therapy, it is necessary for the physician to consider a number of possibilities . The diagnosis should be reviewed, with consideration given to both non-infectious and infectious illnesses . If the diagnosis is correct, the failure may relate to three areas: host-related problems, including overwhelming infection and empyema, pathogen-related problems, including infection caused by an unusual or resistant pathogen, and drug-related problems, including inappropriate dose of drug, poor compliance, malabsorption, and drug interactions . A systematic therapeutic approach including a microbiological evaluation to identify the causative pathogen and its susceptibility will help to ensure that an appropriate antimicrobial agent is used .

Clin Microbiol Rev, 2001 Oct, 14(4), 821 - 35, table of contents
Molecular machinations: chemokine signals in host-pathogen interactions; Chensue SW; Chemokines and their G-protein-coupled receptors represent an ancient and complex system of cellular communication participating in growth, development, homeostasis and immunity . Chemokine production has been detected in virtually every microbial infection examined; however, the precise role of chemokines is still far from clear . In most cases they appear to promote host resistance by mobilizing leukocytes and activating immune functions that kill, expel, or sequester pathogens . In other cases, the chemokine system has been pirated by pathogens, especially protozoa and viruses, which have exploited host chemokine receptors as modes of cellular invasion or developed chemokine mimics and binding proteins that act as antagonists or inappropriate agonists . Understanding microbial mechanisms of chemokine evasion will potentially lead to novel antimicrobial and anti-inflammatory therapeutic agents.

Dent Traumatol, 2001 Aug, 17(4), 185 - 7
Revascularization of an immature permanent tooth with apical periodontitis and sinus tract; Iwaya SI et al.; A necrotic immature mandibular second premolar with periapical involvement in a 13-year-old patient was treated . Instead of the standard root canal treatment protocol and apexification, antimicrobial agents were used in the canal, after which the canal was left empty . Radiographic examination showed the start of apical closure 5 months after the completion of the antimicrobial protocol . Thickening of the canal wall and complete apical closure was confirmed 30 months after the treatment, indicating the revascularization potential of a young permanent tooth pulp into a bacteria-free root canal space.

J Periodontal Res, 2001 Oct, 36(5), 285 - 94
Localized antimicrobial peptide expression in human gingiva; Dale BA et al.; The stratified epithelia of the oral cavity are continually exposed to bacterial challenge that is initially resisted by innate epithelial factors and by the recruitment of neutrophils . Antimicrobial peptides from phagocytes and epithelia contribute to this antimicrobial barrier . Using antibodies and in situ hybridization, we explored antimicrobial peptide expression in the varied epithelia of the periodontium and in cultured gingival epithelial cells . In gingival tissue, mRNA for the beta-defensins, human beta-defensin 1 (hBD-1) and human beta-defensin 2 (hBD-2) was predominately localized in suprabasal stratified epithelium and the peptides were detected in upper epithelial layers consistent with the formation of the stratified epithelial barrier . In cultured epithelial cells, both hBD-1 and -2 peptides were detected only in differentiating, involucrin-positive epithelial cells, although hBD-2 required stimulation by proinflammatory mediators or bacterial products for expression . Beta-defensins were not detected in junctional epithelium (JE) that serves as the attachment to the tooth surface . In contrast, alpha-defensins and cathelicidin family member LL-37 were detected in polymorphonuclear neutrophils (PMNs) that migrate through the JE, a localization that persists during inflammation, when the JE and surrounding tissue are highly infiltrated with PMNs . Thus, the undifferentiated JE contains exogenously expressed alpha-defensins and LL-37, and the stratified epithelium contains endogenously expressed beta-defensins . These findings show that defensins and other antimicrobial peptides are localized in specific sites in the gingiva, are synthesized in different cell types, and are likely to serve different roles in various regions of the periodontium.

J Periodontal Res, 2001 Oct, 36(5), 275 - 84
Chewing sticks: timeless natural toothbrushes for oral cleansing; Wu CD et al.; It is generally accepted that oral hygiene maintenance through regular removal of dental plaque and food deposits is an essential factor in the prevention of dental caries and periodontal disease . Methods for oral hygiene vary from country to country and from culture to culture . Despite the widespread use of toothbrushes and toothpastes, natural methods of tooth cleaning using chewing sticks selected and prepared from the twigs, stems or roots from a variety of plant species have been practised for thousands of years in Asia, Africa, the Middle East and the Americas . Selected clinical studies have shown that chewing sticks, when properly used, can be as efficient as toothbrushes in removing dental plaque due to the combined effect of mechanical cleaning and enhanced salivation . It has also been suggested that antimicrobial substances that naturally protect plants against various invading microorganisms or other parasites may leach out into the oral cavity, and that these compounds may benefit the users by protection against cariogenic and periodontopathic bacteria . Some clinical epidemiological studies are in support of this, and many laboratory investigations have suggested the presence of heterogeneous antimicrobial components extractable using different chemical procedures . A few recent studies have identified some of the active antimicrobial compounds . Today, chewing sticks are still used in many developing countries because of religion and or tradition, and because of their availability, low cost and simplicity . The World Health Organization also encourages their use . The Year 2000 Consensus Report on Oral Hygiene states that chewing sticks may have a role to play in the promotion of oral hygiene, and that evaluation of their effectiveness warrants further research.

Expert Opin Pharmacother, 2001 Aug, 2(8), 1275 - 82
Current pharmacotherapy of pertussis; Kerr JR et al.; Human infection with Bordetella pertussis and Bordetella parapertussis causes significant morbidity and mortality . While universal immunisation represents the mainstay of prevention, the purpose of this review is to summarise the current options for antimicrobial chemotherapy of pertussis . Several chemotherapeutic approaches have an important place in therapy and in infection control . Supportive treatment including nasopharyngeal suction, oxygen and parenteral fluids, is essential for infants < 1 year who are at greatest risk of complications and permanent sequelae . Steroids and beta2-agonists are also used in the management of severe neonatal pertussis . Several antibiotics have been shown to reduce the level of bacterial colonisation of the respiratory tract, however, erythromycin is accepted to be the treatment of choice . Erythromycin reduces severity and duration of disease, even if started during the paroxysmal phase . A 14 day course is recommended although side effects may limit compliance; a recent study indicates that a 7 day course may have similar efficacy in terms of eradication and prevention of relapse . Alternatives to erythromycin are clarithromycin, azithromycin and trimethoprim-sulfamethoxazole . Fluoroquinolones have good in vitro activity against both B . pertussis and B . parapertussis and may be useful in the treatment of adult patients with pertussis, although there are no supporting clinical data at present . Erythromycin prophylaxis is also recommended for close household contacts of patients with pertussis.

J Reprod Med, 2001 Sep, 46(9), 849 - 52
Postpartum herpes simplex endometritis . A case report; Hixson MJ et al.; BACKGROUND: Herpes simplex virus (HSV) can cause postpartum endometritis . The clinical diagnosis of HSV endometritis has been reported previously . The disease is responsive to acyclovir intravenously . CASE: A 22-year-old woman, gravida 2, para 1, status post primary cesarean section for a double footling breech presentation, developed a persistent postpartum fever . Simulating the febrile course of septic pelvic thrombophlebitis, the patient's condition was unresponsive to broad-spectrum antimicrobials and heparin therapy . Active herpetic lesions and a positive cervical culture for herpes simplex prompted the use of intravenous acyclovir . Rapid resolution of the fever and the similarity to previous case reports suggested the clinical diagnosis of herpes simplex endometritis . CONCLUSION: The diagnosis of postpartum herpes simplex endometritis should be considered when managing a persistent postpartum fever unresponsive to aggressive antimicrobial and heparin therapy . Immediate resolution of the fever should occur with the use of acyclovir.

Am J Infect Control, 2001 Oct, 29(5), 281 - 3
National and regional assessment of the antibacterial soap market: a step toward determining the impact of prevalent antibacterial soaps; Perencevich EN et al.; BACKGROUND: Consumer antibacterial soaps contain triclosan or triclocarban . No scientific data have been published to suggest that the use of antibacterial agents in household products prevents infection, and triclosan resistance mechanisms have recently been identified . Little data are available regarding the prevalence of antibacterial agents contained in consumer soaps . METHODS: In a physician-performed survey of 23 stores in 10 states from December 1999 to April 2000, investigators determined the number of national brand liquid and bar soaps and percent of each containing antibacterial agents sold at national chain, regional grocery, and Internet stores . RESULTS: Antibacterial agents were present in 76% of liquid soaps and 29% of bar soaps available nationally . There were no differences found between national, regional, and Internet stores . CONCLUSION: Overall, 45% of surveyed soaps contain antibacterial agents . With limited documented benefits and experimental laboratory evidence suggesting possible adverse effects on the emergence of antimicrobial resistance, consumer antibacterial use of this magnitude should be questioned.

Biologist (London), 2001 Oct, 48(5), 209 - 12
Natures antibiotics: the potential of antimicrobial peptides as new drugs; Diamond G; Animals and plants make a variety of substances to prevent potentially lethal infections . These include small antibiotic proteins, or peptides, which target bacteria, fungi and viruses . Research into these peptides not only give us an insight into how we naturally prevent infections, but can also provide us with new drugs to treat the ever-increasing danger of infections caused by antibiotic-resistant bacteria.

J Nutr, 2001 Oct, 131(10), 2805S - 2808S
Viral induction of type 2 diabetes and autoimmune liver disease; Mason A; Cross-sectional studies performed worldwide have shown that hepatitis C virus (HCV) infection is linked with type 2 diabetes, but these endocrine and liver diseases have an insidious onset, and it has been difficult to establish that patients acquire HCV infection before the development of diabetes . It is likely that investigations in small animal models or in vitro systems will be required to determine whether a causal relationship of HCV infection and the development of diabetes can be established . We have developed an in vitro model to study the viral induction of primary biliary cirrhosis (PBC) based on the phenotype of the diseased biliary epithelial cells . PBC patients make antimitochondrial antibodies and also express proteins reactive to these antibodies on their biliary epithelium . In coculture studies we have found that normal biliary epithelial cells develop the phenotypic manifestation of PBC in vitro specifically when cultivated with lymph nodes from PBC patients and not with relevant liver disease control subjects . We have also cloned a novel human retrovirus from a PBC biliary epithelium cDNA library and confirmed that the development of the PBC phenotype in vitro coincides with the presence of this virus . In clinical trials using antiretroviral therapy, we have observed a reversal of ductopenia as well as improvements in histology and hepatic biochemistry in patients with PBC . As Koch's postulates are not readily applicable to chronic diseases, we have used cocultivation viral transmission model in vitro and antimicrobial clinical studies in vivo to help establish a causal relationship with a retrovirus infection and the phenotypic manifestation of disease.

Am J Med, 2001 Oct 1, 111(5), 367 - 74
Efficacy and safety of oral and early-switch therapy for community-acquired pneumonia: a randomized controlled trial; Castro-Guardiola A et al.; PURPOSE: We sought to determine the safety, efficacy, and cost of oral therapy for patients with community-acquired pneumonia . In patients with nonsevere pneumonia, conventional (parenteral) treatment was compared with the oral route; in patients with severe pneumonia, conventional treatment was compared with early switch from parenteral to oral therapy . SUBJECTS AND METHODS: We randomly assigned 85 hospitalized patients with nonsevere pneumonia to one of two groups: 41 received oral antimicrobials from admission, and 44 received parenteral antimicrobials until they had been afebrile for 72 hours before switching to oral treatment . We randomly assigned 103 patients with severe pneumonia who had initially been treated with parenteral antimicrobials to one of two groups: 48 were switched to oral therapy after 48 hours of treatment (early switch), and 55 received a full 10-day course of parenteral antibiotics . RESULTS: Among patients with nonsevere pneumonia, there were no deaths in the oral treatment group, and one death (2%) in the parenteral treatment group (95% confidence interval {CI} for between-group {oral minus parenteral} difference: -7% to 2%, P = 0.3) . The time to resolution of morbidity was < or =5 days in 34 (83%) patients in the oral treatment group and 39 (88%) patients in the parenteral treatment group (P = 0.5); there were treatment failures in 4 (10%) patients in the oral treatment group and 14 (32%) patients in the parenteral treatment group (P = 0.02) . Among patients with severe pneumonia, there was one (2%) death in the early-switch group and no deaths in the full course of parenteral antibiotics groups (95% CI for between-group {early switch vs . full course} difference: -2% to 6%, P = 0.5) . The time to resolution of morbidity was < or =5 days in 38 (79%) patients in the early-switch group and 41 (75%) in the full-course group (P = 0.3) . There were 12 (25%) treatment failures in the early-switch group and 13 (24%) in the full-course group (P = 0.9) . There were fewer adverse events in the oral and early-switch groups, primarily due to lower rates of infusion-related phlebitis . Significant cost savings, mainly due to a shorter hospitalization, occurred among patients with severe pneumonia in the early-switch group . CONCLUSION: Inpatients with nonsevere community-acquired pneumonia can be effectively and safely treated with oral antimicrobials from the time of admission, whereas those with severe pneumonia can be treated with early-switch therapy.

Infect Control Hosp Epidemiol, 2001 Jul, 22(7), 459 - 63
The role of the laboratory in infection prevention and control programs in long-term-care facilities for the elderly; Simor AE; Hospital infection prevention and control programs rely extensively on diagnostic microbiology laboratory testing . However, specimens for microbiological evaluation are less likely to be obtained from elderly residents of long-term-care facilities (LTCFs) . In this article, issues regarding laboratory utilization and the potential role of the microbiology laboratory in infection prevention and control programs in LTCFs are reviewed . The role of the laboratory in infection surveillance, in the management of antimicrobial resistance, and in outbreak investigation are highlighted.

Biochemistry, 2001 Aug 14, 40(32), 9570 - 8
The membrane-proximal tryptophan-rich region of the HIV glycoprotein, gp41, forms a well-defined helix in dodecylphosphocholine micelles; Schibli DJ et al.; The membrane-proximal tryptophan-rich region of the HIV transmembrane glycoprotein, gp41, plays an important role in the membrane fusion reaction . Using NMR spectroscopy, we have studied the tertiary structure of a synthetic 19-residue amidated peptide (NH2-KWASLWNWFNITNWLWYIK-CONH2) corresponding to this region in membrane-mimetic environments . Initial experiments in sodium dodecyl sulfate/H2O micelles and trifluoroethanol gave poor results, because of low solubility . However, in dodecylphosphocholine micelles, we obtained excellent 500 and 800 MHz NMR spectra, suggesting that the peptide has a preference for a zwitterionic membrane-like environment . The final NMR structures demonstrated a well-defined helical peptide with a backbone rmsd of 0.47 +/- 0.18 A . Four of the five tryptophan residues, as well as the tyrosine residue, formed a "collar" of aromatic residues along the axial length of the helix . By analogy to related tryptophan-rich antimicrobial peptides, the structure indicates that the aromatic residues of the HIV peptide are positioned within the membrane-water interface of a phospholipid bilayer . This is confirmed by the observation of direct NOEs between the aromatic residues of the peptide to the headgroup and interfacial protons of prototonated dodecylphosphocholine . The bulk of the polar residues are positioned on one face of this structure, with the hydrophobic phenylalanine side chain on the opposing face, forming an amphipathic structure . This work shows that the Trp-rich membrane-proximal region of HIV and related viruses can bind to the surfaces of zwitterioninc membranes in a "Velcro-like" manner.

Expert Opin Pharmacother, 2001 Jul, 2(7), 1093 - 7
The role of infectious agents in pulmonary and systemic vascular disease; Egermayer P; With emphasis on the pulmonary circulation, three general types of vascular disease are discussed: fibroproliferative (atherosclerosis), cellular proliferative (endothelial neoplasms) and inflammatory (granulomatous vasculitis) . The causes of these phenotypic responses are invariably multifactorial, but infectious agents including viruses, Chlamydia, Helicobacter, Rickettsia, mycobacteria and other infectious agents have been increasingly implicated in the pathophysiology . The classifications of vascular diseases are complicated and confusing and many eponymous diseases are specific variations of more general disease processes . The pivotal role of the monocyte/macrophage and T-cells is discussed, particularly with regard to intracellular infections . In addition to antimicrobial therapy, modifications of macrophage function by IFN-gamma and blockade of TNF are attractive areas for therapeutic research . Diseases with many synergistic causes will probably also require multifaceted therapeutic interventions.

Biochemistry, 2001 Oct 9, 40(40), 11965 - 74
Reduced outer membrane permeability of Escherichia coli O157:H7: suggested role of modified outer membrane porins and theoretical function in resistance to antimicrobial agents; Martinez MB et al.; Outer membrane permeability of Escherichia coli O157:H7 was determined by an in vivo kinetic model with the periplasmic enzyme alkaline phosphatase {Martinez et al . (1996) Biochemistry 35, 1179-1186} . p-Nitrophenyl phosphate (PNPP) substrate, added to intact bacteria, must diffuse through the outer membrane to reach the enzyme . At low substrate concentration the bacterium was in the perfectly reactive state where all molecules that entered the periplasm were captured and converted to product . Transmembrane diffusion was rate limiting, and the permeability of the outer membrane was determined from kinetic properties . The O157:H7 strain grown at 30 degrees C showed one-sixth the permeability of wild-type E . coli grown at 30 degrees C . Wild-type bacteria grown at >/=37 degrees C show a physiological response with a shift in expression of outer membrane porins that lowered permeability to PNPP by approximately 70% . The O157:H7 strain did not display this temperature-sensitive shift in permeability even though a change in porin expression could be visualized by staining intensity of Omp F and Omp C on acrylamide gels . Altered behavior of the O157:H7 membrane was also indicated by a several thousand-fold lower response to transformation relative to wild-type E . coli . Matrix-assisted laser desorption ionization time of flight mass spectrometry and electrospray ionization mass spectrometry confirmed the expression of the Omp F and Omp C variants that are unique to E . coli O157:H7 . This reduced outer membrane permeability can contribute to enhanced resistance of O157:H7 to antimicrobial agents.

Cutis, 2001 Sep, 68(3), 201 - 6
Selecting topical and systemic agents for recurrent aphthous stomatitis; Eisen D et al.; Recurrent aphthous stomatitis (RAS) is one of the most common oral diseases worldwide . Although the exact etiology of RAS remains unknown, a variety of topical and systemic preparations may be used for palliation or prevention . In most patients with RAS, topical agents, including over-the-counter preparations such as amlexanox, prescribed corticosteroids, or antimicrobial agents, are sufficient to control the disease . Patients with frequent exacerbations or those with a severe form of RAS that is unresponsive to topical treatments often require systemic agents to control their disease . These include corticosteroids, colchicine, dapsone, pentoxifylline, and thalidomide . All therapies are palliative, and none result in permanent remission.

Am Fam Physician, 2001 Sep 15, 64(6), 999 - 1004
Appropriate antimicrobial prescribing: approaches that limit antibiotic resistance; Colgan R et al.; Since the introduction of antimicrobial agents, there has been an association between antibiotic use and the development of antimicrobial resistance . Antibiotic therapy eradicates not only pathogenic organisms but also the protective normal flora . This so-called "selective pressure" results in colonization with bacteria that are resistant to the original therapy . The result has been an increase over the past two decades in antibiotic resistance among common bacterial causes of outpatient infections . Several studies have demonstrated that a substantial portion of the antibiotics prescribed in the outpatient setting are given for viral illnesses or bacterial diseases where the benefit of antibacterial therapy is marginal . The reasons for prescribing antibiotics in these situations are related to medical and social factors . Physicians should be familiar with the clinical situations in which they should provide antibiotics and those in which they may safely be withheld . Physicians should understand the motivations of patients who are seeking antibiotics and provide education, empathy and alternative treatments.

Cell Mol Life Sci, 2001 Aug, 58(9), 1179 - 88
Lipopeptaibols, a novel family of membrane active, antimicrobial peptides; Toniolo C et al.; Lipopeptaibols are members of a novel group of naturally occurring, short peptides with antimicrobial activity, characterized by a lipophilic acyl chain at the N-terminus, a high content of the turn/helix forming alpha-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus . The amino acid sequences range from 6 to 10 residues and the fatty acyl moieties from 8 to 15 carbon atoms . The peptide portion of lipopeptaibols can be shorter than those of the nonlipidated peptaibols that range from 10 to 19 amino acid residues . The longest peptides fold into a mixed 3(10)/alpha helix, whereas the shortest peptides tend to adopt a beta-turn/sheet structure . Using solution methodologies, a series of analogues of trichogin GA IV was synthesized which allowed determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity and exploitation of a number of spectroscopic techniques aimed at determining its preferred conformation under a variety of conditions and investigating in detail its mode of interaction with, and its effect on, the phospholipid membranes.

Clin Infect Dis, 2001 Nov 1, 33(9), 1573 - 8 Epub 2001 Sep 26.
Measuring the economic costs of antimicrobial resistance in hospital settings: summary of the Centers for Disease Control and Prevention-Emory Workshop; Howard D et al.; Health systems administrators and clinicians need refined calculations of the attributable cost of infections due to drug-resistant microorganisms to develop and assess cost-effective prevention strategies that deal with these infections . To date, however, efforts to provide this information have yielded widely variable and often conflicting estimates . This lack of reproducibility is largely attributable to problems in study design and in the methods used to identify and measure costs . Addressing these methodological issues was the focus of a workshop that included participants from a broad range of backgrounds, including economics, epidemiology, health care management, health care outcomes research, and clinical care . This workshop summary presents the advantages and disadvantages of various research designs as well as particular methodological issues related to the measurement of the economic cost of resistance in health care settings . Suggestions are made for needed common definitions and approaches, study areas for future research are considered, and priority investigations are identified.

Mol Pathol, 2001 Oct, 54(5), 289 - 92
Calprotectin inhibits matrix metalloproteinases by sequestration of zinc; Isaksen B et al.; BACKGROUND/AIMS: Calprotectin, a 36 kDa protein present in neutrophil cytoplasm, has antimicrobial and apoptosis inducing activities, which are reversed by the addition of zinc . Matrix metalloproteinases (MMPs), a family of zinc dependent enzymes, are important in many normal biological processes including embryonic development, angiogenesis, and wound healing, but also pathological processes such as inflammation, cancer, and tissue destruction . The aim of this study was to investigate whether calprotectin can inhibit MMP activity, and whether such inhibition could be overcome by the addition of zinc . METHODS: MMP activity was measured by the degradation of substrates precoated on to microwells, and visualised by Coomassie blue staining of residual substrate . Seven metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, and MMP-13) were tested against two substrates: gelatin and alpha-casein . RESULTS: All MMPs except MMP-1 were active against gelatin, whereas MMP-7 was the only enzyme active against alpha-casein . The addition of calprotectin inhibited the activity of all the MMPs, but different concentrations of the protein, from 0.3 microM to > 11microM, were necessary to produce a 50% inhibition of the MMPs . Inhibition by calprotectin was largely overcome by the addition of zinc . CONCLUSIONS: The findings suggest that calprotectin inhibits MMPs by sequestration of zinc . The data also suggest that MMPs have different affinities for zinc and that calprotectin has a lower zinc affinity than the MMPs.

Diagn Microbiol Infect Dis, 2001 Aug, 40(4), 207 - 9
Effect of extended pre-incubation with chlamydia pneumoniae and extended incubation with antimicrobial on the minimum inhibitory concentrations (MICs) of five antimicrobials; Stewart CE et al.; There is no single standard methodology for in vitro susceptibility testing for Chlamydia pneumoniae, but many investigators pre-incubate this organism with the cell monolayer for 1 h prior to adding antimicrobial and incubating for 72 h . The aim of this study was to determine the effect of extended C . pneumoniae pre-incubation, and extended incubation in the presence of antimicrobial, on the MICs of 5 antimicrobials . MICs were determined for 5 ATCC strains of C . pneumoniae by employing similar methods as those previously described in the literature . MICs were then determined following 1, 4, 6, 20 and 24 h C . pneumoniae pre-incubation . Finally, MICs were determined following 1 and 24 h C . pneumoniae pre-incubation, and 48 and 72 h incubation with antimicrobial and organism . Extending the incubation time in the presence of antimicrobial from 48 to 72 h had little or no effect on MICs . Similarly, pre-incubation periods of less than 20 h had little effect on MICs, but MICs increased significantly with 20 and 24 h pre-incubation.

J Pept Res, 2001 Sep, 58(3), 213 - 20
Effects of temporins on molecular dynamics and membrane permeabilization in lipid vesicles; Rinaldi AC et al.; Temporins are a novel family of small (10-13 residues) cationic antimicrobial peptides recently isolated from the skin of the European red frog Rana temporaria . Although recently acquired evidence shows that temporins have the potential to kill bacteria by permeabilizing the cytoplasmic membrane, the molecular mechanisms of membrane selectivity and permeabilization are largely unknown . In this study, it was found that temporins cause the release of fluorescent markers entrapped in phosphatidylcholine liposomes in a manner that depends significantly on the size of the solute . Temporins were also shown to lack a detergent-like effect on lipid vesicles, indicating that marker leakage caused by these peptides is not due to total membrane disruption but to perturbation of bilayer organization on a local scale . Binding of temporins to liposomes did lead to a small increase in lipid hydrocarbon chain mobility, as revealed by EPR spectroscopy of nitroxide-labeled fatty acids incorporated in the bilayer . Reference experiments were conducted using the bee venom peptide melittin, whose properties and behavior in natural and model membrane systems are well known . Our findings for temporins are discussed in relation to the models proposed to date to account for the action of antimicrobial peptides on membranes.

Anaesthesia, 2001 Oct, 56(10), 965 - 79
Pharmaceutics for the anaesthetist; MacPherson RD; Pharmaceutics is that branch of science concerned with the manufacture and formulation of pharmaceutical products, and is a subject almost exclusively in the domain of pharmacists and those concerned with pharmaceutical manufacture . However, there are some aspects of pharmaceutics that are of particular importance to the anaesthetist, such as the pharmacology of the various preservatives, antimicrobials and other additives found in anaesthetic products, and an understanding of basic processes such as emulsification and lyophylisation . This review aims to survey those areas.

Respir Med, 2001 Sep, 95(9), 728 - 33
Benzalkonium chloride as a preservative in nasal solutions: re-examining the data; Graf P; Recent studies have suggested that benzalkonium chloride (BKC), an antimicrobial agent used as a preservative in nasal sprays, lacks deleterious effects on the nasal ciliated epithelium . Other data, including recent in vivo findings, suggest that BKC may, in fact, produce adverse clinical effects on human nasal tissue, including the aggravation of rhinitis medicamentosa . Toxic effects have also been reported . In light of the discrepancy between negative results and studies suggesting no safety concerns, we consider the possibility of problems in the design and methodology of some of the studies and in the interpretation of results . Clearly, further research is warranted to clarify the significance of conflicting findings . In the meantime, without conclusive data regarding BKC and the possibility of harmful effects, the use of nasal formulations without BKC might be a reasonable alternative.

Int J Antimicrob Agents, 2001, 18 Suppl 1, S89 - 91
Non-antimicrobial activities of macrolides; Williams JD; While using macrolides for the treatment of infectious diseases, some non-microbiological effects have been observed . The stimulation of gastrointestinal motility, which is a common side-effect of macrolides, may be advantageous in patients with poor upper gut motility . Macrolides, as well as directly inhibiting bacterial growth, may exert immunomodulatory effects . Utilisation of these properties may be useful in the treatment of chronic inflammatory conditions, especially if bacterial infection is also implicated . Preliminary evidence also suggests that the currently available macrolide antibiotics possess antitumour activity . In the future, an increased understanding of the structure-activity relationships of macrolides may result in the development of new structurally related compounds that concentrate on these pharmacological properties in addition to, or instead of, antimicrobial activity.

Int J Antimicrob Agents, 2001, 18 Suppl 1, S3 - 10
Macrolides: structures and microbial targets; Retsema J et al.; The macrolide class of antibiotics is well established and often recommended for use in the treatment of community-acquired respiratory tract infections . A number of agents with varying antimicrobial activity have been developed via chemical modification of the core macrolide structure, a macrocyclic lactam ring . Although structurally diverse, the macrolides share a common ability to bind to the bacterial 50S ribosome subunit and inhibit protein synthesis, thereby preventing bacterial multiplication . Resistance in the clinic is due to modification of the 50S subunit in the area of the peptidyl transferase center or to an efflux pump . The newer macrolides, and in particular azithromycin, with their broad-spectrum microbiological profile have extended the therapeutic uses of this class of antibiotics and ensured that they remain an integral part of the clinician's armamentarium.

Ann Pharmacother, 2001 Sep, 35(9), 1085 - 95
Is more than one quinolone needed in clinical practice?
Paladino JA.
OBJECTIVE: To review clinical information on fluoroquinolone antimicrobials to distinguish between these agents and help define their place in clinical practice . DATA SOURCES: Primary and review articles on fluoroquinolones available commercially in the US as of August 2000 were identified through MEDLINE (from 1993-August 2000) and secondary sources . STUDY SELECTION AND DATA EXTRACTION: All pertinent, published, clinical trials for levofloxacin, moxifloxacin, and gatifloxacin were included . Minimal data were included for quinolones with restricted or limited uses, including trovafloxacin, sparfloxacin, enoxacin, and lomefloxacin . Due to the quantity of data on ciprofloxacin, only more recent or pivotal trials or articles summarizing data on specific infections were included . Relevant information was included if it was believed to assist in differentiating between the fluoroquinolones for infections for which these agents would most commonly be considered . DATA SYNTHESIS: Fluoroquinolones are a potent class of intravenous and oral broad-spectrum antimicrobial agents used for treating a wide range of community-acquired and nosocomial infections . More than 10 quinolones have been approved for use; although some of these have been withdrawn from the market, numerous others are under investigation . It has become increasingly important to be able to differentiate between these agents . CONCLUSIONS: Differences in safety, antimicrobial spectrum of activity, and resistance development support the selective use of various fluoroquinolones in differing clinical situations.

Arch Surg, 2001 Sep, 136(9), 1027 - 31
Outcome after intestinal transplantation: results from one center's 9-year experience; discussion 1031-2; Farmer DG et al.; HYPOTHESIS: Outcomes after intestinal transplantation have improved during the past decade with refinements in surgical techniques as well as advances in immunosuppression and antimicrobial therapy . DESIGN: Retrospective analysis . SETTING: Tertiary care medical center, August 1991 through December 2000 . PATIENTS: Adult (5) and pediatric (12) patients with intestinal failure . All developed complications from long-term total parenteral nutrition therapy . Median age was 8.6 years and median weight was 22 kg . INTERVENTIONS: Primary intestinal transplantation with (n = 14) or without (n = 3) the liver . MAIN OUTCOME MEASURES: Patient and graft survival, viral infections, rejection, and nutritional autonomy . RESULTS: Twenty-one intestinal grafts were transplanted into the 17 recipients . All donors were cadaveric and were matched by ABO blood group and size . Patient survival at 1 and 3 years was 63% and 55%, respectively . Death-censored graft survival at 1 and 3 years was 73% and 55%, respectively . There were 1.5 acute cellular rejection episodes per graft and 3 grafts were lost to rejection . Incidences of infection with the Epstein-Barr virus and cytomegalovirus were negligible with aggressive prophylaxis and preemptive therapy . Nutritional autonomy was achieved in 69% of grafts surviving more than 30 days after intestinal transplantation . CONCLUSIONS: Intestinal transplantation is now the standard of therapy for patients with intestinal failure and complications resulting from total parenteral nutrition . Outcomes have markedly improved since initiation of the program . Aggressive immunosuppression as well as prophylaxis and preemptive antiviral therapy have led to low incidences of acute cellular rejection, Epstein-Barr virus, and cytomegalovirus . Finally, nutritional autonomy can be achieved after successful intestinal transplantation.

Klin Monatsbl Augenheilkd, 2001 Aug, 218(8), 574 - 7
{Secondary ocular syphilis with chorioretinitis of the posterior pole - a case report}; Stubiger N et al.; BACKGROUND: Diagnosis of syphilis is often very difficult due to the absence of typical organ manifestation . In addition syphilis has the ability to imitate any ocular inflammation . This may result in misdiagnosis and delay of appropriate antimicrobial therapy . Up to now the first choice therapy is penicillin . CASE REPORT: We report about an otherwise healthy, 40 year-old-woman, who was referred to the Department of Ophthalmology, University of Tuebingen, due to an unclear loss of visual acuity (OD 0.1 and OS 0.4) . The fundus examination disclosed focal chorioretinitis on the posterior pole, which was verified in fluorescein angiography . Secondary syphilis was diagnosed due to positive serological testing . Medical treatment consisted in Penicillin (i.m.) for 2 weeks and additional oral corticosteroids, which were tapered down slowly . After 3 months visual acuity had improved to 0.9 in the right and to 1.0 in the left eye . The former chorioretinitis regions showed only hyperpigmentation . CONCLUSIONS: Laboratory syphilitic testing should be performed in every uveitis.

Jpn J Cancer Res, 2001 Sep, 92(9), 959 - 67
PI3-kinase p85alpha is a target molecule of proline-rich antimicrobial peptide to suppress proliferation of ras-transformed cells; Tanaka K et al.; PR-39, which is an endogenous antimicrobial peptide, can bind to Src homology 3 domains of the NADPH complex protein p47(phox) and the signaling adapter protein p130(Cas) . Recently, we have reported that PR-39 gene transduction altered invasive activity and actin structure of human hepatocellular carcinoma cells, suggesting that this peptide affects cellular signaling due to its proline-rich motif . In order to clarify the mechanism of the PR-39 functions, we transfected the PR-39 gene into mouse NIH3T3 cells which had already been transformed with human activated k-ras gene . The PR-39 gene transfectant showed a reorganization of actin structure and suppression of cell proliferation both in vitro and in vivo . Decreases of MAP (mitogen-activated protein) kinase activity, cyclin D1 expression and JNK activity were observed in the PR-39 gene transfectant . Co-immunoprecipitation analysis revealed that PR-39 binds to PI3-kinase p85alpha, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates mitogenesis . The PI3-kinase activity of the PR-39 gene transfectant was decreased compared with that of the ras transformant . These results suggest that PR-39 alters actin structure and cell proliferation rate by binding to PI3-kinase p85alpha and suppressing the PI3-kinase activity.

Am J Dent, 2001 Jun, 14(3), 119 - 22
A model for clinical evaluation of the effect of antimicrobial agents on carious dentin; Garcia MB et al.; PURPOSE: To evaluate, longitudinally, the effect of a chlorhexidine varnish on the proteolytic activity of dentin caries in vivo . MATERIALS AND METHODS: 20 permanent molars and 8 primary molars with carious lesions in dentin were studied in subjects 18-35 yrs old (n=20), and 5-6 yrs old (n=8) respectively . These lesions were clinically evaluated according to texture and color . Carious dentin specimens were obtained by means of biopsies performed with a #4 carbide bur at the initial visit (TO) before application of a 10% chlorhexidine varnish and 2, 4, 8, and 12 wks thereafter . The dentin biopsies were immersed in Sorensen's buffer, vortexed for 30 s, and mixed with a 1.67 mM solution of n-benzoyl-DL-arginine-naphthylamide (BANA), a substrate for proteolytic enzymes . Samples were incubated overnight at 37 degrees C and color was developed with 0.1% fast garnet . The optical density (OD) of reaction mixtures was recorded photometrically . All teeth were grouped for analysis, as Mann-Whitney tests revealed no statistically significant differences between median values for OD for both age groups . ANOVA was used to compare progressive inhibition of proteolytic activity in dentin caries samples over time . RESULTS: The average proteolytic activity at the dentin substrates (OD) at TO and 2, 4, 8 and 12 wks thereafter were 0.794+/-0.089, 0.741+/-0.071, 0.676+/-0.087, 0.600+/-0.094, and 0.508+/-0.108 respectively . The chlorhexidine varnish mediated a significant inhibition of the proteolytic activity present in dentin caries after 12 wks (P<0.0001) . At T0, 100% of the carious lesions examined were characterized as soft upon exploration . After 12 wks, 54% (15/28) of the lesions were partially hardened and 46% (13/28) hardened/nonprogressing . The dentin color was yellow/light brown in 100% of the lesions at baseline, and dark brown/black in 86% (24/28) after 12 wks . CLINICAL SIGNIFICANCE: This study demonstrated that chlorhexidine varnishes arrested active caries in vivo and inhibited the proteolytic activity present in these lesions . These findings strengthen the rationale for including chlorhexidine in the overall treatment strategy for patients with high caries activity.

Ned Tijdschr Geneeskd, 2001 Sep 8, 145(36), 1749 - 51
{Relative adrenocortical insufficiency with sepsis, diagnosed and treated with hydrocortisone supplementation}; Kingma MF et al.; An 82-year-old woman was admitted to the ICU with septic shock and multiple organ failure . Despite the lack of a persistent septic focus she continued to be dependent on large doses of norepinephrine whilst receiving adequate antimicrobial therapy . After a trial treatment with hydrocortisone the norepinephrine infusion could be withdrawn within a few days and she made a full recovery . In the case of seriously ill patients the diagnosis 'relative adrenocortical insufficiency' is predominantly made on the basis of the clinical picture . The remarkable clinical response to the administration of hydrocortisone (400 mg in the first 24 h) confirmed the diagnosis . The dosage of vasopressors can be reduced remarkably quickly . The stimulatory test for adrenocorticotropin hormone (ACTH) has no added value as reference values for critically ill patients are not available and because the results do not predict the response to the treatment.

Clin Lab Med, 2001 Sep, 21(3), 631 - 60
Applying molecular biological techniques to detecting biological agents; Krafft AE et al.; Recent efforts in the civilian and military health care and public health communities are directed at strengthening surveillance systems and our national laboratory capabilities for early detection of infectious disease outbreaks . These new systems will address proper specimen collection, transport, nucleic acid processing, molecular assay diagnostic reagent and equipment development, and standardization for sensitive and rapid detection of bioagents in blood and other clinical samples . A greater understanding of the genetic diversity and virulence factors for each organism that could be used for bioterrorism would aid design of rapid molecular detection strategies . Combinations of appropriate diagnostic technologies (culture, immunoassay, and molecular assay) can provide rapid diagnostic response capabilities to microbial threats with antimicrobial resistant organisms, new emerging infectious disease agents, and possible agents of bioterrorism.

Am J Health Syst Pharm, 2001 Sep 15, 58(18), 1740 - 5
Comparison of therapeutic interchange with standard educational tools for influencing fluoroquinolone prescribing; Goldwater SH et al.; The abilities of therapeutic interchange (TI) and standard educational tools (SET) to change prescribing habits were compared . We evaluated the replacement of ciprofloxacin with levofloxacin in a four-hospital health system during a 14-month study period . Two hospitals used TI and two SET . The demographics, sites of infection, and severity of illness were analyzed for 554 patients treated at SET hospitals and 1323 patients treated at TI hospitals during a total of 2040 hospitalizations over a 14-month period . In TI hospitals, 97% of patients received levofloxacin, whereas 43% received levofloxacin in SET hospitals (p < 0.001) . Clinical outcomes were not significantly different for the two groups, although more patients in the SET hospitals received combination antimicrobial therapy . Differences in savings per patient were significant between TI hospitals ($60) and SET hospitals ($37) (p < 0.001) . The total annualized savings for all four hospitals was $156,444 . TI was more effective than SET in facilitating changes in prescribing patterns in a health care system and resulted in significant cost savings to hospitals and payers.

Exp Physiol, 2001 Sep, 86(5), 543 - 5
Adrenomedullin and proadrenomudullin N-terminal 20 peptide (PAMP) are present in human colonic epithelia and exert an antimicrobial effect; Marutsuka K et al.; The hypotensive and vasorelaxing peptides adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), were found to be distributed on the surface of the colonic mucosa . AM and PAMP showed dose-dependent antimicrobial activity against E . coli . The results suggest that the novel vasoactive peptides AM and PAMP play an important role in mucosal defence.

Arch Intern Med, 2001 Sep 24, 161(17), 2129 - 32
Noninvasive Helicobacter pylori testing for the "test-and-treat" strategy: a decision analysis to assess the effect of past infection on test choice; Chey WD et al.; BACKGROUND: Clinical guidelines support a noninvasive Helicobacter pylori "test-and-treat" strategy for individuals with uncomplicated dyspepsia . However, consensus is lacking regarding the preferred noninvasive testing method . OBJECTIVE: To use decision analytic modeling to estimate the clinical and economic outcomes associated with noninvasive tests designed to detect either H pylori antibody or active H pylori infection . DESIGN: Decision analytic model . PATIENTS: A simulated patient cohort with uncomplicated dyspepsia . INTERVENTIONS: The simulated dyspepsia cohort underwent antibody testing or testing to detect active H pylori infection (active testing) . Individuals testing positive received eradication therapy . MAIN OUTCOME MEASURES: Appropriate and inappropriate treatment prescribed, cost per patient treated, incremental cost per unnecessary treatment avoided . RESULTS: Active testing led to a substantial reduction in unnecessary treatment for patients without active infection (antibody, 23.7; active, 1.4 per 100 patients) at an incremental cost of $37 per patient . The clinical advantage and cost-effectiveness of active testing was enhanced as the percentage of individuals with a positive antibody test result from past, but not current, infection increased . CONCLUSIONS: Active testing for H pylori infection significantly decreases the inappropriate use of antimicrobial therapy when compared with antibody testing . The advantages of active testing should be enhanced as the widespread use of antimicrobial agents increases the proportion of patients with antibody to H pylori, but without active infection.

Arch Intern Med, 2001 Sep 24, 161(17), 2110 - 5
Bloodstream infections after invasive nonsurgical cardiologic procedures; Munoz P et al.; OBJECTIVE: To define the incidence, risk factors, and characteristics of bloodstream infections (BSIs) after invasive nonsurgical cardiologic procedures (ICPs) . METHODS: Retrospective case-control study; multivariate analysis . RESULTS: Between January 1991 and December 1998, 22 006 ICPs were performed in our hospital and 25 BSIs were documented within 72 hours after ICP . Overall incidence of bacteremia was 0.11% (25 cases) (0.24% after percutaneous transluminal coronary angioplasty {14 cases of 5625 patients}, 0.06% {corrected} after diagnostic cardiac catheterization {9 cases of 14 034 patients}, and 0.08% {corrected} after electrophysiologic studies {2 cases of 2347 patients}) . These 25 patients with bacteremia were compared with 50 controls randomly selected among patients who underwent an ICP but did not have BSIs . Patient-related risk factors for BSI were age older than 60 years (20 cases {80%} vs 28 controls {56%}), valvular disease (4 {16%} vs 1 {2%}), congestive heart failure (7 {28%} vs 1 {2%}), indwelling bladder catheter before the ICP (5 {20%} vs 1 {2%}), more than 1 puncture for the ICP (5 {20%} vs 3 {6%}), a prolonged procedure (83.7 vs 65.1 minutes); and/or more than 1 ICP performed (2 {8%} vs 0) . Multivariate analysis identified the presence of congestive heart failure (odds ratio, 21; 95% confidence interval, 6.8-66.0) and age older than 60 years (odds ratio, 1.9; 95% confidence interval, 1.9-6.3) as independent risk factors for BSI after ICP . Bloodstream infection was detected a median of 1.7 days after the procedure . Gram-negative bacteremia accounted for 17 cases (68%) of the BSIs . Among the patients with BSI, the duration of hospital stay was significantly increased (21 vs 6 days) . The overall mortality rate was 0.009% for patients who underwent an ICP (8.0% for the 25 patients with bacteremia documented within 72 hours after ICP) . CONCLUSIONS: Bloodstream infection should be included among the potential complications of ICP . Elderly patients with recent congestive heart failure episodes constitute a subgroup with a higher risk of postprocedure bacteremia . Therapy with antimicrobial agents against gram-positive and gram-negative bacteremia should be initiated after performing blood cultures in patients with signs suggestive of infection.

Int J Paediatr Dent, 2001 Jul, 11(4), 242 - 8
Paediatric antibiotic prescribing by general dental practitioners in England; Palmer NO et al.; OBJECTIVES: The inappropriate use of antibiotics is known to be a major contributory factor to the problem of antimicrobial resistance . No information is available on how practitioners prescribe antibiotics for children . This study investigated the prescribing of liquid-based antibiotics for children by general dental practitioners in England . DESIGN: Analysis of National Health Service liquid-based prescriptions issued by general dental practitioners in England . SAMPLE AND METHODS: All prescriptions issued by practitioners in 10 Health Authorities in England for February 1999 were collected . All the liquid-based antibiotic prescriptions for children were selected and we investigated the type of antibiotic prescribed, whether sugar free, the dose, frequency and duration . RESULTS: A total of 18,614 prescriptions were issued for antibiotics . Of the 1609 liquid-based paediatric prescriptions 88.3% were for generic and 11.7% for proprietary antibiotics, of which 75.5% were for amoxicillin, 15.2% for phenoxymethylpenicillin, 6.6% for erythromycin, 1.7% for metronidazole . Cephalexin, ampicillin, cephadrine and combinations of two antibiotics were also prescribed . There was a wide variation in dosages for all the antibiotics prescribed . A significant proportion of practitioners prescribed at frequencies inconsistent with manufacturers' recommendations and for prolonged periods, with some practitioners prescribing for periods up to 10 days . Only 29.1% of all the prescriptions issued were sugar free . CONCLUSIONS: The results of this study show that some practitioners prescribe liquid-based antibiotics inappropriately for children . This may contribute to the problem of antimicrobial resistance . Clear guidelines on the choice of antibiotic, dose, frequency and duration along with educational initiatives for GDPs might reverse this trend.

C R Acad Sci III, 2001 Oct, 324(10), 953 - 63
{Stimulation of plant natural defenses}; Klarzynski O et al.; Some defense mechanisms of plants are of the passive type while others are induced after perception of the pathogenic microorganism (very specific gene-for-gene recognition) or of microbial components (non specific elicitors) . These recognition events trigger an array of plant signals and a cascade of signalling pathways which activate a battery of metabolic alterations responsible for the observed induced resistance . These include the stimulated production of low molecular weight molecules with antibiotic activity, cell wall reinforcement by deposition and cross-linking of various macromolecules, and accumulation of a wide range of PR ('pathogenesis-related') proteins that exhibit direct and/or indirect antimicrobial activities . The present studies aim to characterize natural elicitors or design chemical messengers capable of triggering an array of plant defense responses . Treatments of plants with elicitors could be an alternative strategy of crop protection with a more satisfactory preservation of the environment.

Boll Chim Farm, 2001 Jul-Aug, 140(4), 233 - 7
Synthesis and biological activity of 2-thiono-{1H}-5-spirocyclohexylimidazo{4,3-b}quinazolone and 8-azaquinazolone derivatives; Hamad AS et al.; The reaction of 5-spirocyclohexylimidazole-2,4-dithion with one and two mole equivalent of b-aminocarboxylic acid derivatives (2a-b and 5) to give new heterocyclic systems of synthetic and potential biological interest viz . compounds (3a-b, 4a-b, 6 and 7) . The structures of the products have established by chemical and spectroscopic evidence . The antimicrobial activity of the synthesized compounds was tested against 10 bacterial and yeast strains.

Boll Chim Farm, 2001 Jul-Aug, 140(4), 228 - 32
Studies on the synthesis and biological activity of 3-arylaminomethyl-5-(3-pyridyl)-1,3,4-oxadiazole-2-thione derivatives; Satyanarayana D et al.; 3-arylaminomethyl-5-(3-pyridyl)-1,3,4-oxadiazole-2-thiones were prepared by reaction of 5-(3-pyridyl)-1,3,4-oxadiazole-2-thione with formaldehyde and appropriate alky and aryl amines in ethanol, as potential biological active agents . These new synthesized Mannich bases were screened for their antimicrobial, antifungal and antiinflammatory activities.

Infect Dis Clin North Am, 2001 Sep, 15(3), 709 - 20, vii
Infections in patients with end-stage renal disease . An overview; Berman SJ; One of the best kept secrets in medicine is the problem of infections in patients with end-stage renal disease . The prescription of chronic hemodialysis has not reduced the problem of infection; it has only changed the paradigm . Dialysis superimposes myriad new problems onto patients with relentless deterioration from underlying multisystem disease and poor wound healing . All end-stage renal disease and transplant programs require the input from an individual with the specialized knowledge of laboratory diagnosis, pharmacokinetics of antibiotics, antibiotic choice, antimicrobial resistance, infection control, and infection prevention . This article gives an overview of some of the complexities of infectious problems experienced by this unique biological model.

Arch Dis Child, 2001 Oct, 85(4), 341 - 5
Diagnostic and therapeutic impact of whole body positron emission tomography using fluorine-18-fluoro-2-deoxy-D-glucose in children with chronic granulomatous disease; Gungor T et al.; AIMS: To compare whole body positron emission tomography (PET) using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) with computed tomography (CT) in detecting active infective foci in children with chronic granulomatous disease . METHODS: We performed 22 whole body FDG PET studies in seven children with X linked (n = 6) or autosomal recessive (n = 1) CGD . All had clinical signs of infection and/or were evaluated prior to bone marrow transplantation (BMT) . Nineteen PET studies were also correlated with chest and/or abdominal CT . All PET scans were interpreted blinded to the CT findings . Diagnoses were confirmed histologically and bacteriologically . RESULTS: We detected 116 lesions in 22 FGD PETs and 126 lesions on 19 CTs . Only two of the latter could be classified reliably as active lesions by virtue of contrast enhancement suggesting abscess formation . PET excluded 59 lesions suspicious for active infection on CT and revealed 49 infective lesions not seen on CT . All seven active infective lesions were identified by PET, allowing targeted biopsy and identification of the infective agent followed by specific antimicrobial treatment, surgery, or subsequent BMT . CONCLUSIONS: Identification of infective organisms is more precise if active lesions are biopsied . CT does not discriminate between active and inactive lesions . Whole body FDG PET can be used to screen for active infective lesions in CGD patients.

J Hosp Infect, 2001 Oct, 49(2), 135 - 8
Multicentre study on the appropriateness of surgical antibiotic prophylaxis; Bailly P et al.; A prospective study was conducted to assess the appropriateness of surgical antibiotic prophylaxis . A total of 72 surgeon-anaesthesist pairs participated in data collection, which assessed five variables: did the surgical procedure justify the use of antimicrobial prophylaxis and was it given? was an appropriate agent used?, is the timing of administration optimal?, is the duration of prophylaxis correct?, and is a proper dose given? Of the 687 procedures reviewed, 513 (74.7%) were entered in the analysis . Of these procedures, the rate of totally compliant prescriptions was 41.7% . Among the 117 patients who received an inappropriate drug, 112 (95.7%) received a drug with a broader spectrum of activity than that recommended . Prolonged prophylaxis occurred in 80 (87.9%) of the 91 patients who received prophylaxis with an incorrect duration . In conclusion, compliance with the principles of prophylactic antimicrobial administration should be strictly reviewed and conducting such audits should be part of the routine activity of infection control teams .

J Hosp Infect, 2001 Oct, 49(2), 94 - 8
Hospital infection control in Poland; Hryniewicz W et al.; During the last 10 years, as in other areas of the public sector in Poland, the healthcare system has undergone important changes presenting a challenge for medical staff and healthcare managers alike . Since 1997, the Polish Government has undertaken important healthcare reforms . New regulations have introduced decentralization of management and a financing system for hospitals . These changes have provided favourable conditions in which to implement an infection control system for hospitals . The most important recent initiatives are training courses and workshops for hospital staff organized in co-operation with microbiologists and epidemiologists as well as preparation of recommendations and guidelines for hospitals . Several non-governmental organizations have been set up to improve hospital hygiene, infection control and monitoring of antimicrobial resistance .

J Bacteriol, 2001 Oct, 183(20), 5803 - 12
Analysis of a complete library of putative drug transporter genes in Escherichia coli; Nishino K et al.; The complete sequencing of bacterial genomes has revealed a large number of drug transporter genes . In Escherichia coli, there are 37 open reading frames (ORFs) assumed to be drug transporter genes on the basis of sequence similarities, although the transport capabilities of most of them have not been established yet . We cloned all 37 putative drug transporter genes in E . coli and investigated their drug resistance phenotypes using an E . coli drug-sensitive mutant as a host . E . coli cells transformed with a plasmid carrying one of 20 ORFs, i.e., fsr, mdfA, yceE, yceL, bcr, emrKY, emrAB, emrD, yidY, yjiO, ydhE, acrAB, cusA (formerly ybdE), yegMNO, acrD, acrEF, yhiUV, emrE, ydgFE, and ybjYZ, exhibited increased resistance to some of the 26 representative antimicrobial agents and chemical compounds tested in this study . Of these 20 ORFs, cusA, yegMNO, ydgFE, yceE, yceL, yidY, and ybjYZ are novel drug resistance genes . The fsr, bcr, yjiO, ydhE, acrD, and yhiUV genes gave broader resistance spectra than previously reported.

J Antimicrob Chemother, 2001 Sep, 48 Suppl T1, 1 - 8
Structures of ketolides and macrolides determine their mode of interaction with the ribosomal target site; Douthwaite S et al.; Ketolides are the most recent generation of antimicrobials derived from the 14-membered ring macrolide, erythromycin A . The main structural feature that differentiates ketolides from erythromycin is the keto group, which replaces the L-cladinose moiety at position 3 of the macrolactone ring . The keto group bestows greater acid stability on the drugs, and enables them to bind to their ribosomal target without causing expression of MLS(B) resistance in inducible strains . Several ketolides are described here, including ABT 773 and telithromycin (HMR 3647), both of which possess a carbamate at C11/C12 of the macrolactone ring . In telithromycin, which is the first ketolide to be approved for clinical use, the carbamate is linked to an alkyl-aryl extension, which is responsible for the increased potency of this compound relative to macrolides . This review examines how the structural differences between macrolides and the new ketolides are related to their antimicrobial activities in inhibiting protein synthesis and blocking the assembly of new ribosomal subunits.

Biophys J, 2001 Oct, 81(4), 2203 - 14
Orientation and dynamics of an antimicrobial peptide in the lipid bilayer by solid-state NMR spectroscopy; Yamaguchi S et al.; The orientation and dynamics of an 18-residue antimicrobial peptide, ovispirin, has been investigated using solid-state NMR spectroscopy . Ovispirin is a cathelicidin-like model peptide (NH(2)-KNLRRIIRKIIHIIKKYG-COOH) with potent, broad-spectrum bactericidal activity . (15)N NMR spectra of oriented ovispirin reconstituted into synthetic phospholipids show that the helical peptide is predominantly oriented in the plane of the lipid bilayer, except for a small portion of the helix, possibly at the C-terminus, which deviates from the surface orientation . This suggests differential insertion of the peptide backbone into the lipid bilayer . (15)N spectra of both oriented and unoriented peptides show a reduced (15)N chemical shift anisotropy at room temperature compared with that of rigid proteins, indicating that the peptide undergoes uniaxial rotational diffusion around the bilayer normal with correlation times shorter than 10(-4) s . This motion is frozen below the gel-to-liquid crystalline transition temperature of the lipids . Ovispirin interacts strongly with the lipid bilayer, as manifested by the significantly reduced (2)H quadrupolar splittings of perdeuterated palmitoyloleoylphosphatidylcholine acyl chains upon peptide binding . Therefore, ovispirin is a curved helix residing in the membrane-water interface that executes rapid uniaxial rotation . These structural and dynamic features are important for understanding the antimicrobial function of this peptide.

Am J Med, 2001 Sep, 111(4), 304 - 15
Antipyretics: mechanisms of action and clinical use in fever suppression; Aronoff DM et al.; Fever is a complex physiologic response triggered by infectious or aseptic stimuli . Elevations in body temperature occur when concentrations of prostaglandin E(2) (PGE(2)) increase within certain areas of the brain . These elevations alter the firing rate of neurons that control thermoregulation in the hypothalamus . Although fever benefits the nonspecific immune response to invading microorganisms, it is also viewed as a source of discomfort and is commonly suppressed with antipyretic medication . Antipyretics such as aspirin have been widely used since the late 19th century, but the mechanisms by which they relieve fever have only been characterized in the last few decades . It is now clear that most antipyretics work by inhibiting the enzyme cyclooxygenase and reducing the levels of PGE(2) within the hypothalamus . Recently, other mechanisms of action for antipyretic drugs have been suggested, including their ability to reduce proinflammatory mediators, enhance anti-inflammatory signals at sites of injury, or boost antipyretic messages within the brain . Although the complex biologic actions of antipyretic agents are better understood, the indications for their clinical use are less clear . They may not be indicated for all febrile conditions because some paradoxically contribute to patient discomfort, interfere with accurately assessing patients receiving antimicrobials, or predispose patients to adverse effects from other medications . The development of more selective fever-relieving agents and their prudent use with attention to possible untoward consequences are important to the future quality of clinical medicine.

J Inorg Biochem, 2001 Sep, 86(2-3), 555 - 63
Platinum(II) complexes with 2-acetyl pyridine thiosemicarbazone . Synthesis, crystal structure, spectral properties, antimicrobial and antitumour activity; Kovala-Demertzi D et al.; An interesting series of new platinum complexes has been synthesized by the reaction of Na(2)PtCl(4) with 2-acetyl pyridine thiosemicarbazone, HAcTsc . The new complexes, {Pt(AcTsc)Cl}, {Pt(HAcTsc)(2)}Cl(2) and {Pt(AcTsc)(2)}, have been characterized by elemental analyses and spectroscopic studies . The crystal structure of the complex {Pt(AcTsc)Cl} has been solved by single-crystal X-ray diffraction . The anion of HAcTsc coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms . Double intermolecular hydrogen bonds (NH-Cl), pi-pi and weak Pt-Pt and Pt-pi contacts lead to aggregation and to a two-dimensional supramolecular assembly . The antibacterial and antifungal effect of the novel platinum(II) complexes and the related palladium(II) complexes, {Pd(AcTsc)Cl}, {Pd(HAcTsc)(2)}Cl(2) and {Pd(AcTsc)(2)}, were studied in vitro . The complexes were found to have a completely lethal effect on Gram+ bacteria, while the same complexes showed no bactericidal effect on Gram- bacteria . Additionally, the complexes {Pt(AcTsc)(2)} and {Pd(AcTsc)(2)} showed effective antifungal activity towards yeast . Among these compounds {33}, the most effective in inducing antitumour and cytogenetic effects are the complexes {Pt(AcTsc)(2)} and {Pd(AcTsc)(2)} while the rest, display marginal cytogenetic and antitumour effects.

Biochim Biophys Acta, 2001 Sep 28, 1537(2), 125 - 31
An unusual intronic mutation in the CYBB gene giving rise to chronic granulomatous disease; Noack D et al.; The most common, X-linked, form of chronic granulomatous disease (CGD) is caused by mutations in the CYBB gene located at Xp21.1 . The product of this gene is the large subunit of flavocytochrome b558, gp91phox, which forms the catalytic core of the antimicrobial superoxide-generating enzyme, NADPH oxidase . In the overwhelming majority of cases, mutations are family-specific and occur in the exonic regions of the gene, or more rarely at the intron/exon borders . Alternatively, they are large (often multi-gene) deletions . In addition, four mutations have been found in the promoter region . In contrast, very few intronic mutations have been reported . Here we describe an intronic mutation that causes X-linked CGD . A single nucleotide substitution in the middle of intron V creates a novel 5' splice site and results in multiple abnormal mRNA products.

Transpl Infect Dis, 1999, 1 Suppl 1, 35 - 9
Prevention of CMV infection in transplant patients; Fishman JA; Cytomegalovirus (CMV) is among the most important pathogens affecting the transplant recipient, with the spectrum of manifestations of CMV infection being quite broad . In the development of optimal strategies for the prevention and treatment of CMV infections, some of the most important information can be gained from patients who have failed either prophylaxis or therapy for CMV disease . Analysis of a cohort of these patients illustrates the role of primary infection in the immunologically naive patient for CMV, incompatibility of major histocompatibility complex (MHC) loci, and resistance to antimicrobial (antiviral) agents . Significant gaps in information include differentiating between viral strains, establishing the nature of viral latency, determination of host immunity to CMV, and optimal therapies for CMV infection . Elucidation of the factors that predispose to CMV infection will help to tailor and implement appropriate prophylactic strategies . New vaccines and orally bioavailable antiviral agents will play a significant role in the future care of transplant patients.

Eur J Gastroenterol Hepatol, 2001 Sep, 13(9), 1067 - 72
Role of Helicobacter pylori infection and its eradication in patients with subclinical hepatic encephalopathy; Miquel J et al.; AIMS: Helicobacter pylori infection in cirrhotic patients has been associated with episodes of hepatic encephalopathy (HE), although conclusive data are still lacking . This prospective study has evaluated the prevalence of H . pylori infection in 37 patients with advanced cirrhosis of the liver and subclinical hepatic encephalopathy (SHE), diagnosed by changes in psychometric tests and/or electrophysiological tests, as well as the repercussion of H . pylori eradication on ammonaemia and the evolution of this disorder . RESULTS: A positive result for H . pylori infection was obtained in 22/37 (59%) patients . Initial fasting blood levels of ammonia were high in both groups . Infected and non-infected patients showed similar levels (62.05 mmol/l v . 62.5 mmol/l), which were lowered by the standard diet, although statistical significance was only reached in the infected patient group (53.05 +/- 26 mmol/l; P < 0.05) . Infection was eradicated in 19 patients, but no reduction of blood levels of ammonia was observed after H . pylori eradication among infected patients (52.37 +/- 29 mmol/l) . No change has been found in either group after the administration of diet or antimicrobials with regard to psychometric and/or electrophysiological tests . CONCLUSIONS: H . pylori infection does not contribute significantly to high blood levels of ammonia in patients with advanced cirrhosis and SHE . Likewise, H . pylori eradication does not induce any improvement in the psychometric and/or electrophysiological tests used to define SHE.

Br J Clin Pharmacol, 2001, 52 Suppl 1, 35S - 43S
The therapeutic monitoring of antimicrobial agents; Begg EJ et al.; AIMS: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents . METHODS: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring . RESULTS: There is a strong historical case for monitoring aminoglycosides . The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined . Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this . A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances . CONCLUSIONS: The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing . It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs . Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended . The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy . Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity . Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.

J Am Anim Hosp Assoc, 2001 Sep-Oct, 37(5), 461 - 5
Histiocytic ulcerative colitis in three non-boxer dogs; Stokes JE et al.; Histiocytic ulcerative colitis (HUC) is described in three non-boxer dogs . Clinical signs were typical of large-bowel diarrhea and included soft stool, hematochezia, tenesmus, and an increased frequency of defecation . Diagnosis in each case was made by light microscopic evaluation of endoscopically obtained colonic biopsy specimens . Treatment regimes varied, but included immunosuppressive agents, anti-inflammatory drugs, antimicrobials, and dietary modification . Clinical response was substantial in two patients, while the third patient was euthanized due to treatment failure . The authors' observations indicate that HUC may be encountered in non-boxer dogs.

Semin Respir Infect, 2001 Sep, 16(3), 210 - 4
Have guidelines had an impact on antimicrobial resistance?
Garau J.
Treatment guidelines can influence and improve clinical practice . Originally, guidelines did not specifically address the problem of antibiotic resistance . A number of studies have shown a reduction in the frequency of antibiotic resistance after the implementation of programs for reduced antibiotic consumption . In future guidelines, reduction of antibiotic resistance should be 1 of the primary objectives to be achieved . It will be critical to better define when not to use antimicrobials and to create graded recommendations (strong evidence vs weak evidence) of the different antibiotic options for a given indication with respect to their eradicating power . Also, pharmacokinetics/pharmacodynamics parameters should be used to design the optimal dosing and dosing intervals . Duration of therapy should become an important consideration not only from the pharmacoeconomic point of view but also from an ecologic one . Finally, appropriate endpoints to measure the impact of the intervention should be included .

J Am Vet Med Assoc, 2001 Sep 15, 219(6), 805 - 8
Multilocation trial of ceftiofur for treatment of postpartum cows with fever; Zhou C et al.; OBJECTIVE: To evaluate the effect of ceftiofur for treatment of postpartum cows with fever . DESIGN: Multilocation randomized complete block design trial . ANIMALS: 330 cows . PROCEDURE: Cows with rectal temperature > or = 39.5 C (103.1 F) during the first 10 postpartum days were randomly assigned to a treatment (ceftiofur; 1 mg/kg {0.45 mg/lb} of body weight daily for 3 days) or untreated control group . Cure (no additional or alternative antimicrobial treatment used, rectal temperature < 39.5 C, and no other concurrent clinical signs of disease when evaluated at 9 or 10 days after enrollment), milk production, and rectal temperature were evaluated . RESULTS: Ceftiofur-treated cows were significantly more likely to be cured than control cows (56.0 vs 28.9%, respectively), with an odds ratio of 3.14 when vaginal discharge (a factor with moderate interaction with treatment) was present at enrollment . Among cows that had an abnormal calving (a significant interaction factor), treated cows had first milking yield 2.27 kg (5 lb) greater than control cows . Treated cows had a significantly greater reduction in rectal temperature (1.19 C {2.14 Fl), compared with control cows (1.04 C {1.87 F}) . CONCLUSIONS AND CLINICAL RELEVANCE: Parenteral administration of ceftiofur significantly improved cure rate, milk yield, and rectal temperature in postpartum cows with fever and vaginal discharge or dystocia . These findings provide information to determine appropriate treatment for postpartum cows, which for years has been debated in the dairy industry.

J Am Vet Med Assoc, 2001 Sep 15, 219(6), 789 - 94
Use of closed-suction drains to treat generalized peritonitis in dogs and cats: 40 cases (1997-1999); Mueller MG et al.; OBJECTIVE: To determine outcome of dogs and cats with generalized peritonitis treated by means of closed-suction drainage . DESIGN: Retrospective study . ANIMALS: 30 dogs and 10 cats with generalized peritonitis . PROCEDURE: Medical records were reviewed, and information on signalment, clinicopathologic abnormalities, contamination source, results of microbial culture, surgical procedure performed, postoperative management, complications, and outcome was obtained . RESULTS: The gastrointestinal tract was the most common source of contamination . Abdominal fluid collected from 34 patients at the time of surgery was submitted for bacterial culture; results were positive for 28 (82%) . The most commonly isolated organism was Escherichia coli . Postoperative complications included anemia (n = 21), hypoproteinemia (21), vomiting (9), edema (7), and diarrhea (5) . Total solids concentration did not decrease during the first 48 hours after surgery, and all drains remained functional until removal . Twenty-eight patients survived to the time of discharge; 8 of the 12 animals that died did so within 18 hours after surgery . The only factor significantly different between patients that survived and patients that died was postoperative systolic blood pressure . Factors that were not significantly associated with outcome included detection of bacteria in the abdominal fluid, number of organisms cultured from the abdominal fluid, selection of antimicrobials for empiric treatment, and source of contamination . CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that closed-suction drainage may be a useful method for treating generalized peritonitis in dogs and cats . No clinically important complications were associated with their use.

Genetics, 2001 Sep, 159(1), 189 - 99
Drosophila immunity: genes on the third chromosome required for the response to bacterial infection; Wu LP et al.; We have screened the third chromosome of Drosophila melanogaster for mutations that prevent the normal immune response . We identified mutant lines on the basis of their failure to induce transcription of an antibacterial peptide gene in response to infection or their failure to form melanized clots at the site of wounding . These mutations define 14 genes {immune response deficient (ird) genes} that have distinct roles in the immune response . We have identified the molecular basis of several ird phenotypes . Two genes, scribble and kurtz/modulo, affect the cellular organization of the fat body, the tissue responsible for antimicrobial peptide production . Two ird genes encode components of the signaling pathways that mediate responses to bacterial infection, a Drosophila gene encoding a homolog of I kappa B kinase (DmIkk beta) and Relish, a Rel-family transcription factor . These genetic studies should provide a basis for a comprehensive understanding of the genetic control of immune responses in Drosophila.

J Antibiot (Tokyo), 2001 Jul, 54(7), 567 - 72
Cedarmycins A and B, new antimicrobial antibiotics from Streptomyces sp . TP-A0456; Sasaki T et al.; Two novel butyrolactone antibiotics, cedarmycins A and B, were isolated from the cultured broth of the actinomycete Streptomyces sp . TP-A0456 . The new compounds were purified by HP-20 resin, silica gel, ODS column chromatographies and preparative HPLC, consecutively . The structure of cedarmycin was determined by spectroscopic methods as an alpha,beta-unsaturated butyrolactone with a fatty acid side chain . These compounds showed antibiotic activity against Gram-positive and -negative bacteria and yeasts . Among the tested organisms, cedarmycins potently inhibited the growth of Candida glabrata IFO 0622 with the MIC of 0.4 microg/ml, comparable to that of amphotericin B.

J Community Health Nurs, 2001 Fall, 18(3), 139 - 50
How clean is the home environment?: a tool to assess home hygiene; Larson EL et al.; The role of the home environment in the transmission of infectious diseases has been well described in the developing world but has received less attention in developed countries . An increasing focus on home hygiene has emerged in debates regarding the use of antimicrobial products in the home and the potential for development of resistance and in discussions regarding "when is clean too clean" and "what is clean." Studies are clearly needed to further explicate the role of the home in the spread of infectious agents, but before these can be conducted, adequate measurement tools are essential . This article describes extensive psychometric testing undertaken to develop valid and reliable methods and tools to measure home hygiene and focuses on a neighborhood that was primarily Spanish speaking in New York City . The Home Hygiene Assessment Tool described in this article can be used by clinicians and researchers to further elucidate the role of the home environment in the prevention and control of infections.

Kaohsiung J Med Sci, 2001 Jun, 17(6), 327 - 30
Primary abscess of the omentum: report of a case and review of the literature; Wang JY et al.; Primary abscess of the omentum is an infrequent disease entity . We report a case of 60-year-old male patient who suffered from left lower quadrant abdominal pain with localized abdominal wall tenderness, nausea and high-grade fever for the previous few days . Computerized tomography scan revealed a heterogeneous lesion that adhered to the abdominal wall . A pre-operative diagnosis of colonic diverticulitis complicated with intra-abdominal abscess was made and a laparotomy was done . At surgical exploration, an indurate mass consisting of abscess within the omentum was identified . The surgical procedure consisted of resection of the omental abscess with abdominal wall debridement, and subsequent antimicrobial therapy was administered . Postoperatively, the patient recovered uneventfully . Clinicians who treated such patients should be aware of this problem because of the difficulty of preoperative diagnosis.

J Virol, 2001 Oct, 75(20), 9644 - 53
Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein; Peters S et al.; Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase . We speculated that mutations in genes other that the drug target could lead to drug resistance . For this purpose, the p1-p6(gag)-p6(pol) region of HIV-1, placed immediately upstream of pol, was analyzed . This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6(Gag)), or by changes in activation of the viral protease (p6(Pol)) . Duplication of the proline-rich p6(Gag) PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naive individuals . Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6(Pol)), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs . This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro . Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.

Lett Appl Microbiol, 2001 Oct, 33(4), 325 - 8
Improved antimicrobial activity of nisin-incorporated polymer films by formulation change and addition of food grade chelator; Cutter CN et al.; AIMS: The following polymers were developed: polyethylene (PE), a PE and polyethylene oxide (70% PE and 30% PEO; PE + PEO) blend, PE and nisin (PE + nisin), PE, nisin, and EDTA (PE + nisin + EDTA), and PE + PEO with nisin (PE + PEO + nisin) . METHODS AND RESULTS: Of the polymers tested, PE and PE + PEO did not exhibit any antimicrobial activity against Brochothrix thermosphacta (BT); however, PE + nisin, PE + nisin + EDTA, and PE + PEO + nisin did . Beef surfaces were experimentally inoculated with 3.50 log10 cfu/cm2 of BT, vacuum packaged with each of the five polymers, and held at 4 degrees C for 21 d . After 3 d at 4 degrees C, BT was reduced > 1.70 log(10) by PE + nisin and > 3.50 log(10) with PE + nisin + EDTA or PE + PEO + nisin . By 21 d at 4 degrees C, BT was reduced to 0.30 log(10) cfu/cm(2) when treated with PE + PEO + nisin . CONCLUSION: It appears that PE + PEO + nisin or PE + nisin + EDTA were more effective for reducing BT, as compared to polymers composed of PE + nisin . SIGNIFICANCE AND IMPACT OF THE STUDY: Nisin-incorporated polymers may control the growth of undesirable bacteria, thereby extending the shelf life and possibly enhancing the microbial safety of meats.

Arch Neurol, 2001 Sep, 58(9), 1357 - 63
Concurrent infection of the central nervous system by Borrelia burgdorferi and Bartonella henselae: evidence for a novel tick-borne disease complex; Eskow E et al.; OBJECTIVES: To investigate Bartonella henselae as a potential human tick-borne pathogen and to evaluate its role as a coinfecting agent of the central nervous system in the presence of neuroborreliosis . DESIGN: Case report study . SETTING: A primary health care center in Flemington, NJ, and the Department of Research and Development at Medical Diagnostic Laboratories LLC in Mt Laurel, NJ . SUBJECTS: Two male patients (aged 14 and 36 years) and 2 female patients (aged 15 and 30 years, respectively) with a history of tick bites and Lyme disease . MAIN OUTCOME MEASURES: Laboratory and diagnostic findings before and after antimicrobial therapy . RESULTS: Patients residing in a Lyme-endemic area of New Jersey with ongoing symptoms attributed to chronic Lyme disease were evaluated for possible coinfection with Bartonella species . Elevated levels of B henselae-specific antibodies were found in these patients using the immunofluorescent assay . Bartonella henselae-specific DNA was detected in their blood . None of these patients exhibited the clinical characteristics of cat-scratch disease . Findings of cerebrospinal fluid analysis revealed the presence of both B henselae- and Borrelia burgdorferi-specific DNA . Bartonella henselae-specific DNA was also detected in live deer ticks obtained from the households of 2 of these patients . CONCLUSIONS: Our data implicate B henselae as a potential human tick-borne pathogen . Patients with a history of neuroborreliosis who have incomplete resolution of symptoms should be evaluated for B henselae infection.

J Agric Food Chem, 2001 Sep, 49(9), 4300 - 3
Composition and antimicrobial activity of the essential oils of Micromeria cristata subsp . phrygia and the enantiomeric distribution of borneol; Tabanca N et al.; Water-distilled essential oils from herbal parts of Micromeria cristata (Hampe) Griseb . subsp . phrygia P . H . Davis (Endemic) (Lamiaceae) collected from three different localities were analyzed by GC-MS . The major component characterized in the three oils was borneol (27-39%) . Other main components were determined as camphor (9-15%), caryophyllene oxide (4-6%), and trans-verbenol (4-6%) in the oils . Enantiomeric distributions of borneol and camphor in the oils were determined on a fused silica Lipodex-E capillary column using a multidimensional GC-MS system . The three essential oils and both enantiomers of borneol have been evaluated for their antimicrobial activity . They showed inhibitory effects on Gr (-) and Gr (+) pathogenic microorganisms.

J Agric Food Chem, 2001 Sep, 49(9), 4168 - 70
Composition and antimicrobial activity of the essential oils of two Origanum species; Aligiannis N et al.; The essential oils obtained from the aerial parts of Origanum scabrum and Origaum microphyllum, both endemic species in Greece, were analyzed by means of GC and GC-MS . Forty-eight constituents were identified, representing 98.59 and 98.66% of the oils, respectively . Carvacrol, terpinen-4-ol, linalool, sabinene, alpha-terpinene, and gamma-terpinene were found as the major components . Furthermore, both samples exhibited a very interesting antimicrobial profile after they were tested against six Gram-negative and -positive bacteria and three pathogenic fungi.

J Vet Med Sci, 2001 Aug, 63(8), 867 - 72
A non-arthropathic dose and its disposition following repeated oral administration of ofloxacin, a new quinolone antimicrobial agent, to juvenile dogs; Yabe K et al.; A non-arthropathic dose and disposition of ofloxacin, a potent new quinolone antimicrobial agent, were assessed in male juvenile (3-month-old) dogs, when administered orally at 5, 10 and 20 mg/kg/day once daily for 8 consecutive days . Ofloxacin concentrations in sera and articular cartilages were analyzed by high-performance liquid chromatography (HPLC) . Macroscopically, arthropathy characterized by fluid-filled vesicles in articular surface of the humerus and femur was observed in animals receiving 10 and 20 mg/kg/day of ofloxacin, but not in those given 5 mg/kg/day . At 20 mg/kg/day, arthropathy of comparable severity also occurred on day 2 . Microscopically, the cavity formation in the middle zone of the articular cartilage was first identified and then necrotic chondrocytes were found numerous around the cavity, followed by appearance of chondrocyte clusters . In pharmacokinetics, peak serum concentration (Cmax) and area under the concentrations (AUC0-24) were increased in a dose-dependent manner . However, no remarkable differences in these two parameters were noted between a single and repeated treatments, suggesting no accumulation of the drug . The articular ofloxacin concentration 2 hr after treatment was approximately 1.8 (day 2) to 2.0 times (day 8) higher than the serum concentration . Based on these results, a non-arthropathic dose of ofloxacin in male juvenile dogs following an 8-day treatment is considered to be 5 mg/kg/ day, and its Cmax, AUC0-24 and articular cartilage concentrations 2 hr after treatment were 3.4 microg/ml, 35.1 microg-hr/m/ and 7.0 microg/g, respectively, under these experimental conditions . Thus, arthropathy due to ofloxacin may be predicted by monitoring serum drug concentration.

Vopr Med Khim, 2001 May-Jun, 47(3), 353 - 67
{Computer searching of new targets for antimicrobial drugs based on comparative analysis of genomes}; Dubanov AV et al.; The progress in genome research allows to use genomic databases for drug discovery . The major interest consists in their usage for searching of new molecular targets for new drugs . It is especially important in the area of new antimicrobial drugs creation . In recent years, the applicability of genome analysis for solution of this problem was shown by different authors . We propose an approach for searching new targets for antimicrobial drugs based upon comparative analysis of genomes and samples from molecular databases . For each protein encoded by the target microorganism genome the conformance to a number of medico-biological and technological requirements was tested . The obtained evaluations were used for selection of potential targets . The approach was implemented in the original software GenMesh . It was successfully tested with known targets of drugs against tuberculosis when correct valuations were obtained . The attempt of new targets selection for design of new drugs against tuberculosis was done with reliable results.

Antimicrob Agents Chemother, 2001 Oct, 45(10), 2933 - 5
Antimicrobial susceptibilities of clinical Desulfovibrio isolates; Lozniewski A et al.; The antimicrobial susceptibilities of 16 clinical isolates of Desulfovibrio spp . were determined . All or most isolates were susceptible to imipenem (MIC(90) {MIC at which 90% of the isolates tested were inhibited}, 0.5 microg/ml), metronidazole (MIC(90), 0.25 microg/ml), clindamycin (MIC(90), 4 microg/ml), and chloramphenicol (MIC(90), 16 microg/ml) but were resistant or intermediate to penicillin G (MIC(90), 64 microg/ml), piperacillin (MIC(90), 256 microg/ml), piperacillin-tazobactam (MIC(90), 256 microg/ml), cefoxitin (MIC(90), >256 microg/ml), and cefotetan (MIC(90), 64 microg/ml) . Among isolates with decreased susceptibility to beta-lactams (n = 15), only six were beta-lactamase positive and susceptible to amoxicillin-clavulanate and ticarcillin-clavulanate.

Antimicrob Agents Chemother, 2001 Oct, 45(10), 2685 - 90
In vitro activity of ABT-773 against Legionella pneumophila, its pharmacokinetics in guinea pigs, and its use to treat guinea pigs with L . pneumophila pneumonia; Edelstein PH et al.; The activity of ABT-773 was studied against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L . pneumophila pneumonia . The ABT-773 MIC at which 50% of isolates are inhibited (MIC(50)) for 20 different Legionella sp . strains was 0.016 microg/ml, whereas the MIC(50)s of clarithromycin and erythromycin were 0.032 and 0.125 microg/ml, respectively . ABT-773 (1 microg/ml) was bactericidal for two L . pneumophila strains grown in guinea pig alveolar macrophages . In contrast, erythromycin and clarithromycin had easily reversible static activity only . Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L . pneumophila pneumonia . When ABT-773 was given to infected guinea pigs by the intraperitoneal route (10 mg/kg of body weight), mean peak levels in plasma were 0.49 microg/ml at 0.5 h and 0.30 microg/ml at 1 h postinjection . The terminal half-life phase of elimination from plasma was 0.55 h, and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was 0.65 microg . h/ml . For the same drug dose, mean levels in the lung were 15.9 and 13.2 microg/g at 0.5 and 1 h, respectively, with a half-life of 0.68 h and an AUC(0-24) of 37.0 microg . h/ml . Ten of 15 L . pneumophila-infected guinea pigs treated with ABT-773 (15 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days post-antimicrobial therapy, as did 14 of 15 guinea pigs treated with erythromycin (30 mg/kg given intraperitoneally twice daily) for 5 days . All of the ABT-773-treated animals that died appeared to do so because of drug-induced peritonitis rather than overwhelming pneumonia . None of 12 animals treated with saline survived . ABT-773 is as effective as erythromycin against L . pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease . These data support studies of the clinical effectiveness of ABT-773 for the treatment of Legionnaires' disease.

Biochim Biophys Acta, 2001 Oct 1, 1514(2), 253 - 60
'Detergent-like' permeabilization of anionic lipid vesicles by melittin; Ladokhin AS et al.; Melittin (MLT), the 26-residue toxic peptide from the European honeybee Apis mellifera, is widely used for studying the principles of membrane permeabilization by antimicrobial and other host-defense peptides . A striking property of MLT is that its ability to permeabilize zwitterionic phospholipid vesicles is dramatically reduced upon the addition of anionic lipids . Because the mechanism of permeabilization may be fundamentally different for the two types of lipids, we examined MLT-induced release of entrapped fluorescent dextran markers of two different molecular masses (4 and 50 kDa) from anionic palmitoyloleoylphosphatidylglycerol (POPG) vesicles . Unlike release from palmitoyloleoylphosphatidylcholine (POPC) vesicles, which is highly selective for the 4 kDa marker, implying release through pores of about 25 A diameter {Ladokhin et al., Biophys . J . 72 (1997) 1762}, release from POPG vesicles was found to be non-selective, i.e., 'detergent-like' . Oriented circular dichroism measurements of MLT in oriented POPG and POPC multilayers disclosed that alpha-helical MLT can be induced to adopt a transbilayer orientation in POPC multilayers, but not in POPG multilayers . The apparent inhibition of MLT permeabilization by anionic membranes may thus be due to suppression of translocation ability.

J Appl Microbiol, 2001 Sep, 91(3), 492 - 7
Interactions between components of the essential oil of Melaleuca alternifolia; Cox SD et al.; AIMS: This study compared the antimicrobial activity of Melaleuca alternifolia (tea tree) oil with that of some of its components, both individually and in two-component combinations . METHODS AND RESULTS: Minimum inhibitory concentration and time-kill assays revealed that terpinen-4-ol, the principal active component of tea tree oil, was more active on its own than when present in tea tree oil . Combinations of terpinen-4-ol and either gamma-terpinene or p-cymene produced similar activities to tea tree oil . Concentration-dependent reductions in terpinen-4-ol activity and solubility also occurred in the presence of gamma-terpinene . CONCLUSION: Non-oxygenated terpenes in tea tree oil appear to reduce terpinen-4-ol efficacy by lowering its aqueous solubility . SIGNIFICANCE AND IMPACT OF THE STUDY: These findings explain why tea tree oil can be less active in vitro than terpinen-4-ol alone and further suggest that the presence of a non-aqueous phase in tea tree oil formulations may limit the microbial availability of its active components.

Arch Biochem Biophys, 2001 Sep 15, 393(2), 222 - 35
Cloning, heterologous expression, and functional characterization of 5-epi-aristolochene-1,3-dihydroxylase from tobacco (Nicotiana tabacum); Ralston L et al.; Capsidiol is a bicyclic, dihydroxylated sesquiterpene produced by several solanaceous species in response to a variety of environmental stimuli . It is the primary antimicrobial compound produced by Nicotiana tabacum in response to fungal elicitation, and it is formed via the isoprenoid pathway from 5-epi-aristolochene . Much of the biosynthetic pathway for the formation of this compound has been elucidated, except for the enzyme(s) responsible for the conversion of 5-epi-aristolochene to its dihydroxylated form, capsidiol . Biochemical evidence from previous studies with N . tabacum (Whitehead, I . M., Threlfall, D . R., and Ewing, D . F., 1989, Phytochemistry 28, 775-779) and Capsicum annuum Hoshino, T., Yamaura, T., Imaishi, H., Chida, M., Yoshizawa, Y., Higashi, K., Ohkawa, H., Mizutani, J., 1995, Phytochemistry 38, 609-613 . suggested that the oxidation of 5-epi-aristolochene to capsidiol was mediated by at least one elicitor-inducible cytochrome P450 hydroxylase . In extending these observations, we developed an in vivo assay for 5-epi-aristolochene hydroxylase activity and used it to demonstrate a dose-dependent inhibition of activity by ancymidol and ketoconazole, two well characterized inhibitors of cytochrome P450 enzymes . Using degenerate oligonucleotide primers designed to the well conserved domains found within most P450 enzymes, including the heme binding domain, cDNA fragments representing four distinct P450 families (CYP71, CYP73, CYP82, and CYP92) were amplified from a cDNA library prepared against mRNA from elicitor-treated cells using PCR . The PCR fragments were subsequently used to isolate full-length cDNAs (CYP71D20 and D21, CYP73A27 and A28, CYP82E1 and CYP92A5), and these in turn were used to demonstrate that the corresponding mRNAs were all induced in elicitor-treated cells, albeit with different induction patterns . Representative, full-length cDNAs for each of the P450s were engineered into a yeast expression system, and the recombinant yeast assessed for functional expression of P450 protein by measuring the CO difference spectra of the yeast microsomes . Only microsomal preparations from yeast expressing the CYP71D20 and CYP92A5 cDNAs exhibited significant CO difference absorbance spectra at 450 nm and were thus tested for their ability to hydroxylate 5-epi-aristolochene and 1-deoxycapsidiol, a putative mono-hydroxylated intermediate in capsidiol biosynthesis . Interestingly, the CYP71D20-encoded enzyme activity was capable of converting both 5-epi-aristolochene and 1-deoxycapsidiol to capsidiol in vitro, consistent with the notion that this P450 enzyme catalyzes both hydroxylations of its hydrocarbon substrate .

Arzneimittelforschung, 2001, 51(8), 667 - 72
Synthesis and antimicrobial activity of new pyrrolecarboxylic acid derivatives of ampicillin and amoxicillin; Bijev AT et al.; Twelve new penicillin derivatives were prepared for microbiological evaluation by N-acylation of ampicillin (CAS 69-53-4) and amoxicillin (CAS 26787-78-0) with activated pyrrolecarbocylic acids via mixed anhydrides following the Schotten-Baumann procedure . An alternative synthetic approach via chloroanhydrides was checked and rejected because of the instability established for these intermediates . NMR and IR spectral data together with TLC confirmed the structure and the purity of the new products . Antimicrobial tests in vitro indicated a reduction of the antibacterial activity compared with that of ampicillin and amoxicillin as reference antibiotics, but their minimal inhibitory concentrations (MIC) were still in the range of 0.62-16 micrograms/ml against standard and clinical Gram positive strains . Preliminary toxicological evaluations showed low toxicity.

Rapid Commun Mass Spectrom, 2001, 15(18), 1726 - 34
Bioactive dahlein peptides from the skin secretions of the Australian aquatic frog Litoria dahlii: sequence determination by electrospray mass spectrometry; Wegener KL et al.; Eleven dahlein peptides are present in the skin secretion of the Australian aquatic frog Litoria dahlii . All peptides have been sequenced using a combination of electrospray mass spectrometry (ES-MS) and Lys-C digestion/MS, with each sequence confirmed by automated Edman sequencing . The 13-residue dahlein 1 peptides (e.g . dahlein 1.1 GLFDIIKNIVSTL-NH(2)) exhibit weak wide-spectrum antimicrobial activity but no significant activity in the anticancer testing program of the National Cancer Institute (Washington) . There are no potent antimicrobial peptides present in the glandular secretion, but the dahleins 5 strongly inhibit the formation of NO by neuronal nitric oxide synthase (e.g . dahlein 5.1 GLLGSIGNAIGAFIANKLKP-OH) .

Otolaryngol Head Neck Surg, 2001 Sep, 125(3), 245 - 52
Craniocervical necrotizing fasciitis: an 11-year experience; Bahu SJ et al.; OBJECTIVE: We review our experience and present our approach to treating craniocervical necrotizing fasciitis (CCNF) . STUDY DESIGN: All cases of CCNF treated at Wayne State University/Detroit Receiving Hospital from January 1989 to April 2000 were reviewed . Patients were analyzed for source and extent of infection, microbiology, co-morbidities, antimicrobial therapy, hospital days, surgical interventions, complications, and outcomes . RESULTS: A review of 250 charts identified 10 cases that met the study criteria . Five cases (50%) had spread of infection into the thorax, with only 1 (10%) fatality . An average of 24 hospital days (7 to 45), 14 ICU days (6 to 21), and 3 surgical procedures (1 to 6) per patient was required . CONCLUSION: Aggressive wound care, broad-spectrum antibiotics, and multiple surgical interventions resulted in a 90% (9/10) overall survival and 80% (4/5) survival for those with thoracic extension . SIGNIFICANCE: This is the largest single institution report of CCNF with thoracic extension identified to date.

Curr Opin Rheumatol, 2001 Jul, 13(4), 305 - 9
Enteropathic arthritis: how do the joints talk with the gut?
Wollheim FA.
Enteropathic arthritis is a label for conditions in which gut pathology is believed to be of pathogenic importance for the developing joint disease . Impaired barrier function, as well as immunogenetic mechanism, are implicated . Recent publications have highlighted strong new support for the homing of lymphocytes from the gut mucosa to joint tissue, persistence of antigen- and cytokine-based immune deficiency . A convincing argument was made for the interesting observation that two distinct types of joint involvement with different class II HLA backgrounds occur in patients with inflammatory bowel disease . A new mechanism implicating dimeric HLA-B27 heavy chains in the pathogenesis of enteropathic arthritis is also presented . Despite evidence for persisting antigen presence, antimicrobial therapy seems ineffective in reactive arthritis.

Chest, 2001 Sep, 120(3), 955 - 70
International Conference for the Development of Consensus on the Diagnosis and Treatment of Ventilator-associated Pneumonia; Rello J et al.; Ventilator-associated pneumonia (VAP) is an important health problem that still generates great controversy . A consensus conference attended by 12 researchers from Europe and Latin America was held to discuss strategies for the diagnosis and treatment of VAP . Commonly asked questions concerning VAP management were selected for discussion by the participating researchers . Possible answers to the questions were presented to the researchers, who then recorded their preferences anonymously . This was followed by open discussion when the results were known . In general, peers thought that early microbiological examinations are warranted and contribute to improving the use of antibiotherapy . Nevertheless, no consensus was reached regarding choices of antimicrobial agents or the optimal duration of therapy . Piperacillin/tazobactam was the preferred choice for empiric therapy, followed by a cephalosporin with antipseudomonal activity and a carbapenem . All the peers agreed that the pathogens causing VAP and multiresistance patterns in their ICUs were substantially different from those reported in studies in the United States . Pathogens and multiresistance patterns also varied from researcher to researcher inside the group . Consensus was reached on the importance of local epidemiology surveillance programs and on the need for customized empiric antimicrobial choices to respond to local patterns of pathogens and susceptibilities.

Infect Immun, 2001 Oct, 69(10), 6156 - 64
Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase; Hayashi T et al.; Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide analogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymphocyte immune responses . Based on these activities, we investigated whether ISS-ODN could modify the course of Mycobacterium avium infection . M . avium growth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and M . avium growth in vivo was similarly inhibited in C57BL/6 mice treated with ISS-ODN . This protective effect of ISS-ODN was largely independent of tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-alpha/beta), and IFN-gamma . In contrast, we found that the induction of indoleamine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect of ISS-ODN . To evaluate the potential for synergism between ISS-ODN and other antimycobacterial agents, treatment with a combination of ISS-ODN and clarithromycin (CLA) was tested in vitro and in vivo . ISS-ODN significantly enhanced the therapeutic effect of CLA in both human and mouse macrophages and in C57BL/6 mice . This study newly identifies IDO as being involved in the antimicrobial activity of ISS-ODN and suggests the usefulness of ISS-ODN when used in combination with conventional chemotherapy for microbial infections.

Infect Immun, 2001 Oct, 69(10), 5967 - 73
Silencing of oxidative stress response in Mycobacterium tuberculosis: expression patterns of ahpC in virulent and avirulent strains and effect of ahpC inactivation; Springer B et al.; Intracellular pathogens such as Mycobacterium tuberculosis are able to survive in the face of antimicrobial products generated by the host cell in response to infection . The product of the alkyl hydroperoxide reductase gene (ahpC) of M . tuberculosis is thought to be involved in protecting the organism against both oxidative and nitrosative stress encountered within the infected macrophage . Here we report that, contrary to expectations, ahpC expression in virulent strains of M . tuberculosis and Mycobacterium bovis grown in vitro is repressed, often below the level of detection, whereas expression in the avirulent vaccine strain M . bovis BCG is constitutively high . The repression of the ahpC gene of the virulent strains is independent of the naturally occurring lesions of central regulator oxyR . Using a green fluorescence protein vector (gfp)-ahpC reporter construct we present data showing that repression of ahpC of virulent M . tuberculosis also occurred during growth inside macrophages, whereas derepression in BCG was again seen under identical conditions . Inactivation of ahpC on the chromosome of M . tuberculosis by homologous recombination had no effect on its growth during acute infection in mice and did not affect in vitro sensitivity to H2O2 . However, consistent with AhpC function in detoxifying organic peroxides, sensitivity to cumene hydroperoxide exposure was increased in the ahpC::Km(r) mutant strain . The preservation of a functional ahpC gene in M . tuberculosis in spite of its repression under normal growth conditions suggests that, while AhpC does not play a significant role in establishing infection, it is likely to be important under certain, as yet undefined conditions . This is supported by the observation that repression of ahpC expression in vitro was lifted under conditions of static growth.

Trends Microbiol, 2001 Sep, 9(9), 438 - 44
The rise and fall of antimicrobial resistance; Lipsitch M; Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent and rate of increase of the problem varies widely with different pathogen-drug combinations . The rate of increase of resistance depends primarily on the availability of resistant variants and the intensity of selection imposed by antimicrobial treatment (appropriately measured) . Declines in resistance following antimicrobial control measures are typically faster in hospital-acquired infections than in community-acquired ones, probably owing to the dependence in the latter case on the fitness cost of resistance . Open questions and approaches for testing the hypotheses proposed here are outlined.

Vet Immunol Immunopathol, 2001 Sep 20, 81(3-4), 311 - 6
The ACVD task force on canine atopic dermatitis (XIX): general principles of therapy; Olivry T et al.; The treatment of canine atopic dermatitis is multifaceted and consists of a combination of actions that include the use of allergen avoidance, anti-inflammatory agents, allergen-specific immunotherapy and antimicrobial drugs . The importance and order of these treatment steps vary from patient to patient . General recommendations for each of the therapeutic steps are highlighted in this paper . Specific details are covered in other papers of this issue.

Aliment Pharmacol Ther, 2001 Sep, 15(9), 1473 - 8
Helicobacter pylori antimicrobial resistance in the United Kingdom: the effect of age, sex and socio-economic status; Parsons HK et al.; BACKGROUND: Helicobacter pylori antimicrobial resistance is the most common reason for eradication failure . Small studies have shown metronidazole resistance to be more prevalent in certain population groups . AIM: To determine the resistance rates in a large cohort of patients from a single centre in the UK, and to evaluate resistance patterns over time, according to age, sex and socio-economic status . METHODS: Consecutive patients with H . pylori-positive antral gastric biopsy samples were studied from 1994 to 1999 . Susceptibility testing was performed to metronidazole, tetracycline, macrolide and amoxicillin by the modified disk diffusion METHOD: The Jarman under-privileged area score was used as a measure of socio-economic status . RESULTS: A total of 1064 patients were studied . Overall metronidazole resistance was 40.3%, decreasing with age (P < 0.0001, odds ratio for patients over 60 years 0.63, 95% CI: 0.48-0.80) . Women were more likely to have metronidazole resistant strains (P=0.003, odds ratio 1.5, 95% CI: 1.15-1.91), but there was no association with Jarman score . Macrolide resistance was associated with metronidazole resistance (P=0.03, odds ratio 2.14, 95% CI: 1.07-4.28) . CONCLUSIONS: Metronidazole resistance in H . pylori is highly prevalent and more common in women and the young, but does not appear to be related to socio-economic status.

Pediatr Pathol Mol Med, 2001 Sep-Oct, 20(5), 349 - 66
In situ hybridization of SP-A mRNA in adult human conducting airways; Khubchandani KR et al.; In our study, surfactant protein (SP)-A was characterized in adult human trachea and bronchi . SP-A mRNA and protein were localized to serous cells in submucosal gland by in situ hybridization and immunohistochemistry, respectively . A 2.2 kb SP-A mRNA transcript was detected in tracheal tissues by Northern blot analysis . Primer extension analysis and gene-specific reverse transcriptase polymerase chain reaction (RT-PCR) revealed the predominance of SP-A2 mRNA . However, using nested PCR, we also detected low amounts of SP-A1 mRNA in the tracheal tissues . A approximately 35 kDa SP-A immunoreactive protein was detected in the tracheal tissues by immunoblot analysis and was shown to be modified by the addition of N-linked oligosaccharides . We conclude that submucosal glands in the conducting airways produce a novel SP-A protein with a molecular weight and post-translational modification similar to the SP-A produced in the distal lung . We speculate that this SP-A2 protein, like other serous secretions from airway submucosal glands, functions in local antimicrobial host defense mechanisms in the conducting airways.

Mutat Res, 2001 Sep 20, 496(1-2), 199 - 206
Antioxidative and antitumor promoting effects of {6}-paradol and its homologs; Chung WY et al.; Recently, considerable attention is focused on anti-carcinogenic phytochemicals, particularly those derived from medicinal or edible plants . {6}-Paradol, a pungent phenolic compound present in certain Zingiberaceae plants, is known to have antimicrobial and analgesic activities . The compound has been reported to attenuate promotion of skin carcinogenesis and TPA-induced ear edema in female ICR mice, and to induce apoptosis in cultured human promyelocytic leukemia (HL-60) cells . In this study, we performed several biochemical studies to evaluate and compare the cancer chemopreventive potential of {6}-paradol and its synthetic derivatives . {6}-Paradol and its synthetic nonpungent analog, {6}-dehydroparadol significantly decreased the incidence and the multiplicity of skin tumors initiated by 7,12-dimethylbenz{a}anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA) . Topical application of {6}-paradol and its derivatives inhibited TPA-induced ear edema and H(2)O(2) production and myeloperoxidase activity in the dorsal skin of mice . Induction of TPA-induced mouse epidermal ornithine decarboxylase (ODC) activity and H(2)O(2)- and UV-induced formation of oxidized DNA bases in vitro were also attenuated by the above compounds . These results indicate that {6}-paradol and its derivatives possess the cancer chemopreventive potential.

Mutat Res, 2001 Sep 20, 496(1-2), 61 - 73
The ability of certain antimutagenic agents to prevent development of antibiotic resistance; Pillai SP et al.; Resistance to multiple antimicrobial agents has now become a prominent fact of contemporary life . It is believed that poor patient compliance, e.g . interrupted or premature cessation of therapy; and misuse or abuse of antibiotics, e.g . wrong antibiotic or insufficient dose, play important roles in resistance development . We present evidence that, this form of resistance often stems from spontaneous mutations accompanied by the positive selecting pressure of the doses of antibiotics being between the MIC and MBC levels . A number of antimutagenic agents, e.g . green tea catechins, and other antioxidants, etc . are able to suppress the emergence of resistance . In many cases, these agents are capable of exerting these effects at doses which by themselves produce no visible effect on growth . In a number of cases antimutagenic substances capable of preventing resistance emergence are present in normal food stuffs . These effects are exerted against resistance to tetracyclines, fluoroquinolones, macrolides, beta-lactams, aminoglycosides and the like . The implications of these laboratory findings for practical chemotherapy are discussed.

Arch Dermatol Res, 2001 Jul, 293(7), 343 - 9
Development and application of monoclonal antibodies against SKALP/elafin and other trappin family members; Vandermeeren M et al.; SKALP/elafin is an epithelial proteinase inhibitor with antimicrobial properties that is not normally expressed in human epidermis, but is induced under inflammatory conditions and in some types of skin cancer . SKALP is a member of the recently described trappin gene family, which encodes a new class of proteins, characterized by a four-disulphide core and a transglutaminase substrate domain . Polyclonal antisera against SKALP have been shown to be useful for monitoring disease activity in psoriasis and tumour differentiation in squamous cell carcinoma . We developed ten different mouse monoclonal antibodies (mAbs) against synthetic peptides corresponding to a hexapeptide epitope in the transglutaminase substrate domain and three mAbs recognizing an epitope in the proteinase-inhibiting domain . The antibodies could be used with high specificity by immunohistochemistry on formalin-fixed tissue, by affinity chromatography, by Western blotting, and by enzyme-linked immunoadsorbent assay (ELISA) for the detection of SKALP/elafin . These antibodies have several advantages over existing polyclonal antisera, such as a defined epitope, the detection of full-length SKALP/elafin and unlimited supply . An antibody against the hexapeptide epitope, which is common to all known human, simian, bovine and swine trappin family members, was used to immunolocalize bovine trappins expressed in trachea, that have recently been discovered . These mAbs will serve as important new tools to measure SKALP/elafin and trappin family members in research and diagnostics.

Zh Mikrobiol Epidemiol Immunobiol, 2001 May-Jun, (3), 14 - 7
{Properties and clinical application of quasi-liquid form of lysozyme}; Strelets EV et al.; The course of transendoscopic quasi-liquid form of lysozyme treatment of the relapse of peptic ulcer was microbiologically and clinically substantiated . A high antimicrobial and sorption activity of the quasi-liquid form of lysozyme with respect to the microflora isolated from the mucous membrane of the stomach and the duodenum was shown . The transendoscopic introduction of this form of lysozyme significantly reduces the time of the cicatrization of ulcers and the stay of patients in the hospital.

Bioorg Med Chem Lett, 2001 Sep 17, 11(18), 2561 - 4
Glutamyl-gamma-boronate inhibitors of bacterial Glu-tRNA(Gln) amidotransferase; Decicco CP et al.; Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme . Although 1 provides potent enzyme inhibition, structure-activity studies revealed a narrow range of tolerated chemical changes that maintained activity . Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development.

South Med J, 2001 Aug, 94(8), 817 - 24
Practical issues in the management of hypersensitivity reactions: sulfonamides; Tilles SA; Approximately 3% of the general population and 60% of patients with human immunodeficiency virus (HIV) infection have adverse reactions when treated with sulfonamide antimicrobials . The most common clinical manifestations of sulfonamide hypersensitivity are fever and a maculopapular rash 7 to 14 days after initiating therapy, though a variety of more severe manifestations may occur . The sulfonamide chemical moiety is present in many medications that are not antimicrobials, and fortunately hypersensitivity reactions to these medications are less common . The immunogenicity of sulfonamide antimicrobials may be due to the presence of an arylamine group at the N4 position of the sulfonamide molecule . No diagnostic tests are available to confirm sulfonamide hypersensitivity, and while avoidance of the drug is generally appropriate when a previous hypersensitivity reaction is suspected, desensitization protocols are available for use in HIV patients in whom Pneumocystis carinii pneumonia prophylaxis or treatment is indicated.

N Z Med J, 2001 Jul 27, 114(1136), 326 - 8
Pneumococcal bacteraemia and opportunities for prevention; Drinkovic D et al.; AIMS: Despite availability of active antimicrobial agents for its treatment, the mortality from pneumococcal bacteraemia (PB) may reach 30% to 40% in high-risk groups . Greater vaccine use may reduce the incidence of PB . The aim of this study was to determine the proportion of patients with PB who had indications for, but had not received, pneumococcal vaccination . METHODS: From December 1998 to March 2000, all episodes of PB in adults in four Auckland hospitals were followed prospectively . Underlying disease, outcome, and pneumococcal vaccination history were recorded . RESULTS: 96 patients had PB: the median age was 63 years, range 16 to 93 years . 42 (44%) were > or = 65 years . The relative risk (RR) of acquiring PB for Maori and Pacific Island people was more than two times that of both European and other ethnic groups: RR 2.3 (95% CI 1.5 - 3.6) and 2.4 (1.6 - 3.8), respectively . The most common presentation was pneumonia; 84 (88%), of which 74 (88%) were community acquired . Five (5%) patients had meningitis . The overall mortality was 18% . Eleven (11%) pneumococcal isolates had intermediate susceptibility to penicillin and six (6%) were resistant . 69 (72%) patients had one or more condition for which pneumococcal vaccination is recommended but only two (2%) patients had received it . 82 (85%) patients were infected with serotypes included in the current pneumococcal vaccine . CONCLUSIONS: Most adult patients with PB have underlying medical conditions for which vaccination is recommended but only rare patients get vaccinated . Emerging antimicrobial resistance is a further incentive to increase the use of pneumococcal vaccination . Greater use of pneumococcal vaccine will probably require a change in its funding status, similar to the current policy for influenza vaccine . It may also be appropriate to consider targeted use of the vaccine in Maori and Pacific Island people given their higher rates of disease.

Infection, 2001 Aug, 29(4), 240 - 2
Acute disseminated encephalomyelitis (ADEM) due to Mycoplasma pneumoniae infection in an adolescent; Riedel K et al.; A 17-year-old boy presented with a severe form of an acute disseminated encephalomyelitis (ADEM) with hemiparesis and coma after initial symptoms of a flu-like febrile infection 1 week previously . Titers against Mycoplasma pneumoniae were significantly increased in serum and cerebrospinal fluid (CSF) . Detection of M . pneumoniae was achieved in the initial CSF sample using M . pneumoniae-specific PCR . The patient improved significantly on antimicrobial therapy with erythromycin and immunosupressive therapy with immunoglobulins and corticosteroids . This case report demonstrates a well-documented course of a central nervous system (CNS) infection resulting in the ADEM syndrome.

Infection, 2001 Aug, 29(4), 228 - 31
Prevalence and analysis of risk factors for infections caused by resistant Escherichia coli strains in Anhui, China; Li JB et al.; BACKGROUND: This study analyzes the prevalence of hospital and community-acquired infections caused by Escherichia coli . PATIENTS AND METHODS: The antibiotic resistance pattern was used to characterize the isolates, and a retrospective observational study was performed to assess the relationship between antimicrobial use and bacterial resistance . The study was conducted during a 1-year and 7-month period in a 1,500-bed tertiary care hospital in Anhui, China . RESULTS: An E . coli infection was diagnosed in 1.4% of patients (519/36,179) admitted to the hospital between March 1, 1999 and August 31, 2000 . Of the 519 isolates, 489 (94.2%) were resistant to at least one antimicrobial; 86% were resistant to ampicillin, 85% to cephalothin, 83% to piperacillin, 77% to ampicillin/sulbactam, 72% to trimethoprim/sulfamethoxazole (TMP-SMZ), 70% to ciprofloxacin, 61% to cefoperazone, 58% to tobramycin, 56% to gentamicin, 48% to ticarcillin-clavulanate, 44% to cefazolin, 43% to cefuroxime, 36% to cefoxitin, 32% to cefepime, 29% to aztreonam, cefetaxime and ceftriaxone, 28% to ceftazidime, 19% to piperacillin/tazobactam, 10% to amikacin, while all strains tested were susceptible to imipenem . CONCLUSION: Prior receipt of amtimicrobial therapy was significantly associated with infection caused by a resistant organism.

Biomaterials, 2001 Oct, 22(20), 2713 - 7
Release profile of antimicrobial agents from alpha-tricalcium phosphate cement; Akashi A et al.; A new method for treating carious dentine with alpha-tricalcium phosphate (alpha-TCP) dental cement containing antimicrobial agents has been recently introduced . However, the release behavior of antimicrobial agents from this cement has not yet been clarified . The aim of this study is therefore to examine the release profile of the antimicrobial agents from the alpha-TCP cement . Three kinds of antimicrobial agents (metronidazole, cefaclor and ciprofloxacin) were added to two commercially available alpha-TCP cements (new apatite liner type I and type II) . The set cements were then immersed in water at 37 degrees C and the released antimicrobial agents and Ca ion were determined at regular intervals for three months . In addition, scanning electron microscopic observations were conducted before and after immersion for three months . The release profile of the cements containing antimicrobial agents varied depending on the types of antimicrobial agents . The incorporation of antimicrobial agents affected the setting reaction of the cements . The release behavior of the drugs also varied depending on the types of the cements . The differences in the release profile between type I and type II cements reflected the structures and compositions of their matrices.

Nature, 2001 Sep 6, 413(6851), 36 - 7
Immune recognition . A new receptor for beta-glucans; Brown GD et al.; The carbohydrate polymers known as beta-1,3-d-glucans exert potent effects on the immune system - stimulating antitumour and antimicrobial activity, for example - by binding to receptors on macrophages and other white blood cells and activating them . Although beta-glucans are known to bind to receptors, such as complement receptor 3 (ref . 1), there is evidence that another beta-glucan receptor is present on macrophages . Here we identify this unknown receptor as dectin-1 (ref . 2), a finding that provides new insights into the innate immune recognition of beta-glucans.

Environ Health Perspect, 2001 Aug, 109 Suppl 4, 609 - 12
Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection; Castranova V et al.; There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent) . In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles . In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product} to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) . Methanol extract exhibited this potential but methanol-washed diesel particles did not . Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages . In contrast, carbon black did not exhibit this inhibitory effect . Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component) . In contrast, exposure to coal dust increased zymosan-stimulated oxidant production . In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria . Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung . These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages . This inhibitory effect appears to be due to adsorbed organic chemicals rather than the carbonaceous core of the diesel particles.

Fitoterapia, 2001 Aug, 72(6), 703 - 5
Antimicrobial activity of Lithocarpus celebicus; Khan MR et al.; The methanol extracts of leaves, stem and root barks of Lithocarpus celebicus showed a broad spectrum of antibacterial activity which was increased on fractionation (petrol, dichloromethane, ethylacetate), particularly in the ethyl acetate fraction of the stem bark and petrol fraction of the root bark . None of the extractives was active against tested moulds.

Fitoterapia, 2001 Aug, 72(6), 692 - 4
Antimicrobial activity of three Mexican Gnaphalium species; Villagomez-Ibarra JR et al.; The antibacterial activity of the hexane, ethyl acetate and methanol extracts of the flowers, leaves and stems of Gnaphalium oxyphyllum var . oxyphyllum, G . liebmannii var . monticola and G . viscosum was investigated . The hexane extracts showed in all cases the higher inhibitions, G . oxyphyllum flower extract exhibiting the wider spectrum of activity.

Fitoterapia, 2001 Aug, 72(6), 666 - 8
Antimicrobial activity of triterpenoids from Heliotropium ellipticum; Jain SC et al.; Seven sterols and triterpenoids have been isolated from H . ellipticum and tested for their antimicrobial activity.

Adv Space Res, 1994 Oct, 14(10), 583 - 6
Survival of irradiated mice treated with WR-151327, synthetic trehalose dicorynomycolate, or ofloxacin; Ledney GD et al.; Spaceflight personnel need treatment options that would enhance survival from radiation and would not disrupt task performance . Doses of prophylactic or therapeutic agents known to induce significant short-term (30-day) survival with minimal behavioral (locomotor) changes were used for 180-day survival studies . In protection studies, groups of mice were treated with the phosphorothioate WR-151327 (200 mg/kg, 25% of the LD(10)) or the immunomodulator, synthetic trehalose dicorynomycolate (S-TDCM; 8 mg/kg), before lethal irradiation with reactor-generated fission neutrons and gamma-rays (n/gamma=1) or 60Co gamma-rays . In therapy studies, groups of mice received either S-TDCM, the antimicrobial ofloxacin, or S-TDCM plus ofloxacin after irradiation . For WR-151327 treated-mice, survival at 180 days for n/gamma=1 and gamma-irradiated mice was 90% and 92%, respectively; for S-TDCM (protection), 57% and 78%, respectively; for S-TDCM (therapy), 20% and 25%, respectively; for ofloxacin, 38% and 5%, respectively; for S-TDCM combined with ofloxacin, 30% and 30%, respectively; and for saline, 8% and 5%, respectively . Ofloxacin or combined ofloxacin and S-TDCM increased survival from the gram-negative bacterial sepsis that predominated in n/gamma=1 irradiated mice . The efficacies of the treatments depended on radiation quality, treatment agent and its mode of use, and microflora of the host.

Pneumologie, 2001 Sep, 55(9), 431 - 7
{Treatment of community-acquired lung abscess associated with aspiration}; Ewig S et al.; The management of community-acquired lung abscess associated with aspiration is based on adequate antimicrobial treatment and effective drainage . Empiric antimicrobial treatment should cover basic microbial patterns and consist of aminopenicillin/beta-lactamase-inhibitor or clindamycin . Since the spectrum of clindamycin is restricted to Gram-positive microorganisms combination treatment of clindamycin with a second-generation cephalosporin may be warranted . It is crucial to continue antimicrobial treatment until complete resolution of the abscess cavity and the corresponding infiltrates . Drainage is frequently present spontaneously . Additional techniques to ensure effective drainage include bronchoscopic and percutaneous drainage . These techniques are only infrequently indicated in case of clinical failure and of delayed cavity closure . Indications for surgical emergency interventions are mainly limited to severe pulmonary hemorrhage . The clinical success rate of adequate antimicrobial treatment together with effective drainage reaches 75 - 90 %.

Med Sci Monit, 2001 Sep-Oct, 7(5), 1016 - 22
A comparative study of cefaclor vs . amoxicillin/clavulanate in tonsillopharyngitis; Haczynski J et al.; BACKGROUND: Acute pharyngotonsillitis (APT) is one of the most common inflammatory processes of adults and children in an outpatient setting . Increasing failure rates, hypersensitivity to penicillin, the required multiple daily doses and common side effects lead to poor patients compliance and thus inadequate treatment duration, providing therefore ground for considering alternative antimicrobial agents . MATERIAL AND METHODS: This multicenter, randomized, single blind study was undertaken in order to compare efficacy and safety of cefaclor (375 mg BID) and amoxicillin/clavulanate (625 mg BID) in 10 days treatment regiment of ambulatory patients with APT . A total of 200 patients (age range between 12-65 years) with symptoms of APT and positive antigen strep test were enrolled into the study . Clinical and bacteriological responses were assessed after the end of treatment (14th-18th day) and at the follow-up visit (38th-45th day) . All GABHS strains, isolated from throat cultures, were tested for in vitro sensitivity to the antibiotics used in the study and no strain was found resistant to both antibiotics . RESULTS: The results indicated that both antibiotics had high--almost 99% effectiveness at the post therapy visit . On the follow up visit an increased tendency of relapses was observed in the amoxicillin/clavulanate treated group, compared to cefaclor treated group (8.33% vs 3.29%) . Relative risk of relapse in patients treated with amoxicillin/clavulanate was 2.6 greater compared to cefaclor . There were significantly higher rates of gastrointestinal adverse events in group treated with amoxicillin/clavulanate (29/97 patients; 29.89%) compared to cefaclor (16/95 patients; 16.84%) - p< 0.03 . Frequency of other adverse events did not differ significantly between the groups . CONCLUSIONS: Cefaclor and amoxicillin/clavulonate provide a clinically and bacteriologically effective treatment for patients with pharyngotonsillitis caused by GABHS, but cefaclor treatment is significantly safer in regard to gastrointestinal side effects.

J Trauma, 2001 Sep, 51(3), 540 - 4
Association of hyperglycemia with increased mortality after severe burn injury; Gore DC et al.; BACKGROUND: Hyperglycemia is commonly associated with the hypermetabolic stress response . However, persistent hyperglycemia may adversely affect wound healing and immunity . The purpose of this study was to assess any relationship between hyperglycemia and clinical outcome after severe burn injury . METHODS: Survey of the medical records from January 1996 to July 1999 identified 58 pediatric patients with burns > or = 60% body surface . Patients were categorized as having poor glucose control (n = 33) if > or = 40% of all plasma glucose determinations were > or = 7.8 mmol/L (140 mg/dL) and compared with patients deemed to have adequate glucose control (n = 25) in whom > or = 40% of all glucose values were > or = 7.8 mmol/L . RESULTS: Despite similar age, burn size, caloric intake, and frequency of wound infection, patients categorized with poor glucose control had a significantly greater incidence of positive blood cultures (positive blood cultures/length of stay days, 0.42 +/- 0.04 for hyperglycemia patients vs . 0.30 +/- 0.03 for normoglycemia patients; mean +/- SEM, p > or = 0.05) . This finding was especially prominent for blood cultures positive for yeast . Hyperglycemia patients had significantly less percentage of skin graft take than did the normoglycemic patients (percent take/operative procedure, 64 +/- 9 for hyperglycemia patients vs . 88 +/- 5 for normoglycemia patients; p < 0.05) . Nine patients (27%) with persistent hyperglycemia died compared with only one death (4%) in patients with adequate glucose control (p > or = 0.05) . CONCLUSION: This association between poor glucose control, bacteremia/fungemia, reduced skin graft take, and subsequent mortality in severely burned children may be related to a hyperglycemia-induced detriment in antimicrobial defense . Although this report fails to establish cause and effect, these findings suggest that aggressive maneuvers to normalize plasma glucose in critically injured patients may be warranted.

Proc Natl Acad Sci U S A, 2001 Sep 11, 98(19), 10614 - 9 Epub 2001 Sep 04.
Biosynthesis and insecticidal properties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affinis; Jennings C et al.; Several members of the Rubiaceae and Violaceae families produce a series of cyclotides or macrocyclic peptides of 29-31 amino acids with an embedded cystine knot . We aim to understand the mechanism of synthesis of cyclic peptides in plants and have isolated a cDNA clone that encodes the cyclotide kalata B1 as well as three other clones for related cyclotides from the African plant Oldenlandia affinis . The cDNA clones encode prepropeptides with a 20-aa signal sequence, an N-terminal prosequence of 46-68 amino acids and one, two, or three cyclotide domains separated by regions of about 25 aa . The corresponding cyclotides have been isolated from plant material, indicating that the cyclotide domains are excised and cyclized from all four predicted precursor proteins . The exact processing site is likely to lie on the N-terminal side of the strongly conserved GlyLeuPro or SerLeuPro sequence that flanks both sides of the cyclotide domain . Cyclotides have previously been assigned an antimicrobial function; here we describe a potent inhibitory effect on the growth and development of larvae from the Lepidopteran species Helicoverpa punctigera.

Contraception, 2001 Jul, 64(1), 67 - 75
Properties of a new acid-buffering bioadhesive vaginal formulation (ACIDFORM); Garg S et al.; Vaginal prophylactic methodology may prevent heterosexual transmission of the HIV and other sexually transmitted disease-causing organisms as well as unplanned pregnancies . A new delivery system (ACIDFORM) was designed with acid-buffering, bioadhesive, and viscosity-retaining properties to (1) maintain the acidic vaginal milieu (the low pH inactivates many pathogens and spermatozoa), (2) form a protective layer over the vaginal/cervical epithelium (minimizing contact with pathogenic organisms), and (3) provide long-term vaginal retention . A Phase I clinical study with ACIDFORM provided initial information about its safety and showed the formation of a layer over the vaginal/cervical epithelium {1; Amaral et al., Contraception 1999;60:361-6} . To study the properties of the gel (without active ingredient) in more detail, ACIDFORM's acid-buffering, bioadhesive, viscosity-retaining, and spermicidal properties were compared in vitro to marketed formulations, and its long-term stability was assessed . ACIDFORM, either when titrated with NaOH or when mixed directly with semen, is highly acid buffering and much more effective than Aci-Jel, a commercial acid-buffering vaginal product . ACIDFORM adheres well to two model membranes (excised sheep vagina and cellophane) and is more bioadhesive than Conceptrol, Advantage S, Replens, Aci-Jel, and K-Y jelly . On dilution, ACIDFORM also retains its viscosity better than these marketed products . ACIDFORM is spermicidal and is stable for at least 2 years . These results suggest that ACIDFORM has advantages over presently marketed vaginal delivery systems . The gel may either be useful by itself as an antimicrobial contraceptive product or as a formulation vehicle for an active ingredient with antimicrobial and/or contraceptive properties.

Intensive Care Med, 2001 Jul, 27(7), 1169 - 78
A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome; Gallagher J et al.; OBJECTIVE: To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha in patients with sepsis . DESIGN: Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial . SETTING: Intensive care units of six academic medical centers in the United States . PATIENTS: Forty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy . Interventions: Patients received 0.3, 1.0, or 3.0 mg/kg afelimomab or placebo intravenously over 20 min . Three patients in each dose group received single doses; the remaining nine patients in each group received multiple (nine) doses at 8-h intervals over 72 h . MEASUREMENTS AND MAIN RESULTS: Afelimomab appeared safe and well tolerated . Single- and multiple-dose kinetics were predictable and dose related . The elimination half-life was 44.7 h . Afelimomab treatment resulted in increased serum concentrations of TNF (includes TNF-antibody complexes) and decreased serum interleukin-6 concentrations, whereas no discernible trends were observed in placebo-treated patients . There was no significant treatment effect on 28-day mortality as was expected given the small number of patients . However, overall mortality was significantly (p = 0.001) associated with baseline interleukin-6 concentration . All patients experienced adverse events, but the vast majority were considered unrelated to the study drug and demonstrated no apparent relationship to afelimomab dose . Although 41% of patients developed human anti-murine antibodies, there were no clinical sequelae . CONCLUSIONS: Multidose therapy with afelimomab was safe, well tolerated, and had predictable linear kinetics . A large randomized trial comparing afelimomab to placebo in patients with well defined sepsis has recently been completed.

Nahrung, 2001 Aug, 45(4), 267 - 72
Composite starch-based coatings applied to strawberries (Fragaria ananassa); Garcia MA et al.; Starch-based coatings were used to the extend storage life of strawberries (Fragaria ananassa) stored at 0 degree C and 84.8% relative humidity . Effects of coating formulation (including starch type, plasticizer, lipid and antimicrobial agent) were analysed with respect to fruit quality . Plasticizer addition was necessary for film and coating integrity to avoid pores and cracks . Plasticizer presence reduced weight losses and maintained surface colour of fruits . Amylomaize coatings showed lower water vapour and gas permeabilities and decreased weight losses for longer periods than corn starch ones . Coatings with sorbitol showed lower permeabilities than glycerol ones . Coatings with antimicrobial agents decreased microbial counts, extending storage life of coated fruits by 10 to 14 days in comparison to the control . The addition of 2 g/l sunflower oil to the formulations decreased the water vapour permeability of starch-based films, maintained the surface colour of coated fruits and controlled effectively fruit weight losses during storage . Lipid addition minimized the effects of starch and plasticizer types . Composite starch-based coatings showed selective gas permeability (CO2 higher than O2) which helps to delay senescence of fruits.

Rev Med Interne, 2001 Aug, 22(8), 737 - 44
{Economic impact of rationalized antibiotic therapy in a general hospital}; Divanon F et al.; PURPOSE: To evaluate the economic impact and the bacterial resistance rates after 2 years of a rationalized antibiotic prescription program in a 502-bed hospital . CURRENT KNOWLEDGE AND KEY POINTS: Prescribing protocols were established by consensus in 1998 and were reinforced a year later by nominative dispensing of the most costly antibiotics . The impact of the program was assessed in terms of changes in the overall cost of antibiotics and in the pattern of bacterial resistance among pathogens isolated in the institution, during the period prior to the onset of the program (1997) and its realization (1998 and 1999) . FUTURE AND PROJECTS: The expenses for antibiotic drugs decreased by 46% in 2 years . Resistance rates among the different pathogens studied have remained stable . No increase of mortality was observed . Our rational policy in antibiotic therapy had a positive economic impact . However, new additional measures should be encouraged to prevent antimicrobial resistance.

Pharmazie, 2001 Aug, 56(8), 643 - 7
Honey, a prospective antibiotic: extraction, formulation, and stability; Zaghloul AA et al.; Old and recent reports show that honey has beneficial effects on the skin as antiseptic for wounds, burns and ulcers and as a healing promoter . Many investigators confirmed the usefulness of honey in the treatment of skin infections as well as internal diseases . The factors behind these effects are not completely explained . The aim of this study is: a) to investigate the antimicrobial activity of crude honey, b) to separate the fractions responsible for its activity, c) to formulate the honey extract as semisolid dosage forms, d) to study its release, and e) to determine its stability . The results showed that the ethylacetate honey extract showed antibacterial, anticandida and antifungal effects at low concentration . The release of honey extract from different ointment bases was depending on the constituents of the base, and its stability was found to be temperature and base dependent.

Pediatrics, 2001 Sep, 108(3), 798 - 808
Clinical practice guideline: management of sinusitis; American Academy of Pediatrics . Subcommittee on Management of Sinusitis and Committee on Quality Improvement; This clinical practice guideline formulates recommendations for health care providers regarding the diagnosis, evaluation, and treatment of children, ages 1 to 21 years, with uncomplicated acute, subacute, and recurrent acute bacterial sinusitis . It was developed through a comprehensive search and analysis of the medical literature . Expert consensus opinion was used to enhance or formulate recommendations where data were insufficient . A subcommittee, composed of pediatricians with expertise in infectious disease, allergy, epidemiology, family practice, and pediatric practice, supplemented with an otolaryngologist and radiologist, were selected to formulate the practice parameter . Several other groups (including members of the American College of Emergency Physicians, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Asthma, Allergy and Immunology, as well as numerous national committees and sections of the American Academy of Pediatrics) have reviewed and revised the guideline . Three specific issues were considered: 1) evidence for the efficacy of various antibiotics in children; 2) evidence for the efficacy of various ancillary, nonantibiotic regimens; and 3) the diagnostic accuracy and concordance of clinical symptoms, radiography (and other imaging methods), and sinus aspiration . It is recommended that the diagnosis of acute bacterial sinusitis be based on clinical criteria in children </=6 years of age who present with upper respiratory symptoms that are either persistent or severe . Although controversial, imaging studies may be necessary to confirm a diagnosis of acute bacterial sinusitis in children >6 years of age . Computed tomography scans of the paranasal sinuses should be reserved for children who present with complications of acute bacterial sinusitis or who have very persistent or recurrent infections and are not responsive to medical management . There were only 5 controlled randomized trials and 8 case series on antimicrobial therapy for acute bacterial sinusitis in children . However, these data, plus data derived from the study of adults with acute bacterial sinusitis, support the recommendation that acute bacterial sinusitis be treated with antimicrobial therapy to achieve a more rapid clinical cure . Children with complications or suspected complications of acute bacterial sinusitis should be treated promptly and aggressively with antibiotics and, when appropriate, drainage . Based on controversial and limited data, no recommendations are made about the use of prophylactic antimicrobials, ancillary therapies, or complementary/alternative medicine for prevention and treatment of acute bacterial sinusitis . This clinical practice guideline is not intended as a sole source of guidance in the diagnosis and management of acute bacterial sinusitis in children . It is designed to assist pediatricians by providing an analytic framework for evaluation and treatment . It is not intended to replace clinical judgment or establish a protocol for all patients with this condition.

Pediatrics, 2001 Sep, 108(3), 591 - 6
Impact of a waiting room videotape message on parent attitudes toward pediatric antibiotic use; Wheeler JG et al.; OBJECTIVE: To reduce the injudicious use of antibiotics, we developed an educational strategy that focused on parents of pediatric patients and their physicians . METHODS: This intervention was conducted in 5 pediatric practices in Arkansas during a 9-month period . Baseline data on parent attitudes about antibiotics and physician practice habits were measured by questionnaire . During the following 36 weeks, an educational videotape about the judicious use of antibiotics was played in waiting rooms . The videotape on antibiotics used a standard script based on the recommendations of the American Academy of Pediatrics . The physicians and staff at each site were actors in the videotape . During week 2 and week 36 of videotape use, parent attitudes were measured again . After the baseline week, the physicians and staff in each site were provided a standard in-service review of the American Academy of Pediatrics recommendations for judicious use of antibiotics . A study nurse recruited patients, administered questionnaires, and reviewed charts on-site . RESULTS: Parents who were exposed to the videotape were significantly less inclined to seek antibiotics for viral infections . Passively provided pamphlets were not read . No significant change in antibiotic prescribing by physicians was seen . CONCLUSION: Parent-focused passive education tools are effective at changing parent attitudes toward the use of antibiotics . Although physicians have blamed parent attitudes and demands for the overuse of antibiotics, changes in parent attitudes in this study were not associated with changes in prescribing rates . Changes in parent attitudes may be necessary but do not seem sufficient for changes in antimicrobial prescribing patterns.

Clin Microbiol Infect, 2001 Jul, 7(7), 345 - 51
Sequence microdiversity at the ribosomal RNA operons of Escherichia coli pyelonephritogenic strains; Anton AI et al.; OBJECTIVE: To determine whether Escherichia coli strains isolated from patients with uncomplicated acute pyelonephritis can be distinguished from those isolated from patients with complicated acute pyelonephritis on the basis of the genetic background . METHODS: In total, 103 E . coli strains isolated from patients with acute pyelonephritis (59 uncomplicated pyelonephritis (UAP) and 44 complicated pyelonephritis (CAP)) were characterized by RFLP of the intergenic spacer region 16S-23S rRNA, the presence of three alternative sequences found in the polymorphic V6 loop of the 16S rRNA gene, the presence of the pap gene, and antibiotic susceptibility . RESULTS: At similarity levels of 70%, four RFLP groups (alpha1, alpha2, beta1 and beta2) were discerned . Strains from UAP were statistically significant for alpha RFLP, with a strong association with the presence of the pap gene, V6-I sequence and antibiotic multisensitivity . Strains from CAP randomly belonged to the alpha or beta RFLP groups, with a very low presence of the pap gene, and random presence of V6 sequences, and were multiresistant to antibiotics . When the CAP strains were distributed according to underlying pathology, non-obstructive cases had RFLP and V6 polymorphisms similar to those of UAP cases, while obstructive cases were clearly distinct . CONCLUSIONS: UAP and non-obstructive CAP E . coli strains are sensitive to antimicrobials, show a high level of the pap gene and belong to the selective, homogeneous and highly protected molecular alpha2 group, where no recombinations, deletions or insertions are present . On the contrary, obstructive and vesicorenal reflux E . coli strains show significant antimicrobial resistance, high intercistronic heterogenicity (wide presence of block nucleotidic substitutions, deletions or insertions) and significantly lower virulence.

Prev Vet Med, 2001 Sep 20, 51(1-2), 37 - 49
Activities to address antimicrobial resistance in the United States; Torrence ME; Antimicrobials are essential for the prevention and treatment of bacterial infections in humans and animals . Subtherapeutic antimicrobials have been used as growth promoters for >40 years . The subject of antimicrobial resistance is not new but has gained increasing attention due to public-health concerns about multi-resistant pathogenic organisms . Numerous United States' activities do exist to address antimicrobial resistance . A surveillance system (the National Antimicrobial Resistance Monitoring System) was established in 1996 to monitor changes over time in resistance for 17 antibiotics in humans and animals . Educational campaigns have been created to promote the judicious therapeutic use of antimicrobials . Producer groups are developing guidelines for judicious therapeutic antimicrobial use for their prospective species . Basic and applied research programs are being expanded to answer many of the unsolved questions regarding development, persistence, and transmission of antimicrobial resistance . This paper focuses on a federal inter-agency public-health action plan to combat antimicrobial resistance; the plan was released for public comment in 2000 . This plan addresses goals and actions to combat antimicrobial resistance in humans and agriculture in four areas: surveillance; research; prevention and control; product development.

J Med Assoc Thai, 2001 Jun, 84 Suppl 1, S474 - 80
Eradication rates of Helicobacter pylori between metronidazole-sensitive and metronidazole-resistant strains with metronidazole containing regimen in Thai patients with peptic ulcer disease; Wongkusoltham P et al.; The results of the in vitro metronidazole resistance on Helicobacter pylori (H . pylori) eradication have been inconclusive . Metronidazole resistance varies among different geographical locations and a previous study from Thailand reported an in vitro metronidazole resistance of H . pylori of 51 per cent . This study was designed to investigate further the effect of the in vitro metronidazole resistance on the outcome of eradication of H . pylori in the Thai population . Fifty two patients with active gastric ulcer (GU) and duodenal ulcer (DU) who had positive culture for H . pylori were studied . All of these patients had positive rapid urease test (CLO test, Delta West, Australia) using gastric biopsy specimens from the antrum and body taken at the time of initial upper endoscopy . In vitro antimicrobial susceptibility test was performed using Epsilometer test (AB Biodisk, Solna, Sweden) . All patients received a one-week triple regimen consisting of omeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, metronidazole 500 mg twice daily . Patients with GU continued with another five weeks of omeprazole 20 mg twice daily and patients with DU received another three weeks of omeprazole 20 mg twice daily . Upper endoscopy was repeated at four weeks after the end of the treatment . Three antral and two body biopsy specimens were obtained for identification of H . pylori using CLO test, histology (modified Giemsa stain) and culture . All of these tests had to be negative to confirm a successful eradication . Metronidazole-resistant (MR) strains with MIC > or = 32 mg/l were identified in 27 of the 52 patients (51.92%), whereas, metronidazole-susceptible (MS) strains were isolated from 25 patients (48.08%) . Five patients were lost to follow-up and one patient had drug allergy . Successful eradication as defined by negative CLO test, histology and culture was attained in 17/23 (73.91%) patients (GU = 6, DU = 16, GU and DU = 1) with MR strains . 20 out of 23 (86.96%) patients (GU = 9, DU = 12 GU and DU = 2) who had MS strains . The difference was not statistically significant in both groups (P > 0.05) . The ulcer healing was, however, highly achieved in both groups (MS = 95.65%, MR = 91.30%, P > 0.05) . In vitro metronidazole resistance was high in this population group although this does not predict the outcome of eradication in patients with GU and DU.

Invest Ophthalmol Vis Sci, 2001 Sep, 42(10), 2157 - 63
Detection of natural peptide antibiotics in human nasolacrimal ducts; Paulsen FP et al.; PURPOSE: To determine the expression and production of antimicrobial peptides by mucosal cells of the lacrimal passage in healthy and pathologic states . METHODS: Detection of bactericidal-permeability-increasing protein (BPI), heparin-binding protein (CAP37), human cationic antimicrobial protein (LL-37), human alpha-defensin 5 (HD5), human alpha-defensin 6 (HD6), human beta-defensin 1 (HBD-1), and human beta-defensin 2 (HBD-2) was performed by reverse transcription-polymerase chain reaction (RT-PCR) . Intracellular deposition of lysozyme, lactoferrin, secretory phospholipase A(2), human neutrophil defensins (HNP-1, -2, and -3), human beta-defensin 1 (HBD-1), and human beta-defensin 2 (HBD-2) was analyzed immunohistochemically . Samples were obtained from 15 patients by surgery and from 10 cadavers . RESULTS: RT-PCR revealed BPI, CAP37, and HBD-1 mRNA in samples of healthy nasolacrimal duct epithelium . Additionally, HBD-2 mRNA was detected in epithelial samples from patients with dacryocystitis . Messenger RNAs for LL-37 and alpha-defensin 5 and 6 were absent in all samples investigated . Immunohistochemistry revealed lysozyme, lactoferrin, secretory phospholipase A(2), and HNP-1, -2, and -3 to be present in all samples, whereas HBD-1 was present only in some of the healthy and inflamed samples . Immunoreactive HBD-2 peptide was visible only in some of the inflamed samples . CONCLUSIONS: The data suggest that the human efferent tear ducts produce a broad spectrum of antimicrobial peptides . Under inflammatory conditions, changes in the expression pattern occurred, revealing induction of the human inducible defensin HBD-2 and in some cases downregulation of HBD-1 and CAP37 . Antimicrobial peptides have a therapeutic potential in dacryocystitis, in that they have a broad spectrum of antimicrobial activity and accelerate epithelial healing . However, caution is appropriate, because defensins also promote fibrin formation and cell proliferation, which are key elements in scarring processes, such as dacryostenosis.

Clin Diagn Lab Immunol, 2001 Sep, 8(5), 1021 - 3
Expression of natural peptide antibiotics in human articular cartilage and synovial membrane; Paulsen F et al.; In view of frequent present use of invasive procedures on limb joints, it is astonishing that articular joint inflammation is a rare event . We questioned whether antimicrobial peptides play a role in protecting human articular cartilage and synovial membrane against inflammatory agents . Our results implicate defensins in the protection of human articular joints against pathogens.

Acta Crystallogr D Biol Crystallogr, 2001 Sep, 57(Pt 9), 1296 - 9 Epub 2001 Aug 23.
Crystallization and preliminary crystallographic analysis of the recombinant N-terminal domain of riboflavin synthase; Meining W et al.; Riboflavin synthase catalyzes the final step in the biosynthesis of riboflavin . Animals and humans lack this enzyme, whereas many bacteria and certain yeasts are absolutely dependent on endogenous riboflavin synthesis . Riboflavin synthase is therefore an attractive target for chemotherapy . The N-terminal domain of riboflavin synthase forms a dimer in solution and is capable of strongly binding riboflavin . It can serve as a model for the binding site of the native enzyme . Structural information obtained from this domain at high resolution will be helpful in the determination of the binding mode of riboflavin and thus for the development of antimicrobial drugs . Here, the crystallization and preliminary crystallographic analysis of the N-terminal domain of riboflavin synthase are reported . The crystals belong to the space group C222(1), with unit-cell parameters a = 50.3, b = 104.7, c = 85.3 A, alpha = beta = gamma = 90 degrees, and diffract to 2.6 A resolution.

J Clin Microbiol, 2001 Sep, 39(9), 3052 - 5
Differentiation of metronidazole-sensitive and -resistant clinical isolates of Helicobacter pylori by immunoblotting with antisera to the RdxA protein; Latham SR et al.; Antimicrobial resistance in Helicobacter pylori is a serious and increasing problem, and the development of rapid, reliable methods for detecting resistance would greatly improve the selection of antibiotics used to treat gastric infection with this organism . We assessed whether detection of the RdxA protein could provide the basis for determining the susceptibility of H . pylori to metronidazole . In order to raise polyclonal antisera to RdxA, we cloned the rdxA gene from H . pylori strain 26695 into the commercial expression vector pMAL-c2, purified the resultant fusion protein by affinity chromatography, and used this recombinant RdxA preparation to immunize rabbits . We then used this specific anti-RdxA antibody to perform immunoblotting on whole bacterial cell lysates of 17 metronidazole-sensitive and 27 metronidazole-resistant clinical isolates of H . pylori . While a 24-kDa immunoreactive band corresponding to the RdxA protein was observed in all metronidazole-sensitive strains, this band was absent in 25 of 27 resistant isolates . Our results indicate that testing for the absence of the RdxA protein would identify the majority of clinical isolates that will respond poorly to metronidazole-containing eradication regimens and have implications for the development of assays capable of detecting metronidazole resistance in H . pylori.

Appl Environ Microbiol, 2001 Sep, 67(9), 3934 - 42
Antimicrobial properties of pyridine-2,6-dithiocarboxylic acid, a metal chelator produced by Pseudomonas spp; Sebat JL et al.; Pyridine-2,6-dithiocarboxylic acid (pdtc) is a metal chelator produced by Pseudomonas spp . It has been shown to be involved in the biodegradation of carbon tetrachloride; however, little is known about its biological function . In this study, we examined the antimicrobial properties of pdtc and the mechanism of its antibiotic activity . The growth of Pseudomonas stutzeri strain KC, a pdtc-producing strain, was significantly enhanced by 32 microM pdtc . All nonpseudomonads and two strains of P . stutzeri were sensitive to 16 to 32 microM pdtc . In general, fluorescent pseudomonads were resistant to all concentrations tested . In competition experiments, strain KC demonstrated antagonism toward Escherichia coli . This effect was partially alleviated by 100 microM FeCl3 . Less antagonism was observed in mutant derivatives of strain KC (CTN1 and KC657) which lack the ability to produce pdtc . A competitive advantage was restored to strain CTN1 by cosmid pT31, which restores pdtc production . pT31 also enhanced the pdtc resistance of all pdtc-sensitive strains, indicating that this plasmid contains elements responsible for resistance to pdtc . The antimicrobial effect of pdtc was reduced by the addition of Fe(III), Co(III), and Cu(II) and enhanced by Zn(II) . Analyses by mass spectrometry determined that Cu(I):pdtc and Co(III):pdtc2 form immediately under our experimental conditions . Our results suggest that pdtc is an antagonist and that metal sequestration is the primary mechanism of its antimicrobial activity . It is also possible that Zn(II), if present, may play a role in pdtc toxicity.

J Periodontol, 2001 Aug, 72(8), 1069 - 77
A combination of a chemically modified doxycycline and a bisphosphonate synergistically inhibits endotoxin-induced periodontal breakdown in rats; Llavaneras A et al.; BACKGROUND: Chemically modified non-antimicrobial tetracyclines (CMTs) have been shown to inhibit pathologically elevated collagenase (and other matrix metalloproteinase, MMP) activity and bone resorption in vivo and in vitro . METHODS: In the current study, suboptimal doses of CMT-8 (a non-antimicrobial chemically modified doxycycline) and a bisphosphonate (clodronate, an anti-bone resorption compound) were administered daily, either as a single agent or as a combination therapy, to rats with experimental periodontitis induced by repeated injection of bacterial endotoxin (LPS) into the gingiva . At the end of the 1-week protocol, the gingival tissues were dissected, extracted, and the extracts analyzed for MMPs (collagenases and gelatinases) and for elastase, and the defleshed jaws were morphometrically analyzed for alveolar bone loss . RESULTS: LPS injection significantly (P<0.001) increased alveolar bone loss and increased collagenase (MMP-8), gelatinase (MMP-9), and elastase activities . Treatment of the LPS-injected rats with suboptimal CMT-8 alone or suboptimal clodronate alone produced slight reductions in the tissue-destructive proteinases and no significant reductions in alveolar bone loss . However, a combination of suboptimal CMT-8 and clodronate "normalized" the pathologically elevated levels of MMPs, elastase, and alveolar bone loss, indicating synergistic inhibition of tissue breakdown in this animal model of periodontitis . CONCLUSIONS: Combination of a CMT and a bisphosphonate may be a useful treatment to optimally suppress periodontal destruction and tooth loss and in other tissue-destructive inflammatory diseases such as arthritis.

Scand J Infect Dis, 2001, 33(8), 627 - 8
Central venous catheter-related infection due to Comamonas testosteroni in a woman with breast cancer; Le Moal G et al.; A 75-y-old woman with breast cancer presented with bacteremia due to Comamonas testosteroni . Evolution was favorable following adapted antimicrobial therapy and removal of a central venous catheter . This germ seems to be a rare pathogen; as reported in the literature, it is mostly encountered in patients with predisposing factors.

Scand J Infect Dis, 2001, 33(8), 604 - 10
Occurrence and antimicrobial susceptibility of Ureaplasma parvum (Ureaplasma urealyticum biovar 1) and Ureaplasma urealyticum (Ureaplasma urealyticum biovar 2) from patients with adverse pregnancy outcomes and normal pregnant women; Martinez MA et al.; A recent phylogenetic analysis of Ureaplasma urealyticum resulted in the proposal to divide their 2 biovars into species . We used PCR to compare the distribution of species and the presence of the tet(M) and int-Tn resistance determinants in 63 strains of Ureaplasma spp . isolated from the amniotic fluid of patients with an adverse pregnancy outcome and in 22 strains obtained from the lower genital tract of healthy pregnant women . We also determined the antimicrobial susceptibility of the organisms to erythromycin and tetracycline . U . parvum was the most frequent Ureaplasma species detected in our study . Thus, 50/63 (79.4%) invasive isolates and 17/22 (77.3%) lower genital tract isolates corresponded to U . parvum, whereas 12/63 (19%) invasive isolates and 4/22 (18.2%) non-invasive strains corresponded to U . urealyticum . A mixture of species was found in 2 women . We found no significant differences in the antimicrobial susceptibility of isolates according to species or origin of isolation . Sixty-two strains of Ureaplasma spp . (74.7%) were susceptible to erythromycin, and 21 strains (25.3%) were intermediately susceptible . Sixty-eight isolates (81.9%) were susceptible to tetracycline, 2 strains (2.4%) were intermediate and 13 strains (15.7%) were resistant . DNA sequences related to the tet(M) determinant and the int-Tn gene were found in all tetracycline-resistant isolates.

Scand J Infect Dis, 2001, 33(8), 585 - 8
Antimicrobial susceptibility of Mycobacterium marinum determined by E-test and agar dilution; Werngren J et al.; Mycobacterium marinum is recognized as a cutaneous pathogen requiring antibiotic treatment . We compared the E-test with a reference agar dilution method for susceptibility testing of M . marinum to amikacin, ciprofloxacin, clarithromycin, doxycycline, rifampicin, trimethoprim-sulfamethoxazole and ethambutol . MICs obtained after 6 d showed agreement between the E-test and agar dilution within +/- 2 dilutions in 95% of all cases for amikacin, ciprofloxacin, doxycycline and rifampicin . Inhibitory concentrations of trimethoprim-sulfamethoxazole were difficult to define using the E-test because of gradually decreased growth in the presence of increasing concentrations . For clarithromycin, results were generally 1-3 dilution steps lower with the E-test and for ethambutol they were often > 3 dilution steps lower . These differences always appeared in the low MIC range and did not affect the categorization of the strains as susceptible to these 2 antimicrobial agents . All strains were interpreted as susceptible to all tested antibiotics, except for doxycycline, according to recommended breakpoints . Overall, our results suggest that the E-test can be considered an alternative for susceptibility testing of certain antibacterial agents against M . marinum.

Izv Akad Nauk Ser Biol, 2001 Jul-Aug, (4), 396 - 401
{Composition of neutrophil peroxisomes}; Rogovin VV et al.; Peroxisomes of neutrophils are formed in promyelocytes . In addition to myeloperoxidase constituting 35% peroxisomes, they contain nonenzymatic antimicrobial cationic peptides and polypeptides, several serine proteases, as well as some other hydrolases and additional components . Similar to serine proteases, these hydrolases can serve as natural antibiotics . Their function can complement the main oxidation function of neutrophilic myeloperoxidase in the protective response . The peroxisomes contain acid glycosaminoglycans functioning as an anionic carrier that reversibly binds cationic proteins, including hydrolases.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S245 - 50
Promoting appropriate antimicrobial drug use: perspective from the Centers for Disease Control and Prevention; Bell DM; Extending the useful life of antimicrobial drugs through appropriate use-that is, use that maximizes therapeutic impact while minimizing toxicity and the development of resistance-is an important component of efforts to prevent and control the emerging threat of antimicrobial resistance . The major paradigms of antimicrobial drug use involve acute infections in outpatients, acute infections in inpatients, chronic infections, and agriculture/veterinary medicine . The factors that influence drug use and the challenges that need to be addressed in promoting more appropriate use are different in each of these paradigms . For acute respiratory infections in outpatients, data from intervention trials suggest that concurrent multifaceted interventions may be effective in promoting appropriate drug prescribing . The next challenge is to extend these interventions to larger populations by incorporating them into routine medical practice.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S227 - 9
Should we reevaluate antibiotic breakpoints?
Ferraro MJ.
The breakpoints used to interpret antimicrobial susceptibility tests should be carefully determined initially, using microbiological, pharmacokinetic, pharmacodynamic, and clinical data, and then reevaluated periodically as changes in bacterial resistance, susceptibility test methods, or antibiotic formulations occur . Throughout the world, different governmental agencies and professional organizations have responsibility for the initial establishment of antibiotic susceptibility breakpoints . In the United States, the National Committee for Clinical Laboratory Standards has a mechanism in place to establish breakpoints initially and to review and publish updates on an annual basis . There should be a continued effort to coordinate both susceptibility testing methods and breakpoint determinations in various parts of the world.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S221 - 6
Perspective on animal models: chronic intracellular infections; Young LS et al.; Systemic human disease caused by organisms of the Mycobacterium avium-Mycobacterium intracellulare complex (MAC) represent a chronic intracellular infection in human hosts who are usually immunocompromised . To develop improved treatment and prophylaxis, and to obtain a better understanding of pathogenesis, we studied the beige mouse (C57 beige(+)/beige(+)) challenged orally or intravenously with a human isolate that causes lethal disease in patients with AIDS (MAC 101, serovar 1) . Encouraging anti-MAC studies in animals, as reviewed here, should provide the basis for considering human trials with a promising agent . The ability of an antimicrobial agent to achieve high intracellular concentrations has correlated with the in vivo activity of several specific compounds.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S206 - 13
Antimicrobial drug use and resistance among respiratory pathogens in the community; Low DE; There is substantial evidence that the overuse of antibiotics is a major cause for the emergence of resistance in respiratory pathogens in the community . However, it is also recognized that the mechanisms of resistance, the cost of resistance to the fitness of the organism, and the ability of the resistant strain to disseminate are all important contributors to this problem . Therefore, when developing strategies to control and/or prevent the emergence of resistance, health care professionals must take each of these factors into consideration . As we enter a new era in the use of fluoroquinolones for the treatment of respiratory tract infections, we have an opportunity to apply such lessons learned in the past to minimize or prevent the development of resistance to this class of antimicrobial drugs in the future.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S180 - 6
Quinolone molecular structure-activity relationships: what we have learned about improving antimicrobial activity; Peterson LR; Recently, understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has progressed rapidly . Three positions (2, 3, and 4) cannot be changed without a significant loss of biological activity . Furthermore, it appears that a cyclopropyl group is optimal at position 1 . Substituents at positions 5 and 8 affect planar configuration, and either a methyl or methoxy appear optimal at these sites . Hydrogen and amino groups have been investigated as useful substituents at position 6, replacing the fluorine of the fluoroquinolones . Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action . For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity . Optimizing overall molecular configuration enhances the number of intracellular targets for antimicrobial action (R-8) and impedes the efficiency of efflux proteins (R-7) that diminish intracellular penetration.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S174 - 9
Mathematical models as tools for evaluating the effectiveness of interventions: a comment on Levin; Kristinsson KG; Possible interventions to minimize resistance rates are numerous and can involve reduction and/or change in antimicrobial use, infection control, and vaccinations . As mathematical models are becoming more realistic they can be useful to quantitatively evaluate the relative contribution of individual risk factors and for the planning of future intervention strategies . The fitness cost associated with resistance is an important parameter and small differences can have a profound effect on the results . The mathematical models presented for communities predicted that even with cessation of antibiotic use, the decline in resistance frequency would be slow . This contrasts with successful interventions in Finland and Iceland . Future models have to include important variables such as herd immunity and take into account the heterogeneity of open communities . Provision of susceptible strains from areas with low resistance rates to areas with high resistance rates can have a profound effect on the success of interventions to minimize resistance.

Clin Infect Dis, 2001 Sep 15, 33 Suppl 3, S157 - 60
Minimizing potential resistance: the molecular view--a comment on Courvalin and Trieu-Cuot; Hooper DC; The complexity of bacterial resistance to antimicrobial agents is driven by the interplay of many mechanistic and epidemiologic factors . Mechanistically, resistance by target alteration, reduced permeation, and drug inactivation can occur by both chromosomal mutation and acquisition of new genetic elements . Epidemiologically, exposure to antimicrobial agents provides a growth or persistence advantage for any existing resistant bacteria, generally irrespective of the mechanism . When a single chromosomal mutation is sufficient to cause resistance, any such exposure provides a risk of selection, as long as a sufficiently large bacterial population is exposed . Transmission of resistant bacteria can also amplify resistance of any type, but it is particularly important for complex resistance mechanisms that have evolved over time and for mechanisms that depend on infrequent biological events in nature . Because true biological barriers to the development of resistance are likely to be elusive, multiple approaches that address both the use of antimicrobial agents and transmission are necessary to slow the advance of resistance.

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