E-test method for detecting antibiotic synergy against Pseudomonas aeruginosa from neutropenic patients: a cost-effective approach.

The aim of this study was to evaluate the accuracy of E-test for the detection of synergy or antagonism of antibiotic combinations against Pseudomonas aeruginosa isolates from neutropenic patients. The activity of levofloxacin or grepafloxacin combined with ceftriaxone or cefotaxime against 20 P. aeruginosa clinical strains was assessed by checkerboard technique in comparison with results performed by E-test. The combination grepafloxacin + ceftriaxone appeared to be most effective (synergy, 55%) by checkerboard technique. The agreement between checkerboard and E-test results was 71.2%. Synergy was detected by checkerboard and E-test methods in 35 (43.8%) and 23 (31.3%) of 80 possible combinations, respectively. Antagonism was detected once (1.2%) by checkerboard method only. No major errors were recorded. E-test was preferable to checkerboard method for the total cost (reagent cost + cost of technologist time) (8,60 vs 21,80 euros/test, respectively). E-test appeared a promising alternative for testing antibiotic combinations although further testing should be performed to better refine this metodology.

Antimicrobial therapy of methicillin resistant Staphylococcus aureus infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is now one of the commonest causes of nosocomial infection worldwide. The mainstay of treatment until now has been the glycopeptides (vancomycin and teicoplanin). They are not without toxicity and need parenteral administration and monitoring of levels. The increasing frequency of MRSA infections, coupled with the emergence of glycopeptide resistance in S. aureus has made the introduction of new drugs active against Gram-positive organisms essential. New agents active against Gram-positive organisms represent either genuinely novel classes of antimicrobials (e.g., oxazolidinones and lipoproteins) or those derived from existing classes (e.g., tetracyclines, glycopeptides, streptogramins and cephalosporins). Some of these newer antibiotics appear to be effective against multi-resistant organisms including MRSA.

Antimicrobial resistance in Haemophilus influenzae isolated during population-based surveillance for meningitis in Salvador, Brazil.

Antimicrobial susceptibility was determined for 150 Haemophilus influenzae isolates obtained during population-based surveillance for meningitis in Salvador, Brazil. Ten (6.7%) isolates were resistant to ampicillin and chloramphenicol. Of these, two isolates, a beta-lactamase and non-beta-lactamase producer, were resistant to amoxacillin-clavulinic acid. These findings indicate that present antibiotic regimens in Brazil may not be appropriate for the treatment of H. influenzae meningitis.

Assessment of the potential for microbial resistance to topical use of multiple antimicrobial agents.

The goal of this study was to reduce the likelihood of the generation and/or persistence of bacterial resistance to some antimicrobial components contained in a topical antimicrobial mixture (neomycin, polymyxin B, mupirocin and ciprofloxacin) for use with cultured skin grafts, by substitution of alternative antimicrobials, specifically fusidic acid for mupirocin and ofloxacin for ciprofloxacin. The alternative agents failed to serve that purpose. However, with the exception of specific genera of bacteria, Proteus sp. and Providencia stuartii, 90% or more of all other bacteria tested were susceptible to the action of one or more of the individual antimicrobial agents contained in the original mixture. This was true when bacteria were highly susceptible to the antimicrobials, generally, or when bacteria resistant to specific antimicrobials such as penicillin-class antibiotics and ciprofloxacin, were tested. These results suggest that the redundancy of antimicrobials contained in this mixture reduces the chance that resistant bacteria generated by the use of this mixture or already present on wounds would persist when the mixture is used clinically.

[Antibiotic resistance of Helicobacter pylori in an infectious disease referral center]. / Resistencia a antimicrobianos de Helicobacter pylori en un centro de referencia infectológico.

OBJECTIVE: To estimate the frequency of H. pylori clinical isolates resistant to six commonly used antimicrobials. DESIGN: Cross-sectional observational study. SETTING: A tertiary-referral health care institution in Mexico City. PARTICIPANTS: 31 isolates of H. pylori from 31 patients with chronic antral gastritis were obtained from gastric mucosal biopsy specimens. MAIN OUTCOME MEASURE: The Minimum Inhibitory Concentration (MIC) to ampicillin, amoxycillin, tetracycline, doxycycline, metronidazole and to colloidal bismuth subcitrate was determined by the agar plate dilution test. RESULTS: All isolates showed to be susceptible to the former four antibiotics but only in 46% and 55% growth was inhibited by 8 micrograms/mL and 16 micrograms/mL of metronidazole, respectively. All isolates were inhibited by < or = 128 micrograms/mL of bismuth. A 50% increase in the percentage of metronidazole-resistant isolates (MIC > or = 8 micrograms/mL) between 1988 to 1992 was observed. CONCLUSION: There is a need of future studies in our setting aimed at assessing the cost/effectiveness of diverse H. pylori-associated peptic ulcer treatment options.

Resistencia a antimicrobianos de helicobacter pylori en un centro de referencia infectológico / Antimicrobial resistance in isolates of Helicobacter pylori in a referral center

Objetivo. Estimar la frecuencia de aislados clínicos de H. pylori resistentes a seis antibióticos de uso común en su erradicación. Diseño. Estudio observacional transversal. Lugar. Institución hospitalaria de referencia de tercer nivel. Participantes. 31 aislamientos de igual número de enfermos con gastritis antral crónica, obtenidos de biopsias de mucosa gástrica. Desenlace principal. Se midió la concentración mínima anhibitoria (CMI) de metronidazol, tetraciclina, doxiciclina, ampicilina, amoxicilina y de subcitrato de bismuto mediante la técnia de dilución en placas de agar. Resultados. Todos los aislados mostraron ser sensibles a tetraciclina, doxiciclina, ampicilina y a amoxicilina; sólo 46 por ciento y 55 por ciento fueron inhibidos a concentraciones menores a 8 µg/mL y a 16 µg/mL de metronidazol, respectivamente. Todos los aislamientos fueron inhibidos a una concentración =128 µg/mL de la sal de bismuto. Se observó un incremento del 50 por ciento en el porcentaje de aislados resistentes a metronidazol (resistencia definida como una CMI = 8µg/mL) al comparar los de 1988 con los de 1992. Conclusión. Se necesitan estudios a futuro que evalúen cuál esquema de antibioticoterapia ofrece un mejor índice costo/beneficio en el tratamiento de la úlcera péptica por H. pylori en nuestro medio

Pharmacological therapy of Helicobacter pylori infection.

Helicobacter pylori has been associated with several diseases including peptic ulcer disease and gastric cancer. Eradication of H pylori not only results in ulcer healing, but reduces recurrences essentially curing peptic ulcer disease. Eradicating H pylori can be difficult. There are several reasons for antimicrobial failure, and the resistance rates for several antibiotics are increasing. The most common drugs used to treat this infection include amoxicillin, clarithromycin, tetracycline, bismuth, and omeprazole and lansoprazole. Dual therapy using a proton pump inhibitor and a single antibiotic gives a suboptimal eradication rate. Triple therapy using at least two antibiotics and either bismuth or a proton pump inhibitor gives satisfactory eradication rates of 90%. However, these regimens are complicated and have significant side effects and compliance problems. The ideal regimen has yet to be developed. In the future, we will prevent infection with immunization. Several vaccines are being developed.

In vitro assessment of the effect of clavulanic acid at concentrations achieved in human serum on the bactericidal activity of amoxicillin at physiological concentrations against Staphylococcus aureus: implications for dosage regimens.

The effects on Staphylococcus aureus viability and beta-lactamase activity of concentrations that simulated those in human serum after a combined dose of 875 mg of amoxicillin and 125 mg of clavulanic acid were studied in an in vitro pharmacodynamic model. Six hours of preexposure to concentrations of the amoxicillin-clavulanic acid combination that were higher than the amoxicillin-clavulanic acid MIC led to a reduction of the initial inoculum of >90% and to a significant decrease of beta-lactamase activity versus those of the control even from 6 h, when concentrations were subinhibitory. The postantibiotic effect and post-beta-lactamase inhibitor effect contributed to these results.

Bacterial resistance mechanisms to beta-lactam antibiotics: assessment of management strategies.

Several mechanisms render antimicrobials inactive; one of these, beta-lactamase hydrolysis of beta-lactam antimicrobials, is a common and serious problem resulting in loss of antimicrobial activity. Resistance in gram-negative organisms may be caused by chromosomally or plasmid-mediated beta-lactamases. Chromosomally mediated resistance may result from exposure to inducer compounds (induction) or by selection of stably derepressed mutants. Plasmids are extrachromosomal elements of DNA that can transfer resistance between bacteria. Common plasmid-encoded beta-lactamases are the TEM- and SHV-type enzymes, which include the newer extended-spectrum beta-lactamases. Infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality, and increased cost of treatment. When bacteria develop resistance during antimicrobial therapy, therapeutic failure ensues in approximately 50% of patients. Clinical studies demonstrate that resistance mediated by beta-lactamases is a critical issue. Strategies for overcoming it include use of beta-lactam-beta-lactamase inhibitor combinations, development of new antimicrobial compounds, and use of regimens that optimize in vivo exposure to drug.

Assessment of therapeutic potential by means of a probability model of antimicrobial action.

The probability model of antimicrobial action is based on the definition of bactericidal activity as the probability, q, that any cell in the population will be killed during a division interval. Bacteriostatic activity is defined as a change in the division intervals (generation times) of the cells. A simplified, homogeneous model is used which assumes that, at a constant concentration of the drug, all cells have the same kill probability and the same generation times. Birth-death analysis techniques require that the combined bacteriostatic and bactericidal effects of the drug (they are not mutually exclusive) are accounted for. Moreover, to suitably reflect the combined effect, the rate of change of the viable population, i.e. the slope of a kill curve (activity), needs to be expressed not in terms of exposure time, but in units of drug-free generations (DFGs), obtained by dividing exposure time by a measured DFG time interval (growth rate). A Discrete MIC (DMIC) is defined as the zero slope kill curve, coinciding with the horizontal axis and dividing population change into a restrained (subinhibitory) growth region, below the DMIC, and population reduction above it. At the DMIC, the probability of a cell being killed is 0.5, resulting in no change from the initial inoculum concentration, since half the cells are killed but the remaining cells double. The DMIC is found to be a measure of bactericidal activity only, even though bacteriostatic activity may also be present. An antibiotic-organism activity profile includes measurement of the DMIC, rate of change of activity at the DMIC and normalized activity at a number of clinically relevant drug concentrations. An overall, quantitative efficacy value over a dosing interval can be obtained from the activity profile and expressed as the number of DFGs which are needed to achieve a 99.9% reduction of the viable population at the site of infection. These reference efficacy values can be used to derive interpretive standards (break-points) based upon a quantitative relationship between laboratory measurements and population reduction at the site of infection. Model-derived measures of efficacy also provide a basis for assessing drug combination activity, including quantitative criteria of synergy and antagonism.

Single-agent versus combination antibiotic therapy in the management of intraabdominal infections.

For the treatment of intraabdominal infection, single-agent antimicrobial regimens such as beta-lactams with good antianaerobic activity are frequent alternatives to combination regimens such as aminoglycosides or aztreonam plus an antianaerobic agent such as clindamycin or metronidazole. The major issues in selecting a regimen are relative efficacy, potential for adverse drug effects, and cost. Single agents are clearly equivalent to combinations in preventing infectious complications after penetrating abdominal trauma and in treating established intraabdominal infections of mild to moderate severity or in relatively low-risk patients. A few trials demonstrated their equivalency in patients at high risk of mortality, although experience is limited. Single-agent regimens may reduce the risks of adverse drug effects compared with combination regimens, but they are not always less expensive.

[A clinico-laboratory assessment of the efficacy of an Augmentin suspension in treating children with suppurative-inflammatory diseases caused by opportunistic bacteria]. / Kliniko-laboratornaia otsenka éffektivnosti Augmentin-suspenzii pri lechenii detei s gnoino-vospalitel'nymi zabolevaniiami, vyzvannymi uslovno-patogennymi bakteriiami.

Augmentin suspension (amoxycillin+clavulanic acid) was estimated in clinico-laboratory studies with respect to children suffering from pyoinflammatory diseases of various localization and its high efficacy was shown. Good and satisfactory results were recorded in 96.3 per cent of the cases in the treatment (monotherapy) and afterwards in the patients, adverse reactions such as nausea and vomiting being recorded only in 1 patient. The therapy with augmentin led to normalization of the microflora of the upper respiratory tract mucosa and a 1.5-fold increase in the neutrophil engulfment index.

Selective decontamination of the digestive tract in intensive care patients: review and commentary.

OBJECTIVE: To evaluate the benefits, risks, and costs of antimicrobial regimens used for selective decontamination of the digestive tract (SDD) in intensive care unit (ICU) patients. DATA SOURCES: Information was obtained from clinical trials, review articles, abstracts, and textbooks. Key indexing terms included antibiotics, selective decontamination, and infections. STUDY SELECTION: Research articles describing controlled clinical trials of SDD in medical or surgical ICU patients were reviewed. Trials that investigated transplant, cirrhotic, leukemic, or oncology patient populations were excluded. DATA EXTRACTION: The details of studies that evaluated nosocomial infection or nosocomial pneumonia rates were extracted. These included study design, demographics, SDD regimens, severity of illness scores, and colonization, infection, and mortality rates. DATA SYNTHESIS: The use of SDD in mechanically ventilated surgical or trauma ICU patients reduces the incidence of colonization, nosocomial pneumonia, and overall infection rates, but does not change the overall mortality rate. Administration of antibiotic and antifungal agents in a nasogastric suspension is required for SDD. The addition of systemic prophylactic antibiotics or oropharyngeal paste was not required to decrease nosocomial infections. The most frequently studied SDD regimen (colistin/amphotericin B/tobramycin) is not feasible for use in the US because of exorbitant drug costs. Less expensive alternatives include norfloxacin/nystatin, or colistin/nystatin/gentamicin. CONCLUSIONS: Additional research is required before SDD regimens can be routinely recommended in surgical and trauma ICU patients. A multicenter study is warranted to determine the long-range benefits, potential for resistance, and cost-effectiveness of SDD.

An assessment of the efficacy of antimicrobial prophylaxis in bone marrow autografts.

Fifty-three patients undergoing autologous bone marrow transplantation received antimicrobial prophylaxis with ciprofloxacin with or without erythromycin and low dose intravenous amphotericin B. Eight patients remained afebrile throughout the neutropenic period. All other patients had one or more febrile episodes. The median time to fever after the onset of neutropenia was 7 days. There were no gram-negative organisms isolated from blood cultures during any of these episodes whereas gram-positive organisms were isolated in 28. There was one death in this series associated with sepsis. The use of low-dose prophylactic parenteral amphotericin did not prevent the subsequent successful use of full dose amphotericin for antibiotic-resistant fever. Ciprofloxacin effectively prevents gram-negative sepsis. The addition of erythromycin does little to prevent gram-positive sepsis. The use of regimens with agents with activity against gram-positive organisms is appropriate initial treatment of all febrile neutropenic episodes.

Crossover assessment of serum bactericidal activity and pharmacokinetics of ciprofloxacin alone and in combination in healthy elderly volunteers.

To better define the pharmacokinetics and serum bactericidal activity (SBA) of ciprofloxacin and other antimicrobial agents in the elderly, six healthy (greater than 65 years) volunteers with normal renal function were given ciprofloxacin alone orally, ciprofloxacin plus rifampin orally, ciprofloxacin plus clindamycin orally, rifampin alone orally (three volunteers), and, for comparison of SBA against gram-positive cocci, vancomycin intravenously. Mean peak ciprofloxacin concentrations and other pharmacokinetic parameters were not altered significantly by coadministration of either rifampin or clindamycin. Ciprofloxacin had somewhat greater SBA against the oxacillin-susceptible and oxacillin-resistant Staphylococcus aureus strains tested than did vancomycin, but rifampin was by far the most active single agent tested. The SBA of rifampin against S. aureus was modestly antagonized during combination therapy with ciprofloxacin, but substantial SBA still was present. The ciprofloxacin SBA against S. aureus was completely antagonized by clindamycin if the strains were susceptible to the latter agent. Ciprofloxacin had modest SBA against group A streptococci and no SBA against the three pneumococcal strains tested. All of the regimens had poor to absent SBA against Enterococcus faecalis. By contrast, ciprofloxacin had excellent SBA against Escherchia coli and Klebsiella pneumoniae and moderate SBA against Pseudomonas aeruginosa. Combination therapy with rifampin or clindamycin in general enhanced the SBA against the nonenterococcal streptococci and had no effect on the SBA against the gram-negative bacilli.

Therapeutic interchange of ampicillin-sulbactam for cefoxitin.

A therapeutic interchange program based on microbial patterns within an institution is described. A change in anaerobic susceptibility patterns, increased prevalence of enterococcal infections, and cost factors provided the rationale for the therapeutic interchange of ampicillin-sulbactam for cefoxitin. Ampicillin-sulbactam was recommended for prophylaxis in intraabdominal or gynecological surgery as well as for treatment for gynecological infections. Cefoxitin was restricted to penicillin-allergic patients and women who were pregnant or breast-feeding. The transition from cefoxitin to ampicillin-sulbactam proceeded smoothly as a result of preliminary education of pharmacists and physicians. Pharmacists participated in continuing-education programs and received concise guidelines for the interchange and follow-up instructions; physicians learned of the program from the drug newsletter published by the pharmacy department. Three months after the program began, only one physician was resistant to the interchange. After the program began, 11 antimicrobials, including cefoxitin, were used less frequently and ampicillin-sulbactam use increased. No adverse clinical consequences from the interchange were detected. A therapeutic interchange program based on institution-specific microbial patterns and educational efforts by the pharmacy department produced a change in physician prescribing.