Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration-dependent bactericidal activity, prolonged half-life and sustained activity in plasma support the clinical evaluation of higher doses of metronidazole given less frequently. Metronidazole-containing regimens for Helicobacter pylori in combination with proton pump inhibitors demonstrate higher success rates than antimicrobial regimens alone. The pharmacokinetics of metronidazole in gastric fluid appear contradictory to these results, since omeprazole reduces peak drug concentration and area under the concentration-time curve for metronidazole and its hydroxy metabolite; however, concentrations remain above the MIC. Other members of this class include tinidazole, ornidazole and secnidazole. They are also well absorbed and distributed after oral administration. Their only distinguishing features are prolonged half-lives compared with metronidazole. The choice of nitroimidazole may be influenced by the longer administration intervals possible with other members of this class; however, metronidazole remains the predominant antimicrobial for anaerobic and protozoal infections.

Recently, a more complete understanding of the pharmacodynamics of aminoglycosides has been recognized, indicating that this class of antibiotics exhibits both concentration-dependent bactericidal activity and a postantibiotic effect. This pharmacodynamic information, along with better knowledge of the mechanisms responsible for aminoglycoside toxicity, established the foundation for once-daily aminoglycoside dosing regimens. This new approach to aminoglycoside dosing appears to be safe, efficacious, and cost-effective, resulting in its increasing popularity in clinical practice.Although aminoglycoside antibiotics have been used sucat the binding site for a finite period of time [5]. The presence cessfully for ú50 years [1], recent data suggest that the convenof the antibiotic prohibits normal biochemical reactions and, tional dosing approach has not optimized bacterial killing. therefore, the organism dies. The concentration needed to ocThese recent observations, together with a more complete uncupy the critical number of sites necessary for this to occur is derstanding of pharmacodynamics, have led to the application not known. However, an easily measured and probably proporof new aminoglycoside dosing regimens [2, 3]. In this report tional concentration, such as the MIC or the MBC, is used in we discuss the pharmacodynamics of aminoglycosides and the its place. new dosing strategies for this class of antibiotics.It is also important to realize that the concentration of drug The in vitro antimicrobial spectrum of activity of the aminoin the area of binding sites is controlled by drug concentration glycosides includes a broad range of aerobic gram-negative in the media in which bacteria reside, usually interstitial-like bacilli, many staphylococci, and certain mycobacteria [4].fluid. Antibiotics in such fluids have generally been found to Aminoglycosides exert their bactericidal effects by irreversibly rapidly become in equilibrium with the blood; therefore, antibibinding to the 30S ribosomal subunit of susceptible bacteria, otic blood (serum, plasma) concentrations are an important which results in the inhibition of protein synthesis [4]. An parameter in bactericidal activity. Bactericidal activity is thereenergy-and oxygen-dependent transport mechanism is required fore a function of antibiotic concentration in the serum and the for aminoglycosides to penetrate the outer bacterial membrane duration of time that antibiotic exists in the body. of susceptible bacteria [4]. It is for this reason that this classIn pharmacodynamic terms, one can say that bactericidal of antibiotics demonstrates poor activity against anaerobes and activity is a function of the time that serum concentrations has decreased ability to penetrate the bacteria within abscesses remain above some critical value, i.e., the MIC. Pharmacokinetthat may have limited oxygen.ically, the product of concentration and time is termed the area In general, the aminoglycosides are clinically used in the under the serum-time curve (AUC), and therefore it i...

The increasing frequency of penicillin-resistant pneumococcus continues to be of concern throughout the world. Newer fluoroquinolone antibiotics, such as levofloxacin, have shown enhanced in vitro activity against Streptococcus pneumoniae. In this study, the bactericidal characteristics and pharmacodynamic profiles of levofloxacin, ciprofloxacin, and ampicillin against four isolates of S. pneumoniae were compared by using an in vitro model of infection. Standard antibiotic dosing regimens which simulated the pharmacokinetic profile observed in humans were used. Control and treatment models were sampled for bacterial CFU per milliliter over the duration of each 24-or 48-h experiment. In addition, treatment models were sampled for MIC determinations and drug concentration. Regrowth of all isolates as well as an increase in MICs throughout the study period was observed in the ciprofloxacin experiments. A limited amount of regrowth was noted during levofloxacin therapy for one isolate; however, no change in MIC was detected for any isolate. Ampicillin showed rapid and sustained bactericidal activity against all isolates. In this study, ratios of effective fluoroquinolone area under the concentration-time curve (AUC):MIC values ranged from 30 to 55. Levofloxacin, owing to its larger AUC 0-24 values, has excellent and sustained activity against different pneumococcal strains superior to that of ciprofloxacin.

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Lack of standardization in antibiogram (ABGM) preparation (the overall profile of antimicrobial susceptibility results of a microbial species to a battery of antimicrobial agents) has not been addressed until recently. The objective of this study was to analyze current antibiograms using the recently published NCCLS M39-A guidelines for preparation of antibiograms to identify areas for improvement in the reporting of antibiogram susceptibility data. Antibiograms from across the United States were obtained by various methods, including direct mailings, Internet searches, and professional contacts. Each ABGM collected was analyzed using prospectively defined elements from the M39-A guidelines. Additionally, seven quality indicators were also evaluated to look for the reporting of any atypical or inappropriate susceptibility data. The 209 antibiograms collected from 149 institutions showed at least 85% compliance to 5 of the 10 M39-A elements analyzed. Clinically relevant elements not met included annual analysis, duplicate isolate notation, and the exclusion of organisms with fewer than 10 isolates. As for the quality indicators evaluated, unexpected results included the 7% of antibiograms that reported <100% vancomycin susceptibility for Staphylococcus aureus, 24% that had inconsistent betalactam susceptibility for Staphylococcus aureus, 20% that reported <100% imipenem susceptibility for Escherichia coli, and 37% that reported >0% ampicillin susceptibility for Klebsiella pneumoniae. These findings suggest that antibiograms should be reviewed thoroughly by infectious disease specialists (physicians and pharmacists), clinical microbiologists, and infection control personnel for identification of abnormal findings prior to distribution.

Trovafloxacin is a new fluoroquinolone that has potent microbiological activity against the pneumococcus, including penicillin-resistant strains. To evaluate the protective effect of trovafloxacin, ciprofloxacin and ampicillin against penicillin-susceptible, -intermediate and -resistant strains of Streptococcus pneumoniae, an intraperitoneal, immunocompetent mouse model of sepsis was used. The minimum lethal dose (MLD) for each isolate was determined in duplicate. A single sc dose of each antibiotic was administered over a wide range of doses 1 h after the ip inoculation of the test isolate at the MLD. The assessment of the protective dose for 50% of the population (PD50) for each antimicrobial/bacteria combination was performed in triplicate and the PD50 value was calculated at the end of 5 days. Results showed that trovafloxacin provided PD50 values that were significantly lower than those of ciprofloxacin for all isolates. For the penicillin-susceptible and -intermediate isolates, the PD50 values of ampicillin were significantly lower than those for either of the fluoroquinolones studied; however, trovafloxacin was statistically superior to both ciprofloxacin and ampicillin against the penicillin-resistant strain. Therefore, regardless of penicillin susceptibility, trovafloxacin has potent activity against Streptococcus pneumoniae and may be a viable alternative for the treatment of penicillin-resistant isolates.

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Antibiograms are an important resource for health care providers. All clinicians involved in antibiotic selection and monitoring should become familiar with the NCCLS M39-A document “Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data: Approved Guideline.” Providers who interpret and apply antibiogram data in clinical practice should know about susceptibility testing methods, the susceptibility breakpoint determination process, and problems associated with antibiogram data analysis. The M39-A guidelines contain more than 40 recommendations, including the following: antibiogram data should be analyzed at least annually, an attempt should be made to remove duplicate isolates, and only organisms with 10 isolates or more should be presented. Accurate antibiograms facilitate improved empiric antibiotic selection and more precise monitoring of bacterial resistance in the hospital. This article reviews common antimicrobial susceptibility testing methods and relevant issues, highlights the major NCCLS M39-A recommendations, discusses the antibiogram preparation process and challenges in data interpretation, and provides a general overview of how antibiogram data may be applied to clinical practice.