Melinda K. Lacy

Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials

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 1g. 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.

The Pharmacodynamics of Aminoglycosides

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.

Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia

A prospective, randomized pilot study was undertaken to compare the efficacy of continuous versus intermittent ceftazidime in ICU patients with nosocomial pneumonia. Ceftazidime was administered either as a 3 g/day continuous infusion (CI) or an intermittent infusion (II) of 2 g every 8 h. In addition, all patients received concomitant once-daily tobramycin. The demographics of the evaluable patients (n = 35) were similar between the groups: age (years), CI 46 +/- 16, II 56 +/- 20; Apache score, CI 14 +/- 4, II 16 +/- 6; time (days) from admission to diagnosis, CI 9 +/- 6, II 9 +/- 6. Clinical efficacy, defined as cure/improvement was similar between groups [n (%), CI 16/17 (94), II 15/18 (83)], while microbiological response was also comparable [n (%), CI 10/13 (76), II 12/15 (80)]. Minimal inhibitory concentrations (MICs) for all isolates were measured throughout the treatment course; there was no development of resistance during therapy for either regimen. While limited clinical data exist, our results suggest that the use of ceftazidime by CI administration maintains clinical efficacy, optimizes the pharmacodynamic profile and uses less antibiotic compared with the standard 2 g every 8 h intermittent dosing regimen.

Nationwide Antibiogram Analysis Using NCCLS M39-A Guidelines

ABSTRACT 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 beta-lactam 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.

Effect of Duplicate Isolates of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus on Antibiogram Data

ABSTRACT Duplicate Staphylococcus aureus isolates were analyzed to determine the impact of multiple isolates from the same patient on annual antibiogram data. During a 6-year period (1996 to 2001), 3,227 patients with 4,844 S. aureus isolates were evaluated. A total of 39% of patients with methicillin-resistant S. aureus (MRSA) (n = 860) and 23% of patients with methicillin-susceptible S. aureus (MSSA) (n = 2,367) infections had duplicate isolates. Cumulative data show that 91% of the patients during this 6-year period with duplicate isolates (2 to 13 duplicates/year) did not switch between MSSA and MRSA but retained the original S. aureus strain whether it was MSSA or MRSA. Rates of MRSA were calculated for each year by using all isolates and then eliminating duplicates. The impact of duplicate MRSA and MSSA isolates was evaluated by using the ratio of isolates per patient such that ratios of >1.0 indicate >1 isolate per patient. The 6-year ratio for MRSA was 1.90 isolates/patient, and the ratio for MSSA was 1.35. A significant difference (P < 0.05) was noted in the MRSA rates in 4 of 6 years when duplicate isolates were removed. Common phenotypic antibiogram patterns were compared for all MRSA isolates during the 6-year period, and 64% were of a single antibiogram phenotype. Eighty-eight percent of patients with duplicate MRSA isolates had phenotypically identical multiple isolates. The rate of MRSA differs when duplicate isolates are removed from the antibiogram data.

Antibiograms: New NCCLS Guidelines, Development, and Clinical Application

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.

PHARMACOKINETICS OF CONTINUOUS AND INTERMITTENT CEFTAZIDIME IN INTENSIVE CARE UNIT PATIENTS WITH NOSOCOMIAL PNEUMONIA

Intensive care unit patients with nosocomial pneumonia participating in a prospective, randomized trial comparing the efficacy of intermittent infusion (II) or continuous infusion (CI) ceftazidime plus an aminoglycoside were studied. The pharmacokinetic profile of ceftazidime administered as either 2 g q8h IV or 3 g CI over 24 hours were compared. Patients (II, n = 13; CI, n = 11) were well matched for demographic variables. The mean pharmacokinetic parameters (mean ± SD) for patients receiving the q8h II dose were as follows: maximum concentration in serum, 105.3 ± 28.0 μg/mL; half-life, 1.9 ± 0.6 hours; and total body clearance (CIT), 162.8 ± 42.7 mL/min. The mean steady concentration achieved with the 3-g CI dose was 15.3 ± 4.2 μg/mL, whereas the CIT was similar at 143.6 ± 30.1 mL/min. Although clinical trial data are required to fully evaluate the efficacy of different antimicrobial administration techniques, CI therapy seems to optimize the pharmacodynamic and phar-macoeconomic profile of ceftazidime by providing adequate concentrations over the 24-hour dosing period with a reduction in the total daily dose.

Comparison of vancomycin pharmacodynamics (1 g every 12 or 24 h) against methicillin-resistant staphylococci

This study compared the duration of serum bactericidal activity for vancomycin, 1 g every 12 or 24 h at steady state, against methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MR-CNS). All four test isolates were susceptible to vancomycin with minimal inhibitory concentration (MIC) values of either 2 or 4 mg/l. Serum bactericidal titres (SBTs) were run in duplicate and serum bactericidal activity (SBA) was defined as the time points at which all subject SBTs were greater than or equal to 1:2. For the every 12-h regimen, SBA was 10-12 h. With the every 24-h regimen, the duration of SBA was 10-16 h for MRSA and 8-10 h for MR-CNS. The pharmacodynamic data suggest that for those with good renal function a Q12h dosing interval is most appropriate for MR-CNS or staphylococcal isolates with MICs of 4.

Comparison of bactericidal activity after multidose administration of clarithromycin, azithromycin, and cefuroxime axetil against Streptococcus pneumoniae

The objective of this study was to compare the duration of serum bactericidal activity (SBA) for clarithromycin, azithromycin, and cefuroxime axetil in 12 young healthy volunteers after 5 days of therapy (dosed to steady-state) against two strains each of penicillin (PCN)-susceptible, -intermediate, and -resistant Streptococcus pneumoniae. This was a randomized, 3-way crossover study. All isolates were susceptible to clarithromycin (MICs 0.125 mg/l) and azithromycin (MICs 0.25-0.5 mg/l), while cefuroxime axetil susceptibilities correlated with PCN. Results showed that SBA was maintained for 100% of the dosing interval for clarithromycin and 50-100% for azithromycin regardless of PCN susceptibility when standard doses were employed. Cefuroxime axetil was active only against the PCN-susceptible isolate for 50% of the dosing interval, indicating that it should only be used for PCN-susceptible S. pneumoniae.