Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Jun 1999
Comparative StudyEmergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents.
Pseudomonas aeruginosa is a leading cause of nosocomial infections. The risk of emergence of antibiotic resistance may vary with different antibiotic treatments. To compare the risks of emergence of resistance associated with four antipseudomonal agents, ciprofloxacin, ceftazidime, imipenem, and piperacillin, we conducted a cohort study, assessing relative risks for emergence of resistant P. aeruginosa in patients treated with any of these drugs. ⋯ Hazard ratios for emergence of resistance to each individual agent associated with treatment with the same agent were as follows: ceftazidime, 0.8 (P = 0.7); ciprofloxacin, 9.2 (P = 0.04); imipenem, 44 (P = 0.001); and piperacillin, 5.2 (P = 0.01). We concluded that there were evident differences among antibiotics in the likelihood that their use would allow emergence of resistance in P. aeruginosa. Ceftazidime was associated with the lowest risk, and imipenem had the highest risk.
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Antimicrob. Agents Chemother. · Sep 1998
Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration.
The pharmacokinetic properties of meropenem were investigated in nine critically ill patients treated by continuous venovenous hemofiltration (CVVH). All patients received one dose of 1 g of meropenem intravenously. High-flux polysulfone membranes were used as dialyzers. ⋯ Peak plasma drug concentrations measured 60 min postinfusion were 28.1 +/- 2.7 microgram/ml, and trough levels after 6 h of CVVH were 6.6 +/- 1.5 microgram/ml. The calculated total daily meropenem requirement in these patients with acute renal failure and undergoing CVVH was 2,482 +/- 321 mg. Based on these data, we conclude that patients with severe infections who are undergoing CVVH can be treated effectively with 1 g of meropenem every 8 h.
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Antimicrob. Agents Chemother. · May 1998
Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection.
Population pharmacokinetic modeling is a useful approach to obtaining estimates of both population and individual pharmacokinetic parameter values. The potential for relating pharmacokinetic parameters to pharmacodynamic outcome variables, such as efficacy and toxicity, exists. A logistic regression relationship between the probability of a successful clinical and microbiological outcome and the peak concentration-to-MIC ratio (and also the area under the plasma concentration-time curve [AUC]/MIC ratio) has previously been developed for levofloxacin; however, levofloxacin assays for determination of the concentration in plasma are not readily available. ⋯ The model for the prediction of CL was relatively robust, with acceptable bias and precision, and explained a reasonable amount of the variance in the CL of levofloxacin from plasma in the population (r2 = 0.396). Estimated CLCR, age, and race were the final model covariates, with CLCR explaining most of the population variance in the CL of levofloxacin from plasma. This model can potentially optimize the benefit derived from the pharmacodynamic relationships previously developed for levofloxacin.
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Antimicrob. Agents Chemother. · Apr 1998
Clinical TrialPopulation pharmacokinetic study of amikacin administered once or twice daily to febrile, severely neutropenic adults.
Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm3) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). ⋯ Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL[CR]) are proposed: for patients with normal renal function (CL[CR] of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL[CR], 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.
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Antimicrob. Agents Chemother. · Dec 1997
Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration.
The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. ⋯ Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.