A multi-centre study to compare meropenem and cefotaxime and metronidazole in the treatment of hospitalized patients with serious infections

Mehtar, Shaheen; Dewar, E. P.; Leaper, David; Taylor, Eric

doi:10.1093/jac/39.5.631

Cited by 31 publications

(16 citation statements)

References 14 publications

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“…Meropenem has an exceedingly broad spectrum of activity and, consequently, represents a good choice for an empirical therapy regimen (25,34,40). Such an empirical therapy regimen may be monotherapy or combination therapy, depending upon the incidence of methicillinresistant Staphylococcus aureus infections and P. aeruginosa or Acinetobacter sp.…”

Section: Discussionmentioning

confidence: 99%

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

Krueger

Bulitta

Kinzig‐Schippers

et al. 2005

Antimicrob Agents Chemother

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Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high-and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens, Klebsiella pneumoniae and Enterobacter cloacae. However, against Pseudomonas aeruginosa, the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.Considerable evidence demonstrates that the amount of time that free drug concentrations exceed the MIC is the measure of drug exposure most closely linked to the ability of a regimen of ␤-lactam antibiotics to kill the target organisms (9,17,19,48). This linkage is likely due to the fact that the rate of organism killing is maximized rapidly with the concentration and maximal killing is attained at drug concentrations of four to six times the MIC (6). Among the ␤-lactam agents, there are differences in the fraction of the dosing interval in which the drug concentration needs to be in excess of the MIC to attain organism stasis or to attain maximal killing of the organism population. Generally, ␤-lactams have some postantibiotic effects against gram-positive cocci but only limited postantibiotic effects against gram-negative rods (4,8,18,22,48). This means that the duration of plasma levels above the MIC is the most critica...

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Section: Discussionmentioning

confidence: 99%

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

Krueger

Bulitta

Kinzig‐Schippers

et al. 2005

Antimicrob Agents Chemother

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“…In the IAI literature, "combination therapy" consists of agents with significantly different spectra of activity, for example, ticarcillinclavulanate versus clindamycin and gentamicin or imipenem versus clindamycin, metronidazole, and tobramycin, etc. (12,49,76,115,164,188,204,223,231,232,234,251). To our knowledge, there is only one RCT comparing the clinical efficacy of a ␤-lactam to that of a ␤-lactam plus an aminoglycoside for IAIs.…”

Section: Intra-abdominal Infectionsmentioning

confidence: 99%

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

2012

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SUMMARY Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa , those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria.

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“…It may therefore be applied as empirical treatment of severe infections in critically ill patients [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Correlation of Meropenem Plasma Levels with Pharmacodynamic Requirements in Critically Ill Patients Receiving Continuous Veno-Venous Hemofiltration

Krueger

Neeser²,

Schuster³

et al. 2003

Chemotherapy

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Background: In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy. Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements. Methods: Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h. Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC. Results: Peak levels in plasma amounted to 39.5 ± 10.5 mg/l (mean ± SD) and trough levels were 2.4 ± 1.5 mg/l. The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients. The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients. The elimination half-life was prolonged to 3.63 ± 0.77 h. The sieving coefficient of meropenem was 0.91 ± 0.10 and the recovery in hemofiltrate amounted to 30.9 ± 11.5% of the dose. Conclusions: A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria. A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates.

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A multi-centre study to compare meropenem and cefotaxime and metronidazole in the treatment of hospitalized patients with serious infections

Cited by 31 publications

References 14 publications

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

Correlation of Meropenem Plasma Levels with Pharmacodynamic Requirements in Critically Ill Patients Receiving Continuous Veno-Venous Hemofiltration

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