Pharmacokinetics of imipenem-cilastatin in patients with renal insufficiency undergoing continuous ambulatory peritoneal dialysis

Somani, Pitambar; Freimer, Earl H.; Gross, Michael L.; Higgins, James T.

doi:10.1128/aac.32.4.530

Cited by 27 publications

(7 citation statements)

References 23 publications

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“…Meropenem/amoxicillin/tazobactam (ME/AX/TZ) maintains high synergy in MRSA N315 only (FICI = 0.04), with a clinical MRSA isolate showing less synergy (FICI = 0.55) ( Supplementary Table 2b ). MICs for components of these substituted triples are all below the mean peak human plasma concentrations of these compounds in vivo 40 , 41 . Similar to ME/PI/TZ, IM/PI/CV shows less-than-additive activity against MSSA ATCC 29213 (FICI = 1.14) ( Supplementary Tables 2b, c ).…”

Section: Resultsmentioning

confidence: 94%

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Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA

et al. 2015

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem/piperacillin/tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA N315 and 72 clinical MRSA isolates in vitro, and clears MRSA N315 infection in a mouse model. ME/PI/TZ suppresses evolution of resistance in MRSA via reciprocal collateral sensitivity of its constituents. We demonstrate that these activities also extend to other carbapenem/penicillin/β-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to β-lactam antibiotics. Furthermore, ME/PI/TZ subverts the function of penicillin-binding protein 2a (PBP2a) action via allostery, which we propose as the mechanism for both synergy and collateral sensitivity. Showing similar in vivo activity to linezolid, ME/PI/TZ demonstrates that combinations of older β-lactam antibiotics could be effective against MRSA infections in humans.

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Section: Resultsmentioning

confidence: 94%

“…The mice were then infected IP with 0.5 ml of this inoculum. In vivo dosing of compounds in mice was compared with mean or range peak human plasma concentrations of studied β-lactams 38 , 40 , 41 , 57 , 58 .…”

Section: Methodsmentioning

confidence: 99%

Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA

et al. 2015

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“…35,37 One pharmacokinetic study was identified describing administration of imipenem/cilastatin 500 mg over 10 minutes in 6 patients undergoing continuous ambulatory peritoneal dialysis; the volume/concentration of the administered solution was not provided. 105 However, IV push administration of imipenem/cilastatin is not recommended due to adverse events associated with rapid administration, such as nausea and vomiting. 61,66 Administration of ertapenem 1 gram IV push over 5 minutes was bioequivalent to the 30-minute infusion for maximum serum concentration (Cmax) and area under the curve (AUC) in a study in 12 healthy volunteers, and no serious adverse events, such as vomiting or seizures, occurred (Table 1).…”

Section: Carbapenemsmentioning

confidence: 99%

Intravenous Push Administration of Antibiotics: Literature and Considerations

et al. 2018

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Intravenous (IV) push administration can provide clinical and practical advantages over longer IV infusions in multiple clinical scenarios, including in the emergency department, in fluid-restricted patients, and when supplies of diluents are limited. In these settings, conversion to IV push administration may provide a solution. This review compiles available data on IV push administration of antibiotics in adults, including preparation, stability, and administration instructions. Prescribing information, multiple tertiary drug resources, and primary literature were consulted to compile relevant data. Several antibiotics are Food and Drug Administration-approved for IV push administration, including many beta-lactams. In addition, cefepime, ceftriaxone, ertapenem, gentamicin, and tobramycin have primary literature data to support IV push administration. While amikacin, ciprofloxacin, imipenem/cilastatin, and metronidazole have limited primary literature data on IV push administration, available data do not support that route. In addition, a discussion on practical considerations, such as IV push best practices and pharmacodynamic considerations, is provided.

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“…Furthermore, in patients with ESRF total imipenem clearance is more reduced than that in patients with ARF (23). Dose recommendations for patients with renal insufficiency are based mostly on the kinetic data obtained from patients with ESRF (11) undergoing either intermittent hemodialysis (3,20) and hemofiltration (1) or continuous ambulatory peritoneal dialysis (30). Few data concerning adjustments of the imipenem-cilastatin dose in patients with ARF are available (23,35), but ARF is a common complication in critically ill patients.…”

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confidence: 99%

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

Tegeder

Bremer

Oelkers

et al. 1997

Antimicrob Agents Chemother

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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. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean ؎ standard deviations) were 122.2 ؎ 28.6 and 29.2 ؎ 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 ؎ 2.5 and 16.1 ؎ 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 ؎ 26.3 and 13.2 ؎ 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 ؎ 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. 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.

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Pharmacokinetics of imipenem-cilastatin in patients with renal insufficiency undergoing continuous ambulatory peritoneal dialysis

Cited by 27 publications

References 23 publications

Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA

Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA

Intravenous Push Administration of Antibiotics: Literature and Considerations

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

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