Pharmacokinetics of imipenem and cilastatin in patients with cystic fibrosis

Reed, Michael D.; Stern, Robert C.; O'Brien, C A; Yamashita, Toyoko S.; Myers, Carolyn M.; Blumer, Jeffrey L.

doi:10.1128/aac.27.4.583

Cited by 30 publications

(11 citation statements)

References 26 publications

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“…Our results are consistent with those of Reed et al [1985] who also studied patients with CF, although the number of subjects was about half. The lower t1/2 of cilastatin was not as apparent from their study.…”

Section: Discussionsupporting

confidence: 82%

Pharmacokinetic Evaluation of Imipenem Combined with Cilastatin in Cystic Fibrosis

Bergan

Michalsen²,

Malmborg³

et al. 1993

Chemotherapy

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The pharmacokinetics of imipenem (MK-787) and cilastatin (MK-791) were studied in 30 patients with cystic fibrosis (CF) receiving the drug for therapeutic purposes at doses of 11 mg/kg given as a 30-min infusion. The serum concentrations and urine elimination were studied after the first dose and during steady state. The concentrations were assayed by high-pressure liquid chromatography. The total areas under the imipenem serum concentration curves (AUCs) to infinity were 30.4 ± 6.8 mg-h/1 after the first dose compared with 29.1 ± 7.1 mg-h/1 during steady state (NS). The cilastatin AUCs on the 2 days were 40.3 ± 9.3 and 38.3 ± 0.4 mg-h/1 (NS), respectively. The urinary recovery of imipenem was 47.8 ± 17.8% after the first dose and 57.8 ± 24.2% during steady state (NS). The amounts of cilastatin eliminated in the urine during 6 h were 6/ 7.3 ± 22.9% after the first dose and 60.5 ± 17.0% of the dose during steady state (NS). The mean half-life of imipenem in these CF patients was 1.2 ± 0.4 h on the first day of the examination and within the same range during steady state. The distribution volume (Vdβ) was in the range of 28 liters, the total body clearance was 16.3 liters/h (285 ml/min) on the first day. The t1/2 of cilastatin was 0.59 ± 0.14 h after the first dose and 0.61 ± 0.14 h during steady state. Thus patients with CF eliminated cilastatin more quickly than imipenem.

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Section: Discussionsupporting

confidence: 82%

Pharmacokinetic Evaluation of Imipenem Combined with Cilastatin in Cystic Fibrosis

Bergan

Michalsen²,

Malmborg³

et al. 1993

Chemotherapy

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“…This is not surprising since studies with another carbapenem, imipenem, also resulted in similar pharmacokinetics when compared with a control group [5,8]. In a previous study, CF subjects had significantly greater clearance when compared to non-CF subjects, but this could have been the result of comparing children versus older adults [14].…”

Section: Discussionmentioning

confidence: 79%

Pharmacokinetics of High-Dose Meropenem in Adult Cystic Fibrosis Patients

Bui

Ambrose²,

Nicolau

et al. 2001

Chemotherapy

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Because patients with cystic fibrosis (CF) have pulmonary exacerbations secondary to multi-antibiotic-resistant Gram-negative bacilli, antibiotics, like meropenem, are often utilized. We studied the pharmacokinetics of meropenem (2 g i.v. administered every 8 h in clinically stable CF patients to determine if the recommended maximum doses could sustain adequate concentrations during the dosing interval. These pharmacokinetic data were similar to those obtained in non-CF populations. Using this regimen, concentrations of meropenem exceed the susceptibility breakpoint (4 µg/ml) for 50% of the dosing interval, and therefore provide optimization of the pharmacodynamic profile of the compound.

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“…2). Since the levels of carbapenems used in this experiment would be much higher than in an in vivo situation (32)(33)(34), the results highlight the difficulty in treating established biofilm infections, regardless of whether or not the strain is resistant to the prescribed antibiotics.…”

Section: Discussionmentioning

confidence: 93%

Sublethal Concentrations of Carbapenems Alter Cell Morphology and Genomic Expression of Klebsiella pneumoniae Biofilms

Laar

Chen²,

You

et al. 2015

Antimicrob Agents Chemother

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b Klebsiella pneumoniae, a Gram-negative bacterium, is normally associated with pneumonia in patients with weakened immune systems. However, it is also a prevalent nosocomial infectious agent that can be found in infected surgical sites and combat wounds. Many of these clinical strains display multidrug resistance. We have worked with a clinical strain of K. pneumoniae that was initially isolated from a wound of an injured soldier. This strain demonstrated resistance to many commonly used antibiotics but sensitivity to carbapenems. This isolate was capable of forming biofilms in vitro, contributing to its increased antibiotic resistance and impaired clearance. We were interested in determining how sublethal concentrations of carbapenem treatment specifically affect K. pneumoniae biofilms both in morphology and in genomic expression. Scanning electron microscopy showed striking morphological differences between untreated and treated biofilms, including rounding, blebbing, and dimpling of treated cells. Comparative transcriptome analysis using RNA sequencing (RNA-Seq) technology identified a large number of open reading frames (ORFs) differentially regulated in response to carbapenem treatment at 2 and 24 h. ORFs upregulated with carbapenem treatment included genes involved in resistance, as well as those coding for antiporters and autoinducers. ORFs downregulated included those coding for metal transporters, membrane biosynthesis proteins, and motility proteins. Quantitative real-time PCR validated the general trend of some of these differentially regulated ORFs. Treatment of K. pneumoniae biofilms with sublethal concentrations of carbapenems induced a wide range of phenotypic and gene expression changes. This study reveals some of the mechanisms underlying how sublethal amounts of carbapenems could affect the overall fitness and pathogenic potential of K. pneumoniae biofilm cells.

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Pharmacokinetics of imipenem and cilastatin in patients with cystic fibrosis

Cited by 30 publications

References 26 publications

Pharmacokinetic Evaluation of Imipenem Combined with Cilastatin in Cystic Fibrosis

Pharmacokinetic Evaluation of Imipenem Combined with Cilastatin in Cystic Fibrosis

Pharmacokinetics of High-Dose Meropenem in Adult Cystic Fibrosis Patients

Sublethal Concentrations of Carbapenems Alter Cell Morphology and Genomic Expression of Klebsiella pneumoniae Biofilms

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