Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae?

Pea, Federico; Siega, Paola Della; Cojutti, Pier Giorgio; Sartor, Assunta; Crapis, Massimo; Scarparo, Claudio; Bassetti, Matteo

doi:10.1016/j.ijantimicag.2016.10.018

Cited by 65 publications

(69 citation statements)

References 19 publications

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“…Early experiences with these types of doses have been encouraging; however, much more data are needed concerning the safety of these exposures. In our study, no drug-related adverse events occurred, even in the presence of C ss of up to 143 mg/liter (14). Conversely, a very recent retrospective study revealed the potential existence of concentration-toxicity relationships for adverse effects of meropenem during high-dose intermittent infusion (1 to 6 g/day at 8-to-12-h intervals) (26).…”

Section: Discussioncontrasting

confidence: 54%

“…Study population. Data from 30 adult patients with KPC-Kp infections who were enrolled in a previously published retrospective study (14) were included for the population pharmacokinetic analysis in this study. Median (range) age, weight, and creatinine clearance (CrCL) level were 62.5 years (34.0 to 87.0 years), 69.5 kg (46.0 to 100.0 kg), and 80.0 ml/min (23.1 to 200.0 ml/min), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Several authors advocated the use of EI meropenem for the treatment of infections caused by KPC-Kp with a meropenem MIC of Յ8 mg/liter (4,(6)(7)(8)(9)12). We recently showed that maintenance of 100% T Ͼ1ϫMIC with HDCI meropenem may represent a valuable tool in improving clinical outcome even in dealing with infections caused by KPC-Kp with a meropenem MIC of Յ64 mg/liter (14). In that study, dosages of meropenem higher than those licensed were used on several occasions (14).…”

Section: Discussionmentioning

confidence: 99%

“…In the retrospective study of HDCI meropenem among patients with KPc-Kp infections, successful clinical outcome was significantly associated with 100% T Ͼ1ϫMIC (odds ratio [OR] ϭ 10.556; 95% confidence interval [CI], 1.612 to 69.122; P ϭ 0.014) and with 100% T Ͼ4ϫMIC (OR ϭ 12.250; 95% CI, 1.268 to 118.361; P ϭ 0.030) (14). Interestingly, favorable clinical response was obtained in more than 60% (8/13) of patients who were infected by meropenem-resistant KPC-Kp strains with a meropenem MIC ranging between 16 and 64 mg/liter.…”

Section: Discussionmentioning

confidence: 99%

“…The possibility that this approach might be feasible even against KpC-Kp infections due to strains with higher meropenem MICs is still to be demonstrated (12,13). In this regard, we recently showed that high-dose CI (HDCI) meropenem, in combination with other antimicrobials with activity against Gram-negative bacteria, was effective in the treatment of KPC-Kp infections (mainly of the bloodstream) due to strains with a meropenem MIC of up to 64 mg/liter (14).…”

mentioning

confidence: 99%

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Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

Cojutti

Sartor

Righi

et al. 2017

Antimicrob Agents Chemother

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We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with carbapenemase (KPC)-producing (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations () of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T, 100% T, 100% T, and 100% T, where "T" represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 ( = 169). Ninety-seven meropenem were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

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Section: Discussioncontrasting

confidence: 54%

Section: Resultsmentioning

confidence: 99%