Pharmacodynamics of carbapenems for the treatment of<i>Pseudomonas aeruginosa</i>ventilator-associated pneumonia: associations with clinical outcome and recurrence

Crandon, Jared L.; Luyt, Charles‐Édouard; Aubry, Alexandra; Chastre, Jean; Nicolau, David P.

doi:10.1093/jac/dkw200

Cited by 26 publications

(24 citation statements)

References 19 publications

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“…The pharmacodynamic threshold for meropenem is 40% f T > MIC [14]. Higher f T > MIC thresholds have been observed in human studies [26, 27], but applying more aggressive meropenem targets would not have resulted in different observations. Among these four patients who were unable to achieve optimal meropenem f T > MIC, all achieved a positive microbiological response, and 3 (75%) achieved a positive clinical response.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Plazomicin, Tigecycline, and Meropenem Pharmacodynamic Exposure against Carbapenem-Resistant Enterobacteriaceae in Patients with Bloodstream Infection or Hospital-Acquired/Ventilator-Associated Pneumonia from the CARE Study (ACHN-490-007)

Kuti

Kim²,

Cloutier³

et al. 2019

Infect Dis Ther

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Introduction CARE was a Phase 3, randomized study evaluating the efficacy and safety of plazomicin-based combination therapy compared with colistin-based combination therapy for the treatment of patients with bloodstream infections or hospital-acquired/ventilator-associated pneumonia due to carbapenem-resistant Enterobacteriaceae (CRE). Adjunctive therapies included either tigecycline or meropenem. We sought to understand the contribution of tigecycline and meropenem to plazomicin-treated-patient outcomes by determining their observed pharmacodynamic exposures against baseline pathogens. Methods Blood samples collected for plazomicin therapeutic monitoring were assayed for tigecycline and meropenem concentrations. Population pharmacokinetic models were constructed for each antibiotic. Using the individual Bayesian posterior or a covariate-based model, concentration time profiles were simulated to estimate the pharmacodynamic exposures for each patient. Pharmacodynamic thresholds for plazomicin, tigecycline, and meropenem were a total area under the curve to minimum inhibitory concentration ratio (AUC/MIC) ≥ 85, free ( f ) AUC/MIC ≥ 0.9, and free time above the MIC ( f T > MIC) of ≥ 40%, respectively. Results Fifteen plazomicin-treated patients were included (12 received tigecycline, 4 received meropenem, 1 received both). Microbiological response was observed in 13 (86.7%) and clinical efficacy was achieved in 11 (73.3%). Plazomicin achieved its pharmacodynamic target in all 15 patients. Meropenem f T > MIC was 0% in all 4 patients, and tigecycline f AUC/MIC was ≥ 0.9 in 9 (75%) patients. Overall, 6 (40%) of 15 patients had a tigecycline or meropenem exposure below the requisite thresholds. Microbiological response and clinical efficacy were observed in 100% (6/6) and 83.3% (5/6) of patients with low threshold attainment by tigecycline and meropenem dosing regimens, respectively. Conclusions Plazomicin successfully achieved its requisite pharmacodynamic exposure, and these data suggest that optimization of tigecycline and meropenem therapy was not required for the combination to achieve microbiological response and clinical efficacy against serious CRE infections. Trial Registration ClinicalTrials.gov number, NCT01970371. Funding Achaogen, Inc. Electronic supplementary material The online version of this article (10.1007/s40121-019-0251-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Plazomicin, Tigecycline, and Meropenem Pharmacodynamic Exposure against Carbapenem-Resistant Enterobacteriaceae in Patients with Bloodstream Infection or Hospital-Acquired/Ventilator-Associated Pneumonia from the CARE Study (ACHN-490-007)

Kuti

Kim²,

Cloutier³

et al. 2019

Infect Dis Ther

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“…Of note, current knowledge on PK/PD targets for meropenem in heterogeneous ICU populations is limited, and a PK/PD target for this special patient population has not been derived yet. In relation to other PK/PD targets derived for meropenem in diverse clinical studies (e.g., 19.2%T >MIC and 47.9%T >MIC [ 21 ], 54%T >MIC [ 19 ] and 76-100%T >MIC [ 20 ]), the two PK/PD targets selected for our analysis were at the upper end (i.e., stricter). The selection of the higher targets seemed reasonable, given (1) limited knowledge on an adequate PK/PD target for heterogeneous ICU populations and (2) the high severity of illness (median APACHE II first study day 27) and the high proportion of patients with transplants (~58%) in the evaluated population.…”

Section: Discussionmentioning

confidence: 99%

“…As a β-lactam antibiotic, meropenem shows time-dependent activity; that is, its antibacterial activity is linked to the percentage of time that meropenem concentrations exceed the MIC value of a pathogen (%T >MIC ) [ 18 ]. The attainment of the pharmacokinetic/pharmacodynamic (PK/PD) index %T >MIC has been associated with clinical success in patients treated with meropenem [ 19 – 21 ]. For example, Ariano et al demonstrated that the probability of clinical response was 80% when %T >MIC was 76–100 in febrile neutropenic patients with bacteraemia but only 36% when %T >MIC was between 0 and 50 [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study

et al. 2017

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BackgroundSevere bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application.MethodsA prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T>MIC, 50%T>4×MIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment.ResultsLarge inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T>MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T>4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment).ConclusionsThe investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.Trial registrationClinicaltrials.gov, NCT01793012. Registered on 24 January 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1829-4) contains supplementary material, which is available to authorized users.

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“…In addition, previous studies suggest that 100% f T>MIC, or even 100% f T>4×MIC, may be considered in critically ill patients . However, a recently published study evaluated the pharmacodynamics of carbapenems in ventilator‐associated pneumonia caused by P aeruginosa . Classification and regression tree (CART) analysis identified that clinical success was associated with 19.2% f T>MIC, and ICU survival was associated with 47.9% f T>MIC …”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients

Chung

Cheatham

Fleming

et al. 2016

The Journal of Clinical Pharma

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The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients-11 nonobese (body mass index [BMI] < 30 kg/m ), 9 obese (30 kg/m ≤ BMI < 40 kg/m ), and 20 morbidly obese (BMI ≥ 40 kg/m )-received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000-patient Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2-compartment linear-elimination model best described the serum concentration-time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.

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Pharmacodynamics of carbapenems for the treatment ofPseudomonas aeruginosaventilator-associated pneumonia: associations with clinical outcome and recurrence

Cited by 26 publications

References 19 publications

Evaluation of Plazomicin, Tigecycline, and Meropenem Pharmacodynamic Exposure against Carbapenem-Resistant Enterobacteriaceae in Patients with Bloodstream Infection or Hospital-Acquired/Ventilator-Associated Pneumonia from the CARE Study (ACHN-490-007)

Evaluation of Plazomicin, Tigecycline, and Meropenem Pharmacodynamic Exposure against Carbapenem-Resistant Enterobacteriaceae in Patients with Bloodstream Infection or Hospital-Acquired/Ventilator-Associated Pneumonia from the CARE Study (ACHN-490-007)

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients

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