Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Alobaid, Abdulaziz; Wallis, Steven C.; Jarrett, Paul; Starr, Therese; Stuart, Janine; Lassig-Smith, Melissa; Mejia, Jenny Lisette Ordóñez; Roberts, Michael S.; Lipman, Jeffrey; Roberts, Jason A.

doi:10.1128/aac.00531-16

Cited by 41 publications

(34 citation statements)

References 22 publications

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“…A significantly lower target attainment (fT >4×MIC ) in obese patients has been previously demonstrated presumably as a drug-specific effect of piperacillin [52]. Therefore, these data emphasize the rationale for TDM particularly in obese patients in the ICU and the necessity for further trials investigating PIP and β-lactam PK alterations in this subgroup of patients [53][54][55].…”

Section: Discussionsupporting

confidence: 59%

Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience

Richter

Frey²,

Röhr³

et al. 2019

Infection

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Purpose Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients. Methods This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)]. Results PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CL PIP ): no RRT CL PIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CL PIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CL PIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m 2 significantly increased CL PIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]). Conclusion TDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.

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Section: Discussionsupporting

confidence: 59%

Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience

Richter

Frey²,

Röhr³

et al. 2019

Infection

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“…30 Prolonged infusion, increasing age, and Cl cr of 100 ml/minute or lower were identified as factors associated with achieving PD targets for meropenem and piperacillin in obese critically ill patients. 43 Simulations of various meropenem regimens up to 2 g every 8 hours given as prolonged infusions in morbidly obese critically ill patients showed better PD target attainment and increased coverage at higher MICs. 44 In clinical practice, lower daily doses, given via continuous infusions, achieved PTA goals in obese patients.…”

Section: Meropenemmentioning

confidence: 98%

“…A subset analysis of critically ill patients showed that obesity did not impact the probability of achieving therapeutic targets at an MIC of 2 mg/L when they received continuous renal replacement therapy (CRRT); however, obese patients not receiving CRRT were more likely to miss targets compared with non‐obese patients . Prolonged infusion, increasing age, and Cl cr of 100 ml/minute or lower were identified as factors associated with achieving PD targets for meropenem and piperacillin in obese critically ill patients . Simulations of various meropenem regimens up to 2 g every 8 hours given as prolonged infusions in morbidly obese critically ill patients showed better PD target attainment and increased coverage at higher MICs …”

Section: Review Of Specific Antimicrobial Agentsmentioning

confidence: 99%

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

et al. 2017

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Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity-specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., β-lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing.

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“…A flowchart of study selection for each drug is provided in Figure . A total of 2082 articles were identified and screened, with 130 studies included in the final analysis . Some studies provided PK parameters for two drugs (e.g.…”

Section: Resultsmentioning

confidence: 99%