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Updated: Apr 27, 2026
Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses
Published on: August 30, 2018
Broad-spectrum β-lactams in obese non-critically ill patients
M Hites1, F S Taccone2, F Wolff3
1Department of Infectious Diseases, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Objectives:
Obesity may alter the pharmacokinetics of β-lactams. The goal of this study was to evaluate if and why serum concentrations are inadequate when standard β-lactam regimens are administered to obese, non-critically ill patients.
Subjects And Methods:
During first year, we consecutively included infected, obese patients (body mass index (BMI) ⩾30 kg m(-2)) who received meropenem (MEM), piperacillin-tazobactam (TZP) or cefepime/ceftazidime (CEF). Patients with severe sepsis or septic shock, or those hospitalized in the intensive care unit were excluded. Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography. We evaluated whether free or total drug concentrations were >1 time (fT>minimal inhibition concentration (MIC)) or >4 times (T>4MIC) the clinical breakpoints for Pseudomonas aeruginosa during optimal periods of time: ⩾40% for MEM, ⩾50% for TZP and ⩾70% for CEF.
Results:
We included 56 patients (median BMI: 36 kg m(-2)): 14 received MEM, 31 TZP and 11 CEF. The percentage of patients who attained target fT>MIC and T>4MIC were 93% and 21% for MEM, 68% and 19% for TZP, and 73% and 18% for CEF, respectively. High creatinine clearance (107 (range: 6-398) ml min(-1)) was the only risk factor in univariate and multivariate analyses to predict insufficient serum concentrations.
Conclusions:
In obese, non-critically ill patients, standard drug regimens of TZP and CEF resulted in insufficient drug concentrations to treat infections due to less susceptible bacteria. Augmented renal clearance was responsible for these low serum concentrations. New dosage regimens need to be explored in this patient population (EUDRA-CT: 2011-004239-29).
Insights
Standard beta-lactam antibiotic doses may be insufficient for obese patients. Augmented renal clearance leads to low serum concentrations, necessitating new dosing strategies for piperacillin-tazobactam and cefepime/ceftazidime in this population.
Area of Science:
- Pharmacology
- Infectious Diseases
- Obesity Medicine
Background:
- Obesity can significantly alter drug pharmacokinetics, potentially impacting treatment efficacy.
- Standard antibiotic dosing may not achieve therapeutic serum concentrations in obese individuals.
- Understanding these pharmacokinetic changes is crucial for optimizing antimicrobial therapy.
Purpose of the Study:
- To evaluate the adequacy of serum concentrations of commonly used beta-lactam antibiotics in obese, non-critically ill patients.
- To identify the reasons for potentially inadequate drug levels in this patient group.
- To assess the achievement of target pharmacokinetic/pharmacodynamic (PK/PD) breakpoints for meropenem, piperacillin-tazobactam, and cefepime/ceftazidime.
Main Methods:
- A prospective study included 56 infected, obese patients (BMI ≥ 30 kg/m²) receiving meropenem, piperacillin-tazobactam, or cefepime/ceftazidime.
- Patients with severe sepsis, septic shock, or ICU admission were excluded.
- Serum drug concentrations were measured during the elimination phase using high-performance liquid chromatography to determine time above minimum inhibitory concentration (T>MIC) and time above 4x MIC (T>4MIC).
Main Results:
- Ninety-three percent of patients achieved target T>MIC for meropenem, but only 68% for piperacillin-tazobactam and 73% for cefepime/ceftazidime.
- Fewer patients attained the T>4MIC target: 21% for meropenem, 19% for piperacillin-tazobactam, and 18% for cefepime/ceftazidime.
- High creatinine clearance was identified as the sole predictor of insufficient serum drug concentrations in both univariate and multivariate analyses.
Conclusions:
- Standard regimens of piperacillin-tazobactam and cefepime/ceftazidime often result in inadequate drug concentrations in obese, non-critically ill patients.
- Augmented renal clearance is the primary driver of these sub-therapeutic serum concentrations.
- Further research into optimized dosing regimens for beta-lactams in obese populations is warranted.
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