Rudy Surin

Case-Control Study of Drug Monitoring of β-Lactams in Obese Critically Ill Patients

ABSTRACT Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum β-lactams (meropenem, ceftazidime/cefepime, and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinetics of these agents. We reviewed our data on critically ill obese patients (body mass index of ≥30 kg/m2) treated with a broad-spectrum β-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically nonobese patients (body mass index of <25 kg/m2) to assess whether there were differences in reaching optimal drug concentrations for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was considerable variability in β-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard drug regimens of β-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a protective factor for insufficient β-lactam serum concentrations. The serum drug levels from the obese cohort were well matched for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 nonobese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of β-lactams should be continued in obese critically ill patients.

Invasive aspergillosis in patients with severe alcoholic hepatitis

BACKGROUND & AIMS Severe alcoholic hepatitis (AH) has a poor short-term prognosis. Although infections are frequent complications of AH, the incidence of invasive aspergillosis (IA) and its impact on outcome remain unknown. METHODS We prospectively followed 94 biopsy-proven severe AH episodes for 3 months. We retrospectively reviewed our diagnosis of IA based on EORTC/MSG and AspICU criteria, except for host factors. RESULTS Fifteen IA (6 proven, 8 probable, and 1 possible) were diagnosed after a median delay of 26 days following diagnosis of AH. The sites of infection were the lungs (n=11) and central nervous system (n=2), while IA was disseminated in 2 cases. Baseline MELD score ≥24 and ICU admission were independent risk factors for IA. Thirteen IA occurred in the context of corticosteroids, and 2 had received no specific treatment for AH. Non-response to corticosteroids at day 7 was not a risk factor for IA, but IA was associated with absence of liver improvement at day 28. Despite antifungal treatment, 3-month transplant-free survival of patients with IA was 0% compared to 53% in those without IA. IA, Lille score ≥0.45, and overt encephalopathy were independent predictors of transplant-free mortality. CONCLUSIONS IA is a frequent complication of severe AH and carries a very high risk of mortality. Systematic screening for IA should be recommended in these patients. Further studies are needed to identify high-risk populations requiring antifungal prophylactic treatment.

Broad-spectrum β-lactams in obese non-critically ill patients

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).

Serum β‐lactam concentrations in critically ill patients with cirrhosis: a matched case‐control study

The pharmacokinetics of β‐lactam antibiotics have not been well defined in critically ill patients with cirrhosis.