Serum ß-lactam concentrations in critically ill patients with cirrhosis: a matched case-control study.

BACKGROUND & AIMS: The pharmacokinetics of ß-lactam antibiotics have not been well defined in critically ill patients with cirrhosis. METHODS: We reviewed data from critically ill patients with cirrhosis and matched controls in whom routine therapeutic drug monitoring of two broad-spectrum ß-lactam antibiotics (piperacillin/tazobactam and meropenem) had been performed. Serum drug concentrations were measured twice by high-performance liquid chromatography. Antibiotic pharmacokinetics were calculated using a one-compartment model. We considered that therapy was adequate when serum drug concentrations were between 4 and 8 times the minimal inhibitory concentration of Pseudomonas aeruginosa during optimal periods of time for each drug (≥ 50% for piperacillin/tazobactam; ≥ 40% for meropenem). RESULTS: We studied 38 patients with cirrhosis (16 for piperacillin/tazobactam and 22 for meropenem) and 38 matched controls. Drug dosing was similar in the two groups. The pharmacokinetics analysis showed a lower volume of distribution of meropenem (P = 0.05) and a lower antibiotic clearance of piperacillin/tazobactam (P = 0.009) in patients with cirrhosis than in the matched controls. Patients with cirrhosis were more likely than those without cirrhosis to have excessive serum ß-lactam concentrations (P = 0.015), in particular for piperacillin/tazobactam. CONCLUSIONS: Standard ß-lactam antibiotics regimens resulted in excessive serum concentrations in two thirds of the patients with cirrhosis. This was particularly true for piperacillin/tazobactam, probably because of reduced drug clearance.

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.

Case-control study of drug monitoring of ß-lactams in obese critically ill patients.

Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum ß-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/m(2)) treated with a broad-spectrum ß-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/m(2)) 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 ß-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard drug regimens of ß-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 ß-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 ß-lactams should be continued in obese critically ill patients.