Predictive Factors of Piperacillin Exposure and the Impact on Target Attainment after Continuous Infusion Administration to Critically Ill Patients.

Critically ill patients undergo significant pathophysiological changes that affect antibiotic pharmacokinetics. Piperacillin/tazobactam administered by continuous infusion (CI) improves pharmacokinetic/pharmacodynamic (PK/PD) target attainment. This study aimed to characterize piperacillin PK after CI administration of piperacillin/tazobactam in critically ill adult patients with preserved renal function and to determine the empirical optimal dosing regimen. A total of 218 piperacillin concentrations from 106 patients were simultaneously analyzed through the population PK approach. A two-compartment linear model best described the data. Creatinine clearance (CLCR) estimated by CKD-EPI was the covariate, the most predictive factor of piperacillin clearance (CL) interindividual variability. The mean (relative standard error) parameter estimates for the final model were: CL: 12.0 L/h (6.03%); central and peripheral compartment distribution volumes: 20.7 L (8.94%) and 62.4 L (50.80%), respectively; intercompartmental clearance: 4.8 L/h (26.4%). For the PK/PD target of 100% fT>1×MIC, 12 g of piperacillin provide a probability of target attainment > 90% for MIC < 16 mg/L, regardless of CLCR, but higher doses are needed for MIC = 16 mg/L when CLCR > 100 mL/min. For 100% fT>4×MIC, the highest dose (24 g/24 h) was not sufficient to ensure adequate exposure, except for MICs of 1 and 4 mg/L. Our model can be used as a support tool for initial dose guidance and during therapeutic drug monitoring.

Continuous Infusion of Piperacillin/Tazobactam and Meropenem in ICU Patients Without Renal Dysfunction: Are Patients at Risk of Underexposure?

BACKGROUND AND OBJECTIVES: Morbidity and mortality from serious infections are common in intensive care units (ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment. RESULTS: We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC) [median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02-0.12) mg/l; piperacillin: 3 (1-4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [ß = - 0.01 (95% CI - 0.02 to - 0.0; p = 0.043)] and piperacillin [ß = - 0.01 (95% CI - 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [ß = - 0.36 (95% CI - 0.61 to - 0.11; p = 0.005)]. CONCLUSION: Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainments in ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.

Clinical characteristics and outcome of bacteraemia caused by Enterobacter cloacae and Klebsiella aerogenes: more similarities than differences.

OBJECTIVES: The genus Enterobacter is a common cause of nosocomial infections. Historically, the most frequent Enterobacter species were those of Enterobacter cloacae complex and Enterobacter aerogenes. In 2019, E. aerogenes was re-classified as Klebsiella aerogenes owing to its higher genotypic similarity with the genus Klebsiella. Our objective was to characterise and compare the clinical profiles of bacteraemia caused by E. cloacae and K. aerogenes. METHODS: This 3-year multicentre, prospective cohort study enrolled consecutive patients with bacteraemia by E. cloacae or K. aerogenes. Baseline characteristics, bacteraemia features (source, severity, treatment), antibiotic susceptibility, resistance mechanisms and mortality were analysed. RESULTS: The study included 285 patients with bacteraemia [196 (68.8%) E. cloacae and 89 (31.2%) K. aerogenes]. The groups showed no differences in age, sex, previous use of invasive devices, place of acquisition, sources or severity at onset. The Charlson score was higher among patients with E. cloacae bacteraemia [2 (1-4) vs. 1 (0.5-3); P = 0.018], and previous antibiotic therapy was more common in patients with K. aerogenes bacteraemia (57.3% vs. 41.3%; P = 0.01). Mortality was 19.4% for E. cloacae and 20.2% for K. aerogenes (P = 0.869). Antibiotic susceptibility was similar for both species, and the incidence of multidrug resistance or ESBL production was low (6% and 5.3%, respectively), with no differences between species. CONCLUSION: Bacteraemias caused by E. cloacae and K. aerogenes share similar patient profiles, presentation and prognosis. Patients with E. cloacae bacteraemia had more co-morbidities and those with K. aerogenes bacteraemia had received more antibiotics.

A prospective, multicenter case control study of risk factors for acquisition and mortality in Enterobacter species bacteremia.

BACKGROUND: Enterobacter is among the main etiologies of hospital-acquired infections. This study aims to identify the risk factors of acquisition and attributable mortality of Enterobacter bacteremia. METHODS: Observational, case-control study for risk factors and prospective cohort for outcomes of consecutive cases with Enterobacter bacteremia. This study was conducted in five hospitals in Spain over a three-year period. Matched controls were patients with negative blood cultures and same sex, age, and hospitalization area. RESULTS: The study included 285 cases and 570 controls. E. cloacae was isolated in 198(68.8%) cases and E. aerogenes in 89(31.2%). Invasive procedures (hemodialysis, nasogastric tube, mechanical ventilation, surgical drainage tube) and previous antibiotics or corticosteroids were independently associated with Enterobacter bacteremia. Its attributable mortality was 7.8%(CI95%2.7-13.4%), being dissimilar according to a McCabe index: non-fatal=3.2%, ultimately fatal=12.9% and rapidly fatal=0.12%. Enterobacter bacteremia remained an independent risk factor for mortality among cases with severe sepsis or septic shock (OR 5.75 [CI95%2.57-12.87], p<0.001), with an attributable mortality of 40.3%(CI95%25.7-53.3). Empiric therapy or antibiotic resistances were not related to the outcome among patients with bacteremia. CONCLUSIONS: Invasive procedures, previous antibiotics and corticosteroids predispose to acquire Enterobacter bacteremia. This entity increases mortality among fragile patients and those with severe infections. Antibiotic resistances did not affect the outcome.