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.

OTAC: Optimización de la Terapia Antibiótica en el paciente Crítico. Antibióticos betalactámicos en perfusión continua / OTAC: Optimization of Antibiotic Therapy in Critically ill Patients. Using beta-lactam antibiotics by continuous infusion

Objetivo: Determinar el porcentaje de pacientes, a los que se les administró dosis estándar de piperacilina/tazobactam o meropenem en perfusión continua, que alcanzaban el índice farmacocinético/farmacodinámico diana definido como el 100% del intervalo de administración en que las concentraciones de antibiótico libre fueron cuatro veces iguales o superiores a la concentración mínima inhibitoria (100% fT ≥ 4 x CMI). Método: Datos preliminares obtenidos de un estudio clínico prospectivo que analiza el comportamiento farmacocinético/farmacodinámico de los antibióticos betalactámicos administrados en perfusión continua en pacientes críticos. Se realizó en unidades de cuidados intensivos de un hospital universitario de tercer nivel, desde junio de 2015 a mayo de 2017. Criterios de inclusión: adultos con función renal correcta (filtrado glomerular según la fórmula CKD-EPI ≥ 60 ml/min/1,73 m2) y tratados con dosis estándar de antibióticos betalactámicos en perfusión continua. Las concentraciones en estado de equilibrio estacionario fueron determinadas mediante cromatografía líquida acoplada a espectrometría de masas (UHPLC-MS/MS). Se utilizaron valores de concentración mínima inhibitoria teóricos para microorganismos más resistentes (piperacilina/ tazobactam: 16 mg/l para Pseudomonas aeruginosa y 8 mg/l para Enterobacteriaceae; meropenem: 2 mg/l, independientemente del microorganismo). Además, se realizó un subanálisis de los pacientes con aislamiento microbiológico (concentraciones mínimas inhibitorias reales). Resultados: Se incluyeron 61 pacientes (25 meropenem y 36 piperacilina/tazobactam). Edad media 59 años (15), mediana de filtrado glomerular 95 ml/min/1,73 m2 (83-115). Mediana de concentraciones en estado de equilibrio estacionario libre: 16 mg/l (11-29) meropenem y 40 mg/l (2151) piperacilina. El 88% de los pacientes tratados con meropenem alcanzaron el objetivo farmacocinético/farmacodinámico, sin diferencias entre Enterobacteriaceae y Pseudomonas. En el caso de piperacilina/tazobactam, el 61% y el 11% de los pacientes alcanzaron la diana, considerando Enterobacteriaceae y Pseudomonas como microorganismo sospechoso. Un total de 35 (57%) pacientes presentaron aislamiento microbiológico. El 94% de ellos alcanzaron la diana, sin diferencias entre los dos antibióticos. Conclusiones: Ante la sospecha de infecciones por microorganismos con concentraciones mínimas inhibitorias elevadas (Pseudomonas aeruginosa o enterobacterias), se observa que dosis convencionales de meropenem en perfusión continua son suficientes para lograr la diana 100% fT≥ 4 x MIC. Sin embargo, se requerirían dosis superiores de piperacilina/tazobactam. En casos de aislamiento microbiológico, dosis estándar de ambos antibióticos fueron suficientes para lograr la diana. La monitorización farmacocinética es altamente recomendable para la optimización terapéutica

Objective: To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous infusion who achieved the target pharmacokinetic/pharmacodynamic index, which was defined as free concentrations four times more than the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT≥ 4 x MIC). Method: Preliminary data from a larger prospective clinical study analysing the pharmacokinetic/pharmacodynamic behaviour of ß-lactams antibiotics Continuous infusion (CI) in critical patients. The study was conducted in the intensive care units of a tertiary university hospital for adults (June 2015-May 2017). Inclusion criteria: normal renal function (glomerular renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and treatment with standard dose ß-lactams CI. Concentrations at steady state (Css) conditions were determined using UHPLC-MS/MS. We selected the highest susceptible MIC for all likely organisms according to European Commitee on Antimicrobial Susceptibility Testing's (i.e. piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for Pseudomonas aeruginosa; meropenem: 2 mg/L for any microorganism). In addition, a subanalysis of patients was conducted using actual MIC values. Results: 61 patients were enrolled (25 to meropenem and 36 to piperacillin/tazobactam). Average age was 59 (15) years and median GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21-51), respectively. 88% of patients treated with meropenem reached the PK/PD target, without differences between both microorganisms. For piperacillin/tazobactam, 61% and 11% of patients reached the target, with enterobacteriaceae and Pseudomonas as suspected microorganisms, respectively. The pathogen was isolated in 35 (57%) patients: 94% reached the target PK/ PD, without differences between both antibiotic therapies. Conclusions: Standard doses of meropenem CI are sufficient to achieve a PK/PD target of 100% fT≥ 4 x MIC in suspected infections with high MICs (Pseudomonas aeruginosa or enterobacteriaceae). However, higher doses of piperacillin/tazobactam could be considered to achieve this goal. In patients with isolated microorganisms, a standard dose of both antibiotic therapies would be sufficient to achieve the target. Therapeutic drug monitoring is highly recommended for therapeutic optimization