Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. METHODS: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen. RESULTS: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ±â€Šstandard deviation parameters were: CL0, 15.21 ±â€Š6.52 L/h; Vc, 10.13 ±â€Š2.26 L; K12, 2.45 ±â€Š1.16 h-1 and K21, 1.76 ±â€Š0.49 h-1 for imipenem, and 6.95 ±â€Š1.34 L/h, 9.81 ±â€Š2.69 L, 2.43 ±â€Š1.13 h-1 and 1.52 ±â€Š0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. CONCLUSIONS: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.

Relationship of imipenem therapeutic drug monitoring to clinical outcomes in critically ill patients: a retrospective cohort study.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.

Assessing the pharmacodynamic profile of intravenous antibiotics against prevalent Gram-negative organisms collected in Colombia

OBJECTIVES: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. METHODS: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40 percent of the dosing interval. RESULTS: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90 percent cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20 percent lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90 percent CFR against bloodstream and respiratory isolates of K. pneumoniae. CONCLUSIONS: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra-abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials.

Aspectos farmacológicos de meropenem / Pharmacological topics of meropenem

Meropenem is more stable than imipenem to renal dehydropeptidase I and can be used as a monodrug. It is bactericidal against most grampositive and gramnegative, aerobic and anaerobic species. Compared to imipenem, meropenem is more active against pseudomonas aeuginosa, burkholderia cepacia and some multiresistant nosocomial gramnegative strains because it is less inductor of extended spectrum B lactamases but may favor resistance against other antibiotic groups by an efflux pump induction. Its systemicdistribution in the extracellular space includes the central nervous system and is most excreted by glomerular filtration. As meropenem is more soluble than imipenem, it can be administered in bolus. Security profile: it rarely causes seizures, a frecuent effect observed with imipenem during tratment of bacterial meningitis in children. Other adverse reactions (local pain, pruritus and diarrhea) are as frecuent as described with imipenem

Identificación de especies de enterococcus en muestras clínicas y susceptibilidad a agentes antimicrobianos / Identification of enterococcus species from clinical samples and susceptibility to antimicrobial agents

The genus enterococcus has 12 species of which, E faecalis and E faecium are most important in human infections. A progressive resistance to penicillin and ampicillin has been detected in these species. The aim of this work was to identify Enterococcus species isolated in a hospital and to study their antimicrobial susceptibility. We studied 209 Enterococcus species coming from patients admitted to a public hospital. Their susceptibility to penicillin, ampicillin, imipenem, vancomycin, tetracycline, chloramphenicol, ciprofloxacin, gentamycin and streptomycin was determined with the agar dilution technique. Eighty seven percent of species were E faecalis and 7,1 percent were E fecium, other isolated species were E hirae, E casseliflaws, E avium, E solitarius and E faecalis variant. 38 percent of these species were isolated from the urinary tract, 22 percent from the skin and 14 percent from surgical wounds. All E faecalis species were susceptible to penicillin, ampicillin, imipenem and vancomycin; 27,3 percent were susceptible to tetracycline, 54,7 percent to chloramphenicol and 80 percent to ciprofloxacin. Seventy three percent of E faecium species were susceptible to penicillin, 80 percent to ampicillin and 60 percent to imipenem. 62 percent of E faecalis and 42.4 percent of E faecium were resistant to streptomycin. It is concluded that the correct identification of Enterococcus species has therapeutic implications

Uso de imipenem-cilastatin / Imipenem-cilastatin use

El Imipenem-Cilastatín es un nuevo antibiótico ß-lactámico que pertenece a la familia de los carbapenem. Se trata de una combinación fija (1:1) de un derivado de la tienamicina (imipenenm) con un inhibidor de una dipeptidasa renal; la dehidropeptidasa I (Cilastatín), la combinación del abtibiótico con esta última sustancia, impide su hidrólisis e inactivación renal. Este antimicrobiano tiene la actividad antibacterial más amplia de todos los antibióticos disponibles para uso en humanos. Es activo contra estreptococos (incluyendo enterecocos), estafilococos y los aerobios gram-negativos, incluso P.aeruginosa. Las principales reacciones adversas han sido náuseas y vómitos los cuales ocurren durante la infusión intravenosa; además de convulsiones. La dosis pediátrica varía de 60 a 100 mg/kg/día cada 6 horas. El imipenem no debe ser utilizado rutinariamente. Su uso está justificado en infecciones producidas por gérmenes multiresistentes, no susceptibles a otros ß-lactámicos.

Actividad comparativa in vitro de imipenem y otros 20 antimicrobianos contra 1434 cepas bacterianas aisladas en el medio hospitalario / In vitro comparative activity of imipenem and other 20 antimicrobials against 1434 bacterial nosocomial isolated strains

Se estudió la actividad in vitro de imipenem y otros 20 antimicrobianos contra 1434 cepas de cultivos provenientes de pacientes atendidos en el hospital durante un periodo de ocho meses. Se determinaron laws concentraciones inhibidoras mínimas (CIM) por la técnica de dilución en agar. Se informan los porcentajes de resistencia antimicrobiana de enterobacterias Pseudomonas aeruginosa, Acinetobacter y estaqfilococos. Los patrones de resistencia de las enterobacterias (975 cepas) a amikacina, netilmicina, cefalosporinas de tercera generación y piperacilina fueron bajos (<20 por ciento), en comparación con el resto de los antimicrobianos estudios. Comparativamente el promedio de resistencia de las enterobacterias a imipenem fue de 1.4 por ciento, con significncia estaqdística (p<0.05) en relación con el resto de los antimicrobianos. El promedio de resistencia de Pseudomonas aeruguinosa (251 cepas) a imipenem fue de 6.4 por ciento, con significancia estadística (p<0.05) con el resto de los antimicrobianos. Resultados similares se informan con Acinetobacter. En cuanto a los estafilococos, todas las cepas de S. aureus fueron sensibles a imipenem, y 3.5 por ciento de cepas de estafilococo coagulasa negativo fueron resistentes al mismo. Se concluye por el comportamaiento in vitro de las cepas bacterianas estudiadas, que imipenem es una excelente alternativa para el manejo de infecciones causadas por bacilos gramnegativos multirresistentes y estafilococos.