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.

Carbapenem resistance and phenotypic detection of carbapenemases in clinical isolates of acinetobacter baumannii.

Background and Objectives: Multidrug-resistant Acinetobacter baumannii (MDR-Ab) reported worldwide has become one of the most difficult nosocomially acquired Gram-negative pathogens to control and treat. The clinical utility of carbapenems is under threat with the emergence of acquired carbapenemases, particularly Ambler class B metallo-lactamases (MBL). Because of the global increase in the occurrence and dissemination of MBLs, early detection is critical. This study was undertaken to detect resistance to carbapenems in clinical isolates of A. baumannii from hospitalized patients by both disk-diffusion and minimum inhibitory concentration (MIC) methods and to assess the rate of carbapenemase and MBL production among the isolates. Materials and Methods : A. baumannii were identified from various clinical samples and antibiotic susceptibility profile was determined by the standard disk-diffusion method. Meropenem-resistant strains were tested further by agar dilution MIC for meropenem. Resistant isolates were screened for carbapenemase production by the modified Hodge test and positive isolates were further checked for metallo-β-lacatmase production by the EDTA disk synergy test. Results : 42 isolates (31.81%) showed resistance to meropenem by the disk diffusion method. 47.6% were carbapenemase positive by the modified Hodge test and 19% were MBL producers phenotypically by the EDTA disc synergy test (EDS). These meropenem-resistant isolates were resistant to most of the other antibiotics tested. These 42 isolates were recovered mostly from patients admitted to intensive care units. Four isolates of the A. baumannii complex were pan drug resistant and showed resistance to even tigecycline and polymyxin B. Conclusion : Carbapenem resistance has been increasingly reported, necessitating their detection. This study reports simple, carbapenemase, and MBL detection method that can be easily incorporated into the daily routine of a clinical laboratory.

Ertapenem: Una nueva clase de carbapenem / Ertapenem: Anew class of carbapenems

Ertapenem es un nuevo carbapenem que, comparativamente con imipenem y meropenem, tiene una prolongada vida media que permite su administración una vez al día abriendo la posibilidad a su indicación en infecciones severas en etapa de manejo ambulatorio. Su espectro antimicrobiano está dirigido principalmente hacia bacilos Gram negativos entéricos incluyendo especies productoras de b­-lactamasas de espectro extendido pero no tiene buena actividad sobre Pseudomonas spp ni Acinetobacter spp. También es activo sobre Haemophilus influenzae y Streptococcus pneumoniae incluyendo cepas resistentes a penicilina y anaerobios estrictos no Bacteroides. Su actividad sobre Enterococcus spp es nula. Por las características de espectro y perfil de seguridad ertapenem es una buena indicación en infecciones de etiología mixta: sepsis abdominal y pélvica, infecciones mayores de tejidos blandos, infecciones urinarias complejas y neumonías adquiridas en la comunidad con sospecha de etiologías mixtas.

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

Actividad in vitro de meropenem e imipenem sobre 288 cepas facultativas y aerobias aisladas de materiales clínicos de pacientes hospitalizados / In vitro activity of the meropenem e imipeem on 288 facultative and aerobe strains isolated of clinical materials of hospitalized patients

Con el objetivo de determinar la actividad de menopenem (MP) e imipenem (IP) en cepas de Enterobacteriaceae, se estudiaron 288 cepas facultativas y anaerobias de pacientes hospitalizados del Gran Buenos Aires (Argentina). Las concentraciones inhibitorias mínimas (CIM) se determinaron mediante macrodilución en agar. Se presentan tablas de CIM acumulativas, CIM50-90, rangos y porcentajes de sensibilidad obtenidos con 108 cepas de Enterobacteriaceae. Se discuten los resultados obtenidos del estudio. Menopenm muestra una efectividad in vitro que la hace adecuada para el tratamiento de infecciones graves, tanto en adultos como en niños