In Vivo High Plasticity of Multi-Drug Resistant ST258 Klebsiella pneumoniae.

Carbapenemase production in Enterobacterales clinical isolates is a global threat. Multi-drug resistant Klebsiella pneumoniae harboring carbapenemases are a major concern among the hospital settings in Latin America. Aim: The aim of this study was to analyze the genetic relatedness between three isolates of K. pneumoniae recovered from one patient in the same bacteriological round on the same day, which exhibited different susceptibility profiles to carbapenems (CP) and to colistin (Col). Isolates' profiles were as follows (susceptible-S/resistant-R): CPS/ColR, CPR/ColR, and CPR/ColS. Pulse-field gel electrophoresis, multilocus sequence typing, and whole genome sequencing were performed. Conjugation assays were carried out and PCR determination in transconjugants (Tcs) was made for: blaCTX-M-groups, blaNDM, blaKPC, blaTEM, qnr alleles, aac(6')Ib-cr, ermB, and plasmid incompatibility groups (Inc). Results: All isolates belonged to the same clone, to ST258 and harbored blaCTX-M-14, blaCTX-M-15, qnrA1, qnrB1, aac(6')Ib-cr, and wzi154 (capsule-locus KL107). One isolate had additional wzi gene, wzi109 (capsule-locus KL36). In CPR isolates, the pattern was explained for blaNDM-1 or blaNDM-1/blaKPC-2 presence, and in ColR for IS5-like element insertion in mgrB at different positions. Co-mobilization of blaNDM-1/qnrA1 was associated to a different plasmid Inc (A/C-FII) in both blaNDM-1 donors. Mobilization of blaCTX-M-14 was related to IncI1 in one donor. Conclusion: These findings highlight the potential plasticity of ST258 K. pneumoniae clone. To the best of our knowledge, this is the first description of blaNDM-1/blaKPC-2-producing K. pneumoniae ST258 in Latin America.

Combination therapy for carbapenem-resistant Gram-negative bacteria.

The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.

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.

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% 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% 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% 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% 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.

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

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