Evaluation of in vitro activity of ceftolozane-tazobactam against recent clinical bacterial isolates from Brazil - the EM200 study

ABSTRACT Background: The emergence of antibiotic resistance is increasing and there are few effective antibiotics to treat infections caused by resistant and multidrug resistant bacterial pathogens. This study aimed to evaluate the in vitro activity of ceftolozane-tazobactam against clinical bacterial isolates from Brazil. Methods: A total of 673 Gram-negative bacterial isolates including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and other Enterobacterales collected from 2016 to 2017 were tested, most of them isolated from patients in intensive care units. Minimum inhibitory concentrations (MIC50/90) were determined by broth microdilution for amikacin, aztreonam, cefepime, cefotaxime, cefoxitin, ceftolozane-tazobactam, ceftazidime, ceftriaxone, ciprofloxacin, colistin, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam using dried panels. Antimicrobial susceptibility results were interpreted according to Clinical and Laboratory Standards Institute criteria. Results: Susceptibility rates to ceftolozane-tazobactam ranged from 40.4% to 94.9%. P. aeruginosa susceptibility rate to ceftolozane-tazobactam was 84.9% (MIC50/90, 1/16 µg/mL) and 99.2% to colistin. For E. coli, ceftolozane-tazobactam inhibited 94.9% (MIC50/90, 0.25/1 µg/mL) of the microorganisms. The susceptibility rate of K. pneumoniae to ceftolozane-tazobactam was 40.4% (MIC50/90, 16/>32 µg/mL). Other Enterobacterales have shown susceptibility rates of 81.1% (MIC50/90, 0.5/16 µg/mL) to ceftolozane-tazobactam, 93.9% to meropenem, 90.9% to amikacin (90.9%), and 88.6% to ertapenem. In non-carbapenemase producing isolates, AmpC mutations were found three isolates. Conclusions: Ceftolozane-tazobactam has shown relevant activity against a large variety of the analyzed microorganisms collected from multiple centers in Brazil, showing promising results even in multidrug resistant strains.

Evaluación de la sensibilidad de cepas de Pseudomonas aeruginosa multi-resistentes frente a ceftolozano/tazobactam / Evaluation of susceptibility of multidrug-resistant Pseudomonas aeruginosa strains against ceftolozane/tazobactam

Resumen Introducción: Pseudomonas aeruginosa es un patógeno oportunista asociado a alta morbi-mortalidad. Para cepas multi-resistentes (MDR), ceftolozano/tazobactam (CTZ) se ha autorizado por la Agencia Europea del Medicamento (EMA) para infecciones del tracto urinario complicadas, pielonefritis aguda e infecciones intra-abdominales complicadas. Objetivo: Determinar la sensibilidad a CTZ de P. aeruginosa MDR en muestras clínicas aisladas en el Hospital Universitario Puerto Real. Material y Métodos: Se estudió la sensibilidad según criterios EUCAST a CTZ de cepas de P. aeruginosa MDR, entre enero de 2015 y agosto de 2017. Los criterios de multi-resistencia fueron definidos por el Centers for Disease Control and Prevention. La sensibilidad antimicrobiana se obtuvo mediante sistema MicroScan® (Beckman Coulter). La sensibilidad a CTZ se determinó mediante tiras de gradiente (Liofilchem®, Werfen). Resultados: De 1253 cepas, 7% fueron MDR. Se estudió la sensibilidad de 78 cepas de P. aeruginosa MDR, de las cuales cinco (6,4%) resultaron resistentes a CTZ según criterios EUCAST. Conclusiones: En nuestro medio la resistencia in vitro a CTZ en cepas de P. aeruginosa MDR es aproximadamente 6%; CTZ es una opción de tratamiento de infecciones por cepas de P. aeruginosa MDR cuando no exista otra alternativa y se haya comprobado su sensibilidad in vitro.

Background: Pseudomonas aeruginosa is an opportunistic pathogen associated with high morbidity and mortality. For multidrug-resistant strains (MDR), ceftolozane/tazobactam (CTZ) has been authorized by the European Medicines Agency (EMA) for complicated urinary tract infections, acute pyelonephritis, and complicated intraabdominal infections. Aim: To determine the susceptibility to CTZ of P. aeruginosa MDR in isolated clinical samples at the University Hospital Puerto Real. Methods: The susceptibility according to the EUCAST to CTZ criteria of strains of P. aeruginosa MDR, between January 2015 and August 2017 has been studied. The multiresistance criteria were those defined by the Centers for Disease Control and Prevention. The antibiotic susceptibility was obtained by automated MicroScan® system (Beckman Coulter). Susceptibility to CTZ was determined using gradient strips (Liofilchem®, Werfen). Results: Of 1253 strains isolated, 7% presented MDR. We studied the susceptibility of a total of 78 strains of MDR P. aeruginosa, of which 5 (6.4%) were resistant to CTZ according to the EUCAST criteria. Conclusions: In our environment, the in vitro resistance to CTZ in MDR P. aeruginosa strains is approximately 6%. CTZ is an option for the treatment of infections by MDR P. aeruginosa when there is no other alternative and its in-vitro susceptibility has been proven.

Nuevas cefalosporinas / New cephalosporins

Resumen La resistencia bacteriana se ha incrementado en América Latina y el mundo, por lo que se requiere investigación y creación de nuevos antimicrobianos capaces de erradicar a los microorganismos resistentes. Se realizó una revisión acerca de nuevas cefalosporinas y sus combinaciones con un inhibidor de β-lactamasas, recopilando información de espectro, farmacocinética, farmacodinamia y estudios clínicos de las indicaciones actuales para ceftarolina, ceftazidima/avibactam y ceftolozano/tazobactam. La primera, con actividad frente a Staphylococcus aureus y Staphylococcus coagulasa negativa sensibles y resistentes a meticilina, y contra Streptococcus pneumoniae resistente a penicilina; por lo tanto, aprobada para uso en neumonía bacteriana adquirida en comunidad e infecciones bacterianas de piel y tejidos blandos. Entre las nuevas combinaciones, ceftazidima, una cefalosporina de tercera generación con actividad anti-pseudomonas, asociada a avibactam, un inhibidor de β-lactamasas, ha demostrado efectividad en el tratamiento de infecciones abdominales e infecciones urinarias complicadas. Por último, la combinación ceftolozano y el conocido tazobactam presenta acción comparable a la combinación de ceftazidima y avibactam por su actividad contra bacilos gramnegativos y, en combinación con metronidazol no presenta inferioridad a meropenem en infecciones intra-abdominales. Se presentan los estudios clínicos y las potenciales indicaciones y escenarios de uso de estas cefalosporinas.

Bacterial resistance has increased in Latin America and the world, making research and creation of new antimicrobials capable of eradicating resistant microorganisms essential. A review of new cephalosporins and their combinations with a beta-lactamase inhibitor was conducted, collecting data on the spectrum, pharmacokinetic and pharmacodynamic profile and clinical studies of the current indications for ceftaroline, and the combinations ceftazidime with avibactam and ceftolozane with tazobactam. The first one has activity against methicillin-resistant Staphylococcus aureus and coagulase negative Staphylococcus (SCoN) and against penicillin-resistant Streptococcus pneumoniae, therefore approved for use in community-acquired pneumonia and acute bacterial skin and skin structure infections. Among the new combinations, ceftazidime, a third generation cephalosporin with antipseudomonal activity, associated with avibactam, a betalactamase inhibitor, has been shown to be effective in the treatment of abdominal infections and complicated urinary infections. Finally, the combination of ceftolozane with tazobactam has comparable action to ceftazidime with avibactam due to its activity against Gram negative rods, and in combination with metronidazole they do not present inferiority to meropenem in intra-abdominal infections. The clinical studies are presented, as well as the potential indications and clinical scenarios for their use of this cephalosporins.