Evaluation of in-vitro susceptibility of ß-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil

ABSTRACT Background: The spread of carbapenemase- and extended-spectrum β-lactamase (ESBL)-producing gram-negative bacilli (GNB) represent a global public health threat that limits therapeutic options for hospitalized patients. This study aimed to evaluate the in-vitro susceptibility of β-lactam-resistant GNB to ceftazidime-avibactam (C/A) and ceftolozane-tazobactam (C/T), and investigate the molecular determinants of resistance. Methods: Overall, 101 clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected from a general hospital in Brazil were analyzed. Susceptibility to the antimicrobial agents was evaluated using an automated method, and the minimum inhibitory concentrations (MIC50/90) of C/A and C/T were determined using Etest®. The β-lactamase-encoding genes were investigated using polymerase chain reaction. Results: High susceptibility to C/A and C/T was observed among ESBL-producing Enterobacterales (100% and 97.3% for CLSI and 83.8% for BRCAST, respectively) and carbapenem-resistant P. aeruginosa (92.3% and 87.2%, respectively). Carbapenemase-producing Klebsiella pneumoniae exhibited high resistance to C/T (80%- CLSI or 100%- BRCAST) but high susceptibility to C/A (93.4%). All carbapenem-resistant K. pneumoniae isolates were susceptible to C/A, whereas only one isolate was susceptible to C/T. Both antimicrobials were inactive against metallo-β-lactamase-producing K. pneumoniae isolates. Resistance genes were concomitantly identified in 44 (44.9%) isolates, with bla CTX-M and bla SHV being the most common. Conclusions: C/A and C/T were active against microorganisms with β-lactam-resistant phenotypes, except when resistance was mediated by metallo-β-lactamases. Most C/A- and C/T-resistant isolates concomitantly carried two or more β-lactamase-encoding genes (62.5% and 77.4%, respectively).

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.

In silico and In vitro activity of ceftolozane/tazobactam against pseudomonas aeruginosa collected across Indian hospitals

Ceftolozane/tazobactam is a novel antimicrobial agent with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens. In this study, we determined the antimicrobial susceptibility for a total of 149 clinical isolates of P. aeruginosa for the most commonly used antimicrobials including the new agent ceftolozane/tazobactam (C/T). Broth microdilution was performed to determine the minimum inhibitory concentration against various antimicrobials including C/T. Among the ?-lactam/?-lactamase inhibitor, overall susceptibility was 67%, 55% and 51% for C/T, Piperacillin/Tazobactam (P/T) and Cefoperazone/Sulbactam, respectively. The variations in the susceptibility rates were noted among the three different ?-lactam/?-lactamase inhibitors. Interestingly, 33% susceptibility was noted for C/T against isolates that were resistant to P/T, indicating the higher activity of C/T. This finding suggests about 33% of the P/T-resistant isolates can still be treated effectively with C/T. C/T could be a better alternative for the treatment of ESBL-producing organism, and thereby usage of higher antimicrobials can be minimised.

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.

Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Latin America: report from an antimicrobial surveillance program (2013-2015)

ABSTRACT This study evaluated the in vitro activity of ceftolozane-tazobactam and comparator agents tested against Latin American isolates of Enterobacteriaceae and Pseudomonas aeruginosa from patients with health care-associated infections. Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor.A total of 2415 Gram-negative organisms (537 P. aeruginosa and 1878 Enterobacteriaceae) were consecutively collected in 12 medical centers located in four Latin American countries. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A10 document and the results interpreted according to EUCAST and CLSI breakpoint criteria. Results: Ceftolozane-tazobactam (MIC50/90, 0.25/32 µg/mL; 84.2% susceptible) and meropenem (MIC50/90, ≤0.06/0.12 µg/mL; 92.6% susceptible) were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates tested, 6.6% were carbapenem-resistant Enterobacteriaceae and 26.4% exhibited an extended-spectrum β-lactamase non-carbapenem-resistant phenotype. Whereas ceftolozane-tazobactam showed good activity against extended-spectrum beta-lactamase, non-carbapenem-resistant phenotype strains of Enterobacteriaceae (MIC50/90, 0.5/>32 µg/mL), it lacked useful activity against strains with a (MIC50/90, >32/>32 µg/mL; 1.6% S) carbapenem-resistant phenotype. Ceftolozane-tazobactam was the most potent (MIC50//90, 0.5/16 µg/mL) β-lactam agent tested against P. aeruginosa isolates, inhibiting 86.8% at an MIC of ≤4 µg/mL. P. aeruginosa exhibited high rates of resistance to cefepime (16.0%), ceftazidime (23.6%), meropenem (28.3%), and piperacillin-tazobactam (16.4%). Conclusions: Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins and piperacillin-tazobactam when tested against Enterobacteriaceae.