Win Ratio Analyses of Piperacillin-Tazobactam Versus Meropenem for Ceftriaxone-Nonsusceptible Escherichia coli or Klebsiella pneumoniae Bloodstream Infections: Post Hoc Insights From the MERINO Trial.

BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Antimicrobial activity of cefepime-tazobactam combination against extended spectrum beta-lactamase and/or AmpC beta-lactamase- producing gram-negative bacilli.

BACKGROUND: The problem of resistance to beta-lactam antibiotics, which is caused by ESBL and AmpC ß-lactamases, is getting worse globally. Infections caused by bacterial isolates harboring these enzymes are difficult to treat with carbapenems being the sole effective treatment option for such infections. The objective of this study was to determine the frequency of ESBLs and AmpC-producing Gram-negative bacilli isolated from clinical specimens and to evaluate the sensitivity of cefepime-tazobactam combination against them. METHODS: This is an observational cross-sectional study carried out on 100 Gram-negative bacilli at Theodor Bilharz Research Institute Hospital during the period from February 2015 to January 2016. ESBL production was screened by using the disc diffusion test followed by confirmation by the combined disc confirmatory test, the screening for AmpC production was conducted using the cefoxitin disc test, which was subsequently confirmed by the AmpC disc test. Isolates confirmed positive for ESBL and/ or AmpC production were investigated for their susceptibility to antibiotics. RESULTS: Among 100 Gram-negative bacilli, 44 isolates were confirmed as ESBL producers by the combined disc confirmatory test out of 56 isolates that tested positive for ESBL production through the disc diffusion test. The presence of AmpC production was assessed using the cefoxitin disc test, 32 isolates were screened to be AmpC producers, and the AmpC disc test confirmed AmpC production in 9 isolates of them. Using the Mast® D68C set, 32 isolates were ESBL producers, 3 were AmpC producers, and 4 isolates were ESBL/AmpC co-producers. The highest sensitivity was to cefepime-tazobactam (91.48%) followed by the carbapenems. CONCLUSION: Cefepime-tazobactam showed remarkable activity against ESBL and/or AmpC-producing Gram-negative bacilli and may be considered as a therapeutic alternative to carbapenems.

Lessons learned from an external quality assurance program in applying CLSI interpretive criteria for reporting piperacillin/tazobactam susceptibility.

We evaluated the performance of automated susceptibility testing for piperacillin/tazobactam (PTZ) MICs against the reference microbroth dilution method. The Minimum Inhibitory Concentration of PTZ against a clinical isolate of Klebsiella pneumoniae was determined by reference broth micro-dilution method in 10 replicates which yielded a modal MIC of 16 mg/L (susceptible dose-dependent). Out of 434 laboratories who obtained MIC of 16 mg/L correctly, only 301 interpreted the result as susceptible dose dependent as per 2022 revised CLSI criteria. Educating the clinical laboratories in validating AST methods as per latest CLSI guidelines is of utmost important.

Susceptibilidad de enterobacterias a piperacilina/tazobactam en un hospital pediátrico de Chile / Enterobacteriaceae susceptibility to piperacillin/tazobactam in a Chilean pediatric hospital

Resumen Introducción: Las enterobacterias son bacilos gram-negativos responsables de infecciones graves en el ser humano. Se reporta una susceptibilidad en Klebsiella pneumoniae de 79,4% a piperacilina/tazobactam (PIP/TAZO) en hospitales pediátricos de Chile, pero según nuestro conocimiento, no existen datos publicados a la fecha respecto a la susceptibilidad de otras enterobacterias a PIP/TAZO en la población pediátrica chilena. Objetivo: Determinar la susceptibilidad in vitro a PIP/TAZO en cepas obtenidas de infecciones por Enterobacteriaceae en un hospital pediátrico de Chile. Material y Método: Estudio descriptivo y prospectivo de cepas de Enterobacteriaceae en Hospital de Niños Roberto del Río (HRRIO) entre 1 de enero de 2013 y el 27 de agosto de 2014. Se definió la susceptibilidad a PIP/TAZO por método de gradiente (E-test®) según puntos de corte CLSI 2014. Resultados: Se incluyeron 163 casos. El promedio de edad fue de 4 años 15 días. 70,6% de sexo femenino. El 79,7% de las cepas fueron aisladas en urocultivos. La susceptibilidad de Enterobacteriaceae a PIP/TAZO fue 95,1% (n = 155). La susceptibilidad intermedia fue 1,8% (n = 3). Discusión: Los aislados estudiados presentan alta susceptibilidad a PIP/TAZO. Este hallazgo puede explicarse por la baja circulación de microrganismos productores de BLEE y el limitado uso de PIP/TAZO en esta población pediátrica.

Introduction: Enterobacteriaceae are a group of gram-negative rods that can cause serious infections in humans. A susceptibility in Klebsiella pneumoniae of 79.4% to piperacillin/tazobactam (PIP/TAZO) is reported in pediatric hospitals in Chile. There is no published data published to date regarding PIP/TAZO susceptibility to other Enterobacteriaceae species in this population. Aim: To measure the in vitro PIP/TAZO susceptibility in Enterobacteriaceae isolates from patients in a pediatric hospital in Chile. Methods: Descriptive and prospective study of Enterobacteriaceae positive cultures from patients assisting to the "Hospital de niños Roberto del Río" (HRRIO) between January 2013 and August 2014. PIP/TAZO susceptibility was established by gradient diffusion method (E-test®) according to the 2014 CLSI standards. Results: 163 cases were included. The average age was 4 years and 15 days. 70.6% were female. 79.7% of samples were urine cultures. PIP/TAZO susceptibility in Enterobacteriaceae was 95.1% (n = 155). The intermediate susceptibility was 1.8% (n = 3). Discussion: The isolates studied present high susceptibility to PIP/TAZO. This finding could be explained by the fact that this population has not been exposed to this antimicrobial therapy and also the low rates for ESBL in pediatric infections.

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.

Pharmacodynamic profiling of commonly prescribed antimicrobial drugs against Escherichia coli isolates from urinary tract

Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: car-bapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.

Control of multi-resistant bacteria and ventilator-associated pneumonia: is it possible with changes in antibiotics?

Potent antimicrobial agents have been developed as a response to the development of antibiotic-resistant bacteria, which especially affect patients with prolonged hospitalization in Intensive Care Units (ICU) and who had been previously treated with antimicrobials, especially third-generation cephalosporins.This study was to determine how changes in the empirical treatment of infections in ICU patients affect the incidence of Gram-negative bacteria species and their susceptibility to antimicrobials, and examine the impact of these changes on nosocomial infections. A prospective interventional study was performed in a university hospital during two periods: 1) First period (September 1999 to February 2000); and 2) Second period (August 2000 to December 2000); empirical treatment was changed from ceftriaxone and/or ceftazidime in the first period to piperacillin/tazobactam in the second. ICU epidemiological and infection control rates, as well as bacterial isolates from upper airways were analyzed. Ceftazidime consumption dropped from 34.83 to 0.85 DDD/1000 patients per day (p=0.004). Piperacillin/tazobactam was originally not available; its consumption reached 157.07 DDD/1000 patients per day in the second period (p=0.0002). Eighty-seven patients and 66 patients were evaluated for upper airway colonization in the first and second periods, respectively. There was a significant decrease in the incidence of K. pneumoniae (p=0.004) and P. mirabilis (p=0.036), restoration of K. pneumoniae susceptibility to cephalosporins (p<0.0001) and reduction of ventilator-associated pneumonia rates (p<0.0001). However, there was an increase in P. aeruginosa incidence (p=0.005) and increases in ceftazidime (p=0.003) and meropenem (p<0.0001) susceptibilities. Changing antimicrobial selective pressure on multi-resistant Gram-negative bacteria helps control ventilator-associated pneumonia and decreases antimicrobial resistance.

Inibidores das beta-lactamases e seu uso clínico / Beta-lactamase inhibitors and its clinical use

Os autores fazem uma revisäo bibliográfica sobre as drogas inibidoras das beta-lactamases e abordam sua farmacologia e seu uso clínico atual, baseando-se na combinaçäo dos antimicrobianos e no próprio inibidor da beta-lacatamse. Há muito tempo é conhecido o fato de que germes gram positivos e germes gran negativos säo capazes de produzir enzimas de composiçäo química complexa denominadas beta-lactamases, as quais têm a propriedade de atuar sobre o anel beta-lactamases, beta-lactâmico (componente da estrutura química de alguns antimicrobianos) inativando-o e fazendo com que tais germes se tornem resistentes a estes antimicrobianos (3). Investigaçöes clínicas recentes levaram a descoberta de certas moléculas que podem se ligar de forma irreversível as beta-lactamases e inativá-las, impedindo assim a destruiçäo dos antimicrobianos beta-lactâmicos (3), fazendo com que drogas antigas como ampicilina, amoxacilina e ticarcilina passem a atuar, quando associadas a estas novas substâncias, sobre germes produtores de beta-lactamases, propiciando ao paciente ao mesmo tempo o acesso a uma terapia de custo menor e de menor toxicidade intrínseca. Os agentes inibidores das beta-lactamases têm propriedades, consideravelmente diferentes daquelas das penicilinas e cefalosporinas, assim como säo estruturalmente diferentes destas, tendo baixa atividade intrínseca sobre micoorganismos (4) quando isolados mas que acreditamos de grande valor terapêutico no futuro. Atualmente säo conhecidos dois agentes inibidores das beta-lactamases: o ácido clavulcânico e o sulbactam, os quais passaremos a abordar (5)