RESUMO
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.
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Ácido Penicilânico/análogos & derivados , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/efeitos dos fármacos , Hospitais Pediátricos , Antibacterianos/farmacologia , Piperacilina/farmacologia , Valores de Referência , Testes de Sensibilidade Microbiana , Chile , Estudos Prospectivos , Ácido Penicilânico/farmacologia , Farmacorresistência Bacteriana , Combinação Piperacilina e TazobactamRESUMO
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.
Assuntos
Humanos , Pseudomonas aeruginosa/efeitos dos fármacos , Cefalosporinas/farmacologia , Infecção Hospitalar/microbiologia , Ácido Penicilânico/análogos & derivados , Enterobacteriaceae/efeitos dos fármacos , Antibacterianos/farmacologia , Fenótipo , Pseudomonas aeruginosa/isolamento & purificação , Ácido Penicilânico/farmacologia , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/classificação , Monitoramento Epidemiológico , Tazobactam , América LatinaRESUMO
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 ß-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, 0.25/32µg/mL; 84.2% susceptible) and meropenem (MIC50/90, ≤0.06/0.12µg/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 ß-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/>32µg/mL), it lacked useful activity against strains with a (MIC50/90, >32/>32µg/mL; 1.6% S) carbapenem-resistant phenotype. Ceftolozane-tazobactam was the most potent (MIC50//90, 0.5/16µg/mL) ß-lactam agent tested against P. aeruginosa isolates, inhibiting 86.8% at an MIC of ≤4µg/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 ß-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins and piperacillin-tazobactam when tested against Enterobacteriaceae.
Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Infecção Hospitalar/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Ácido Penicilânico/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/classificação , Enterobacteriaceae/isolamento & purificação , Monitoramento Epidemiológico , Humanos , América Latina , Ácido Penicilânico/farmacologia , Fenótipo , Pseudomonas aeruginosa/isolamento & purificação , TazobactamRESUMO
Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of ß-lactam/ß-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 ß-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT>threshold index described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log10 kill. The non-equivalent generic required a longer exposure (fT>threshold 33%) to suppress resistance compared with the innovator (fT>threshold 22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence.
Assuntos
Antibacterianos/farmacocinética , Farmacorresistência Bacteriana , Medicamentos Genéricos/farmacocinética , Infecções por Escherichia coli/tratamento farmacológico , Ácido Penicilânico/análogos & derivados , Seleção Genética , Inibidores de beta-Lactamases/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Modelos Animais de Doenças , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/farmacologia , Feminino , Camundongos , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/administração & dosagem , Piperacilina/farmacocinética , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Resultado do Tratamento , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Hospitais Pediátricos , Ácido Penicilânico/análogos & derivados , Criança , Pré-Escolar , Chile , Farmacorresistência Bacteriana , Feminino , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Estudos Prospectivos , Valores de ReferênciaRESUMO
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.
Assuntos
Humanos , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Ceftriaxona/farmacologia , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Escherichia coli/isolamento & purificação , Método de Monte Carlo , Testes de Sensibilidade Microbiana/métodos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/farmacocinética , Piperacilina/farmacologia , Pielonefrite/microbiologia , Índice de Gravidade de Doença , Tienamicinas/farmacocinética , Tienamicinas/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
Several studies have demonstrated that piperacillin/tazobactam produces a false-positive result for the galactomannan antigen test. However, the most recent literature has demonstrated that this interaction is no longer a concern. There is little information regarding the drug-laboratory interaction with the generics of piperacillin/tazobactam or other broad-spectrum beta-lactams, such as ceftaroline, doripenem, imipenem/cilastatin, and meropenem. The purpose of this study was to determine if a drug-laboratory interaction exists with these antibiotics. Tests showed that one lot of imipenem/cilastatin by Hospira Healthcare India Private Limited produced a false-positive result for the galactomannan antigen test. All other medications tested, including piperacillin/tazobactam from seven manufacturers and imipenem/cilastatin by Hospira Inc., did not produce positive results. Since the reason for this drug-laboratory interaction with imipenem/cilastatin is unknown, more studies are needed to further investigate this interaction. Providers also should be educated of these findings: no drug-laboratory interaction with piperacillin/tazobactam and a possible drug-laboratory interaction with imipenem/cilastatin (Hospira Healthcare India Private Limited).
Assuntos
Antígenos de Fungos/farmacologia , Aspergillus/imunologia , Medicamentos Genéricos/farmacologia , Mananas/imunologia , beta-Lactamas/farmacologia , Aspergillus/efeitos dos fármacos , Interações Medicamentosas , Reações Falso-Positivas , Galactose/análogos & derivados , Humanos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e TazobactamRESUMO
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: carbapenems 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.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Ceftriaxona/farmacologia , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacologia , Ertapenem , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Humanos , Meropeném , Testes de Sensibilidade Microbiana/métodos , Método de Monte Carlo , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/farmacocinética , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Pielonefrite/microbiologia , Índice de Gravidade de Doença , Tienamicinas/farmacocinética , Tienamicinas/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
Bacteroides fragilis is the anaerobe most frequently isolated from clinical specimens and piperacillin/tazobactam is among the drugs that can be used to treat polymicrobial infections in which this bacteria is often involved. During antibiotic therapy, inhibitory concentrations of antibiotics are always followed by subinhibitory concentrations which can generate phenotypic changes in bacteria. So, in this study we aimed to evaluate changes in the proteomic profile of B. fragilis grown in a sub-MIC of PTZ, using 2-D electrophoresis followed by matrix-assisted laser desorption/ionization time-of-flight/time of-flight. Analysis of the 2-DE gels showed 18 spots with significantly different volume percentages between experimental conditions and 12 were successfully identified by MS/MS. Two proteins with decreased abundance in sub-MIC condition were involved in the glycolysis (glyceraldehyde-3-phosphate dehydrogenase and triose phosphate isomerase), others two involved in amino acid metabolism (Oxoacyl-(acyl-carrier protein) synthase II and dihydrodipicolinate reductase), and finally, one protein involved in fatty acid metabolism (UDP-N-acetylglucosamine acyltransferase). Among the proteins with increased abundance, we founded three ATP synthase (alpha, beta, and alpha type V), which could be involved in antibiotic bacterial resistance by efflux pump, one protein involved in glycolysis (enolase), and one involved in protein degradation (aminoacyl-histidine dipeptidase). In conclusion, our data show overall changes in the proteome of B. fragilis conducted by sub-MIC of PTZ, whose consequences on bacterial physiology deserve further investigation.
Assuntos
Antibacterianos/farmacologia , Bacteroides fragilis/química , Bacteroides fragilis/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , ProteômicaRESUMO
Ertapenem and piperacillin/tazobactam are beta-lactam antibiotics with a broad spectrum of activity, used for the treatment of mixed infections, in which Bacteroides fragilis plays an important etiological role. The aim of this study was to select strains of B. fragilis resistant to these drugs and correlate the phenotype profiles of these lineages with changes in the virulence of the original bacterium. B. fragilis ATCC 25285, sensitive to the drugs listed, was used in this study. Strains resistant to these drugs were obtained by multi-step method and this condition was confirmed by comparing the time-kill curve of the original strain with those curves obtained from derived-resistant strains. To assess the virulence, germ-free mice were challenged intragastrically with the original strain or those derived-resistant. The mouse infection by the piperacillin/tazobactam-resistant B. fragilis strain produced increased levels of C-reactive protein, alkaline phosphatase and white blood cells and reduced platelet counts, what may indicate that acquisition of piperacillin/tazobactam resistance may enhance the pathogenic properties of these B. fragilis strains.
Assuntos
Antibacterianos/farmacologia , Infecções por Bacteroides/microbiologia , Bacteroides fragilis/efeitos dos fármacos , Bacteroides fragilis/patogenicidade , Resistência beta-Lactâmica , Animais , Infecções por Bacteroides/metabolismo , Ertapenem , Vida Livre de Germes , Técnicas In Vitro , Camundongos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Fenótipo , Piperacilina/farmacologia , Tazobactam , Virulência/efeitos dos fármacos , beta-Lactamas/farmacologiaRESUMO
The worldwide emergence of antibiotic-resistant bacteria poses a serious threat to human health. In addition to the difficulties in controlling infectious diseases, the phenotype of resistance can generate metabolic changes which, in turn, can interfere with host-pathogen interactions. The aim of the present study was to identify changes in the subproteome of a laboratory-derived piperacillin/tazobactam-resistant strain of Escherichia coli (minimal inhibitory concentration [MIC] = 128 mg/L) as compared with its susceptible wild-type strain E. coli ATCC 25922 (MIC = 2 mg/L) using 2-D fluorescence difference gel electrophoresis (2D-DIGE) followed by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF MS). In the resistant strain, a total of 12 protein species were increased in abundance relative to the wild-type strain, including those related to bacterial virulence, antibiotic resistance and DNA protection during stress. Fourteen proteins were increased in abundance in the wild-type strain compared to the resistant strain, including those involved in glycolysis, protein biosynthesis, pentose-phosphate shunt, amino acid transport, cell division and oxidative stress response. In conclusion, our data show overall changes in the subproteome of the piperacillin/tazobactam-resistant strain, reporting for the first time the potential role of a multidrug efflux pump system in E. coli resistance to piperacillin/tazobactam.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Ácido Penicilânico/análogos & derivados , Piperacilina/farmacologia , Proteômica , Eletroforese em Gel Bidimensional , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Espectrometria de Massas , Dados de Sequência Molecular , Ácido Penicilânico/farmacologia , TazobactamRESUMO
BACKGROUND: The antimicrobial resistance is a global problem, probably due to the indiscriminate and irrational use of antibiotics, prescriptions for incorrect medicines or incorrect determinations of dose, route and/or duration. Another consideration is the uncertainty of patients receiving antibiotics about whether the quality of a generic medicine is equal to, greater than or less than its equivalent brand-name drug. The antibiotics behaviors must be evaluated in vitro and in vivo in order to confirm their suitability for therapeutic use. METHODS: The antimicrobial activities of Meropenem and Piperacillin/Tazobactam were studied by microbiological assays to determine their potencies (content), minimal inhibitory concentrations (MICs), critical concentrations and capacity to produce spontaneous drug-resistant mutants. RESULTS: With respect to potency (content) all the products fulfill USP requirements, so they should all be considered pharmaceutical equivalents. The MIC values of the samples evaluated (trade marks and generics) were the same for each strain tested, indicating that all products behaved similarly. The critical concentration values were very similar for all samples, and the ratios between the critical concentration of the standard and those of each sample were similar to the ratios of their specific antibiotic contents. Overall, therefore, the results showed no significant differences among samples. Finally, the production of spontaneous mutants did not differ significantly among the samples evaluated. CONCLUSIONS: All the samples are pharmaceutical equivalents and the products can be used in antimicrobial therapy.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Infecções por Campylobacter/tratamento farmacológico , Infecções por Campylobacter/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Infusões Intravenosas , Injeções Intravenosas , Meropeném , Camundongos , Camundongos Endogâmicos BALB C , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Ácido Penicilânico/uso terapêutico , Piperacilina/farmacologia , Piperacilina/uso terapêutico , Tazobactam , Tienamicinas/farmacologia , Tienamicinas/uso terapêutico , Distribuição Tecidual , Inibidores de beta-LactamasesRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Cefalosporinas/farmacologia , Infecção Hospitalar/prevenção & controle , Feminino , Hospitais Universitários , Humanos , Unidades de Terapia Intensiva , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Estudos Prospectivos , TazobactamRESUMO
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.
Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos/farmacologia , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Cefalosporinas/farmacologia , Infecção Hospitalar/prevenção & controle , Hospitais Universitários , Unidades de Terapia Intensiva , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Pneumonia Associada à Ventilação Mecânica/prevenção & controleRESUMO
Ertapenem and piperacillin/tazobactam are beta-lactam antibiotics with a broad spectrum of activity used for the treatment of mixed infections in which Bacteroides fragilis and Escherichia coli play an important aetiological role. In this study, the activities of piperacillin/tazobactam and ertapenem (MIC and time-kill kinetics) against these bacteria were compared. MICs were determined by the agar dilution method, and the time and slope of time-kill curves were analysed. In the in vitro pharmacodynamic assays, pure and mixed cultures of E. coli and B. fragilis were exposed to peak concentrations of ertapenem (8.0 microg ml(-1)) and piperacillin/tazobactam (64.0/8.0 microg ml(-1)) for 48 h. Treatment with ertapenem reduced the viability of E. coli and/or B. fragilis by 3 logs in all experiments, whereas piperacillin/tazobactam only affected the viability of B. fragilis. Both drugs exhibited their fastest rates of killing when bacteria were grown in mixed cultures. According to the results, ertapenem exhibited activity similar to that of piperacillin/tazobactam against B. fragilis alone or in mixed culture. However, ertapenem exhibited a markedly higher activity against E. coli alone or in combination with B. fragilis relative to piperacillin/tazobactam.
Assuntos
Antibacterianos/farmacologia , Bacteroides fragilis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , beta-Lactamas/farmacologia , Contagem de Colônia Microbiana , Ertapenem , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Fatores de TempoRESUMO
The in vitro activity of piperacillin-tazobactam and several antibacterial drugs commonly used in Argentinean hospitals for the treatment of severe infections was determined against selected but consecutively isolated strains from clinical specimens recovered from hospitalized patients at 17 different hospitals from 9 Argentinean cities from different geographic areas during the period November 2001-March 2002. Out of 418 Enterobacteriaceae included in the Study 84% were susceptible to piperacillin-tazobactam. ESBLs putative producers were isolated at an extremely high rate since among those isolates obtained from patients with hospital acquired infections 56% of Klebsiella pneumoniae, 32% of Proteus mirabilis and 25% Escherichia coli were phenotypically considered as ESBLs producers Notably P.mirabilis is not considered by for screening for ESBL producers. ESBLs producers were 100% susceptible to imipenem and 70% were susceptible to piperacillin-tazobactam whereas more than 50% were resistant to levofloxacin. The isolates considered as amp C beta lactamase putative producers showed 99% susceptibility to carbapenems while 26.7% were resistant to piperacillin-tazobactam and 38.4% to levofloxacin. Noteworthy only 4% of the Enterobacteriaceae isolates were resistant to amikacin. Piperacillin-tazobactam was the most active agent against Pseudomonas aeruginosa isolates (MIC(90): 128 microg/ml; 78% susceptibility) but showed poor activity against Acinetobacter spp (MIC(90):>256 microg/ml; 21.7% susceptibility). Only 41.7% Acinetobacter spp isolates were susceptible to ampicillin-sulbactam. Piperacillin-tazobactam inhibited 100% of Haemophilus influenzae isolates (MIC(90) < 0.25 microg/ml) but only 16.6% of them were ampicillin resistant. The activity of piperacillin-tazobactam against oxacillin susceptible Staphylococcus aureus or coagulase negative staphylococci was excellent (MIC(90) 2 microg/ml; 100% susceptibility). Out of 150 enterococci 12 isolates (8%) were identified as E.faecium and only three isolates (2%), 2 E.faecium and 1 E.faecalis were vancomycin resistant. All the enterococci isolates were susceptible to linezolid. Piperacillin-tazobactam showed excellent activity (MIC(90) 2 microg/ml; 92% susceptibility). Regarding pneumococci all the isolates showed MICs of 16 microg/ml for piperacillin-tazobactam. Among 34 viridans group streptococci only 67% were penicillin susceptible and 85.2% ceftriaxone susceptible whereas piperacillin-tazobactam was very active (MIC(90) 4 microg/ml).Piperacillin-tazobactam is therefore a very interesting antibacterial drug to be used, preferably in combination (IE: amikacin-vancomycin) for the empiric treatment of severe infections occurring in hospitalized patients in Argentina. Caution must be taken for infections due to ESBL producers considering that the inoculum effect MICs can affect MIC values.
Assuntos
Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Adulto , Antibacterianos/farmacologia , Argentina , Resistência Microbiana a Medicamentos , Feminino , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Hospitalização , Humanos , Masculino , Testes de Sensibilidade Microbiana , Sensibilidade e Especificidade , TazobactamRESUMO
Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase producing bacteria. Thus, piperacillin/tazobactam is highly active against most clinically important species of Gram-negative and Gram-positive bacteria, including anaerobes. We evaluated the in vitro activity of piperacillin/tazobactam against clinical isolates from a tertiary university hospital located in Sao Paulo, Brazil. Its activity was compared to that of ticarcillin/clavulanic acid, ampicillin/sulbactam, ceftazidime, ceftriaxone, cefotaxime, cefoxitin, aztreonam, and imipenem against 820 isolates (608 Gram-negative and 212 Gram-positive) collected from hospitalized patients in 1999. The most frequent species tested were Pseudomonas aeruginosa (168/20%), Escherichia coli (139/17%), Acinetobacter spp. (131/16%), and Staphylococcus aureus (76/9%). Of the isolates studied, 30% were from the bloodstream, 16% from the lower respiratory tract, and 11% from surgical wounds or soft tissue. The isolates were susceptibility tested by the broth microdilution method according to NCCLS procedures. The isolates tested were highly resistant to most antimicrobial agents evaluated. Imipenem resistance was not verified among Enterobacteriaceae, and piperacillin/tazobactam was the second most active beta-lactams against this group of bacteria (80.0% susceptibility). Extended-spectrum beta-lactamase production was very high among E. coli (approximately 20%) and Klebsiella pneumoniae (approximately 40%). Imipenem was uniformly active against these species (100% susceptibility) and piperacillin/tazobactam was the second most active compound inhibiting 84.4% of isolates. Pseudomonas aeruginosa was highly resistant to all beta-lactams evaluated and piperacillin/tazobactam was the most active compound against this species. Our results demonstrate an extremely high level of antimicrobial resistance in the hospital evaluated, especially among non-enteric Gram-negative bacilli. Due to this high level of resistance, piperacillin/tazobactam represents an important contribution to the treatment of nosocomial infections.
Assuntos
Bactérias/efeitos dos fármacos , Infecção Hospitalar/microbiologia , Quimioterapia Combinada/farmacologia , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , beta-Lactamas/farmacologia , Bactérias/isolamento & purificação , Infecções Bacterianas/microbiologia , Brasil , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Hospitais Universitários , Humanos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Combinação Piperacilina e TazobactamRESUMO
Recently, two new combinations of Beta-lactam antibiotics with Beta-lactamase inhibitors became commercially available in Brazil: piperacillin/tazobactam and ampicillin/sulbactam. This study was designed to assess and compare the in-vitro activity of these new compounds, as well as that of ticarcillin/clavulanic acid, against bacteria isolated in our environment. A total of 749 bacteria isolated at São Paulo Hospital were tested using the disk diffusion method, in compliance with NCCLS standardization, using strict quality control. Only one sample per patient was included in the study. Oxacillin-resistant staphylococcus samples were not included in this study. Of the total samples tested, 84.5% were susceptible to piperacillin/tazobactam, 81.2% to ticarcillin/clavulanic acid, and 77.6% to ampicillin/sulbactam. Piperacillin/tazobactam was also found to be the most active combination of the three against Enterobacteriaceae ( n = 312), inhibiting 91.7% of the bacteria tested. Ticarcillin/clavulanic acid was active against 85.8% of the Enterobacteriaceae, while ampicillin/sulbactam inhibited 83.2% of the samples. This order of the spectrum of action (piperacillin/tazobactam > ticarcillin/clavulanic acid >ampicillin/sulbactam )was maintained for the majority of Enterobacteriaceae species analyzed. Pseudomonas aeruginosa ( n = 117) showed extremely high resistance to the three combinations. Piperacillin/tazobactam was active against 61.5% of the samples, while ticarcillin/clavulanic acid was active against 56.4% of the samples of this species. The activity of ampicillin/sulbactam against P. aeruginosa was extremely low; however, this was the most active combination against Acinetobacter baumannii ( 87.0% susceptibility). Piperacillin/tazobactam was the most active combination against Stenotrophomonas (Xanthomonas )maltophilia (100% susceptibility) and Burkholderia cepacia (90.9% susceptibility). The three combinations showed excellent activity against the Gram-positive cocci tested (97.3% to 98.2% susceptibility). In sum, piperacillin/tazobactam was more active against all Gram-negative species than the other two combinations, with the exception of A. baumannii, and showed similar activity against Gram-positive cocci.
Assuntos
Antibacterianos/farmacologia , Quimioterapia Combinada/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores de beta-Lactamases , Ampicilina/farmacologia , Ácido Clavulânico/farmacologia , Infecção Hospitalar/prevenção & controle , Humanos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Sulbactam/farmacologia , Tazobactam , Ticarcilina/farmacologia , Resistência beta-LactâmicaRESUMO
PURPOSE: The aim of the study was to investigate the in vitro antiinfective effect of piperacillin-tazobactam (PIP-TZB) combinations on Escherichia coli in simulations of free concentration time profiles of both drugs, similar to those obtained in human tissue after i.v. bolus administrations. METHODS: An in vitro dilution model was used to expose E. coli ATCC 35218 (beta-lactamase producer) to various piperacillin-tazobactam concentration profiles obtained after i.v. bolus multiple dose, using different dose ratio combinations (1:4, 1:8, 1:16) and dosing regimens, ranging from once-a-day to 4 times a day. The antimicrobial effect was evaluated by determination of the number of bacteria over time. The concentration of PIP in the model was determined by HPLC. RESULTS: A modified Emax model was used to describe the pharmacodynamic effect. The model was linked with the piperacillin concentrations determined experimentally to provide a pharmacokinetic-pharmacodynamic (PK-PD) model. The EC50 for piperacillin alone averaged 5.66 +/- 0.29 micrograms/ml. The EC50 for all doses of piperacillin combined with 0.5 g of tazobactam were dose-dependent and averaged 1.70 +/- 0.56, 3.95 +/- 1.02, and 6.14 +/- 1.24 micrograms/ml for PIP 2, 4, and 8 g, respectively. By increasing the dose of TZB in combination with a fixed dose of PIP, a decreased EC50 was observed. CONCLUSIONS: The PK-PD model allowed a detailed evaluation of the dosing regimens investigated. The results suggested that for these combinations, 3 times a day administration is as effective as 4 times a day. Pharmacodynamic activity of the combinations can be prolonged by sufficiently high inhibitor concentrations.
Assuntos
Ácido Penicilânico/análogos & derivados , Penicilinas/farmacocinética , Piperacilina/farmacologia , Piperacilina/farmacocinética , Ensaio de Unidades Formadoras de Colônias , Simulação por Computador , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Humanos , Modelos Biológicos , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Penicilinas/farmacologia , Tazobactam , Inibidores de beta-LactamasesRESUMO
The benzyl 6-fluoro-penicillanate sulfides 4a, 6a, 7a; and sulfones 6c, 7d were synthesized. The conversion to their free acids 4b, 6b, 6d, 7b, 7e and potassium salts 7c, 7f are described. These acids and salt 7c were evaluated as beta-lactamase inhibitors using beta-lactamase I from Bacillus cereus. The data indicate that substitution of the 6 alpha-hydrogen by a 6 alpha-fluorine atom on 6 beta-bromopenicillanic acid (1), leads to loss of beta-lactamase inhibitory activity. In the case of the isomers 6 beta- and 6 alpha-fluoropenicillanic acids the 6 beta-enantiomer proved to be considerably more potent. Potassium salts of 6 beta-fluoropenicillanate sulfide and sulfone were unstable in solid state and in water solution. The fragmentation of the sulfone in two parts in water solution is consistent with the hydrolytic behavior to the penicillanic acid sulfone (2) with 0.5 N NaOH.