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.

Evaluation in an animal model and in vitro of the combination clavulanic acid and cephalosporins against ß-lactamase producing and nonproducing staphylococcus aureus strains

ß-lactamase enzymes are the most common case of bacterial reistance to ß-lactam antibiotics. They hydrolyse the amide bound in the ß-lactam ring and produce acidic derivatives that have no antibacterial properties. The aim of this study was to evaluate a combination of clavulanic acid with cephalosporins against ß-lactamase-producing and nonproducing stains of Staphylococcus aureus using in vitro tests and a rat animal model. In vitro test (MIC) of the drug combination were done using standard methods. In an animal model, rats were submitted to surgical implantation of polyurethane sponges in their backs to induce granulomatous tissue. After seven days, the animals received cephalexin, cephalexin with clavulanic acid, ceftriaxone, ceftriaxone with clavulanic acid or clavulanic acid alone. One hour after the drug administration, granulomatous tissue was removed and placed in Petri dishes previously inoculated with 10 eight cfu of producing or non-producing ß-lactamase Staphylococcus aureus. After 24h at 37§C, the inhibition zones formad by granulomatous tissue was measured and scored for statistical analysis. Both tests (ex vivo {animal model} and in vitro) showed that the cephalexin was more active than ceftriaxone against non-producing ß-lactamase. S. aureus (p<0.01). Against ß-lactamase producing S. aureus, ceftriaxone was more active than cephalexin, which was inactive. Combinations of clavulanic acid with cephalexin or ceftriaxone had similar antimicrobial activity against non-producing ß-lactamase S. aureus compared to the cephalosporins used alone. When tested using ß-lactamase produzing strains, the combination of clavulanic acid with cephalosporins showed synergism. We conclude that the combination of cephalosporins with clavulanic acid could be useful in staphylococcal infections cauded by ß-lactamase producing strains.

Ceftriaxona: farmacocinética e farmacodinâmica; aplicações no tratamento da otite média aguda na criança / Ceftriaxone: pharmacokinetic and pharmacodinamic: aplications in the treatment of acute otitis media in child

Objetivos: A frequência das otites médias agudas na criança (OMA) e os riscos de fracassos terapêuticos relacionados com a resistência das bactérias responsáveis aos ß-lactamatos, principalmente o S. pneumoniae, determinaram a pesquisa de tratamentos alternativos. A escolha de uma antibioticoterapia adequada repousa na atividade antimicrobiana, bem como nas características farmacocinéticas gerais e locais do antibiótico de escolha; neste estudo säo analisadas as propriedades da ceftriaxona. Farmacocinética: Deve-se ter em mente a cinética plasmática, muito especial, desta cefalosporina de 3ª geraçäo: meia-vida muito prolongada, fixaçäo às proteínas plasmáticas de forma dose-dependente, liberando o antibiótico de forma progressiva e subsequente distribuiçäo extravascular importante. Cinética da ceftriaxona no ouvido médio: Desde o modelo experimental no gerbo(*) até o estudo em Pediatria e no adulto, encontram-se na criança as mesmas características de difusäo no ouvido médio: concentraçöes elevadas (até 35mg/l) e persistentes (19mg/l até a 48ª hora). Interpretaçäo destes dados em termos de farmacodinâmica: Ela é fundamentada em dois parâmetros principais: o tempo acima da CIM(T>CIM), que é, em todos os casos, >24 horas e, portanto, de 100 porcento entre duas doses; os quocientes inibidores (QI) que säo estabelecidos, mesmo para as taxas tardias em 24h na criança, em QI=35 ou QI=8,75, conforme a CIM90 da ceftriaxona como sendo de 1mg/l para os pneumococos. Conclusäo: Entre os ß-lactamatos, a ceftriaxona ocupa um lugar privilegiado, poeque oferece um tempo de 100 porcento acima da CIM para os agentes bacterianos da OMA. Estes dados conferem a esta molécula aplicaçäo terapêutica no tratamento da OMA, uma indicaçäo atualmente aprovada