Pharmacodynamic evaluation of fosfomycin against Enterobacteriaceae from urinary tract infections and the influence of pH on fosfomycin activity

Abstract

RESUMO: A fosfomicina e amplamente utilizada no tratamento de infeccao do trato urinario (ITU) e recentemente tem sido recomendada ate mesmo para o tratamento bacilos Gram-negativos multirresistentes (MDR). Os regimes posologicos de fosfomicina em organismos MDR e a influencia do pH urinario nao estao estabelecidos. Assim, o estudo avaliou a farmacodinamica da fosfomicina contra enterobacterias urinarias e a otimizacao do pH do ambiente para proporcionar um melhor alcance do resultado terapeutico. Um total de 314 isolados consecutivos nao-duplicados (158 Escherichia coli, 87 Klebsiella spp., 30 Enterobacter cloacae, 23 Proteus mirabilis, 11 Citrobacter spp., 3 Morganella morganii e 2 Serratia marcescens) identificados atraves do sistema automatizado BD Phoenix. entre janeiro 2011 e junho de 2015 foram incluidos no estudo. A concentracao minima inibitoria (CIM) foi determinada atraves do metodo de agar diluicao em pH 7.0 e 6.0 conforme recomendado pelo Clinical and Laboratory Standards Institute (CLSI) 2016. O CIM50 e CIM90 foram determinadas para os regimes de dosagem de fosfomicina (4 g cada 8h [q8h], 6 g q6h, 8 g q8h) em bolus (0,5-h) e infusao prolongada (4-h) utilizando a simulacao de Monte Carlo para avaliar a porcentagem tempo que a concentracao de farmaco livre permance acima da CIM durante o intervalo de dosagem (fT>CIM). A fosfomicina foi eficaz contra E. coli (CIM90 . 16ƒÊg/mL) e tambem Citrobacter spp. e P. mirabilis (> 82% dos isolados), mas nao contra Klebsiella spp. e E. cloacae (<27% dos isolados). A acidificacao do pH do ambiente aumentou a sensibilidade bacteriana para 65% dos isolados e favoreceu uma diminuicao estatisticamente significativa na sobrevivencia dos isolados de E. coli e Klebsiella spp.. Os regimes de fosfomicina de 6g q6h e 8g q8h em ambas as infusoes de 0,5 h e 4 h contra CIM 32ƒÊg/mL foram capazes de alcancar .90% de uma probabilidadede de atingir o alvo (PTA) de 70% fT>CIM. Nenhuma dosagem conseguiu PTA adequada contra a CIM . 64ƒÊg/mL. As analises PK/PD de fosfomicina mostraram que a diminuicao do pH melhora a PTA e o alcance do indice PD na maioria dos isolados de Enterobacteriaceae, exceto para especies de Klebsiella e E. cloacae, deste modo o uso da fosfomicina associado a acidificacao da urina pode tornar mais eficiente o tratamento de ITU

ABSTRACT: Fosfomycin is widely used to treat urinary tract infection (UTI) and recently have been recommended even for treating multidrug-resistant (MDR) Gram-negative bacilli. Fosfomycin dosing regimens in challenging MDR organisms and the influence of urinary pH have not been established. Thus the study assessed the pharmacodynamics of fosfomycin against urinary enterobacteria and pH environment optimization to provide better achievement of therapeutic outcome. A total of 314 consecutive nonduplicate isolates (158 Escherichia coli, 87 Klebsiella spp., 30 Enterobacter cloacae, 23 Proteus mirabilis, 11 Citrobacter spp., 3 Morganella morganii e 2 Serratia marcescens) identified by means of the BD PhoenixTM automated microbiology system between January 2011 and June 2015 were included in the study. Minimal inhibitory concentration (MIC) was determined using agar dilution in pH 7.0 and 6.0 as recommended by the Clinical and Laboratory Standards Institute (CLSI) 2016. The MIC50 and MIC90 were challenged against short (0.5-h) and prolonged (4-h) infusion regimens of fosfomycin (4 g every 8h [q8h], 6 g q6h, 8 g q8h) using Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT>MIC). Fosfomycin was effective against E. coli (MIC90 ? 16?g/mL) and also Citrobacter spp. and P. mirabilis isolates (>82% of isolates) but not against Klebsiella spp. and E. cloacae (<27% of isolates). Acidification of pH environment increased bacterial susceptibility to 65% of isolates and favored a statistically significant decrease in the survival of E. coli and Klebsiella spp. isolates. Fosfomycin regimens of 6g q6h and 8g q8h as both 0.5-h and 4-h infusion against MIC 32?g/mL were able to achieving ?90% probability of target attainment (PTA) of 70% fT>MIC. No dosage achieved adequate PTA against the MIC ? 64?g/mL. PK/PD analyses of fosfomycin showed that decreased pH improves PTA of the target PD index in majority of Enterobacteriaceae isolates, except Klebsiella species and E. cloacae, thus the use of fosfomycin associated with urine acidification can make the UTI treatment more efficient