Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI), and it has recently been recommended that fosfomycin be used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimens has not been analyzed. The MIC of fosfomycin for 245 Gramnegative bacterial isolates, consisting of 158 Escherichia coli isolates and 87 Klebsiella isolates which were collected from patients with urinary tract infections, were determined at pH 6.0 and 7.0 using the agar dilution method. Monte Carlo simulation of the urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3,000 mg fosfomycin and the MIC distribution were used to determine the probability of target attainment (PTA). Fosfomycin was effective against E. coli (MIC 90 Յ 16 g/ml) but not against Klebsiella spp. (MIC 90 Ͼ 512 g/ml). Acidification of the environment increased the susceptibility of 71% of the bacterial isolates and resulted in a statistically significant decrease in bacterial survival. The use of a regimen consisting of a single oral dose of fosfomycin against an E. coli isolate with an MIC of Յ64 mg/liter was able to achieve a PTA of Ն90% for a target pharmacodynamic index (AUC/MIC) of 23 in urine; PTA was not achieved when the MIC was higher than 64 mg/liter. The cumulative fractions of the bacterial responses (CFR) were 99% and 55% against E. coli and Klebsiella spp., respectively, based on simulated drug exposure in urine with an acidic pH of 6.0. A decrease of the pH from 7.0 to 6.0 improved the PTA and CFR of the target pharmacodynamic index in both E. coli and Klebsiella isolates.KEYWORDS Enterobacteriaceae, fosfomycin, Monte Carlo simulation, acidic pH, pharmacodynamics, urinary tract infection U rinary tract infections (UTIs) are the most common infections worldwide, and members of the family Enterobacteriaceae are the main pathogens responsible for UTIs (1). The rise in the rate of antibiotic resistance over the last several years has resulted in limited treatment options currently available for the treatment of infections caused by multidrug-resistant (MDR) bacteria. Fosfomycin is an old antibiotic agent frequently used to treat uncomplicated UTIs and has been reevaluated as a potential option for the treatment of infections caused by MDR Gram-negative bacteria (2). The dosage currently approved for the treatment of an uncomplicated UTI is a single

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Significance and Impact of the Study: Acinetobacter baumannii can colonize inpatients and health workers. The ability to survive in hostile environments allows this bacterium to persist in intensive care units, causing serious infections with high mortality. This study describes, for the first time, the aggregated adherence pattern of a majority of A. baumannii isolates to human epithelial cells, which can favour human colonization. The bacterium was also able to adhere to polystyrene in medical devices and escape the host's defence responses. We believe that this information can help to understand certain factors in the virulence of A. baumannii, enabling its control.

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