Urinary Concentrations and Bactericidal Activity Against Amoxicillin-Nonsusceptible Strains of Escherichia coli with Single-Dose, Oral, Sustained-Release Amoxicillin/Clavulanic Acid: A PhaseI, Open-Label, Noncomparative Clinical Trial in Healthy Volunteers

Abstract

Urinary tract infections (UTIs) account for 5 to 6 million medical consultations in the United States each year. Worldwide, an estimated 20% to 30% of women aged 20 to 40 years have at least 1 episode of the most common type of UTI (uncomplicated cystitis) in their lifetime, with Escherichia coli being the causative pathogen in 80% of cases. Antibacterial activity in urine has been shown to be correlated with outcomes of uncomplicated cystitis. The objectives of this study were to determine urinary concentrations and ex vivo bactericidal activity of sustained-release (SR) amoxicillin/clavulanic acid 2000/125 mg against intermediately resistant and resistant strains of E coli over 72 hours and compare them with those of a susceptible strain. This study also investigated whether urinary concentrations obtained after dosing cover E coli strains categorized as intermediately resistant and resistant based on current Clinical and Laboratory Standards Institute (formerly NCCLS) breakpoints in uncomplicated cystitis. This Phase I, open-label, noncomparative study in healthy male volunteers was conducted at the Pharmacology Unit, Autónoma University, Madrid, Spain. Subjects received a single oral dose of amoxicillin/clavulanic acid 2000/125 mg SR. The amoxicillin/clavulanic acid MICs were 8/4 microg/mL (susceptible), 16/8 microg/mL (intermediately resistant), and 32/16 and 64/32 microg/mL (resistant). Urine samples were collected before (baseline; time 0) and at the following intervals: 0-2, 2-4, 4-8, 8-12, 12-16, 16-24, 24-36, 36-48, 48-60, and 60-72 hours after dosing. Killing curves with urine samples were performed with initial inocula of approximately 10(7) colony-forming units (CFU)/mL, and bactericidal activity (defined as >3 log(10) CFU/mL and >99.9% reduction in bacterial counts) was calculated as the difference between log(10) initial inoculum and log(10) CFU/mL after 4 hours of incubation of each sample. Twelve volunteers were included (mean [SD] age, 24.83 [5.64] years; mean [SD] height, 175.75 [7.56] cm; and mean [SD] weight, 73.55 [9.19] kg). No statistically significant differences between the activities in the 12-16-hour interval compared with baseline were found in any of the strains tested. Bactericidal activity against the susceptible and intermediately resistant strains (MICs 8/4 and 16/8 g/mL, respectively) was obtained up to 8 hours after dosing. Bactericidal activity against the resistant strains (MICs 32/16 and 64/32 microg/mL) was obtained in the 2-4-hour interval. In this Phase I study in healthy volunteers, urinary concentrations after dosing with amoxicillin/clavulanic acid 2000/125 mg SR showed bactericidal activity against the amoxicillin-susceptible and intermediately resistant strains of E coli.