Original Research
Urologist Workforce Variation Across the VHA
Distribution of urologists varies significantly at the facility rather than at the regional level, according to a large-scale study, but regional...
Enterococcus species account for about 110,000 urinary tract infections (UTIs) annually in the U.S.1 The most common species isolated are Enterococcus faecalis and Enterococcus faecium (E faecium). Amoxicillin is the drug of choice for the treatment of enterococcal UTIs. Second-line therapies include vancomycin and nitrofurantoin. Alternative therapies include daptomycin and linezolid; however, these newer agents ideally would be reserved for more serious infections to preserve activity.2
Increased E faecium resistance to ampicillin and vancomycin has limited the therapeutic options. The results of a study by Zhanel and colleagues assessed the prevalence of resistant enterococcal urine isolates in North America.3 Of the 658 E faecium urine isolates, about 96% were resistant to ampicillin and 94% were resistant to vancoymcin.3 Nitrofurantoin has much lower resistance rates; however, its use is contraindicated in patients with a creatinine clearance (CrCl) < 60 mL/min.4 Data supporting the contraindication are limited, but the results of a study by Oplinger and Andrews suggested that using nitrofurantoin in patients with a CrCl ≥ 40 mL/min may be safe and effective.5 A therapeutic dilemma may occur when resistant E faecium UTIs are encountered and viable treatment options are limited due to intolerances, administration difficulties, lack of susceptibility data, or cost.
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Based on the current Clinical and Laboratory Standards Institute standard, Enterococcus species with a minimal inhibitory concentration (MIC) ≥ 16 μg/mL are considered ampicillin resistant. Microbiology laboratories use the same breakpoint regardless of the site of infection.6 Amoxicillin concentrates in the urine; therefore, urinary concentrations are much higher than serum concentrations. The mean serum peak concentration after a single dose of oral amoxicillin 500 mg is 7.6 μg/mL.7 After a single dose of oral amoxicillin 500 mg, the average concentration in pooled urine collected over 6 hours was 1,100 μg/mL.8
In 2002, Williamson and colleagues analyzed 30 ampicillin- resistant E faecium urine isolates. Reported MICs were 128 μg/mL (30%), 256 μg/mL (60%), and 512 μg/mL (10%).9 A more recent retrospective analysis analyzed 234 ampicillin-resistant E faecium urine isolates. The MIC ranged from 32 to 1,024 μg/mL, with a median MIC of 256 μg/mL. Only 5 isolates had an MIC value > 1,000 μg/mL, but each of these isolates was within 1 dilution of 512 μg/mL.10 Because penicillins exhibit time-dependent killing, an optimal response will occur as long as the urine concentration is above the MIC for at least 50% of the dosing interval.11 Therefore, therapeutic doses of amoxicillin are expected to produce urine concentrations that exceed the MIC of resistant E faecium urine isolates. The purpose of this study was to determine if amoxicillin was a viable treatment option for ampicillin-resistant E faecium UTIs based on this in vitro theory.
Methods
Veterans aged ≥ 18 years with a positive urine culture for ampicillin- resistant E faecium who received antibiotic therapy for cystitis at the Jesse Brown VA Medical Center (JBVAMC) from January 1, 2005, through June 22, 2010, were evaluated in this retrospective cohort study. Exclusion criteria were the presence of any other organisms in the initial urine culture, prostatic involvement, and the presence of E faecium in a blood culture. Subjects treated with multiple antibiotics concurrently and with sequential treatment of different antibiotics with no evaluation of efficacy between courses were also excluded.
Related: Urologist Workforce Variation Across the VHA
All included subjects were evaluated for resolution of symptoms; improvement in leukocyte esterase count and white blood cell (WBC) count from urine analysis (UA); and eradication of E faecium from a repeat urine culture. The response to treatment was classified as cure, presumed cure, or failure. The criteria for cure were based on the following: resolution of symptoms if present at baseline; repeat UA indicating improvement from the initial positive UA (if obtained); and eradication of E faecium in a repeat urine culture (if obtained).
At least 1 of the aforementioned criteria must have been met to be classified as cure. If more than 1 of the aforementioned criteria was present, then each one must have been met to be classified as cure. To be evaluated for presumed cure, the subject must have had symptoms at baseline. No documentation of ongoing symptoms in subjects who had an appropriate follow-up but did not have a repeat UA or urine culture indicated presumed cure. Persistence or worsening of pretreatment symptoms, a repeat UA without improvement from the initial positive UA, or a repeat urine culture demonstrating continued presence of E faecium indicated failure. The primary endpoint for the study was to determine whether amoxicillin was effective for the management of ampicillin-resistant E faecium UTIs. This study was conducted in compliance with the University of Illinois at Chicago Institutional Review Board and JBVAMC Human Subjects Research Committee requirements.