Ampicillin for the treatment of complicated urinary tract infections caused by vancomycin–resistant Enterococcus spp (VRE): a single-center university hospital experience

Highlights

• Analysis of ampicillin for treatment of vancomycin-resistant Enterococcus spp (VRE) urinary tract infections.

• Largest data set that evaluates this in-vitro strategy in a clinical setting.

• Exploratory analyses to evaluate cure rates in patients with variables that may impact clinical outcomes are reported.

Abstract

Vancomycin-resistant enterococci (VRE) are a common cause of urinary tract infections (UTIs) and are typically multidrug resistant, including ampicillin. This retrospective study evaluated outcomes of 84 adult patients hospitalized between January 2007 and December 2015 with ampicillin– and vancomycin–resistant enterococcus isolates causing UTI and treated with ampicillin. Treatment response was classified as clinical cure and microbiological eradication. Clinical cure was achieved in 88.1% (74/84) of patients. In patients with follow–up cultures, microbiological eradication was achieved in 86% (50/58) of patients. Cure rates were similar in patients with indwelling urinary catheters (n = 45) receiving catheter exchange/removal (90.47%; 19/21) versus catheter retention (87.5%; 21/24). Presence of co–morbidities, such as diabetes and chronic kidney disease, were not associated with increased risk of treatment failure. Immunocompromised patients achieved lower cure rates of 78.1% (25/32) compared with 94.2% (49/52) among those without immune impairment (P = 0.038). Presence of an underlying urinary tract abnormality was also associated with a lower cure rate of 71.4% (15/21) compared with 93.7% (59/63) in those without urinary tract abnormalities (P = 0.0135). Overall cure rates remained high in all groups providing good evidence to support ampicillin for the treatment of complicated UTI caused by ampicillin– and vancomycin–resistant enterococci.

Introduction

Enterococci are a common cause of urinary tract infections (UTIs), particularly among hospitalized patients. In the United States, the volume and incidence of hospitalization with vancomycin-resistant Enterococcus spp (VRE) infection has doubled during the period from 2000 to 2006 [1]. Furthermore, 2011–2014 data reported from the National Healthcare Safety Network identified enterococci as the third most common cause of catheter–associated urinary tract infections (CAUTI), among which 86% of E. faecium isolates and 7.4% of E. faecalis isolates were vancomycin resistant [2].

VRE, particularly E. faecium strains, are typically multidrug resistant, including resistant to ampicillin. Due to this susceptibility profile, linezolid, daptomycin, nitrofurantoin, and fosfomycin have emerged as plausible treatment options [3], [4], [5], [6]. Although these strategies have proven successful, their use may be limited because of concerns for development of resistance, increased monitoring, need for intravenous access, ill-defined dosing strategies, and cost. An option that may mitigate some of these concerns is ampicillin. Despite the presence of ampicillin resistance, clinicians may solve this problem through a pharmacodynamic approach. First, renal tubular secretion of ampicillin gives rise to urinary concentrations many fold higher than concentrations attained in serum [7]. Eickhoff et al evaluated urinary excretion of ampicillin following parenteral administration. Single 1-gram doses of intramuscular ampicillin produced urine concentrations in the range 1500–3300 mcg/mL [8]. Second, comparing minimum inhibitory concentrations (MIC) reported in the literature for E. faecium strains exhibiting high-level β-lactam resistance (i.e. ampicillin MIC > 64 and up to 512 mcg/mL) [9] to achievable urine concentrations, these data indicate an opportunity to optimize antibiotic exposure by achieving the desired pharmacodynamic variable (i.e. time above the MIC) associated with clinical success. Lastly, in the absence of urine–specific breakpoints for relevant antimicrobials against enterococci according to the Clinical and Laboratory Standards Institute guidelines [10], approaching this problem from a pharmacodynamic perspective is rational.

Although prescribing ampicillin for the treatment of UTIs caused by VRE has been common practice at our facility, there remains a paucity of published literature for this in-vitro concept in the clinical setting. Additionally, despite low levels of resistance amongst enterococcus isolates [11], [12], [13], several reports have highlighted selection for linezolid and daptomycin resistance within select populations [14], [15]; therefore, overuse may threaten their utility. Given the need to preserve the antimicrobial activity of the newer Gram-positive antimicrobial agents, we were interested in evaluating outcomes in patients with vancomycin– and ampicillin–resistant enterococcal UTI treated with ampicillin.