The incidence of vancomycin-resistant enterococci has nearly doubled in recent years.
Urinary tract infections (UTIs) are the most common type of infection in the world.1 One of the most common causative pathogens for uncomplicated, lower urinary tract infections is enterococcus species.
The Infectious Diseases Society of America currently recommends amoxicillin and ampicillin, aminopenicillin (AP) antibiotics, as drugs of choice for treating enterococcus UTIs.2 Prevalence of ampicillin-resistant enterococcus has been increasing.
In particular, the incidence of vancomycin-resistant enterococci (VRE) has nearly doubled in recent years, with 30% of clinical enterococcal isolates being reported as resistant to vancomycin.3 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 this same breakpoint regardless of the site of infection. Pharmacokinetic, pharmacodynamics, and clinical trial data support the use of aminopenicillin antibiotics in the treatment of enterococcus UTIs, even when the isolates have a MIC that exceeds the susceptibility breakpoint.4,5
Because AP antibiotics are cleared through the kidneys, we can achieve much higher concentrations in the urine than in the blood stream. One study was able to demonstrate an average urine concentration of 1100 μg/mL collected over 6 hours after just a single dose of oral amoxicillin 500 mg.
Another study analyzed ampicillin-resistant enterococcus faecium (E. Faecium) urine isolates with reported MICs of 128 μg/mL (30%), 256 μg/mL (60%), and 512 μg/mL (10%).4 Using data from these trials, it is reasonable to say that AP concentrations reach sufficient concentrations in the urinary tract to treat many reported resistant infections.
In another study, it was found that ampicillin-resistant E. faecium urine isolates had varying MICs, with a median MIC of 256 μg/mL5. Only 5 isolates had a MIC value >1000 μg/mL, but each of these isolates was within 1 dilution of 512 μg/mL.
Penicillin antibiotics display time-dependent killing and an optimal response will occur as long as the urine concentration is above the MIC for at least 50% of the dosing interval.5 Therefore, we can reasonably conclude that therapeutic doses of AP antibiotics will not only effectively treat Enterococcus species, but also ampicillin-resistant enterococcus isolated in lower UTIs, as long as reasonably dosed.
Educating prescribers is one way that we can decrease the amount of broad-spectrum antibiotics used to treat these infections, such as linezolid and daptomycin. Another way is to develop a protocol at individual institutions to help guide prescribers toward guideline-directed prescribing.
One of the best ways to combat this problem starts in the microbiology lab. Urine-specific breakpoints would give us more reliable susceptibility data; however, this is not widely available at this time.
Many hospitals discontinued their routine susceptibility testing for enterococcus urinary isolates and report all as routinely susceptible to aminopenicillins.6 One study evaluated the treatment outcomes between patients treated for a VRE UTI with an AP antibiotic compared to those treated with a non-beta-lactam antibiotic.
In this study, AP therapy was considered active in all cases, regardless of the ampicillin susceptibility. Within the AP group, the most common agent selected for definitive therapy was amoxicillin followed by intravenous ampicillin, ampicillin-sulbactam, and amoxicillin-clavulanate.
In the non-beta-lactam group, the most common agent selected for definitive therapy was linezolid, followed by daptomycin and fosfomycin. The rate of clinical cure was 83.9% patients in the AP group and 73.3% in the non-beta-lactam group.
Clinical cure with AP therapy was observed in 84% of all cases and in 86% of patients with ampicillin-resistant isolates, with no statistical difference detected between results for those treated with non-β-lactams.
Take Home Points
Based on pharmacokinetic data from numerous clinical trials, it can be reasonably concluded that aminopenicillin antibiotics, such as amoxicillin and ampicillin, achieve sufficient urinary concentrations to eradicate E. species, regardless of ampicillin susceptibility. Educating pharmacists and physicians on PK/PD data, antibiotic sensitivities, and clearance are vital steps.
Discussion with microbiology lab can lead to improved reporting and/or possible lab comments to cut down on unnecessary broad and expensive antibiotics. Institutions should consider implementing ways to encourage appropriate prescribing for treatment of these common hospital infections.
This will combat unnecessary broad-spectrum antibiotic prescribing practices and improve antibiotic stewardship, cut down on microbiology lab costs and cost to patients, and improve outcomes in these relatively common infections.
1. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon. 2003 Feb;49(2):53-70. doi: 10.1067/mda.2003.7. PMID: 12601337.
2. Clinical Infectious Diseases, Volume 52, Issue 5, 1 March 2011, Pages e103–e120, https://doi.org/10.1093/cid/ciq257. Published:01 March 2011
3. Ramsey AM, Zilberberg MD. 2009. Secular trends of hospitalization with vancomycin-resistant enterococcus infection in the United States, 2000–2006. Infect Control Hosp Epidemiol 30:184–186.
4. Cole KA, Kenney RM, Perri MB, Dumkow LE, Samuel LP, Zervos MJ, Davis SL. Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections. Antimicrob Agents Chemother. 2015 Dec;59(12):7362-6. doi: 10.1128/AAC.01817-15. Epub 2015 Sep 14. PMID: 26369973; PMCID: PMC4649236. Williamson JC, Craft DW, Butts JD, Raasch RH. In vitro assessment of urinary isolates of ampicillin-resistant enterococci. Ann Pharmacother. 2002;36(2):246–250.
5. Dumkow LE, Perri MB, Zervos M. Time to stop using alternatives to ampicillin for enterococcal UTIs? In-vitro susceptibility trends for enterococcus urinary isolates over a one-year period in Detroit. Poster presented at: 53rd Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC); September 10–13, 2013; Denver, CO.
6. Cole, Kelli, et al. “Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections.” American Society for Microbiology Journals, 17 Nov. 2015.