Abstract
BackgroundFluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis. Elevated drug concentrations of fluoroquinolones in the urine and therapy with high-dose levofloxacin are believed to overcome resistance and effectively treat infections caused by resistant bacteria. The ASPECT-cUTI phase 3 clinical trial (ClinicalTrials.gov, NCT01345929 and NCT01345955, both registered April 28, 2011) provided an opportunity to test this hypothesis by examining the clinical and microbiological outcomes of high-dose levofloxacin treatment by levofloxacin minimum inhibitory concentration.MethodsPatients were randomly assigned 1:1 to ceftolozane/tazobactam (1.5 g intravenous every 8 h) or levofloxacin (750 mg intravenous once daily) for 7 days of therapy. The ASPECT-cUTI study provided data on 370 patients with at least one isolate of Enterobacteriaceae at baseline who were treated with levofloxacin. Outcomes were assessed at the test-of-cure (5–9 days after treatment) and late follow-up (21–42 days after treatment) visits in the microbiologically evaluable population (N = 327).ResultsTest-of-cure clinical cure rates above 90% were observed at minimum inhibitory concentrations ≤4 μg/mL. Microbiological eradication rates were consistently >90% at levofloxacin minimum inhibitory concentrations ≤0.06 μg/mL. Lack of eradication of causative pathogens at the test-of-cure visit increased the likelihood of relapse by the late follow-up visit.ConclusionsResults from this study do not support levofloxacin therapy for complicated urinary tract infections caused by organisms with levofloxacin minimum inhibitory concentrations ≥4 μg/mL.Trial registrationClinicalTrials.gov, NCT01345929 and NCT01345955 Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-2057-2) contains supplementary material, which is available to authorized users.
Highlights
Fluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis
Hospitalization for Complicated urinary tract infection (cUTI) caused by Gram-negative bacteria in the United States increased by approximately 50% from 2000 to 2009, whereas the incidence of infections caused by extended-spectrum β
Fluoroquinolones such as levofloxacin have historically been an attractive therapy for cUTI because of their high drug concentrations in the urine and their demonstrated clinical efficacy [4]
Summary
Fluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis. Lactamase (ESBL)–positive organisms increased by approximately 300% in the same time period [3] Fluoroquinolones such as levofloxacin have historically been an attractive therapy for cUTI (including pyelonephritis) because of their high drug concentrations in the urine and their demonstrated clinical efficacy [4]. Their future usefulness is threatened by alarmingly high rates of fluoroquinolone resistance, often occurring in combination with other resistance mechanisms including ESBL production. The spread of these resistance mechanisms has been facilitated by their strong association with the worldwide pandemic clone of E. coli, ST-131 [9]
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