title: Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.
abstract: Fluoroquinolones 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.
  
  
  
  Patients 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).
  
  
  
  Test-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.
  
  
  
  Results from this study do not support levofloxacin therapy for complicated urinary tract infections caused by organisms with levofloxacin minimum inhibitory concentrations ≥4 μg/mL.
  
  
  
  ClinicalTrials.gov, NCT01345929 and NCT01345955.
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. eliana.s.armstrong@gmail.com.
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Armstrong
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Mikulca
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. danieljcloutier44@gmail.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cloutier
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
authors.forename: Caleb A
authors.initials: CA
authors.lastname: Bliss
authors.affiliation: Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Steenbergen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage* / Q000627:therapeutic use; D002511:Cephalosporins / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007275:Injections, Intravenous; D064704:Levofloxacin / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012008:Recurrence; D000078142:Tazobactam; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000892:Anti-Infective Agents, Urinary; D002511:Cephalosporins; C000594038:ceftolozane, tazobactam drug combination; D064704:Levofloxacin; D010397:Penicillanic Acid; D000078142:Tazobactam
keywords: Ceftolozane/tazobactam; Fluoroquinolones; Levofloxacin; Resistance; cUTI