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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 ?g/mL. Microbiological eradication rates were consistently >90% at levofloxacin minimum inhibitory concentrations ?0.06 ?g/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 ?g/mL.ClinicalTrials.gov, NCT01345929 and NCT01345955.

SUBMITTER: Armstrong ES

PROVIDER: S-EPMC5124239 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.

Armstrong Eliana S ES Mikulca Janelle A JA Cloutier Daniel J DJ Bliss Caleb A CA Steenbergen Judith N JN

BMC infectious diseases 20161125 1

<h4>Background</h4>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 ...[more]

PMID: 27887579

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Project description:The rise in resistant Gram-negative pathogens continues to challenge clinicians treating infections. These resistant infections have inspired the development of new antimicrobial agents, including ceftolozane-tazobactam, a novel ?-lactam/?-lactamase inhibitor combination approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in combination with metronidazole. Ceftolozane exhibits bactericidal activity by inhibiting penicillin-binding proteins (PBPs), with high affinity for PBP1b, PBP1c, and PBP3. The addition of tazobactam protects ceftolozane from hydrolysis by irreversibly binding to some ?-lactamase enzymes. Ceftolozane-tazobactam is active against a wide range of Gram-negative pathogens, including extended-spectrum ?-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa, several streptococcal species, and Bacteroides fragilis. When anaerobic coverage is needed, it should be used in combination with metronidazole. Ceftolozane demonstrates linear pharmacokinetics, low protein binding, and minimal accumulation with repeated dosing. The major pharmacokinetic/pharmacodynamic index for ceftolozane is the percentage of the dosing interval in which the plasma free drug concentration remains higher than the minimum inhibitory concentration (%T.MIC). Phase III clinical trials for the treatment of cUTIs and cIAIs have been completed, showing that it is an effective and safe alternative for the treatment of these infections. The approved dose for cUTIs and cIAIs is 1.5 g (1 g ceftolozane and 500 mg tazobactam) infused over 1 hour every 8 hours. A higher 3 g dose is currently in Phase III trials for the treatment of ventilated nosocomial pneumonia. Dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Current data suggest that ceftolozane-tazobactam is a promising carbapenem-sparing alternative agent for the treatment of cUTIs and cIAIs, including those caused by ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.

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Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.

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Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.

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