Jennifer A Huntington1, George Sakoulas2, Obiamiwe Umeh3, Daniel J Cloutier3, Judith N Steenbergen3, Caleb Bliss3, Ellie J C Goldstein4. 1. Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA jennifer.huntington@merck.com. 2. University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA. 3. Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. 4. R.M. Alden Research Laboratory, 2021 Santa Monica Boulevard, Suite 740-E, Los Angeles, CA 90404, USA UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Abstract
OBJECTIVES: Empirical fluoroquinolone therapy is widely used in treating complicated urinary tract infections (cUTIs), even in areas of high fluoroquinolone resistance. While it is believed that high antibiotic concentrations in urine might be sufficient to overcome and effectively treat infections caused by resistant bacteria, clinical trial data validating this assumption are limited. This post hoc analysis evaluated the efficacy of ceftolozane/tazobactam versus levofloxacin in the subgroup of patients with cUTIs caused by levofloxacin-resistant pathogens in a randomized, controlled trial (NCT01345929/NCT01345955). METHODS:Hospitalized adults with cUTI/pyelonephritis were randomized to 7 days of 1.5 g of ceftolozane/tazobactam every 8 h or 750 mg of levofloxacin once daily, before availability of culture and susceptibility data. A composite of microbiological eradication and clinical cure 5 to 9 days post-therapy was assessed in the microbiological modified ITT (mMITT; n = 800) and microbiologically evaluable (ME; n = 694) populations. RESULTS: In the mMITT population, there were 212 patients (26.5%) with at least one baseline uropathogen that was resistant tolevofloxacin. The majority of uropathogens in this subgroup were Enterobacteriaceae (n = 186) that were susceptible to ceftolozane/tazobactam [MIC ≤2 mg/L, 88.7% (165/186)]. Among patients with levofloxacin-resistant pathogens, ceftolozane/tazobactam demonstrated significantly higher composite cure rates than levofloxacin in both the mMITT [60.0% (60/100) versus 39.3% (44/112); 95% CI for the treatment difference, 7.2%-33.2%] and ME [64.0% (57/89) versus 43.4% (43/99); 95% CI for the treatment difference, 6.3%-33.7%] populations, respectively. CONCLUSIONS: High urinary levels of levofloxacin did not reliably cure cUTIs. Seven day treatment with ceftolozane/tazobactam was more effective than high-dose levofloxacin treatment in patients with cUTI caused by levofloxacin-resistant bacteria, and it may be an alternative treatment in settings of increased fluoroquinolone resistance.
RCT Entities:
OBJECTIVES: Empirical fluoroquinolone therapy is widely used in treating complicated urinary tract infections (cUTIs), even in areas of high fluoroquinolone resistance. While it is believed that high antibiotic concentrations in urine might be sufficient to overcome and effectively treat infections caused by resistant bacteria, clinical trial data validating this assumption are limited. This post hoc analysis evaluated the efficacy of ceftolozane/tazobactam versus levofloxacin in the subgroup of patients with cUTIs caused by levofloxacin-resistant pathogens in a randomized, controlled trial (NCT01345929/NCT01345955). METHODS: Hospitalized adults with cUTI/pyelonephritis were randomized to 7 days of 1.5 g of ceftolozane/tazobactam every 8 h or 750 mg of levofloxacin once daily, before availability of culture and susceptibility data. A composite of microbiological eradication and clinical cure 5 to 9 days post-therapy was assessed in the microbiological modified ITT (mMITT; n = 800) and microbiologically evaluable (ME; n = 694) populations. RESULTS: In the mMITT population, there were 212 patients (26.5%) with at least one baseline uropathogen that was resistant to levofloxacin. The majority of uropathogens in this subgroup were Enterobacteriaceae (n = 186) that were susceptible to ceftolozane/tazobactam [MIC ≤2 mg/L, 88.7% (165/186)]. Among patients with levofloxacin-resistant pathogens, ceftolozane/tazobactam demonstrated significantly higher composite cure rates than levofloxacin in both the mMITT [60.0% (60/100) versus 39.3% (44/112); 95% CI for the treatment difference, 7.2%-33.2%] and ME [64.0% (57/89) versus 43.4% (43/99); 95% CI for the treatment difference, 6.3%-33.7%] populations, respectively. CONCLUSIONS: High urinary levels of levofloxacin did not reliably cure cUTIs. Seven day treatment with ceftolozane/tazobactam was more effective than high-dose levofloxacin treatment in patients with cUTI caused by levofloxacin-resistant bacteria, and it may be an alternative treatment in settings of increased fluoroquinolone resistance.
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