Intravenous Doripenem at 500 Milligrams versus Levofloxacin at 250 Milligrams,with an Option To Switch to Oral Therapy,for Treatment of Complicated Lower Urinary Tract Infection and Pyelonephritis |
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| Authors: | K. G. Naber L. Llorens K. Kaniga P. Kotey D. Hedrich R. Redman |
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| Affiliation: | Technical University of Munich, Munich, Germany,1. Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey2. |
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| Abstract: | The prospective, multicenter, double-blind study presented in this report evaluated whether or not intravenous (IV) administration of doripenem, a carbapenem with bactericidal activity against gram-negative and gram-positive uropathogens, is inferior to IV administration of levofloxacin in the treatment of complicated urinary tract infection (cUTI). Patients (n = 753) with complicated lower UTI or pyelonephritis were randomly assigned to receive IV doripenem at 500 mg every 8 h (q8h) or IV levofloxacin at 250 mg q24h. Patients in both treatment arms were eligible to switch to oral levofloxacin after 3 days of IV therapy to complete a 10-day treatment course if they demonstrated significant clinical and microbiological improvements. The microbiological cure rate (primary end point) was determined at the test-of-cure (TOC) visit occurring 5 to 11 days after the last dose of antibiotic. For the microbiologically evaluable patients (n = 545), the microbiological cure rates were 82.1% and 83.4% for doripenem and levofloxacin, respectively (95% confidence interval [CI] for the difference, −8.0 to 5.5%); in the microbiological modified intent-to-treat cohort (n = 648), the cure rates were 79.2% and 78.2%, respectively. Clinical cure rates at the TOC visit were 95.1% in the doripenem arm and 90.2% in the levofloxacin arm (95% CI around the difference in cure rates [doripenem cure rate minus levofloxacin cure rate], 0.2% to 9.6%). Both treatment regimens were generally well tolerated. Doripenem was found not to be inferior to levofloxacin in terms of therapeutics and is now approved for use in the United States and Europe for the treatment of adults with cUTI, including pyelonephritis. As fluoroquinolone resistance increases, doripenem may become a more important option for successful treatment of cUTIs, including treatment of pyelonephritis.Urinary tract infections (UTIs) are the leading cause of gram-negative bacteremia for patients of all ages and can be associated with a high risk of morbidity and mortality, especially in the elderly, for whom they can account for nearly 25% of all infections (2). UTIs are responsible for nearly 7 million office visits and 1 million emergency department visits, which result in 100,000 hospitalizations each year, in the United States alone (2, 22) and account for at least 40% of all nosocomial infections (22, 23). Complicated lower UTIs (cLUTIs) and complicated pyelonephritis occur in patients who have a functionally, metabolically, or anatomically abnormal urinary tract. Unlike the narrow and predictable spectrum of pathogens associated with uncomplicated UTIs, a broad range of bacteria can cause complicated infections, and many are resistant to multiple antimicrobial agents (22). For patients with complicated UTIs (cUTIs) requiring intravenous (IV) antibiotic therapy, empirical treatment with a broad-spectrum antibiotic can help avoid the unnecessary risk and cost of disease progression associated with treatment failure.Fluoroquinolones are indicated for the management of acute uncomplicated UTIs as well as cUTIs and pyelonephritis for adults, but uropathogen resistance to them is increasing (20). The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance program demonstrated increasing rates of fluoroquinolone resistance in bacterial isolates from U.S. medical centers, especially among Escherichia coli, Enterobacter, Proteus mirabilis, and indole-positive Proteae spp. (17). Resistance to ciprofloxacin and levofloxacin in E. coli reached 21.6% and 20.4%, respectively, of isolates tested in 2005 (16). In the North American Urinary Tract Infection Collaboration Alliance surveillance study, 5.5% and 5.1% of urinary E. coli isolates from outpatients in the United States and Canada were resistant to ciprofloxacin and levofloxacin, respectively (24). Similar results were reported for a cohort in Israel (12). Pseudomonas aeruginosa fluoroquinolone resistance is also problematic, with rates now exceeding 35% (7). As fluoroquinolone resistance increases, alternative therapies will become more important for successful treatment of cUTIs, particularly for patients at risk for infection with fluoroquinolone-resistant pathogens.Doripenem is a broad-spectrum carbapenem that has been approved for use in the United States and Europe for the treatment of adults with cUTIs, including pyelonephritis, and for the treatment of complicated intra-abdominal infections. It has also been approved in Europe for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. Doripenem is primarily eliminated by the kidneys and is concentrated in the urine (Doripenem package insert; Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ). It has potent in vitro activity against the gram-negative aerobic bacteria commonly encountered in cUTIs, including E. coli, other members of the Enterobacteriaceae, and P. aeruginosa (3, 22). Like other carbapenems, doripenem is resistant to hydrolysis by a variety of β-lactamases, including extended-spectrum β-lactamases (ESBLs). Several in vitro studies have shown that doripenem has greater activity than other carbapenems against recent isolates of key gram-negative pathogens, including ESBL-producing strains of E. coli and P. aeruginosa (8, 10, 11). Moreover, under experimental conditions, doripenem was less likely than other carbapenems to select for carbapenem-resistant mutants of P. aeruginosa (14, 19). This profile makes doripenem an attractive agent for the treatment of cLUTIs and pyelonephritis. Doripenem has moderate activity against Enterococcus faecalis (4, 9), with MIC90 values of 4 to 16 μg/ml, i.e., one dilution lower than ertapenem and meropenem. Most current clinical isolates of Enterococcus faecium are resistant to doripenem.This trial was designed in compliance with Food and Drug Administration guidelines for registration studies to compare the microbiological and clinical cure rates of patients with cUTIs who received at least 3 days of IV doripenem or IV levofloxacin therapy, with an option for patients in both treatment arms to switch from IV therapy to oral levofloxacin if specified favorable clinical and microbiological criteria were satisfied. |
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