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

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.

[1]  D. Chinitz,et al.  Empiric Treatment of Uncomplicated Urinary Tract Infection with Fluoroquinolones in Older Women in Israel: Another Lost Treatment Option? , 2006, The Annals of pharmacotherapy.

[2]  Clyde Thornsberry,et al.  Multidrug-Resistant Urinary Tract Isolates ofEscherichia coli: Prevalence and Patient Demographics in the United States in 2000 , 2001, Antimicrobial Agents and Chemotherapy.

[3]  G. Woods,et al.  A prospective, multicenter, randomized, double-blind study comparing ertapenem and ceftriaxone followed by appropriate oral therapy for complicated urinary tract infections in adults. , 2002, Urology.

[4]  K. Abe,et al.  Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics. , 2006, Toxicology.

[5]  Ronald N. Jones,et al.  Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations. , 2004, The Journal of antimicrobial chemotherapy.

[6]  D. Low,et al.  Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). , 2006, International journal of antimicrobial agents.

[7]  Tetsurou Matsumoto,et al.  Urinary tract infection caused by fluoroquinolone- and cephem-resistant Enterobacteriaceae. , 2006, International journal of antimicrobial agents.

[8]  Ronald N. Jones,et al.  Contemporary activity of meropenem and comparator broad-spectrum agents: MYSTIC program report from the United States component (2005). , 2007, Diagnostic microbiology and infectious disease.

[9]  J. Karlowsky,et al.  In Vitro Antimicrobial Activity of Doripenem, a New Carbapenem , 2004, Antimicrobial Agents and Chemotherapy.

[10]  K. Naber,et al.  Emergence of antibiotic resistance amongst hospital-acquired urinary tract infections and pharmacokinetic/pharmacodynamic considerations. , 2005, The Journal of hospital infection.

[11]  Betsy Foxman,et al.  Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. , 2002, The American journal of medicine.

[12]  S. Norrby.  Neurotoxicity of Carbapenem Antibacterials , 1996, Drug safety.

[13]  A. Schaeffer.  The expanding role of fluoroquinolones. , 2002, Disease-a-month : DM.

[14]  D. Livermore,et al.  Doripenem versus Pseudomonas aeruginosa In Vitro: Activity against Characterized Isolates, Mutants, and Transconjugants and Resistance Selection Potential , 2004, Antimicrobial Agents and Chemotherapy.

[15]  Ronald N. Jones,et al.  Comparative activity of doripenem and three other carbapenems tested against Gram-negative bacilli with various beta-lactamase resistance mechanisms. , 2005, Diagnostic microbiology and infectious disease.

[16]  M. Pfaller,et al.  Spectrum and activity of three contemporary fluoroquinolones tested against Pseudomonas aeruginosa isolates from urinary tract infections in the SENTRY Antimicrobial Surveillance Program (Europe and the Americas; 2000): more alike than different! , 2001, Diagnostic microbiology and infectious disease.

[17]  G. Woods,et al.  Ertapenem versus Ceftriaxone Followed by Appropriate Oral Therapy for Treatment of Complicated Urinary Tract Infections in Adults: Results of a Prospective, Randomized, Double-Blind Multicenter Study , 2002, Antimicrobial Agents and Chemotherapy.

[18]  R. Jones,et al.  Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003). , 2005, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[19]  O. Ergönül,et al.  Risk factors for ciprofloxacin resistance among Escherichia coli strains isolated from community-acquired urinary tract infections in Turkey. , 2005, The Journal of antimicrobial chemotherapy.

[20]  K. Naber,et al.  Treatment of bacterial urinary tract infections: presence and future. , 2006, European urology.

[21]  K. Tanimoto,et al.  Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa , 2006, The Journal of Antibiotics.

[22]  Ronald N. Jones,et al.  Activities of Doripenem (S-4661) against Drug-Resistant Clinical Pathogens , 2004, Antimicrobial Agents and Chemotherapy.

[23]  Ronald N. Jones,et al.  Clonal occurrences of multidrug-resistant Gram-negative bacilli: report from the Meropenem Yearly Susceptibility Test Information Collection Surveillance Program in the United States (2004). , 2006, Diagnostic microbiology and infectious disease.