Oral Temafloxacin for the Treatment Tract Infections CLAIR
E. Cox,
M.D.,
Compared to Norfloxacin of Complicated Urinary
Memph/s, Tennessee
Temafloxacin is a new oral fluoroquinolone with broad-spectrum antimicrobial activity against gram-negative and gram-positive pathogens. The safety and efficacy of temafloxacin were evaluated in a multicenter, double-blind study of patients with complicated urinary tract infections. Patients were randomized to receive temafloxacin 400 mg (n = 138) or norfloxacin 400 mg (n = 141). Treatment was given orally twice daily for lo-14 days. Clinical response (cure or improvement) occurred in 75 of 78 patients (96%) in the temafloxacin group and in 89 of 91 patients (98%) in the norfloxatin group. Bacteriologic eradication rates in both treatment groups exceeded 95%. Adverse events occurred in a similar, low percentage of patients in both treatment groups and consisted primarily of nausea and dizziness. Temafloxacin appears to be as safe and effective as norfloxacin in the treatment of complicated urinary tract infections.
I
n comparison with acute, uncomplicated urinary tract infections (UTIs), management of complicated UTIs is more challenging. By definition, the latter infections are complicated by the presence of urinary calculi, urethral strictures, multiple recurrences, or other factors [l]. Resistant organisms are more likely to be isolated [2], and severe complications of infection are more common [1,3]. Therapy for complicated CJTIs requires a more prolonged course of antibiotics. Some active agents yield disappointing results, however, even with an adequate course of therapy [21. The use of fluoroquinolone antimicrobial agents for the treatment of complicated UTIs has been reviewed [4,5]. In comparison with the prototype quinolone, nalidixic acid, newer fluoroquinolones have broader spectrum in vitro activity, and resistant pathogens are less likely to emerge during treatment. Newer fluoroquinolones also possess more desirable pharmacokinetic characteristics, which result in higher serum and tissue concentrations. Temafloxacin is a member of the 6-fluoro-‘7piperazino-4-quinolone group. Its activity against gram-negative bacilli is similar to that of ciprofloxatin and ofloxacin [6], although temafloxacin has superior activity against gram-positive, anaerobic, and intracellular organisms [7,8]. Its pharmacokinetic features include excellent oral bioavailability, long elimination half-life, and high urine concentration [9]. The present article summarizes the results of a study designed to evaluate the efficacy and safety of temafloxacin in the treatment of complicated urinary tract infections.
MATERIALSAND METHODS The multicenter study was conducted in a randomized and double-blind fashion. The study protocol was approved by the Institutional Review Boards of participating institutions, and patients gave written informed consent prior to enrollment. From the Department of Urology, Umversity of Tennessee College of Medlclne, Memphis, Tennessee. Requests for reprints should be addressed to Clalr E. Cox, M.D., Department of Urology, Unlverslty of Tennessee College of Medicine, 956 Court Avenue, Box 10, Memphis, Tennessee 38102116.
December
Patients
Patients who were older than 18 years of age and required treatment for complicated UTIs were con30, 1991
The American
Journal
of Medune
Volume
91 (suppl
6A]
6A-129s
SYMPOSIUM
ON FLUOROOUINOLONES/COX
sidered for entry. UT1 was diagnosed if the following were present: (a) symptoms of UT1 or asymptomatic bacteriuria (two consecutive cultures containing 210” colony-forming units (CFU)/mL same bacteria, 148 hours prior to treatment); and (b) pyuria (>5 leukocytes/high power field) and bacteriuria on microscopic examination of urine sediment within 48 hours prior to treatment. Complications consisted of one or more of the following: structural abnormalities, 524 hours posturologic instrumentation, UT1 symptoms plus ~24 hours postcatheterization, or recurrent UT1 (more than two infections within the last year). All patients had creatinine clearance of >30 mL/min. Patients were excluded if they were pregnant or nursing mothers; had simple cystitis or prostatitis; had a permanent catheter or other indwelling urinary tract device; had urinary diversion and external appliance; had staghorn calculi or severe structural or functional abnormality causing intractable infection or requiring prolonged (>14 days) therapy; had >3 pathogens isolated, or a resistant organism on urine culture; had underlying disease that might compromise safety or efficacy of therapy; or had quinolone hypersensitivity. Patients were not allowed to take other antimicrobials during the study. Interventions
Participants were randomized to receive temafloxacin 400 mg or norfloxacin 400 mg, each twice daily for lo-14 days. All study medications were identical in appearance. Physicians and patients were blinded to the study medications. Patients had to receive at least 3 days of therapy to be considered evaluable. Those enrolled were scheduled for four evaluations: within 48 hours prior to treatment; on study day 3, 4, or 5 (visit 2); within 48 hours after the last dose (visit 3); and 5-9 days after the last dose (visit 4). Initially, all patients received a complete medical workup including evaluation of signs and symptoms of infection, physical examination, medical and urologic history, and blood and urine specimens for laboratory evaluation. Examination and history were repeated at the second and third visits, while signs and symptoms were reevaluated at each visit; laboratory studies were repeated at visit 3, and urine culture was repeated at visits 2 and 4. Urine samples for culture and sensitivity were obtained via clean catch, catheterization, or suprapubic aspiration. For clean catch and catheterized specimens, the sample was considered valid if one to three pathogens were isolated and the colony count was ~10’ (lo4 for coagulase-negative staphylococci) CFU/mL per pathogen. With suprapubic 6A-130s
December 30, 1991
The American Journal of Medicine
aspiration, a colony count of 25,000 CFU/mL was required. An isolate was considered susceptible to temafloxacin if the minimal inhibitory concentration (MIC) was 12 pg/mL, intermediate if it was 4 pg/mL, and resistant if it was 28 pg/mL. Corresponding breakpoints for norfloxacin were 4, 8, and 16 PgimL. On disk susceptibility testing, an isolate was considered susceptible to temafloxacin if the diameter was ~20 mm, intermediate if it was 17-19 mm, and resistant if it was 116 mm. Corresponding breakpoints for norfloxacin were 217 mm, 13-16 mm, and 512 mm. Definitions of Response
At the final visit, clinical response was categorized as cure (no signs/symptoms present); improvement (pretreatment signs/symptoms improved but not completely resolved); failure (worsening or lack of improvement at the final visit or upon stopping treatment); or nonevaluable. Clinical response was defined as cure or improvement. Bacteriologic response included: eradication, defined as absence of original pathogen or reduction of urine colony counts to
E. Cox,
M.D.,
Compared to Norfloxacin of Complicated Urinary
Memph/s, Tennessee
Temafloxacin is a new oral fluoroquinolone with broad-spectrum antimicrobial activity against gram-negative and gram-positive pathogens. The safety and efficacy of temafloxacin were evaluated in a multicenter, double-blind study of patients with complicated urinary tract infections. Patients were randomized to receive temafloxacin 400 mg (n = 138) or norfloxacin 400 mg (n = 141). Treatment was given orally twice daily for lo-14 days. Clinical response (cure or improvement) occurred in 75 of 78 patients (96%) in the temafloxacin group and in 89 of 91 patients (98%) in the norfloxatin group. Bacteriologic eradication rates in both treatment groups exceeded 95%. Adverse events occurred in a similar, low percentage of patients in both treatment groups and consisted primarily of nausea and dizziness. Temafloxacin appears to be as safe and effective as norfloxacin in the treatment of complicated urinary tract infections.
I
n comparison with acute, uncomplicated urinary tract infections (UTIs), management of complicated UTIs is more challenging. By definition, the latter infections are complicated by the presence of urinary calculi, urethral strictures, multiple recurrences, or other factors [l]. Resistant organisms are more likely to be isolated [2], and severe complications of infection are more common [1,3]. Therapy for complicated CJTIs requires a more prolonged course of antibiotics. Some active agents yield disappointing results, however, even with an adequate course of therapy [21. The use of fluoroquinolone antimicrobial agents for the treatment of complicated UTIs has been reviewed [4,5]. In comparison with the prototype quinolone, nalidixic acid, newer fluoroquinolones have broader spectrum in vitro activity, and resistant pathogens are less likely to emerge during treatment. Newer fluoroquinolones also possess more desirable pharmacokinetic characteristics, which result in higher serum and tissue concentrations. Temafloxacin is a member of the 6-fluoro-‘7piperazino-4-quinolone group. Its activity against gram-negative bacilli is similar to that of ciprofloxatin and ofloxacin [6], although temafloxacin has superior activity against gram-positive, anaerobic, and intracellular organisms [7,8]. Its pharmacokinetic features include excellent oral bioavailability, long elimination half-life, and high urine concentration [9]. The present article summarizes the results of a study designed to evaluate the efficacy and safety of temafloxacin in the treatment of complicated urinary tract infections.
MATERIALSAND METHODS The multicenter study was conducted in a randomized and double-blind fashion. The study protocol was approved by the Institutional Review Boards of participating institutions, and patients gave written informed consent prior to enrollment. From the Department of Urology, Umversity of Tennessee College of Medlclne, Memphis, Tennessee. Requests for reprints should be addressed to Clalr E. Cox, M.D., Department of Urology, Unlverslty of Tennessee College of Medicine, 956 Court Avenue, Box 10, Memphis, Tennessee 38102116.
December
Patients
Patients who were older than 18 years of age and required treatment for complicated UTIs were con30, 1991
The American
Journal
of Medune
Volume
91 (suppl
6A]
6A-129s
SYMPOSIUM
ON FLUOROOUINOLONES/COX
sidered for entry. UT1 was diagnosed if the following were present: (a) symptoms of UT1 or asymptomatic bacteriuria (two consecutive cultures containing 210” colony-forming units (CFU)/mL same bacteria, 148 hours prior to treatment); and (b) pyuria (>5 leukocytes/high power field) and bacteriuria on microscopic examination of urine sediment within 48 hours prior to treatment. Complications consisted of one or more of the following: structural abnormalities, 524 hours posturologic instrumentation, UT1 symptoms plus ~24 hours postcatheterization, or recurrent UT1 (more than two infections within the last year). All patients had creatinine clearance of >30 mL/min. Patients were excluded if they were pregnant or nursing mothers; had simple cystitis or prostatitis; had a permanent catheter or other indwelling urinary tract device; had urinary diversion and external appliance; had staghorn calculi or severe structural or functional abnormality causing intractable infection or requiring prolonged (>14 days) therapy; had >3 pathogens isolated, or a resistant organism on urine culture; had underlying disease that might compromise safety or efficacy of therapy; or had quinolone hypersensitivity. Patients were not allowed to take other antimicrobials during the study. Interventions
Participants were randomized to receive temafloxacin 400 mg or norfloxacin 400 mg, each twice daily for lo-14 days. All study medications were identical in appearance. Physicians and patients were blinded to the study medications. Patients had to receive at least 3 days of therapy to be considered evaluable. Those enrolled were scheduled for four evaluations: within 48 hours prior to treatment; on study day 3, 4, or 5 (visit 2); within 48 hours after the last dose (visit 3); and 5-9 days after the last dose (visit 4). Initially, all patients received a complete medical workup including evaluation of signs and symptoms of infection, physical examination, medical and urologic history, and blood and urine specimens for laboratory evaluation. Examination and history were repeated at the second and third visits, while signs and symptoms were reevaluated at each visit; laboratory studies were repeated at visit 3, and urine culture was repeated at visits 2 and 4. Urine samples for culture and sensitivity were obtained via clean catch, catheterization, or suprapubic aspiration. For clean catch and catheterized specimens, the sample was considered valid if one to three pathogens were isolated and the colony count was ~10’ (lo4 for coagulase-negative staphylococci) CFU/mL per pathogen. With suprapubic 6A-130s
December 30, 1991
The American Journal of Medicine
aspiration, a colony count of 25,000 CFU/mL was required. An isolate was considered susceptible to temafloxacin if the minimal inhibitory concentration (MIC) was 12 pg/mL, intermediate if it was 4 pg/mL, and resistant if it was 28 pg/mL. Corresponding breakpoints for norfloxacin were 4, 8, and 16 PgimL. On disk susceptibility testing, an isolate was considered susceptible to temafloxacin if the diameter was ~20 mm, intermediate if it was 17-19 mm, and resistant if it was 116 mm. Corresponding breakpoints for norfloxacin were 217 mm, 13-16 mm, and 512 mm. Definitions of Response
At the final visit, clinical response was categorized as cure (no signs/symptoms present); improvement (pretreatment signs/symptoms improved but not completely resolved); failure (worsening or lack of improvement at the final visit or upon stopping treatment); or nonevaluable. Clinical response was defined as cure or improvement. Bacteriologic response included: eradication, defined as absence of original pathogen or reduction of urine colony counts to
