Treatment of Uncomplicated, Infections with Temanoxacin ABDOLLAH



From the Dlvwon of Pediatric Nephrology, Orlando Regional Medical Center, Orlando, Florida. Requests for reprlnts should be addressed to Abdollah Iravanl, M.D., Division of Pedlatrlc Nephrology, Orlando Regtonal Medical Center, 85 West Miller Street, Suite 202, Orlando, Florida 32806.



Oriando, Florida

Temafloxacin is a new fluoroquinolone that achieves a high urine concentration and has potent, broad-spectrum antimicrobial activity against most pathogens associated with urinary tract infections. The clinical efficacy and safety of temafloxacin were assessed in adult females with acute, uncomplicated urinary tract infection in a series of three randomized, double-blind trials. A total of 555 clinically evaluable females of 919 enrolled from 75 centers received temafloxacin 200 or 400 mg once daily for 3 or 7 days, or a control regimen. The latter consisted of trimethoprimkulfamethoxazole 160 mg/800 mg, ciprofloxacin 250 mg, or norfloxacin 400 mg, each given twice daily for 7-10 days. Clinical cure or improvement occurred in 305 of 308 temafloxacin patients (99%) and in 247 of 247 controls (100%). Corresponding bacterial eradication rates were 99% (2891292) and 96.7% (237/245), respectively. The most frequently observed adverse events were nausea (3.5% of the temafloxacin group, 6.5% of the reference quinolone group, and 6.6% of the trimethoprimkulfamethoxazole group) and headache (5.4%, 3.7%, and 3.1% of the same respective groups). These results demonstrate the clinical efficacy and safety of temafloxacin, given once daily, in a large number of females with acute, uncomplicated urinary tract infection.



30, 1991

The American Journal of Medicine


emafloxacin (6-fluoro-7-piperazino-4-quinolone) is a new fluoroquinolone that exhibits a high degree of in vitro activity against a broad range of gram-negative and gram-positive bacterial pathogens [l-3]. Temafloxacin also has favorable pharmacokinetic characteristics in humans [4-61. The drug is eliminated primarily via renal excretion, with 57% of a dose appearing in the urine unchanged. The terminal elimination half-life is 6.87.7 hours [4,5]. Because of the in vitro and pharmacokinetic profiles of temafloxacin, clinical trials have been designed and executed to evaluate its effectiveness in the treatment of acute, uncomplicated urinary tract infections. This article describes three major multicenter studies that were conducted in the United States and Europe. Because similar methods were used, the results of these studies were integrated for the purpose of this article.

MATERIALSAND METHODS Protocols were approved by the investigational review board of each participating institution. All enrolled patients gave written consent after receiving appropriate directions regarding the study.

Patients Eligible patients were nonpregnant, nonfertile females ~18 years of age who manifested clinical signs and symptoms of urinary tract infection. Clinical signs and symptoms included gross hematuria, chills, fever (>100”F or 37.8”C), dysuria, frequency, urgency, suprapubic tenderness or pain, costovertebral angle pain or tenderness, and low back pain or tenderness. Infection was documented by urine culture, which was obtained via clean catch collection or urinary catheter and colony counts; antibiotic sensitivity testing was performed. Patients were excluded if there was evidence of complicated or recurrent urinary tract infection, structural or functional abnormality of the urinary tract, immunosuppression, or bacterial resistance to the study drugs. In addition, patients were not eligible for study inclusion if they gave a recent or current history of coagulation disorder, renal dysfunction (serum creatinine >2 mg/mL), hepatic

Volume 91 (suppl







Summary of Clinical and Bacteriologic Nonevaluability

Summary of Demographics for Clinically Evaluable Patients*

Reference Overall (n = 919) No baseline pathogen Necessary examrnatton (culture) missing IntermedIate susceptibrlrty lnsufhcient treatment duration ResIstant pathogen No susceptibikty test Study drug noncomplrance Concurrent anbbiotrcs Clrrrcally (bactenologrcally) nonevaluable patrents

250 ;$ (64)

Temafloxacin (n = 478) 127 10 (26)





Race Caucasian Black Other Aee “Mean (years) 535 years 235 years

;; (381


10 i;


11 2




i 0 1

170 (186)

Temafloxacin (n = 308)







7 40.2 288 267

Ww;;pl 411 patients

364 (3821

Overall (n = 555)







120 64.7


were female.

194 (196)


dysfunction, hypersensitivity to quinolones, central nervous system symptoms or illness, or ophthalmologic abnormality not correctable with lenses. Patients were not allowed to take an antimicrobial within 7 days (30 days for benzathine penicillin), an investigational drug within 4 weeks, or cancer chemotherapy within 2 months prior to enrollment. Study Design

Three randomized, double-blind multicenter studies were conducted [7,8]. Protocols were identical except for study drugs and dosages. In the largest study, agents were temafloxacin 400 mg for 7 days and trimethoprim/ sulfamethoxazole 160 mgi 800 mg for 10 days. In the second study, drugs were temafloxacin 200 or 400 mg and norfloxacin 400 mg, each given for 7 days. In the third study, drugs were temafloxacin 400 mg for 3 days or ciprofloxacin 250 mg for 7 days. Temafloxacin was given once daily, and all control agents were given twice daily. For the purposes of this report, results of the three control regimens were integrated and referred to as the “reference regimen.” Assessment

Following randomization, patients were evaluated clinically during treatment, within 48 hours after completion of therapy, and 5-9 days posttreatment. At the final evaluation, clinical outcome was categorized as cure (resolution of all signs and symptoms of urinary tract infection), improvement (signs and symptoms improved, but not completely resolved), or failure (no improvement or worsening of pretreatment signs and symptoms). Clinical response was defined as cure or improvement. Urine for culture and sensitivity was obtained before treatment, during treatment, and at the last assessment. At the midtherapy evaluation and at 5-9 days post-treatment, bacteriologic response December

Clinical and Bacteriologic Response to TreatmentPercentage of Patients Response


Clinical Cure Improvement Farlure Bacteriologrc Cure Farlure

Reference Regiment

n = 308

n = 247



7.8 1.0

6.5 0

n = 292 99

n = 245 96.7



*ZOO or 400 mg q.d. for 3 or 7 days. ~rlmethoprlmisulfamethoxazole 160 mg/BOO mg, ciprofloxacin 400 mg b.i.d. for 7-10 days,

250 mg. or noriloxacrn

was categorized as cure (absence of the original pathogen or a count of 104 CFU/mL [lo3 CFU for coagulase-negative staphylococci]). Patients were nonevaluable if the clinical or bacteriologic evaluation was indeterminable or confounded. All patients who received at least one dose of study drug were included in the safety analysis. Adverse events considered to be possibly or probably related to treatment and occurring in at least 1% of patients are described in this analysis. Statistical analysis for these integrated results involved either the F-test in one-way ANOVA for continuous variables or chi-square test for discrete variables.

RESULTS In these three double-blind studies, 919 patients (from 53 U.S. centers and 22 centers in Great Britain) were randomized to receive either temafloxacin (n = 478) or a reference agent (n = 441). Approximately 40% of patients were not clinically (n = 364) or bacteriologically (n = 382) evaluable. The reasons for exclusion are summarized in Table I, with the most common reason involving 30, 1991

The American


of Medicine


91 (suppl







Bacteriologic Response to Treatment Number Eradicated or Persisted/Number

Isolated (%)


Escherichlaco/i Proteus mirab//is Klebsieliapneumoniae Staphylococcusepldermidis Staphylococcussaprophflicus Others Total





2301232 (99) 17117 (100) IO/l0 (100) 717(100) 616(100) 21122(95) 2911294(99)

21232(1) 0117 Oil0 017 016 1122(5) 31294(1)

1941201(97) ‘;;W;/

E’i# 017 015 013 0123 81257j3)

the outcome of the pretreatment urine culture, the results of which were unknown at the time of the initial dose. Other frequent reasons for nonevaluability included lack of baseline pathogen, necessary examination or culture missing, resistant or intermediately susceptible pathogen, or failure to obtain susceptibility testing. There were no differences between the treatment groups. The failure to identify a baseline pathogen may have been related to excessive fluid consumption and frequent voiding prior to study entry or to the presence of a nonbacterial urogenital infection. Of 308 clinically evaluable patients in the temafloxacin group, a minority (n = 25) received the 200 mg dose of once-daily temafloxacin, so that all temafloxacin results were combined. Of 247 clinically evaluable patients treated with reference drugs, 118 (47.8%) received trimethoprimisulfamethoxazole, 106 (42.9%) received ciprofloxacin, and 23 (9.3%) received norfloxacin. As shown in Table II for all evaluable patients, the mean age was 40.2 years (range 17-92 years). Age exceeded 35 years in 267 patients (48.1%). Both temafloxacin and the reference regimens produced high clinical response rates (Table III). Overall clinical response (cure plus improvement) rates were 99% in the temafloxacin group and 100% in the controls. In the subset of 125 patients treated with the 3-day course of temafloxacin, 89.6% achieved clinical cures and 10.4% improved for an overall response rate of 100%. When patients were stratified by age, no differences emerged in response rates between the temafloxacin and reference groups. In the three studies, 734 pretreatment pathogens were isolated and identified. Escherichia coli (77%) comprised the majority of pathogens. Other less common isolates included Proteus mirabilis, staphylococci, Klebsiella pneumoniae, and other Enterobacteriaceae. Temafloxacin eliminated pathogens from 289 of 292 patients (99%). The corresponding 6A-126s

December 30,

Reference Regimen

1991 The American Journal of Medicine

515(100) 313(100) 23123(100) 2491257 (97)

patient bacteriologic cure rate for reference regimens was 96.7% (237/245). When results were stratified according to causative pathogen, eradication rates ranged from 95-100% in the temafloxacin group and from 94-100% in the control group (Table IV). There were no differences between the two groups on the basis of eradication rates for overall or individual bacteria. The bacteriologic eradication rate for the 3-day course of temafloxacin was 97.4%. An analysis of patients receiving temafloxacin 400 mg once daily evaluated the effect of any underlying medical condition on response. All patients with mild renal disease (n = 14) or diabetes mellitus (n = 14) achieved a successful clinical response (cure or improvement) and bacteriologic eradication. The most frequently observed adverse events were nausea (temafloxacin, 3.5%; reference quinolones, 6.5%; and trimethoprimisulfamethoxazole, 6.6%) and headache (5.4%, 3.7%, 3.1% of the same respective groups.) Table V summarizes the most common adverse events that were possibly or probably related to treatment. No adverse events were considered definitely related to treatment. Severe reactions associated with temafloxacin were, unless otherwise indicated, one case each of headache (n = 2>, abdominal pain, pain, diarrhea (n = 2), constipation, somnolence, nausea and vomiting with palpitations, and altered taste perception. Control regimens were associated with severe headache (n = 2), asthenia, chest pain, vomiting (n = 2), diarrhea, dizziness, dyspnea, and rash (n = 2). Compared with temafloxacin, the subset of patients treated with trimethoprim/sulfamethoxazole experienced a higher overall frequency of reactions (23.5% versus 19.6%) and of severe reactions (4.6% versus 0.5%).

COMMENT In this series of randomized, double-blind studies, temafloxacin, given once daily for 3-7 days,

Volume 91 (suppl 6A)


produced clinical response and bacteriologic eradication rates of 99% each. These response rates were comparable to those seen with standard reference regimens given over at least 7 days in this series and with those previously reported for other fluoroquinolones [9-E]. Temafloxacin response rates did not diminish in patients >35 years, in diabetics, or in patients with mild renal failure. The high efficacy rate of once-daily temafloxacin in the treatment of uncomplicated urinary tract infection reflects its excellent in vitro activity [l3,131 in conjunction with its good oral absorption and urine penetration [4,5]. After multiple oral doses of 400 mg, maximum serum drug concentrations are 4 PgimL. At steady-state, urine concentrations of temafloxacin are approximately 100 times higher than corresponding serum concentrations [6]. The subset of patients treated with the 3-day, once-daily temafloxacin regimen achieved clinical and bacteriologic response rates comparable to those associated with longer courses of temafloxacin and reference antibiotics. In contrast, 3-day courses of p-lactam antibiotics are often insufficient, whereas 3-day courses of trimethoprimi sulfamethoxazole may be adequate [14]. Although uncomplicated infections of the lower urinary tract are easily treated with single-dose therapy, response rates following short-course therapy are often unacceptably low when occult upper urinary tract infection is present [ 141. Since approximately one-third of patients with symptoms of acute cystitis may also have acute pyelonephritis [15], 3-day therapy may achieve desirable efficacy rates, improve compliance, and decrease the risk of adverse drug events when compared with 7-day regimens. The excellent findings in the current studies may be due to the persistence of high urinary concentrations of temafloxacin following oral administration, as well as other factors. Temafloxacin was well tolerated in these studies. Analysis of the subset of patients treated with either temafloxacin or trimethoprimisulfamethoxazole revealed a greater frequency of adverse events, particularly those judged severe, in the latter group. This finding has been reported in other comparisons between quinolones and trimethoprimisulfamethoxazole [16-171. The collective results of three studies demonstrate the consistent effectiveness of temafloxacin, given once daily, for the treatment of acute, uncomplicated urinary tract infection in women. The excellent in vitro activity of this agent, combined with its good pharmacokinetic and safety profiles, make once-daily temafloxacin an excellent choice for the treatment of acute, uncomplicated urinary tract infections. December



TABLE V Adverse Events Possibly or Probably Related to Treatment and Occurring in at Least 1% of Patients Number of Patients (%) Reference Quinolones


(n = 245)

Adverse Event Nervous system Headache Dizziness Somnolence Gastrointestinal Nausea Abdominal pain Diarrhea Nausea and vomltlng Dyspepsia Urogenital Monllial vaglnltls Skin Rashes Pruntus Other Asthenia


Trimethoprimi Sulfamethoxazole (n = 196)

9 13.71

6 (3.1) 2 (1.0)


1616.51 4 (1.6)

5(1.0) 4(

Treatment of uncomplicated urinary tract infections with temafloxacin.

Temafloxacin is a new fluoroquinolone that achieves a high urine concentration and has potent, broad-spectrum antimicrobial activity against most path...
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