Preliminary Study

Cla i r E . C o x , Susan V. Ca l l e ry , K. J. T a c k

Clinical Experience with Ofloxacin in

Summary: Preliminary data from the U.S. regarding the safety and efficacy of ofloxacin in the treatment of urinary tract infections are presented. Treatment of uncomplicated urinary tract infections with either 200 mg or 300 mg ofloxacin b.i.d, was as effective as treat- ment with a standard therapy, co-trimoxazole. In an- other series of patients with underlying abnormalities of the urinary tract, ofloxacin therapy resulted in fewer failures and relapses than co-trimoxazole treatment. Ofloxacin was well tolerated in these studies.

Zusammenfassung: Klinische Erfahrungen mit Oflox- acin bei Harnwegsinfektionen. Vorl~iufige Ergebnisse von in den USA durchgeffihrten klinischen Studien zur Sicherheit und Wirksamkeit yon Ofloxacin in der Be- handlung von Harnwegsinfektionen werden vorge- stellt. Die Behandlung komplizierter Harnwegsinfek- tionen mit 200 mg oder 300 mg Ofloxacin zweimal t~ig- lich erwies sich als ebenso wirksam wie die Standard- therapie mit Co-trimoxazol. Bei Patienten mit Infek- tion bei anatomischen Verfinderungen der Harnwege wurden bei Behandlung mit Ofloxacin weniger Thera- pieversager beobachtet als mit Co-trimoxazol. In die- sen Studien erwies sich Ofloxacin als gut vertr~iglich.

Introduction

Ofloxacin is a new broad-spectrum carboxyquinolone an- timicrobial agent. It is active against many organisms re- sistant to commonly-used antimicrobial agents such as Pseudomonas. The high tissue concentrations and urinary levels achieved after oral administration of the drug make it a promising agent for the treatment of urinary tract in- fections (UTI), including those infections involving renal parenchymal tissue. In this paper, preliminary United States experience with ofloxacin in the treatment of both uncomplicated and complicated urinary tract infections are reviewed.

Patients and Methods

The results presented represent a preliminary analysis of initial data available from two clinical trials performed in the United States in I985 and 1986. One of these studies was directed at the treatment of uncomplicated UTI, i.e. UTI without underlying abnormality of the urinary tract. The second involved patients with complicated UTI, defined as an infection in the presence of an anatomic or functional abnormality of the urinary system. To be eligible for either study patients were required to have - 105 cfu/ml of at least one pathogen in a clean-catch urine spec- imen. They were seen during therapy three to four days after en-

Urinary Tract Infection

rollment and again five to nine days after completion of therapy, when repeat urine cultures were obtained. Patients were also asked to return for additional follow-up at four to six weeks. To be considered a cure, the urine culture during therapy and five to nine days post-therapy had to be negative.

Uncomplicated UTI study: The uncomplicated UTI study was performed at several centers; the pooled results are presented here. Patients had no known abnormalities of the urinary tract. After admission to the study, patients were randomized to re- ceive one of three treatment regimens: a) ofloxacin, 200 mg p.o. q12h, b) ofloxacin, 300 mg p.o. ql2h, or c) co-trimoxazole, 960 mg p.o. ql2h. All regimens were given for a total of seven days. Investigators participating in the study were: C. Cox, Memphis, TN; C. Horsburgh, Denver, CO; J. Kann, Pittsburgh, PA; R. Latham, Salt Lake City, UT; W. Mogabgab, New Orleans, LA; F. Randall, Montgomery, AL; M. Rein, Charlottesville, VA; W. Stature, Seattle, WA; B. Umland, Alburquerque, NM; (7. Wlodaver, Oklahoma City, OK; and E. Wong, Richmond, VA.

Complicated UTI study: The complicated UTI study patients re- ported here were enrolled at a single center, as part of a larger multicentric study. All patients had documented anatomic and/ or neurologic abnormalities of the urinary tract. After admis- sion, patients were randomized to receive either a) ofloxacin, 200 mg p.o. ql2h, or b) co-trimoxazole, 960 mg p,o. ql2h, both regimens given for ten days.

Results

317 Patients were entered into the uncomplicated UTI study. A total of 209 patients are evaluable, i.e. had a pa- thogen identified at admission and returned for required follow-up visits. Efficacy results are shown in Table 1 for each of the three treatment groups. Cure rates ranged from 98.5% to 100%. There was one failure in each of the two ofloxacin treatment groups, consisting of a positive culture for the original pathogen at five to nine days post- therapy. Both failures were due to ofloxacin-susceptible Escherichia coil Relapses (re-appearance of original pa- thogen four to six weeks post-therapy) were seen with comparable frequency in the co-trimoxazole and ofloxa- cin groups. Superinfections (appearance of a new urinary pathogen during antimicrobial therapy) was also seen in each treatment group, and were due to S. agalactiae, Can- dida albicans, and enterococcus in the ofloxacin groups, and S. agalactiae in the co-trimoxazole group. All three treatment regimens were well tolerated in this study. Two patients dropped out of the uncomplicated UTI study for adverse drug effects, one patient in the ofloxacin 300 mg treatment group, and one patient in the

Prof. Clair E. Cox, M.D., Department of Urology', University of Ten- nessee, Memphis, U.S.A.; Susan V. Callery, K. J. Tack, M.D., Ortho Pharmaceutical Corpor- ation, Raritan, New Jersey 08869, U.S.A.

Infection 14 (1986) Suppl. 4 © MMV Medizin Verlag GmbH Mtinchen, M0nchen 1986 S 303

C. E. Cox et al.: Ofloxacin in UTI

Table t : Demographics, pathogens, and results, uncompli- cated UTI study.

Patients 69 67 73 Male 19 12 14

Escherichia coli 45 49 57 Klebsiella spp. 10 4 5 Staphylococcus saplvphyticus 4 5 2 Proteus mirabilis 3 2 2 Citrobacter spp. 2 3 4 Enterobacter spp. 3 2 3 Enterococcus 0 1 0 Streptococcus agalactiae 1 0 0 Staphylococcus aureus 1 1 0

Failures 1 l 0 Relapses at 4 to 6 weeks 3 2 2 Superinfections 2 2 1

Table 2: Susceptibility data on 71 pathogens* from the complicated urinary tract study.

* 30 Escherichia coli, 10 Klebsiella pneumoniae, 10 Proteus mi- rabilis, 3 each of Enterobacter aerogenes, Enterobacter cloa- cae, Citrobacter freundii, Proteus vulgaris, Proteus rettgeri, and Serratia marscescens, 2 Citrobacter diversus and 1 entero- COCCUS.

Table 3: Microbiological results in complicated urinary tract infection

i!ii iill ¸!i!i!i!iiii i!i i!i!ii!!i!!li i ii

Patients entered 36 35

Patients evaluable 5 to 9 days post-therapy 35 34

Microbiological cure 35 30 Microbiological failure 0 1 Superinfections 0 3

Patients evaluable 4 to 6 weeks post-therapy 32 29

Microbiological relapses 0 2 Microbiological 0 1 re-infections

co-trimoxazole treatment group. Both complained of diz- ziness. For the complicated UTI study, a total of 71 patients were entered. On admission, all patients had underlying disease of the urinary tract, and all pathogens were sus- ceptible to both study drugs. Pathogen identity and sus- ceptibility data are shown in Table 2. Efficacy results are shown in Table 3. All patients in the ofloxacin treatment group were cured microbiologically. One patient in the co-trimoxazole group, with a Klebsiella pneumoniae in- fection failed. Her organism became resistant during ther- apy, with a pretreatment MIC of 2.0 mg/l, and a post- treatment MIC of > 256 rag/1. Three superinfections also occurred in the co-trimoxazole group. Two were due to co-trimoxazole-resistant but ofloxacin-susceptible Pseu- domonas aeruginosa, and one due to co-trimoxazole-sus- ceptible Acinetobacter anitratus. Evaluation of the complicated UTI patients four t o six weeks post-therapy showed no relapses in the ofloxacin group, but two relapses in the co-trimoxazole group, both due to co-trimoxazole-susceptible E. coli. There was also one reinfection in the co-trimoxazole group, due to an E. coli isolate with an MIC for co-trimoxazole of > 256 mg/1. One patient dropped out of each study arm in the compli- cated UTI study due to adverse drug reactions, both rash- es. There were no other clinical adverse effects of the drugs.

Discussion

A variety of antimicrobial agents can be used for the treatment of urinary tract infections. Increasing antimi- crobial resistance, however, has led to a tendency to treat wi th intrinsically more active agents such as co-trimox- azole rather than sulfonamides alone or ampicillin. The data presented here show that treatment of uncom- plicated UTI ' s with ofloxacin is as effective as treatment with co-trimoxazole, with a high cure rate (98.5 to 100%) in each of the three treatment groups. Superinfection rates and relapses were also comparable in ofloxacin and co-trimoxazole treated groups. In UTI 's in patients with underlying abnormalities of the urinary tract, a more resistant group of infecting agents was seen, as expected. Again, ofloxacin and co-trimoxa- zole cure rates were essentially equivalent, 97 to 100% in each group. Of note is the development of resistance to co-trimoxazote in one isolate of K. pneumoniae during therapy in the co-trimoxazole treatment group, and superinfection due to co-trimoxazole-resistant organisms (P. aeruginosa) in the same group. Both ofloxacin and co-trimoxazole appeared to be well tolerated, with similar drop-out rates due to adverse drug reactions. Rashes and dizziness were responsible for pa- tients discontinuing therapy. In conclusion, based on the data available for analysis at this time, ofloxacin is a safe and effective agent for the treatment of both uncomplicated and complicated urinary tract infections.

S 304 Infection 14 (1986) Suppl. 4 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1986