Originalia C. Timmerman, I. Hoepelman, J. de Hond, T. Boon, L. Schreinemachers, H. Mensink, J. Verhoef

Open, Randomized Comparison of Pefloxacin and Cefotaxime in the Treatment of Complicated Urinary Tract Infections Summary: In an open, randomized study, the effect of pefloxacin (400 mg b.i.d.) was compared with that of cefotaxime (1 g t.i.d.) in the treatment of complicated urinary tract infections. In total 87 patients entered the study under the clinical diagnosis of complicated urinary tract infection, of whom 49 were eligible for evaluation. Most isolates (90%) belonged to the family of Enterobacteriaceae. Isolates were eradicated from 96% (28/29) of patients treated with pefloxacin and 89% (16/18) of those receiving cefotaxime 48 h after the end of therapy. After one week a total of 92% (22/24) of patients treated with pefloxacin were culture negative, while in the group treated with cefotaxime a total of 82% (9/11) were culture negative. After four to six weeks, 68% (13/19) in the pefloxacin and 80% (8/10) in the cefotaxime study group showed a negative urine culture (difference non-significant; p > 0.5). Clinical cure at the end of treatment was 97% (30/31) in the pefloxacin group vs. 89% (16/18) in the cefotaxime group. Both groups showed similar relapse and reinfection rates at 48 h and one week after therapy. Adverse effects were mild and reversible for both drugs. It is concluded that pefloxacin is a safe and effective alternative for treatment of complicated urinary tract infection.

Zusammenfassung: Offene, randomisierte Vergleichsstudie zur Behandlung komplizierter Harnwegsinfektionen mit Pefloxacin oder Cefotaxim. In einer offenen,

randomisierten Vergleichsstudie wurde die Wirksamkeit von Pefloxacin (400 mg zweimal t~iglich) mit der von Cefotaxim (1 g dreimal t~iglich) bei der Behandlung komplizierter Harnwegsinfektionen verglichen. Mit der klinischen Diagnose komplizierte Harnwegsinfektion wurden 87 Patienten in die Studie aufgenommen; 49 davon standen ffir die Auswertung zur Verffigung. Die meisten Isolate geh6rten zur Gruppe der Enterobacteriaceae. 48 Stunden nach Ende der Therapie waren in der Pefloxacingruppe bei 28 der 29 Patienten (96%) und in der Cefotaximgruppe bei 16 von 18 Patienten (89%) die Erreger eliminiert. Untersuchungen eine Woche nach Therapieende zeigten negative Urinkulturen bei 22 von 24 mit Pefloxacin (92%) und bei 9 von 11 mit Cefotaxim behandelten Patienten (82%). Nach sechs Wochen waren die Kulturen noch bei 13 von 19 der mit Pefloxacin (68%) und bei 8/10 der mit Cefotaxim (80%) behandelten Patienten negativ (der Unterschied ist mit p > 0,5 nicht signifikant). Die klinische Heilungsrate betrug nach Pefloxacin-Therapie 97% (30/31) und nach Cefotaxim-Therapie 89% (16/18). Die Rezidiv- und Reinfektionsraten waren nach 48 Stunden und eine Woche nach Therapieende vergleichbar. Die Nebenwirkungen der beiden Therapien waren leicht und reversibel. Es kann folglich angenommen werden, dab Pefloxacin eine sichere und wirksame Alternative ffir die Behandlung komplizierter Harnwegsinfektionen darstellt.

Introduction Comparative studies have shown the fluoroquinolones to be effective for the treatment of uncomplicated and complicated urinary tract infections [1]. Pefloxacin is a fluorinated quinolone with a broad spectrum of in vitro activity against pathogens commonly found in complicated urinary tract infections [2]. After administration of a single oral or intravenous 400 mg dose of pefloxacin, maximum plasma concentrations of 3.84 to 6.6 mg/1 and 5.8 to 8.2 mg/l, respectively, are achieved [3]. Tissue levels of pefloxacin after intravenous administration of 400 mg doses are equivalent or higher than plasma concentrations [4]. Pefloxacin is metabolised into the active N-desmethyl metabolites and the non-active N-oxide metabolites. Fifty-nine percent of pefloxacin and its metabolites is recovered from the urine. Elimination half-life ranges between 8.6 and 13 h after a single dose, while multiple 38 / 34

dosing leads to a prolonged elimination half-life approximating 14 to 15 h [4]. The present study was designed to compare the efficacy and safety of pefloxacin and cefotaxime in the treatment of complicated urinary tract infections.

Received: 13 June 1991/Revisionaccepted: 11 November1991 Dr. med. C. Timmerman, Oostereind 115, NL-1212VH Hilversum;Dr. med. L Hoepelman, Prof. Dr. med. J. Verhoef, Dept. of Clinical Microbiology and Laboratory of Infectious Diseases and U-Gene Research, Dr. med. J. de Hond, Dr. reed. T. Boon, Dept. of Urology, University of Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht; Dr. med. L. Schreinemachers, Dept. of Urology, Groot Ziekengasthuis, Nieuwstraat 34, NL-5211 NL Den Bosch; Prof. Dr. med. 1-1.Mensink, Dept. of Urology,Universityof Groningen,Oostersinge159,NL-9713EZ Groningen;The Netherlands.

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C. Timmerman et al.: Pefloxacin vs. Cefotaxime in Complicated UTI

Table 1: Summary of patients treated with pefloxacin or cefotaxime.

Table 2: In vitro activity of pefloxacin and cefotaxime against the initially isolated microorganisms.

Sex

Male Female Mean age (years) (range) Mean therapy duration (days) (range) Symptoms Fever (temperature, -----38 °C) Dysuria Pyuria Clinical diagnosis Pyelonephritis Cystitis Epididymitis Urosepsis Creatinine clearance -->80 ml/min 25-50 ml/min 10-25 ml/min

13 18 56 (21-86) 11 (5-14)

9 9 57 (33-86) 9 (5-14)

27 (87) 7 (22) 24 (77)

16 (89) 6(33) 12 (67)

11 8 1 11

11 4 0 3

26 4 1

13 4

Escherichia coli Proteus spp. Klebsiella spp.

Patients and Methods Patient population. Patients were hospitalized at the University Hospital Utrecht, the University Hospital Groningen and the Groot Ziekengasthuis Den Bosch. Approval for the study was given by the Ethical Committee of each hospital. Minimum criteria for enrollment included [5] (i) fever -> 38°C (without the presence of other infection sites) or signs (frequency, urgency, dysuria) and symptoms (flank pain) of urinary tract infection; (ii) five or more leukocytes per high power field of a urine sediment; (iii) microscopic evidence of bacteruria; (iv) patients 16 years of age or older. Patients with an indwelling catheter were only randomized if they had fever. Complicated urinary tract infection was defined as the presence of an anatomical or functional abnormality of the urinary tract, urinary tract instrumentation and/or a serious medical illness such as diabetes mellitus, immunosuppression or renal failure [6]. Patients were excluded from the study if they had a history of hypersensitivity to nalidixic acid or cephalosporins, impaired liver function (> 2.5 times normal values for transaminases, serum bilirubin or alkaline phosphatase) or a glucose-6-phosphate dehydrogenase deficiency. Pregnant or nursing women were not included in the study. Prior unsuccessful treatment of patients with other antibiotics was not considered an exclusion criterium. All patients gave oral informed consent. After informed consent was obtained, a presealed envelope containing a card with the name of the drug was opened. Cards were randomized in a 2:1 ratio for the pefloxacin and cefotaxime study groups. Treatment with pefloxacin was started with a single dose of 800 mg intravenously; subsequently, 400 mg doses were administered every 12 h. Pefloxacin was given intravenously for 72 h; medication was continued orally (400 mg every 12 h). Cefotaxime was given as i g every 8 h intravenously. Treatment was given for five to 14 days. During therapy, patients were examined daily for evidence of drug-related toxicity and for evaluation of their clinical response to treatment.

Pseudornonas aeruginosa Staphylococcus epiderrnidis Enterococcus faecalis

pefloxacin (17) cefotaxime (12) pefloxacin (6) cefotaxime (2) pefloxacin (2) cefotaxime (2) pefloxacin(3) cefotaxime (0) pefloxacin(1) cefotaxime (0) pefloxacin (2) cefotaxime (2)

0.12-0.25 --< 0.06-0.12 0.25-0.50 < 0.06 --< 0.06-0.25 0.25-8.0 n.d. 0.12 0.12 >-- 16

Laboratory studies. Urine was obtained by clean-clatch midstream collection or by single straight catheterization within 24 h prior to treatment. Urine cultures were done four to five days after initiation of treatment; 48 h after end of treatment; and one week and four to six weeks after termination of treatment. A urine culture was considered positive if -> 105 CFU/ml were grown. Bacteria were identified by standard bacteriological and serological methods. The susceptibility of all infecting organisms was determined by the standard antibiotic disk technique using the modified Kirby-Bauer procedure [7] with pefloxacin (10~g) and cefotaxime (30ttg) tablets (Neosensitabs; Rosco, Denmark). Bacterial isolates were considered to be resistant to both drugs if the zone of inhibition was -< 20 mm; susceptible if the zone of inhibition was >- 24 mm, and intermediate if the zone of inhibition was between those values. Laboratory tests (complete blood cell count, differential leukocyte count, platelet count, blood urea nitrogen, serum creatinine, serum glutamic oxalic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), total bilirubin plus conjugated fraction, alkaline phosphatase, gamma-glutamyl transferase, creatinine clearance and urinanalysis) were performed before initiation of treatment, during and at the end of treatment. Definitions. Clinical cure was determined when all clinical signs and symptoms subsided during treatment, no clinical evidence of infection existed at the time the drug was discontinued, and urine cultures during and one week after discontinuation of treatment remained negative. Microbiological cure was defined as a bacterial response of -< 104 CFU/ml post-therapy; persistence was defined as --> 105 CFU/ml of an isolate of the same species during therapy; superinfection was defined as --> 105 CFU/ml of a different isolate; relapse was defined as -> l0 s CFU/ml in post-therapy (1 week) cultures; reinfection was defined as bacterial response during therapy with -----105 CFU/ml of a new isolate post-therapy. Results O f 87 patients enrolled, 38 were excluded. Seven patients were treated for less than five days as a result o f n o n c o m p l i a n c e to intravenous therapy, 24 patients h a d p r e t h e r a p y urine cultures with < 105 CFU/ml, and seven

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C. T i m m e r m a n et al.: Pefloxacin vs. Cefotaxime in Complicated LrI'I

patients had positive urine cultures at start of treatment, of which four became negative after four to five days, however follow-up cultures w e r e missing for further evaluation. A total of 31 patients received pefloxacin and 18 received cefotaxime for a mean duration of therapy of 11 and 9 days, respectively. Demographic characteristics were similar in both groups (Table 1). The majority of pretherapy isolates consisted of members of the family of Enterobacteriaceae as listed in Table 2. Other isolates consisted of Pseudomonas aeruginosa (n = 3), Enterococcus faecalis (n = 4) and Staphylococcus epidermidis (n = 1). The bacteriological response to treatment is shown in Table 3. Rates of eradication of urinary pathogens during treatment were equal for pefloxacin and cefotaxime, 93% (27/29) and 94% (16/17), respectively. Persistence in the pefloxacin group occurred in one patient with complicated cystitis caused by streptococci and in one patient with pyelonephritis caused by Proteus mirabilis. In the cefotaxime group one patient had persistent pyelonephritis caused by P. mirabilis. Both study groups showed similar bacteriological response rates 48 h after treatment, 96% (28/29) and 89% (16/18), respectively. Reinfections occurred with both study drugs: one reinfection in the pefloxacin group occurred in a patient with pyelonephritis caused by an enterococcus; in the cefotaxime group Pseudomonas strains were responsible for reinfections, in one patient with an obstructive pyelonephritis and in one patient after surgery of the urinary bladder. Urine cultures taken one week after therapy showed an eradication rate of 92% (22/24) in the Table 3: Bacteriological response to treatment of complicated urinary tract infections, pefloxacin compared to cefotaxime.

ii!i!ii ilii!iiii? iii!iiliiiiiiiii ; ii!?iiiiil}IIIIN!iiiiiiii}i iiiiNiiii iNNiii i During treatment

Eradication Persistence Relapse Reinfection Unassessable 48 h after treatment Eradication Persistence Relapse Reinfection Unassessable 1 week after therapy Eradication Persistence Relapse Reinfection Unassessable 4--6 weeks after therapy Eradication Persistence Relapse Reinfection Unassessable

40 / 36

27 (93) 2 (7)

16 (94) 1 (6)

2 28 (96)

1 16 (89)

1 (4) 2 22 (92)

2 (11)

2 (8)

2 (18)

7 13 (68)

7 8 (80)

5 (26) 1 (6) 12

2 (20) 8

9 (82)

pefloxacin group vs. 82% (9/11) in the cefotaxime group. Subsequent cultures performed four to six weeks after therapy showed eradication rates to be similar in both groups. Relapse after one week of therapy occurred twice in both study groups; in one patient with renal calculi complicated by a urinary tract infection caused by Escherichia coli and in one with epididymitis caused by P. aeruginosa in the pefloxacin group; in the cefotaxime group both relapses were caused by E. coti, in one patient with obstructive pyelonephritis and in one with an indwelling urinary catheter. In total four to six weeks after therapy five relapses and one reinfection occurred in the pefloxacin group, while two reinfections occurred in the cefotaxime group. In the pefloxacin patients relapses were due to E. coli strains (n=5) sensitive to pefloxacin; three patients with pyelonephritis (one with renal calculi) and two patients with urinary tract calculi. One reinfection caused by a S. epidermidis strain occurred in a patient with a carcinoma of the bladder. In the cefotaxime group one reinfection occurred in a patient with a carcinoma of the bladder and one in a patient with prostate hypertrophy: both infections were caused by enterococci. At the end of treatment clinical cure rate was 97% (30/31) in the pefloxacin group compared to 89% (16/18) in the cefotaxime group. Patients with negative pretherapy urine cultures showed a clinical cure rate of 93% (14/15) in the pefloxacin group and 100% (9/9) in the cefotaxime group at the end of treatment. Since improvement during therapy was 90% vs. 78%, earlier resolution of symptoms was seen in the pefloxacin group compared to the cefotaxime group. An explanation for this phenomenon was not found. Adverse effects in patients treated with pefloxacin (n = 18) included eosinophilia with low-grade fever in one patient, which resolved after discontinuation of treatment. Other adverse effects included rash (n= 1), headache (n= 1), nausea (n= 1) and vomiting (n= 1). In the cefotaxime group one patient developed a rash that disappeared within 36 h after discontinuation of treatment. The rate of phlebitis was the same in both study groups: pefloxacin 23% (7/31) vs. cefotaxime 22% (4/18). Discussion Recent studies have shown good clinical efficacy for 4-fluoroquinolones in the treatment of complicated urinary tract infections [1,8-10]. The usefulness of these agents is attributed to their excellent pharmacokinetic properties [4] and broad antibacterial spectrum including strains of the family of Enterobacteriaceae, Pseudomonas spp. as well as gram- positive microorganisms [2,4]. Due to their especially good absorption after oral administration, prolonged high urinary levels and high tissue concentrations, 4-fluoroquinolones are particularly well suited for the treatment of urinary tract infections. Pefloxacin has in addition to these properties the advantage of a prolonged serum half-life, which allovJs a

Infection 20 (1992) No. 1 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1992

C. Timmerman et al.: Pefloxacin vs. Cefotaxime in Complicated UTI reduction in the n u m b e r of dosages to one or two a day, which possibly has a positive influence on patients' compliance. Moreover, therapy can be continued orally after initial p a r e n t e r a l therapy. This study presents an open, r a n d o m i z e d c o m p a r i s o n b e t w e e n pefloxacin and cefotaxime in the t r e a t m e n t of complicated urinary tract infections. T h e overall rate of bacteriological response, defined as cure or reinfection, was 96% (28/29) in the pefloxacin group and 89% (16/18) in the cefotaxime group 48 h after the end of therapy, while one w e e k after end of t r e a t m e n t , r e s p o n s e rates were 92% (22/24) vs. 82% (9/11), respectively. Similar bacteriological r e s p o n s e rates have b e e n shown in other studies on 4- fluoroquinolones and [5-1actam antibiotics in patients with complicated urinary tract infections [1,5,8--12]. Concerning the clinical cure during t r e a t m e n t in both study groups, a 90% i m p r o v e m e n t rate was seen in the pefloxacin group, while in the cefotaxime group 78% of the patients showed clinical i m p r o v e m e n t . At the end of t r e a t m e n t both groups were c o m p a r a b l e , with 97% in the pefloxacin group clinically cured vs. 89% in the cefotaxime

References

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group. It has thus b e e n shown that oral t r e a t m e n t of complicated urinary tract infections with pefloxacin gave clinical results c o m p a r a b l e with intravenous therapy, as has b e e n shown in o t h e r studies [9]. Side effects, including eosinophilia ( n = 1), rash ( n = 1), vomiting (n = 1), n a u s e a (n = 1) and h e a d a c h e (n = 1) were seen in the pefloxacin group. O n e patient receiving cefotaxime developed a rash. In a study by Halkin [13] adverse effects were seen in 4 % - 8 % of the cases. This is c o m p a r a b l e to the rate of adverse effects seen with third-generation cephalosporins [14]. In our study all side effects were reversible after discontinuation of the study drug. It can be concluded that quinolones are as safe as cephalosporins. In conclusion, we showed that pefloxacin is as effective as cefotaxime in the t r e a t m e n t of complicated urinary tract infections. Acknowledgements

We thank Mrs. T. Branger for assistance in the collection and evaluation of the data.

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