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Cinoxacin in therapy of urinary tract infections comparison of two dosage regimens
CINOXACIN
IN THERAPY
OF URINARY TRACT
INFECTIONS* Comparison C. E. COX,
of Two Dosage Regimens
M.D.
J. R. SIMMONS From the Department of Urology, School of Medicine, University of Tennessee Center for the Health Sciences, Memphis, Tennessee
- Two dosage regimens of cinoxacin, 250 mg. four times a day (QZD) versus 500 mg. twice a day (BID), were compared fn- efficacy and safety in the treatment of initial and recurrent urinary tract infections. Patient dosage assignments were by a random table. Analysis of the 91 evaluable adult patients showed no difference between the two regimens, each group having 98 per cent bacteriologic cures at the f&e-to-nine-day post-therapy culture. The incidence of side effects was low and mild in degree.
ABSTRACT
Cinoxacin is a new antimicrobial agent for oral administration. This synthetic organic compound was first subjected to bacteriologic evaluation in 1973 and was shown to be effective against gram-negative bacteria commonly found in urinary tract infections. 1 Later studies supported these initial findings. 2-4 Pathogens susceptible to cinoxacin include Escherichia coli, Klebsiella species, Enterobacter species, Proteus mirabilis, and other indole-positive Proteus strains. Early clinical investigation of cinoxacin indicated a need to compare the safety and efficacy of two dosage regimens in the therapy of urinary tract infections caused by susceptible organisms. Thus, qualified inpatients and outpatients were assigned by a computer-generated random table to cinoxacin 250 mg. four times a day or 500 mg. twice daily for fourteen days. Our study demonstrated no significant difference in the therapeutic results, the safety, or the efficacy of cinoxacin therapy based on the dosage schedules used. *Supported by a grant from Lilly Research Laboratories, Indianapolis, Indiana.
UROLOGY
/ JUNE 1931 / VOLUME
XVII, NUMBER 6
Material and Methods One hundred ten patients with urinary tract infections were entered into the study; 55 were assigned to cinoxacin therapy of 250 mg. four times a day for fourteen days and 55 to 500 mg. twice a day for fourteen days. Urinary tract infection was confirmed by quantitative cultures from pretherapy urine specimens that revealed at least 100,000 bacteria per milliliter of urine. Susceptibility of the cultured organisms was determined according to the standardized FDA disk diffusion method utilizing a 30-mg. cinoxatin disk and an inhibition zone diameter of greater than 13 mm. Serious complications such as neurogenic bladder, bilateral staghorn calculi, or other major disorders were criteria for exclusion from the study. Also excluded were those patients with known or suspected renal or hepatic impairment and pregnant females. Written informed consent was obtained from all participants prior to administration of cinoxacin. Bacteriologic efficacy was assessed by quantitative cultures of urine obtained at the following times: (1) three to four days after initiation of
539
TABLE I.
_____________~_--_~~_--~--~
Bacteriologic results* of cinosna’n tlzempy in 91 patients tract infections randomized into two tlosclge .schedules
Total
Infecting Species ---____ E. coli Klebsiella P. lnirabilis P. vulgaris Enterobacter Serratia
37 19 23 6 5 -1
TOTALS 91 __-______---~-__-~~~--__-*Cure
= pathogen
eradicated;
250 mg. QID No.
NO.
failure
Cure
500 mg. BID
Failure
No.
Cure
Failure
13
13
0
24
23
13 13
12 13
1
0
6 10
6 10
1 0 0
4 2
4 2
0 0
e 3
2 3
0 0
- 1
- 1
-0
46
45(987@)
= pathogen
2
1
0
45
i&98%)
0
1
not eradicated.
cinoxacin therapy; (2) five to nine days posttherapy; and (3) four to six weeks post-therapy. Close observation was maintained for evidence of clinical response. Monitoring for adverse reactions, either side effects or toxicity, occurred prior to treatment (by the taking of a history and a physical examination) and during treatment and post-treatment coincident with the timing of urine cultures. Participants were asked to report any side effects they might be experiencing. Studies for toxicity included complete blood cell count, chemistry profile (blood urea nitrogen, serum creatinine, bilirubin, serum glutamic oxaloacetic transaminase, alkaline phosphatase) and urinalysis. Results One hundred ten patients were entered in the study. In 19 of these cases the patient failed to return for a sufficient number of visits to evaluate response. Therefore, 91 patients completed the study requirements and were available for evaluation for safety and efficacy. Of these, 46 received cinoxacin in a 250-mg. dose four times a day and 45 received 500 mg. twice a day. Participants ranged in age from eighteen to eighty-nine years, with a median age of fiftysix. There were 46 males and 45 females with evaluable results. Fifty-four patients had an initial urinary tract infection having had no history of a urinary tract infection in the last twelve months, and 37 had a recurrent urinary tract infection having had one or more infections in the preceding twelve months. Urologic complications were present in 23 of the patients. A complicated urinary tract infection was defined as one in which the integrity of the urinary tract was impaired or a foreign body was present. The remaining 68 patients had uncomplicated infections.
540
with wincq
The 91 infections evaluated for efficacy were due to the following organisms: 37 E. coli, 19 Klebsiella, 23 P. mirabilis, 6 Proteus vulgaris, 5 Enterobacter, and 1 Serratia (Table I). All organisms were susceptible to cinoxacin. In 45 of the 46 patients (98 per cent) treated with 250 mg. four times daily the infecting organism was eradicated at the five-to-nine-day post-therapy urine culture. In 44 of the 45 patients (98 per cent) treated with 500 mg. twice daily the infecting organism was eliminated at the five-tonine-day post-therapy culture. All who had a satisfactory bacteriologic response also had a satisfactory clinical response, i.e., the disappearance or improvement of symptoms related to their infection. There was one bacteriologic failure on each of the dosage schedules: one an infection caused by E. coli and one by Klebsiella. Bacteriologic failure was reported when the infecting pathogen was not eliminated at the time of the fiveto-nine-day post-therapy culture. The E. coli infection that failed to respond to therapy was uncomplicated, but recurrent, and had been assigned to the 500-mg. dosage schedule. The Klebsiella infection that failed to respond was associated with an underlying complication, but was initial. This patient received the 250-mg. dosage schedule and had a satisfactory clinical response. Tolerance of cinoxacin was good, with only 5 of the 110 participants experiencing problems. Three patients reported nausea and one reported nausea and dizziness. In these cases cinoxacin therapy was discontinued. Of the four reporting nausea and/or dizziness, two had received the 250-mg. dosage and two were on the 500-mg. schedule. The fifth patient noted to have an adverse reaction had an elevated BUN. Whether or not this was drug related could
UROLOGY
/ JUNE
1981
/
VOLUSfE XVII, NUMBER 6
not be determined, continued.
and the drug was not dis-
Comment The desirable features of a good antimicrobial agent are a wide spectrum of activity against common causative pathogens, high urinary concentrations, ease of administration, and relative freedom from side effects and toxicity.5*6 Our data and that of other investigators indicate that cinoxacin has these properties at either of the two dosage schedules investigated.4 Cinoxacin therapy was both safe and effective in the treatment of both complicated and uncomplicated gram-negative urinary tract infections. The over-all bacteriologic response rate was 98 per cent for both dosage schedules, and clinical response was satisfactory in all who had a successful bacteriologic response. Incidence of side effects was not a significant problem, with only 4.5 per cent of the participants experiencing adverse reactions. Since no difference was discernible in the safety and efficacy of cinoxatin between the two dosage regimens used in this study and in others, it is reasonable to assume that patients with susceptible urinary
UROLOGY
/ JUNE 1981
/ VOLUME
XVII, NUMBER
6
tract infections treated with the 500 mg. twice daily would achieve a satisfactory. therapeutic result. Our experience indicated that reducing the required number of daily doses improves patient compliance with dosage instructions and thus, the probability of a successful course of therapy is increased. FvIemphis, ACKNOWLEDGMENTS.
Tennessee
To Ms. Cornelia
38163
McIlvain
for
clinical assistance. References 1. Wick WE, Preston DA, White WA, and Cordee RS: Compound 64716, a new synthetic antihacteri‘d agent, Antimicrob. Agents Chemother. 4: 415 (.1973). in vitro anti2. Lumish RM, and Norden CE: Cinoxacin: bacterial studies of a new synthetic organic acid, ihid. 7: 159 (1975). 3. Landes RR, and Hall JW: Cinoxacin: new antimicrobial agent for urinary tract infections, Urology 10: 312 (19771. 4. Rous SN: Cinoxacin in the treatment of acute urinary tract infections: an evaluation of efftcacy and a comparison of dosage schedules, J. Ural. 120: 196 (1978). 5. McCabe WR, and Jackson CC: Treatment of pyelonephritis: bacterial, drug and host factors in success or failure among 252 patients, N. Engl. J. Med. 272: 1037 (1965). 6. Stamey TA, et (I/: Serum versus urinary antimicrobial concentrations in cure of urinary tract infections, ihid. 291: 1159 (1974).
541
IN THERAPY
OF URINARY TRACT
INFECTIONS* Comparison C. E. COX,
of Two Dosage Regimens
M.D.
J. R. SIMMONS From the Department of Urology, School of Medicine, University of Tennessee Center for the Health Sciences, Memphis, Tennessee
- Two dosage regimens of cinoxacin, 250 mg. four times a day (QZD) versus 500 mg. twice a day (BID), were compared fn- efficacy and safety in the treatment of initial and recurrent urinary tract infections. Patient dosage assignments were by a random table. Analysis of the 91 evaluable adult patients showed no difference between the two regimens, each group having 98 per cent bacteriologic cures at the f&e-to-nine-day post-therapy culture. The incidence of side effects was low and mild in degree.
ABSTRACT
Cinoxacin is a new antimicrobial agent for oral administration. This synthetic organic compound was first subjected to bacteriologic evaluation in 1973 and was shown to be effective against gram-negative bacteria commonly found in urinary tract infections. 1 Later studies supported these initial findings. 2-4 Pathogens susceptible to cinoxacin include Escherichia coli, Klebsiella species, Enterobacter species, Proteus mirabilis, and other indole-positive Proteus strains. Early clinical investigation of cinoxacin indicated a need to compare the safety and efficacy of two dosage regimens in the therapy of urinary tract infections caused by susceptible organisms. Thus, qualified inpatients and outpatients were assigned by a computer-generated random table to cinoxacin 250 mg. four times a day or 500 mg. twice daily for fourteen days. Our study demonstrated no significant difference in the therapeutic results, the safety, or the efficacy of cinoxacin therapy based on the dosage schedules used. *Supported by a grant from Lilly Research Laboratories, Indianapolis, Indiana.
UROLOGY
/ JUNE 1931 / VOLUME
XVII, NUMBER 6
Material and Methods One hundred ten patients with urinary tract infections were entered into the study; 55 were assigned to cinoxacin therapy of 250 mg. four times a day for fourteen days and 55 to 500 mg. twice a day for fourteen days. Urinary tract infection was confirmed by quantitative cultures from pretherapy urine specimens that revealed at least 100,000 bacteria per milliliter of urine. Susceptibility of the cultured organisms was determined according to the standardized FDA disk diffusion method utilizing a 30-mg. cinoxatin disk and an inhibition zone diameter of greater than 13 mm. Serious complications such as neurogenic bladder, bilateral staghorn calculi, or other major disorders were criteria for exclusion from the study. Also excluded were those patients with known or suspected renal or hepatic impairment and pregnant females. Written informed consent was obtained from all participants prior to administration of cinoxacin. Bacteriologic efficacy was assessed by quantitative cultures of urine obtained at the following times: (1) three to four days after initiation of
539
TABLE I.
_____________~_--_~~_--~--~
Bacteriologic results* of cinosna’n tlzempy in 91 patients tract infections randomized into two tlosclge .schedules
Total
Infecting Species ---____ E. coli Klebsiella P. lnirabilis P. vulgaris Enterobacter Serratia
37 19 23 6 5 -1
TOTALS 91 __-______---~-__-~~~--__-*Cure
= pathogen
eradicated;
250 mg. QID No.
NO.
failure
Cure
500 mg. BID
Failure
No.
Cure
Failure
13
13
0
24
23
13 13
12 13
1
0
6 10
6 10
1 0 0
4 2
4 2
0 0
e 3
2 3
0 0
- 1
- 1
-0
46
45(987@)
= pathogen
2
1
0
45
i&98%)
0
1
not eradicated.
cinoxacin therapy; (2) five to nine days posttherapy; and (3) four to six weeks post-therapy. Close observation was maintained for evidence of clinical response. Monitoring for adverse reactions, either side effects or toxicity, occurred prior to treatment (by the taking of a history and a physical examination) and during treatment and post-treatment coincident with the timing of urine cultures. Participants were asked to report any side effects they might be experiencing. Studies for toxicity included complete blood cell count, chemistry profile (blood urea nitrogen, serum creatinine, bilirubin, serum glutamic oxaloacetic transaminase, alkaline phosphatase) and urinalysis. Results One hundred ten patients were entered in the study. In 19 of these cases the patient failed to return for a sufficient number of visits to evaluate response. Therefore, 91 patients completed the study requirements and were available for evaluation for safety and efficacy. Of these, 46 received cinoxacin in a 250-mg. dose four times a day and 45 received 500 mg. twice a day. Participants ranged in age from eighteen to eighty-nine years, with a median age of fiftysix. There were 46 males and 45 females with evaluable results. Fifty-four patients had an initial urinary tract infection having had no history of a urinary tract infection in the last twelve months, and 37 had a recurrent urinary tract infection having had one or more infections in the preceding twelve months. Urologic complications were present in 23 of the patients. A complicated urinary tract infection was defined as one in which the integrity of the urinary tract was impaired or a foreign body was present. The remaining 68 patients had uncomplicated infections.
540
with wincq
The 91 infections evaluated for efficacy were due to the following organisms: 37 E. coli, 19 Klebsiella, 23 P. mirabilis, 6 Proteus vulgaris, 5 Enterobacter, and 1 Serratia (Table I). All organisms were susceptible to cinoxacin. In 45 of the 46 patients (98 per cent) treated with 250 mg. four times daily the infecting organism was eradicated at the five-to-nine-day post-therapy urine culture. In 44 of the 45 patients (98 per cent) treated with 500 mg. twice daily the infecting organism was eliminated at the five-tonine-day post-therapy culture. All who had a satisfactory bacteriologic response also had a satisfactory clinical response, i.e., the disappearance or improvement of symptoms related to their infection. There was one bacteriologic failure on each of the dosage schedules: one an infection caused by E. coli and one by Klebsiella. Bacteriologic failure was reported when the infecting pathogen was not eliminated at the time of the fiveto-nine-day post-therapy culture. The E. coli infection that failed to respond to therapy was uncomplicated, but recurrent, and had been assigned to the 500-mg. dosage schedule. The Klebsiella infection that failed to respond was associated with an underlying complication, but was initial. This patient received the 250-mg. dosage schedule and had a satisfactory clinical response. Tolerance of cinoxacin was good, with only 5 of the 110 participants experiencing problems. Three patients reported nausea and one reported nausea and dizziness. In these cases cinoxacin therapy was discontinued. Of the four reporting nausea and/or dizziness, two had received the 250-mg. dosage and two were on the 500-mg. schedule. The fifth patient noted to have an adverse reaction had an elevated BUN. Whether or not this was drug related could
UROLOGY
/ JUNE
1981
/
VOLUSfE XVII, NUMBER 6
not be determined, continued.
and the drug was not dis-
Comment The desirable features of a good antimicrobial agent are a wide spectrum of activity against common causative pathogens, high urinary concentrations, ease of administration, and relative freedom from side effects and toxicity.5*6 Our data and that of other investigators indicate that cinoxacin has these properties at either of the two dosage schedules investigated.4 Cinoxacin therapy was both safe and effective in the treatment of both complicated and uncomplicated gram-negative urinary tract infections. The over-all bacteriologic response rate was 98 per cent for both dosage schedules, and clinical response was satisfactory in all who had a successful bacteriologic response. Incidence of side effects was not a significant problem, with only 4.5 per cent of the participants experiencing adverse reactions. Since no difference was discernible in the safety and efficacy of cinoxatin between the two dosage regimens used in this study and in others, it is reasonable to assume that patients with susceptible urinary
UROLOGY
/ JUNE 1981
/ VOLUME
XVII, NUMBER
6
tract infections treated with the 500 mg. twice daily would achieve a satisfactory. therapeutic result. Our experience indicated that reducing the required number of daily doses improves patient compliance with dosage instructions and thus, the probability of a successful course of therapy is increased. FvIemphis, ACKNOWLEDGMENTS.
Tennessee
To Ms. Cornelia
38163
McIlvain
for
clinical assistance. References 1. Wick WE, Preston DA, White WA, and Cordee RS: Compound 64716, a new synthetic antihacteri‘d agent, Antimicrob. Agents Chemother. 4: 415 (.1973). in vitro anti2. Lumish RM, and Norden CE: Cinoxacin: bacterial studies of a new synthetic organic acid, ihid. 7: 159 (1975). 3. Landes RR, and Hall JW: Cinoxacin: new antimicrobial agent for urinary tract infections, Urology 10: 312 (19771. 4. Rous SN: Cinoxacin in the treatment of acute urinary tract infections: an evaluation of efftcacy and a comparison of dosage schedules, J. Ural. 120: 196 (1978). 5. McCabe WR, and Jackson CC: Treatment of pyelonephritis: bacterial, drug and host factors in success or failure among 252 patients, N. Engl. J. Med. 272: 1037 (1965). 6. Stamey TA, et (I/: Serum versus urinary antimicrobial concentrations in cure of urinary tract infections, ihid. 291: 1159 (1974).
541