0022-5347 /92/14 74-1053$03.00/0 Vol. 147, 1053-1055, Aprii 1992 Printed in U.S.A.
THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
PREVENTION OF URINARY TRACT INFECTION AND BACTEREMIA FOLLOWING TRANSURETHRAL SURGERY: ORAL LOMEFLOXACIN COMPARED TO PARENTERAL CEFOTAXIME E. DAVID CRAWFORD, NANCY S. BERGER, MARILYN A. DAVIS
AND
ROBERT E. DONOHUE
From the Department of Veterans Affairs, University of Colorado Health Sciences Center, Denver, Colorado
ABSTRACT
A multicenter, randomized, open label study compared the safety and efficacy of a single dose of oral lomefloxacin, a broad-spectrum antimicrobial agent of the quinolone class, to a single parenteral dose of cefotaxime, a third generation cephalosporin, for prophylaxis in transurethral surgery. Of the 230 patients initially recruited 182 were considered evaluable: 92 in the lomefloxacin group and 90 in the cefotaxime group. Both study groups were well balanced with respect to demographics and transurethral procedures. Efficacy and safety were evaluated with urine cultures, clinical laboratory evaluations and monitoring of adverse events. The success rate among the lomefloxacin patients was 98% versus 94% in the cefotaxime patients. The difference was not statistically significant. Adverse events, regardless of attributability, were reported by 16% of the lomefloxacin patients and 17% of the cefotaxime patients, respectively. Our results indicate efficacy and safety profiles of lomefloxacin equivalent to cefotaxime. Lomefloxacin has the economic advantage of an oral route of administration compared to the parenteral route of cefotaxime for prophylaxis in transurethral genitourinary procedures. KEY WORDS: urinary tract infection, hydroxyquinolones, septicemia
The role of prophylactic antibiotics in decreasing the rate of infectious complications of transurethral surgery remains controversial. Chodak and Plaut reviewed antibiotic prophylaxis in urological surgery and noted several weaknesses of previous studies, including retrospective nature, lack of appreciation of ongoing infection, lack of postoperative cut-off date for infection, inappropriate drugs and dosing schedules, small number of study subjects and uncontrolled study designs. 1 In recent clinical trials preoperative urinary tract infection was not well defined nor was there a specified time frame in which the preoperative urine culture was obtained. 2 Others concluded that effective antibiotic prophylaxis for a transurethral genitourinary operation can significantly decrease the rate of nosocomial urinary tract infections and bacteremia. 3 - 5 Due to design flaws of previous clinical trials the indication for antibiotic prophylaxis in the patient undergoing a transurethral operation remains unclear. The efficacy of the third generation of cephalosporins in preventing postoperative urinary tract infections has been documented. 5· 6 More recently, the use of the fluoroquinolone class of antimicrobials has been recommended for prophylaxis before a transurethral operation. 7 • 8 Lomefloxacin is a synthetic, broadspectrum antibacterial agent of the quinolone class of antimicrobials. High urine concentrations of lomefloxacin are achieved after a single 400 mg. dose, with urine levels greater than 127 µg./ml. found 12 to 24 hours after administration. 9 Lomefloxacin has a long half-life (approximately 8 hours) and excellent tissue penetration. 9 • 10 Lomefloxacin is active against a variety of organisms, including those found in the urinary tract, such as Klebsiella species, Escherichia coli and Pseudomonas aeruginosa. 11 Cefotaxime is a parenteral, third generation cephalosporin that is approved in the United States for prophylaxis before a genitourinary operation. It is a broad-spectrum antibiotic with activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime has a half-life of approximately 1 hour. Administered preoperatively, it has been shown to decrease the incidence of infections in patients undergoing surAccepted for publication August 9, 1991. Supported by G. D. Searle & Co.
gery (such as a genitourinary tract operation) that may be classified as contaminated or potentially contaminated. To evaluate the safety and efficacy of lomefloxacin in the prophylaxis of urinary tract infections after a transurethral procedure a multicenter phase 3 study was initiated. MATERIALS AND METHODS
This multicenter, prospectively randomized, open label, controlled study was designed to evaluate the safety and efficacy of a single oral dose of lomefloxacin versus a single parenteral dose of cefotaxime as prophylactic agents in transurethral genitourinary surgery. Eligibility criteria included men or women 18 years old or older, inpatients or outpatients requiring a transurethral genitourinary operation and negative urine culture (10 4 colony-forming units per ml. or less) obtained within 48 hours preoperatively. Ineligible patients had a history of hypersensitivity to penicillins or cephalosporins, antimicrobial therapy within 72 hours before enrolling in the study, an indwelling urinary catheter for 4 or more days preoperatively (due to the possibility of bacterial resistance developing in these patients), or impaired renal and/or hepatic function. Patients undergoing simple cystoscopy were not eligible for the study. Written informed consent was obtained from each patient before study participation. Patients were randomly assigned to treatment in consecutive order based on a computer generated code in a 1:1 fashion. Patients randomized to lomefloxacin received 2, 200 mg. capsules 2 to 6 hours preoperatively and at least 1 hour before the preoperative medications. Patients randomized to cefotaxime received 1 gm. via intravenous piggyback or intramuscular injection 30 to 90 minutes preoperatively. Laboratory parameters assessed included urine cultures obtained within 48 hours preoperatively, 24 hours postoperatively, immediately before removal of the Foley catheter and at discharge from the hospital or on postoperative day 5. All cultures were collected by clean-catch, midstream technique when a Foley catheter was not indwelling. Chemistry and hematology evaluations, including liver function tests, serum creatinine, electrolytes and a complete blood count, were obtained preop-
1053
CRAWFORD AND ASSOCIATES
1054
eratively and 3 to 5 days postoperatively. Urinalysis was per- patient age or body weight. In the lomefloxacin group 90 of the 92 evaluable patients were considered to have a treatment formed preoperatively and postoperatively. Clinical assessments were performed preoperatively and success, compared to 85 of 90 in the cefotaxime group. This postoperatively for signs and symptoms of urinary tract infec- difference is not statistically significant. tion. Highest daily temperature, duration of indwelling catheSignificant bacteriuria, classified as treatment failure ter, adverse events and postoperative complications were re- (greater than 105 colony-forming units per ml.), was observed corded. Fever was defined as an oral temperature of 100.4F postoperatively in 7 patients: 2 in the lomefloxacin group and (38C) or greater. Identification and susceptibility testing was 5 in the cefotaxime group (table 3). Pathogens occurring in the performed on all isolates with a colony count of 105 colony- 2 lomefloxacin patients were enterococcus in 1 and P. aerugiforming units per ml. or greater. Additional urine or blood nosa in 1. Of the 2 lomefloxacin treatment failures, suscepticultures were obtained if the patient was febrile, or exhibited bility data to an alternative antibiotic were not available in 1 other signs or symptoms of infection. Success was defined as a patient, while in 1 the second pathogen was of intermediate pathogen count of less than 105 colony-forming units per ml. susceptibility to lomefloxacin and resistant to cefotaxime. from all urine cultures obtained within 5 days postoperatively. Pathogens occurring in the 5 cefotaxime patients were enteroFaiture was-definetlas-isolation-of-1()5-cohmy fmming units-per -- co-ccus (2-p-ati-entsJ, Staphylococcus-aureus-;-Enterohacter cloa0 ml. or greater of pathogens from any postoperative urine culture cae and P. aeruginosa. Of the 5 cefotaxime treatment failures the pathogen in 1 patient was susceptible to lomefloxacin and or bacteremia. cefotaxime. Another cefotaxime treatment failure was in a RESULTS patient with P. aeruginosa that was susceptible to lomefloxacin A total of 230 patients was entered into the study (118 in the and of intermediate susceptibility to cefotaxime. In the other 3 lomefloxacin group and 112 in the cefotaxime group). Of the treatment failures in this group susceptibility testing in 1 patients 182 were considered evaluable for analysis of efficacy patient was not available, while in 1 the pathogen was suscep(92 in the lomefloxacin group and 90 in the cefotaxime group). tible to lomefloxacin and cefotaxime, and in 1 the pathogen Among the 230 patients entered in the study, the breakdown was resistant to lomefloxacin and cefotaxime. All susceptibility by sex was 112 (95%) men and 6 (5%) women in the lomeflox- testing was done by the Kirby-Bauer technique. There were no acin group, and 109 (97%) men and 3 (3%) women in the documented cases of bacteremia in either treatment group. The incidence of adverse experiences within the 2 treatment cefotaxime group. Reasons for inevaluability are listed in table groups was not statistically different (p = 0.861). Adverse 1. A summary of the surgical procedures is presented in table 2. Transurethral resection of the prostate was the most common reactions were reported for 19 (16%) lomefloxacin patients and procedure in both groups. Of the 118 lomefloxacin patients and 19 (17%) cefotaxime patients. None of these adverse events the 112 cefotaxime patients 68 and 49, respectively, underwent reported was considered by the investigator to be related to the prostate resection. Among the 182 evaluable patients transure- study drug. The most common adverse event was nausea (lothral prostatic resection was performed on 57 of 92 in the mefloxacin 4% and cefotaxime 2%). Patients also underwent lomefloxacin group and 39 of 90 in the cefotaxime group. Other anesthesia and the contribution of anesthesia to this side effect procedures included bladder biopsy, bladder tumor resection remains conjectural. One patient in each treatment group experienced a serious and transurethral prostatic biopsy. There were no significant differences between the 2 treatment groups with respect to sex, adverse event and both were withdrawn from the study. The serious adverse event in the lomefloxacin patient (dyspnea) was considered by the investigator to be related to administraTABLE 1. Protocol deviations resulting in patient inevaluability tion of preoperative medication and not attributable to the Cefotaxime study drug. The serious adverse event in the cefotaxime patient Lomefloxacin (a possible cerebrovascular accident) was considered by the 1 1 Baseline culture missing investigator to be of uncertain relation to cefotaxime. There 3 2 Urinary tract infection at baseline 0 4 Baseline culture not within 48 hrs. were no significant differences in laboratory values between of surgery the 2 treatment groups (p >0.05 for all comparisons). Several 5 4 Final culture taken too early patients in each treatment group experienced changes in labo7 10 No final culture ratory values that were believed to be clinically significant but 4 6 Indwelling catheter 4 days or longer of no relationship to the study drug. 0
Concomitant systemic antimicrobial Concomitant medication No surgery Total inevaluable
4
6
0 6
1
DISCUSSION
2
26
22
Postoperative urinary tract infection can present significant risks to the patient. A urinary tract infection in an older patient is often complicated. Gram-negative bacteria are the predominant pathogens in these infections. A patient who has bacteremia from a nosocomial urinary tract infection has a 10% chance of mortality. 3 The overall incidence of bacteriuria after
Note, reasons are not mutually exclusive. TABLE
2. Types of operations performed Lomefloxacin
Procedure
(400 mg. orally)
No.(%) Prostate resection Bladder cauterization Bladder biopsy Bladder neck resection Stone basket extraction Prostate biopsy (transurethral) Bladder resection Other All procedures No surgery
68 (44) 1 10 4 4
(1) (6) (3) (3)
6
(4)
7 (4) 56 (36) 156 (100)
6
Note, the procedures are not mutually exclusive.
Cefotaxime (1 gm. intravenously /intramuscularly) No.(%) 49 (38) 0 (O) 11 (9) 2 (2) 2 (2) 7 (5)
TABLE 3.
Treatment failures
Lomefloxacin Pt. No.
Organism
1
Greater than 106 P. aeruginosa (4 days postop.) Greater than 105 enterococcus (6 days postop.)
2
Cefotaxime Pt. No.
2
14 (11) 45 (35)
3
130 (100)
4
2
5
Organism Greater than 105 enterococcus (5 days postop.) Greater than 105 P. aeruginosa (3-5 days postop.) Greater than 105 E. cloacae (4 days postop.) Greater than 105 enterococcus (6 days postop.) Greater than 105 Staph. aureus (4 days postop.)
URINARY TRACT INFECTION AND BACTEREMIA AFTER TRANSURETHRAL SURGERY
a transurethral operation when no antimicrobial prophylaxis agent is used has been reported to range from 26 to 70%. 12 - 14 This broad range of postoperative bacteriuria could be due to the fact that in various previous studies preoperative urine cultures were not part of the eligibility criteria. For prophylaxis in transurethral surgery a single preoperative oral dose of 400 mg. lomefloxacin was as efficacious as a single 1 gm. parenteral dose of cefotaxime in preventing postoperative urinary tract infections. No significant difference existed in patients receiving lomefloxacin or cefotaxime. Lomefloxacin is the first once a day quinolone antimicrobial offering the advantages of oral therapy with efficacy that is equal to parenteral cefotaxime. Additionally, it has the advantage of having no cross-reactivity in patients allergic to penicillin. In conclusion, single dose therapy with lomefloxacin is well tolerated and appears to be equally as effective as cefotaxime in ameliorating the incidence of postoperative urinary tract infections in patients undergoing a transurethral genitourinary operation, with the advantage of oral administration and lower cost. The patients reported were treated at the San Juan Veterans Administration Medical Center (Dr. C. Ramirez-Ronda), Louisville Veterans Administration Medical Center (Dr. M. Amin), University of Colorado Health Sciences Center (E. D. C.), University of Tennessee Medical Center (Dr. C. Cox) and Louisiana State University Medical Center (Dr. D. Culkin). REFERENCES 1. Chodak, G. W. and Plaut, M. E.: Systemic antibiotics for prophy-
2. 3. 4. 5.
6. 7.
8. 9. 10.
11. 12.
laxis in urologic surgery: a critical review. J. Urol., 121: 695, 1979. Shah, P. J. R., Williams, G. and Chaudary, M.: Short-term antibiotic prophylaxis and prostatectomy. J. Urol., 53: 339, 1981. Childs, S. J.: Appropriate surgical prophylaxis in transurethral genitourinary surgery and potential reduction in nosocomial infections. Urology, 27: 415, 1986. Nielsen, 0. S., Maigaard, S., Frimodt-M01ler, N. and Madsen, P. 0.: Prophylactic antibiotics in transurethral prostatectomy. J. Urol., 126: 60, 1981. Williams, M., Hole, D. J., Murdoch, R. W. G., Ogden, A. C. and Hargreave, T. B.: 48-hour cephradrine and post-prostatectomy bacteriuria. Brit. J. Urol., 52: 311, 1980. Childs, S. J., Wood, P. D. and Kosola, J. W.: Antibiotic prophylaxis in genitourinary surgery. A comparison of cefotaxime and cefazolin. Clin. Ther., suppl. A, 5: 48, 1982. Desai, K. M., Abrams, P. H. and White, L. 0.: A double-blind comparative trial of short-term orally administered enoxacin in the prevention of urinary infection after elective transurethral prostatectomy: a clinical and pharmacokinetic study. J. Urol., 139: 1232, 1988. Hellsten, S., Forsgren, A., Bjork, T. and Grabe, M.: Use of ciprofloxacin in patients undergoing transurethral prostatic surgery. Scand. J. Infect. Dis., suppl., 60: 104, 1989. Morrison, P. J.: Single and multiple dose pharmacokinetics of lomefloxacin: rationale for once-a-day dosing. Unpublished data. Klimberg, I. W. and Chiids, S. J.: Penetration of lomefloxacin into the prostate. Unpublished data. Jones, R. N.: Lomefloxacin international surveillance trial: 20month report. Unpublished data. Prokocimer, P., Quazza, M., Gibert, C., Lemoine, J. E., Joly, M. L., Dureuil, B., Moulonguet, A., Manuel, C. and Desmonts, J. M.: Short-term prophylactic antibiotics in patients undergoing prostatectomy: report of a double-blind randomized trial with 2 intravenous doses of cefotaxime. J. Urol., 135: 60, 1986.
1055
13. Falkiner, F. R., Ma, P. T. S., Murphy, D. M., Cafferkey, M. T. and Gillespie, W. A.: Antimicrobial agents for the prevention of urinary tract infection in transurethral surgery. J. Urol., 129: 766, 1983. 14. Stamey, T. A.: Pathogenesis and Treatment of Urinary Tract Infections. Baltimore: Williams & Wilkins, p. 592, 1980.
EDITORIAL COMMENTS This is not a study to answer the question as to whether prophylactic antibiotics lessen the infectious complications oftransurethral surgery. Indeed, most physicians believe that if the urine is uninfected and the patient is not catheterized before a transurethral operation antibiotics are not necessary. Instead, the authors are comparing 2 antibiotics to determine safety and efficacy of a single-dose treatment with the 2 drugs. They conclude that there is no statistical difference between the 2 drugs tested. To get around type 1 error, they have randomized the patients using a computer-generated randomization. However, the investigators could not be double-blinded, since 1 drug was given orally and 1 was given parenterally. While patients undergoing cystoscopy were not eligible for the study multiple types of transurethral surgery, including transurethral resection of the prostate, bladder tumor and so forth, were included. The authors have not paid attention to the possibility of type 2 error, that situation when there is a statistical difference but standard statistical tests between the 2 groups shows no difference. In the latter instance statistical power is too poor to tell whether there is a difference. Such power is based upon the number of patients per group. The authors do not present evidence to suggest that the power of their study (the number of patients per group) is sufficient to show a difference. Therefore, their conclusions remain in doubt.
James A. Roberts Delta Regional Primate Research Center Covington, Louisiana This study demonstrates that oral lomefloxacin is as effective as parenteral cefotaxime for prophylaxis in transurethral genitourinary surgery. Both drugs were given as a single dose and have a broad spectrum of activity. Lomefloxacin offers the advantage of oral administration. The incidence of bacteriuria after a transurethral operation varies significantly among institutions and no controls were used in this study. Therefore, the absolute advantage of either of these antimicrobials over no therapy is not established. The theoretical advantages of prophylaxis could be offset by side effects, such as allergic reactions and development of bacterial resistance. Bacterial resistance is already a major problem with many parenteral agents and, unfortunately, also with the new fluoroquinolones, particularly in patients with a foreign body, such as an indwelling urethral catheter. Therefore, the decision to use antimicrobial prophylaxis must weigh the theoretical advantages and disadvantages for individual patients and different hospital settings. Cefotaxime and the fluoroquinolone were given in a single dose and offered a broad spectrum of activity.
Anthony J. Schaeffer Department of Urology Northwestern University Chicago, Illinois
REPLY BY AUTHORS
This phase 3 study was not designed to investigate the value of antibiotic prophylaxis in transurethral surgery; rather, it was performed to compare a new quinilone agent to an antibiotic that is commonly used for prevention of urinary tract infections and sepsis in patients undergoing transurethral procedures. Because of the different routes of administration the study could not be double-blinded.
THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
PREVENTION OF URINARY TRACT INFECTION AND BACTEREMIA FOLLOWING TRANSURETHRAL SURGERY: ORAL LOMEFLOXACIN COMPARED TO PARENTERAL CEFOTAXIME E. DAVID CRAWFORD, NANCY S. BERGER, MARILYN A. DAVIS
AND
ROBERT E. DONOHUE
From the Department of Veterans Affairs, University of Colorado Health Sciences Center, Denver, Colorado
ABSTRACT
A multicenter, randomized, open label study compared the safety and efficacy of a single dose of oral lomefloxacin, a broad-spectrum antimicrobial agent of the quinolone class, to a single parenteral dose of cefotaxime, a third generation cephalosporin, for prophylaxis in transurethral surgery. Of the 230 patients initially recruited 182 were considered evaluable: 92 in the lomefloxacin group and 90 in the cefotaxime group. Both study groups were well balanced with respect to demographics and transurethral procedures. Efficacy and safety were evaluated with urine cultures, clinical laboratory evaluations and monitoring of adverse events. The success rate among the lomefloxacin patients was 98% versus 94% in the cefotaxime patients. The difference was not statistically significant. Adverse events, regardless of attributability, were reported by 16% of the lomefloxacin patients and 17% of the cefotaxime patients, respectively. Our results indicate efficacy and safety profiles of lomefloxacin equivalent to cefotaxime. Lomefloxacin has the economic advantage of an oral route of administration compared to the parenteral route of cefotaxime for prophylaxis in transurethral genitourinary procedures. KEY WORDS: urinary tract infection, hydroxyquinolones, septicemia
The role of prophylactic antibiotics in decreasing the rate of infectious complications of transurethral surgery remains controversial. Chodak and Plaut reviewed antibiotic prophylaxis in urological surgery and noted several weaknesses of previous studies, including retrospective nature, lack of appreciation of ongoing infection, lack of postoperative cut-off date for infection, inappropriate drugs and dosing schedules, small number of study subjects and uncontrolled study designs. 1 In recent clinical trials preoperative urinary tract infection was not well defined nor was there a specified time frame in which the preoperative urine culture was obtained. 2 Others concluded that effective antibiotic prophylaxis for a transurethral genitourinary operation can significantly decrease the rate of nosocomial urinary tract infections and bacteremia. 3 - 5 Due to design flaws of previous clinical trials the indication for antibiotic prophylaxis in the patient undergoing a transurethral operation remains unclear. The efficacy of the third generation of cephalosporins in preventing postoperative urinary tract infections has been documented. 5· 6 More recently, the use of the fluoroquinolone class of antimicrobials has been recommended for prophylaxis before a transurethral operation. 7 • 8 Lomefloxacin is a synthetic, broadspectrum antibacterial agent of the quinolone class of antimicrobials. High urine concentrations of lomefloxacin are achieved after a single 400 mg. dose, with urine levels greater than 127 µg./ml. found 12 to 24 hours after administration. 9 Lomefloxacin has a long half-life (approximately 8 hours) and excellent tissue penetration. 9 • 10 Lomefloxacin is active against a variety of organisms, including those found in the urinary tract, such as Klebsiella species, Escherichia coli and Pseudomonas aeruginosa. 11 Cefotaxime is a parenteral, third generation cephalosporin that is approved in the United States for prophylaxis before a genitourinary operation. It is a broad-spectrum antibiotic with activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime has a half-life of approximately 1 hour. Administered preoperatively, it has been shown to decrease the incidence of infections in patients undergoing surAccepted for publication August 9, 1991. Supported by G. D. Searle & Co.
gery (such as a genitourinary tract operation) that may be classified as contaminated or potentially contaminated. To evaluate the safety and efficacy of lomefloxacin in the prophylaxis of urinary tract infections after a transurethral procedure a multicenter phase 3 study was initiated. MATERIALS AND METHODS
This multicenter, prospectively randomized, open label, controlled study was designed to evaluate the safety and efficacy of a single oral dose of lomefloxacin versus a single parenteral dose of cefotaxime as prophylactic agents in transurethral genitourinary surgery. Eligibility criteria included men or women 18 years old or older, inpatients or outpatients requiring a transurethral genitourinary operation and negative urine culture (10 4 colony-forming units per ml. or less) obtained within 48 hours preoperatively. Ineligible patients had a history of hypersensitivity to penicillins or cephalosporins, antimicrobial therapy within 72 hours before enrolling in the study, an indwelling urinary catheter for 4 or more days preoperatively (due to the possibility of bacterial resistance developing in these patients), or impaired renal and/or hepatic function. Patients undergoing simple cystoscopy were not eligible for the study. Written informed consent was obtained from each patient before study participation. Patients were randomly assigned to treatment in consecutive order based on a computer generated code in a 1:1 fashion. Patients randomized to lomefloxacin received 2, 200 mg. capsules 2 to 6 hours preoperatively and at least 1 hour before the preoperative medications. Patients randomized to cefotaxime received 1 gm. via intravenous piggyback or intramuscular injection 30 to 90 minutes preoperatively. Laboratory parameters assessed included urine cultures obtained within 48 hours preoperatively, 24 hours postoperatively, immediately before removal of the Foley catheter and at discharge from the hospital or on postoperative day 5. All cultures were collected by clean-catch, midstream technique when a Foley catheter was not indwelling. Chemistry and hematology evaluations, including liver function tests, serum creatinine, electrolytes and a complete blood count, were obtained preop-
1053
CRAWFORD AND ASSOCIATES
1054
eratively and 3 to 5 days postoperatively. Urinalysis was per- patient age or body weight. In the lomefloxacin group 90 of the 92 evaluable patients were considered to have a treatment formed preoperatively and postoperatively. Clinical assessments were performed preoperatively and success, compared to 85 of 90 in the cefotaxime group. This postoperatively for signs and symptoms of urinary tract infec- difference is not statistically significant. tion. Highest daily temperature, duration of indwelling catheSignificant bacteriuria, classified as treatment failure ter, adverse events and postoperative complications were re- (greater than 105 colony-forming units per ml.), was observed corded. Fever was defined as an oral temperature of 100.4F postoperatively in 7 patients: 2 in the lomefloxacin group and (38C) or greater. Identification and susceptibility testing was 5 in the cefotaxime group (table 3). Pathogens occurring in the performed on all isolates with a colony count of 105 colony- 2 lomefloxacin patients were enterococcus in 1 and P. aerugiforming units per ml. or greater. Additional urine or blood nosa in 1. Of the 2 lomefloxacin treatment failures, suscepticultures were obtained if the patient was febrile, or exhibited bility data to an alternative antibiotic were not available in 1 other signs or symptoms of infection. Success was defined as a patient, while in 1 the second pathogen was of intermediate pathogen count of less than 105 colony-forming units per ml. susceptibility to lomefloxacin and resistant to cefotaxime. from all urine cultures obtained within 5 days postoperatively. Pathogens occurring in the 5 cefotaxime patients were enteroFaiture was-definetlas-isolation-of-1()5-cohmy fmming units-per -- co-ccus (2-p-ati-entsJ, Staphylococcus-aureus-;-Enterohacter cloa0 ml. or greater of pathogens from any postoperative urine culture cae and P. aeruginosa. Of the 5 cefotaxime treatment failures the pathogen in 1 patient was susceptible to lomefloxacin and or bacteremia. cefotaxime. Another cefotaxime treatment failure was in a RESULTS patient with P. aeruginosa that was susceptible to lomefloxacin A total of 230 patients was entered into the study (118 in the and of intermediate susceptibility to cefotaxime. In the other 3 lomefloxacin group and 112 in the cefotaxime group). Of the treatment failures in this group susceptibility testing in 1 patients 182 were considered evaluable for analysis of efficacy patient was not available, while in 1 the pathogen was suscep(92 in the lomefloxacin group and 90 in the cefotaxime group). tible to lomefloxacin and cefotaxime, and in 1 the pathogen Among the 230 patients entered in the study, the breakdown was resistant to lomefloxacin and cefotaxime. All susceptibility by sex was 112 (95%) men and 6 (5%) women in the lomeflox- testing was done by the Kirby-Bauer technique. There were no acin group, and 109 (97%) men and 3 (3%) women in the documented cases of bacteremia in either treatment group. The incidence of adverse experiences within the 2 treatment cefotaxime group. Reasons for inevaluability are listed in table groups was not statistically different (p = 0.861). Adverse 1. A summary of the surgical procedures is presented in table 2. Transurethral resection of the prostate was the most common reactions were reported for 19 (16%) lomefloxacin patients and procedure in both groups. Of the 118 lomefloxacin patients and 19 (17%) cefotaxime patients. None of these adverse events the 112 cefotaxime patients 68 and 49, respectively, underwent reported was considered by the investigator to be related to the prostate resection. Among the 182 evaluable patients transure- study drug. The most common adverse event was nausea (lothral prostatic resection was performed on 57 of 92 in the mefloxacin 4% and cefotaxime 2%). Patients also underwent lomefloxacin group and 39 of 90 in the cefotaxime group. Other anesthesia and the contribution of anesthesia to this side effect procedures included bladder biopsy, bladder tumor resection remains conjectural. One patient in each treatment group experienced a serious and transurethral prostatic biopsy. There were no significant differences between the 2 treatment groups with respect to sex, adverse event and both were withdrawn from the study. The serious adverse event in the lomefloxacin patient (dyspnea) was considered by the investigator to be related to administraTABLE 1. Protocol deviations resulting in patient inevaluability tion of preoperative medication and not attributable to the Cefotaxime study drug. The serious adverse event in the cefotaxime patient Lomefloxacin (a possible cerebrovascular accident) was considered by the 1 1 Baseline culture missing investigator to be of uncertain relation to cefotaxime. There 3 2 Urinary tract infection at baseline 0 4 Baseline culture not within 48 hrs. were no significant differences in laboratory values between of surgery the 2 treatment groups (p >0.05 for all comparisons). Several 5 4 Final culture taken too early patients in each treatment group experienced changes in labo7 10 No final culture ratory values that were believed to be clinically significant but 4 6 Indwelling catheter 4 days or longer of no relationship to the study drug. 0
Concomitant systemic antimicrobial Concomitant medication No surgery Total inevaluable
4
6
0 6
1
DISCUSSION
2
26
22
Postoperative urinary tract infection can present significant risks to the patient. A urinary tract infection in an older patient is often complicated. Gram-negative bacteria are the predominant pathogens in these infections. A patient who has bacteremia from a nosocomial urinary tract infection has a 10% chance of mortality. 3 The overall incidence of bacteriuria after
Note, reasons are not mutually exclusive. TABLE
2. Types of operations performed Lomefloxacin
Procedure
(400 mg. orally)
No.(%) Prostate resection Bladder cauterization Bladder biopsy Bladder neck resection Stone basket extraction Prostate biopsy (transurethral) Bladder resection Other All procedures No surgery
68 (44) 1 10 4 4
(1) (6) (3) (3)
6
(4)
7 (4) 56 (36) 156 (100)
6
Note, the procedures are not mutually exclusive.
Cefotaxime (1 gm. intravenously /intramuscularly) No.(%) 49 (38) 0 (O) 11 (9) 2 (2) 2 (2) 7 (5)
TABLE 3.
Treatment failures
Lomefloxacin Pt. No.
Organism
1
Greater than 106 P. aeruginosa (4 days postop.) Greater than 105 enterococcus (6 days postop.)
2
Cefotaxime Pt. No.
2
14 (11) 45 (35)
3
130 (100)
4
2
5
Organism Greater than 105 enterococcus (5 days postop.) Greater than 105 P. aeruginosa (3-5 days postop.) Greater than 105 E. cloacae (4 days postop.) Greater than 105 enterococcus (6 days postop.) Greater than 105 Staph. aureus (4 days postop.)
URINARY TRACT INFECTION AND BACTEREMIA AFTER TRANSURETHRAL SURGERY
a transurethral operation when no antimicrobial prophylaxis agent is used has been reported to range from 26 to 70%. 12 - 14 This broad range of postoperative bacteriuria could be due to the fact that in various previous studies preoperative urine cultures were not part of the eligibility criteria. For prophylaxis in transurethral surgery a single preoperative oral dose of 400 mg. lomefloxacin was as efficacious as a single 1 gm. parenteral dose of cefotaxime in preventing postoperative urinary tract infections. No significant difference existed in patients receiving lomefloxacin or cefotaxime. Lomefloxacin is the first once a day quinolone antimicrobial offering the advantages of oral therapy with efficacy that is equal to parenteral cefotaxime. Additionally, it has the advantage of having no cross-reactivity in patients allergic to penicillin. In conclusion, single dose therapy with lomefloxacin is well tolerated and appears to be equally as effective as cefotaxime in ameliorating the incidence of postoperative urinary tract infections in patients undergoing a transurethral genitourinary operation, with the advantage of oral administration and lower cost. The patients reported were treated at the San Juan Veterans Administration Medical Center (Dr. C. Ramirez-Ronda), Louisville Veterans Administration Medical Center (Dr. M. Amin), University of Colorado Health Sciences Center (E. D. C.), University of Tennessee Medical Center (Dr. C. Cox) and Louisiana State University Medical Center (Dr. D. Culkin). REFERENCES 1. Chodak, G. W. and Plaut, M. E.: Systemic antibiotics for prophy-
2. 3. 4. 5.
6. 7.
8. 9. 10.
11. 12.
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EDITORIAL COMMENTS This is not a study to answer the question as to whether prophylactic antibiotics lessen the infectious complications oftransurethral surgery. Indeed, most physicians believe that if the urine is uninfected and the patient is not catheterized before a transurethral operation antibiotics are not necessary. Instead, the authors are comparing 2 antibiotics to determine safety and efficacy of a single-dose treatment with the 2 drugs. They conclude that there is no statistical difference between the 2 drugs tested. To get around type 1 error, they have randomized the patients using a computer-generated randomization. However, the investigators could not be double-blinded, since 1 drug was given orally and 1 was given parenterally. While patients undergoing cystoscopy were not eligible for the study multiple types of transurethral surgery, including transurethral resection of the prostate, bladder tumor and so forth, were included. The authors have not paid attention to the possibility of type 2 error, that situation when there is a statistical difference but standard statistical tests between the 2 groups shows no difference. In the latter instance statistical power is too poor to tell whether there is a difference. Such power is based upon the number of patients per group. The authors do not present evidence to suggest that the power of their study (the number of patients per group) is sufficient to show a difference. Therefore, their conclusions remain in doubt.
James A. Roberts Delta Regional Primate Research Center Covington, Louisiana This study demonstrates that oral lomefloxacin is as effective as parenteral cefotaxime for prophylaxis in transurethral genitourinary surgery. Both drugs were given as a single dose and have a broad spectrum of activity. Lomefloxacin offers the advantage of oral administration. The incidence of bacteriuria after a transurethral operation varies significantly among institutions and no controls were used in this study. Therefore, the absolute advantage of either of these antimicrobials over no therapy is not established. The theoretical advantages of prophylaxis could be offset by side effects, such as allergic reactions and development of bacterial resistance. Bacterial resistance is already a major problem with many parenteral agents and, unfortunately, also with the new fluoroquinolones, particularly in patients with a foreign body, such as an indwelling urethral catheter. Therefore, the decision to use antimicrobial prophylaxis must weigh the theoretical advantages and disadvantages for individual patients and different hospital settings. Cefotaxime and the fluoroquinolone were given in a single dose and offered a broad spectrum of activity.
Anthony J. Schaeffer Department of Urology Northwestern University Chicago, Illinois
REPLY BY AUTHORS
This phase 3 study was not designed to investigate the value of antibiotic prophylaxis in transurethral surgery; rather, it was performed to compare a new quinilone agent to an antibiotic that is commonly used for prevention of urinary tract infections and sepsis in patients undergoing transurethral procedures. Because of the different routes of administration the study could not be double-blinded.
