Urinary Tract Infections and Their Effects on the Urogenital and

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1986, p Vol. 29, No /86/ $02.00/0 Copyright 1986, American Society for Microbiology Amoxicillin-Clavulanic Acid Versus Cefaclor in the Treatment of Urinary Tract Infections and Their Effects on the Urogenital and Rectal Flora ABDOLLAH IRAVANI* AND GEORGE A. RICHARD Division of Nephrology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida Received 2 January 1985/Accepted 11 October 1985 In a double-blind randomized study, amoxicillin-clavulanic acid (AM-CL) was compared with cefaclor for the treatment of acute urinary tract infections in 107 college women. A total of 53 patients received amoxicillin (250 mg) and clavulanic acid as the potassium salt (125 mg), and 54 received cefaclor (250 mg); each drug was administered every 8 h for 10 days. The cure rates at 1 and 4 weeks after treatment were 96 and 78%, respectively, in the AM-CL group and 92 and 75%, respectively, in the cefaclor group (P > 0.10). After AM-CL treatment, the prevalence of amoxicillin-resistant Eschenichia coli significantly increased in the rectal flora. Also, the frequency of bacterial resistance to amoxicillin, AM-CL, and cefaclor increased among the urinary pathogens causing subsequent urinary tract infections (P< 0.05). There were no adverse reactions in the cefaclor group; however, six patients in the AM-CL group (12%) experienced diarrhea, nausea, or vomiting (P< 0.05). Elevated transaminase enzyme levels were observed in 23% of the patients in the AM-CL group and in 6% of the patients in the cefaclor group (P< 0.05). Symptomatic Candida vaginitis developed in 16 and 13% of the patients in the AM-CL and cefaclor groups, respectively (P > 0.10). Bacterial resistance to the P-lactam antibiotics is largely due to the production of a,-lactamase (1, 5, 20). Clavulanic acid inhibits many of these enzymes (16). A combination of amoxicillin (AM) and clavulanic acid (CL) is effective against a variety of,-lactamase-positive bacteria (2, 4, 10, 12, 15). The purposes of this study were (i) to compare the efficacy and safety of AM-CL with the efficacy and safety of cefaclor in the treatment of acute urinary tract infections (UTIs) in young women, (ii) to relate therapeutic responses to the results of the antibody-coated bacteria test (ACBT), and (iii) to assess the emergence of resistant members of the Enterobacteriaceae in the rectal and urogenital areas after treatment. MATERIALS AND METHODS Patient criteria. The study group consisted of college women who came to the Kidney Clinic of the University of Florida Student Health Services with symptoms of acute UTIs. The criteria for inclusion were as follows: (i) symptoms such as dysuria, urgency, and suprapubic or flank pain; (ii) at least one bacterium in each random high-power microscopic field of an unstained and uncentrifuged urine specimen; and (iii) 2105 CFU of a bacterium per ml in each of three consecutive urine specimens. Initially, 111 patients entered the study, but 4 had negative urine cultures and did not qualify, leaving 107 patients in the study. Excluded from the study were pregnant or lactating women and women with impaired renal or liver function, radiographically proven obstructive uropathy, or a history of allergy to penicillins or cephalosporins. Patients who had received antimicrobial agents during the preceding week were also excluded. Collection, processing, and analysis of specimens. A specially trained nurse instructed each patient to submit three * Corresponding author. 107 clean-catch midstream urine specimens within 24 h before treatment. Each urine specimen was analyzed and cultured. Specimens were collected from the vagina, periurethral area, and rectum with Culturette rayon-tipped swabs (Scientific Products Div., Evanston, Ill.) for culture and susceptibility testing before treatment and 1 week after treatment ended. These specimens were also obtained before treatment of recurrent UTIs. Bacteriologic techniques. Isolation and quantitative bacterial counts were performed with a calibrated platinum loop which delivered 0.01 ml of urine onto blood agar and MacConkey plates. Gram-negative organisms were identified by using the API-20E system (Analytab Products, Plainview, N.Y.) (8, 19). Staphylococcus saprophyticus was identified by a previously described method (13). Antibiotic susceptibility was tested by the disk diffusion method using 30-,I.g disks of AM-CL (20,g of AM and 10,g of the potassium salt of CL), 10-,ug disks of ampicillin (for AM), and 30-,ug disks of cefaclor (3). Bacterial isolates were considered susceptible to ampicillin and cefaclor when the disk zone sizes were.14 and -15 mm, respectively. Members of the Enterobacteriaceae and gram-positive cocci were considered susceptible to AM-CL when disk zone sizes were.17 and.24 mm, respectively. The swabs from vaginal, periurethral, and rectal areas were streaked onto MacConkey and blood agar plates. Each colony type was identified, and susceptibility was tested as described above. Vaginal specimens were also tested for the presence of Candida albicans by using potassium hydroxide smears and culture on Nickerson agar (GIBCO Diagnostics, Lawrence, Mass.). Escherichia coli isolates identified to serotype were obtained from the Centers for Disease Control, Atlanta, Ga. Antisera to various Escherichia coli 0 antigens were produced by the method described by Ewing (9). Each working antiserum solution contained 19.8 ml of sterile saline, 2

2 108 IRAVANI AND RICHARD ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Pretreatment clinical characteristics Age (yr) Days of symptoms No. of patients with: Treatment No. before treatment group MeanMeannRange ±esd CVATe' Range Leukocytosis of Vaginal Initial Recurrent + SD + SD >10.800/mm3 candidiasis UTI UTI AM-CL ± Cefaclor ± ± a CVAT, Costovertebral angle tenderness. drops of 1.0% merthiolate, 100,ul of formaldehyde, and 100,ul of prepared antiserum. Escherichia coli 0 antigen was serotyped by a modification of the technique of Orskov et al. (18). A bacterial suspension was made by using Escherichia coli isolates which were grown overnight in 10 ml of brain heart infusion broth at 37 C, autoclaved for 2 h at 120 C, and set aside to cool. This bacterial suspension was blended in a Vortex mixer, 0.2 ml was added to 0.2 ml of antiserum solution, and the suspension was incubated overnight at 32 C; determinations were made the next morning. The following Escherichia coli serotypes were tested: 01, 02, 04, 06, 07, 08, 015, 017, 018, 025, 069, 075, 086, and 112. Localization of infection. The site of infection was determined by a modification of the ACBT of Thomas et al. (21). The sediment from 10 ml of pretreatment urine was examined for antibody-coated bacteria by using 0.55 ml of a 1:10 dilution of fluorescence-conjugated anti-human globulin processed from goats (Hyland Diagnostics, Deerfield, Ill.). Specimens were examined for nonspecific fluorescence by testing washed subcultures of the bacterial isolates. The test was considered positive when fluorescent bacteria were present in the initial test and absent in subcultures. The test was considered negative when fluorescent bacteria were not observed after 20 microscopic fields had been examined. Treatment. The study was double-blind. Neither the physicians nor the patients knew which one of the two test drugs was dispensed. The 107 patients were assigned to two treatment groups by a computer-generated randomized list. One group of 53 women received AM (250 mg) and CL as the potassium salt (125 mg) in tablet form (Augmentin; Beecham Laboratories, Bristol, Tenn.), and 54 women received 250 mg of cefaclor in capsule form (Ceclor; Eli Lilly & Co., Indianapolis, Ind.). A dose was taken every 8 h for 10 days. Clinical and bacteriologic evaluations were repeated on day 2 of treatment, 2 days after treatment ended, and at weeks 1, 2, 4, 8, and 12 after treatment. At least one clean-catch midstream urine specimen was obtained at each visit. During the first 3 days of treatment, each patient used a diary to record the time that medication was taken, the time of voiding, and the resolution of dysuria and urgency. Complete disappearance of the symptoms by the last day of treatment was termed a clinical cure, and persistence of the symptoms was regarded a clinical failure. Bacteriologic responses were classified as follows: (i) short-term cure, when a urine culture was sterile by day 2 of treatment and remained sterile or contained <104 CFU/ml of urine through 1 week after treatment ended; (ii) long-term cure, when urine cultures remained sterile or contained <i10 CFU/ml of urine through 4 weeks after treatment ended; (iii) failure, if the initial urinary pathogen persisted or reappeared at a level of 2105 CFU/ml of urine at 2 days after treatment ended; (iv) superinfection, if a different pathogen emerged at a level of i105 CFU/ml of urine during treatment or up to 2 days after treatment ended; and (v) relapse, if an organism similar to the initial pathogen reappeared at a level of 2105 CFU/ml of urine beyond 2 days and up to 4 weeks after treatment ended; and (vi) reinfection, when a different pathogen emerged at a level of 2105 CFU/ml of urine beyond 2 days after treatment ended. Additional urine cultures were obtained from patients with colony counts of 104 to <105 in order to verify their therapeutic responses. During treatment, patients were assessed for symptoms, such as rashes, nausea, vomiting, or diarrhea. Blood specimens were analyzed for aspartate aminotransferase (serum glutamic oxalacetic transaminase), alanine aminotransferase (serum glutamic pyruvic transaminase), alkaline phosphatase, bilirubin, serum creatinine, urea nitrogen, and complete blood cell counts before treatment and 2 days after treatment ended. Statistical analysis. The life table method and the chisquare test were used to analyze the data (6, 7). RESULTS Pretreatment clinical and bacteriologic findings. All patients were symptomatic with a combination of dysuria, urgency, and suprapubic pain; 23% of the patients had costovertebral angle tenderness, but none had a fever of -38 C. Pretherapy clinical findings are shown in Table 1. The distribution of the urinary pathogens and their in vitro TABLE 2. Distribution of urinary pathogens and results of in vitro susceptibility testinga No. of patients in each group % Of No. of bacteria resistant to: Pathogen(s) AM-CL Cefaclor total AM AM-CL Cefaclor Escherichia coli S. saprophyticus Klebsiella pneumoniae Proteus mirabilis Enterobacter species Citrobacter freundii Enterococci Salmonella species a Ampicillin disks were used to test susceptibility to AM.

3 VOL. 29, 1986 AM-CL AND CEFACLOR in UTI TREATMENT TABLE 3. Distribution of patients by treatment group and bacteriologic response through 4 weeks after treatment ended No. of patients with: Treatment No. who completed group treatment Short-term Failure Relapse Reinfection Long-term cure cure AM-CL (96)" 0 4 (8) 7 (14) 40 (78) Cefaclor (92) 0 11 (21) 2 (4) 40 (75) The numbers in parentheses are percentages. susceptibilities are shown in Table 2. Of the 77 E. coli urinary pathogen isolates, 69 were serotyped. The common serotypes were 018 (19%), 06 (17%), 01 (10%), and 075 (6%). A total of 38% of the E. coli isolates were not typeable to the serogroups used. Of the urinary pathogens tested, 95% were susceptible to AM-CL, 95% were susceptible to cefaclor, and 78% were susceptible to AM. Clinical and bacteriologic responses to treatment. The mean duration for disappearance of symptoms after initiation of treatment was 27 h (range, 3 to 82 h) in the AM-CL group and 26 h (range, 2 to 116 h) in the cefaclor group. A total of 51 of 53 patients in the AM-CL group and 53 of 54 patients in the cefaclor group completed treatment. Urine cultures were sterile on day 2 of treatment and 2 days after treatment ended in these patients. At 1 and 4 weeks after treatment ended, the AM-CL group had cure rates of 96 and 78%, respectively, and in the cefaclor group the cure rates were 92 and 75%, respectively (Table 3). There were 15 recurrences in the AM-CL group and 20 recurrences in the cefaclor group by 12 weeks after treatment ended. As determined by the life table method (6), the cumulative recurrence rates by 12 weeks after treatment ended were 33% in the AM-CL group and 39% in the cefaclor group (Fig. 1). The overall therapeutic results did not differ significantly in the two groups. One patient in the AM-CL group had an AM-CL-resistant Enterobacter aerogenes in vitro, but she achieved long-term cure. Four patients in the cefaclor group, two infected with a cefaclor-resistant Escherichia coli strain and two infected with a cefaclor-resistant Enterobacter cloacae strain, relooj ,,' U) W218-" Z w 26 Ck 24- D 22 - Q 20 / - -8 / No. 53, omoxicillin - potassium clovuknote --- No. = 54, cefoclor WEEKS AFTER COMPLETION OF THERAPY FIG. 1. Cumulative rates of recurrence within 12 weeks after treatment. sponded well to treatment. Three of the four had long-term cure, and one had a reinfection 24 days after treatment was completed. Test of localization. Of the 53 patients in the AM-CL group, 9 were ACBT positive, and 44 were ACBT negative. Of the 54 patients in the cefaclor group, 9 were ACBT positive, 43 were ACBT negative, and 2 had nonspecific test results. The clinical characteristics of the patients were similarly distributed in the ACBT-positive and -negative groups. All patients in both groups with positive ACBT maintained a long-term cure, whereas the long-term cure rate was 78% in the ACBT-negative AM-CL group and 75% in the ACBT-negative cefaclor group (P > 0.10). Bacterial resistance and colonization in the urogenital and rectal areas. Specimens were obtained from periurethral, vaginal, and rectal areas of 49 patients in the AM-CL group and 49 patients in the cefaclor group. Table 4 shows the distribution of bacterial isolates according to culture area before treatment and 1 week after the end of treatment. After AM-CL treatment, the prevalence of Escherichia coli isolates resistant to AM increased 20% in the rectal area (P<0.05) and did not significantly change in the periurethral and vaginal areas. The prevalence of other members of the Enterobacteriaceae resistant to AM did not significantly change in the periurethral, vaginal, and rectal areas. No significant change occurred in the prevalence of Escherichia coli and other members of the Enterobacteriaceae resistant to AM-CL or cefaclor in these areas. After treatment with cefaclor, no significant change occurred in the susceptibility pattern of Escherichia coli and other members of the Enterobacteriaceae colonizing urogenital and rectal areas. Emergence of resistant urinary pathogens. In patients in the AM-CL group with recurrent UTIs which occurred within 12 weeks after treatment ended, the prevalence of AM-resistant urinary pathogens increased 30%, the prevalence of AM-CLresistant urinary pathogens increased 18%, and the prevalence of cefaclor-resistant urinary pathogens increased 18% (P< 0.05) compared with the pathogens causing the initial infections. In patients in the cefaclor group with recurrent UTIs, the prevalence of resistant urinary pathogens did not significantly change compared with the pathogens causing the initial infections (Table 5). Side effects. There were no adverse reactions in the cefaclor group. Six patients (12%) in the AM-CL group experienced adverse drug reactions (P < 0.05). Five had transient diarrhea without interruption of therapy, and one developed mild nausea and vomiting on the last day of therapy. A total of 50 patients in the AM-CL group and 52 patients in the cefaclor group were screened for vaginal candidiasis before treatment and 1 week after the end of treatment. The prevalence of vaginal candidiasis in the initial patient screening is shown in Table 1. After treatment, Candida vaginitis, with vaginal discharge or vulvar irritation or both, developed in eight patients (16%) in the AM-CL group and in seven

4 110 IRAVANI AND RICHARD ANTIMICROB. AGENTS CHEMOTHER. TABLE 4. Distribution of bacterial isolates according to culture area before treatment and 1 week after treatment ended" ~Other members of the Escherichia coli Treatment No. of Area of Relation to No. with Enrobcteriaceae group patients culture treatment cultures positive No. of No. resistant to: No. of No. resistant to: isolates AM AM-CL Cefaclor isolates AM AM-CL Cefaclor AM-CL 49 Periurethral Before After Vaginal Before After Rectal Before * After b Cefaclor 49 Periurethral Before After Vaginal Before After Rectal Before After aampicillin disks were used to test susceptibility to AM. p < patients (13%) in the cefaclor group (P > 0.10). Twelve additional patients (24%) in the AM-CL group and five patients (10%) in the cefaclor group became asymptomatic carriers of vaginal candidiasis (P > 0.10). Blood chemistry and hemograms. After completion of treatment, elevated transaminase enzyme levels were found in 12 patients (23%) in the AM-CL group and in 3 patients (6%) in the cefaclor group (P < 0.05). In the AM-CL group, 8 of the 12 patients had elevated serum glutamic oxalacetic transaminase levels (44 to 117; normal is 0 to 40 IU/liter), and four had elevated serum glutamic pyruvic transaminase levels (43 to 81; normal is 0 to 40 IU/liter). In the cefaclor group, two of the three patients had serum glutamic oxalacetic transaminase levels of 43 to 62, and one patient had a serum glutamic pyruvic transaminase level of 46. In the AM-CL group, 6 other patients (12%) had eosinophilia (absolute count, -500/mm3), and one patient (2%) had neutropenia (absolute polymorphonuclear count, 1,500/ mm3). All abnormal laboratqry findings were transient and returned to normal within 2 weeks after treatment ended. DISCUSSION AM-CL and cefaclor both had a broader in vitro antibacterial activity than AM alone; 5% of urinary pathogens were resistant in vitro to AM-CL in this study. Bacterial resistance to AM-CL is occasionally reported, which may be explained.by the inactivity of CL against some varieties of P-lactamases (4, 16, 20). Both AM-CL and cefaclor were efficacious in eliminating urinary pathogens regardless of the in vitro resistance of the organisms. The therapeutic results were in agreement with previous results (2, 4, 10, 12, 14, 15). Compared with cefaclor treatment, treatment with AM- CL was associated with an increase in the prevalence of Escherichia coli isolates resistant to AM in the rectal flora and an increase in the prevalence of resistance among urinary pathogens of subsequent UTIs to AM, AM-CL, and cefaclor. However, these results may not be conclusive since quantitative culture tests were not done in this study. Emergence of resistant bacterial strains has been reported with the use of broad-spectrum P-lactam antibiotics (18). The exact mechanism of this phenomenon and the development of cross-resistance to other antibiotics is not fully understood. The response to therapy based on the ACBT was paradoxical. Patients with positive ACBTs had a higher cure rate at 1 and 4 weeks after treatment ended than patients with negative ACBTs in both treatment groups. If patients with positive ACBTs had renal involvement, one would expect them to respond less favorably to treatment than patients with negative ACBTs. However, the positive ACBT group was small (18 patients), and in our opinion these results are not conclusive. In previous studies we have found no correlation between response to treatment and ACBT results (11, 12; A. Iravani and G. A. Richard, Pediatr. Res. 15:443,1981). By 12 weeks after therapy ended, a recurrent infection had developed in 33 and 39% of the patients in the AM-CL and cefaclor groups, respectively. In our experience, regardless of the antibiotic used in treatment, about one-third of women with acute UTIs develop recurrent infections by 3 months after treatment ends (11). Cefaclor was tolerated well by all the patients, and the adverse reactions occurring with AM-CL (12%) were comparable to the reactions described in previous reports (4, 12, 14). The frequency of elevated transaminase levels (serum TABLE 5. Emergence of resistant urinary pathogens in patients with recurrences occurring after treatment ended within 12 weeks Initial infections Recurrences Treatment group No. of bacterial No. resistant to: No. of bacterial No. resistant to: isolates AM AM-CL Cefaclor isolates AM AM-CL Cefaclor AM-CL 53 9 (17)" 1 (2) 1 (2) 15 Cefaclor (20) 4 (9) 4 (9) 20 7 (47) 4 (20) 3 (20) 2 (10) 3 (20) 2 (10) a The numbers in parentheses are percentages.

5 VOL. 29, 1986 glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase) was significantly higher in the AM-CL group (23%) than in the cefaclor group (6.%) and was higher than our previous report of 4% in patients treated with AM-CL (12). These observations warrant further safety evaluation of AM-CL. The incidence of symptomatic vaginal candidiasis was relatively high following both AM-CL (16%) and cefaclor (13%) treatment. In a previous trial we found an incidence of symptomatic vaginal candidiasis of 14% following the use of AM-CL (12). Both AM-CL and cefaclor appeared to be equally efficacious in the treatment of UTIs in college women. However, there was a high incidence of vaginal candidiasis following the use of both drugs. Elevated transaminase enzyme levels and emergence of resistant bacteria were associated with AM-CL treatment. Further investigations are warranted in order to better understand the extent and mechanisms of these findings. ACKNOWLEDGMENTS We thank Barbara Peters, Dorothy Ellerbe, Deborah Swails, and Bruce R. Newton for assistance. LITERATURE CITED 1. Abraham, E. P., and E. B. Chain An enzyme from bacteria able to destroy penicillin. Nature (London) 146: Ball, A. P., A. M. Geddes, P. G. Davey, I. D. Farrell, and G. R. Brooks Clavulanic acid and amoxicillin: a clinical, bacteriological, and pharmacological study. Lancet i: Bauer, A. C. O., W. M. M. Kirby, J. L. Sherris, and M. Turck Antibiotic susceptibility testing by a standardized single dose method. Am. J. Clin. Pathol. 45: Brogden, R. N., A. Carmine, R. C. Heel, P. A. Morley, T. M. Speight, and G. S. Avery Amoxycillin/clavulanic acid. A review of its antibacterial activity, pharmacokinetics and therapeutic use. Drugs 22: Bush, K., and R. B. Sykes Lactamase inhibitors in perspective. J. Antimicrob. Chemother. 11: Colton, T Statistics in medicine, 1st ed., p Little, Brown & Co., Boston. 7. Cutler, S. J Maximum utilization of the life table method AM-CL AND CEFACLOR IN UTI TREATMENT 111 in analyzing survival. J. Chronic Dis. 8: Edwards, P. R., and W. H. Ewing Identification of Enterobacteriaceae, 3rd ed., p Burgess Publishing Co., Minneapolis. 9. Ewing, W. H Production of Escherichia coli antiserum. Public Health Lab. 14: Goldstein, F. W., M. D. Kitzis, and J. F. Acar Effects of clavulanic acid and amoxicillin formulation against,b-lactamase producing gram-negative bacteria in urinary tract infections. J. Antimicrob. Chemother. 5: Iravani, A., N. Pryor, and G. A. Richard Treatment of acute uncomplicated urinary tract infections by cephalexin, with special reference to the antibody-coated bacteria. Int. J. Pharmacol. 20: Iravani, A., and G. A. Richard Treatment of urinary tract infections with a combination of amoxicillin and clavulanic acid. Antimicrob. Agents Chemother. 22: Jordan, P. A., A. Iravani, G. A. Richard, and H. Baer Urinary tract infection caused by Staphylococcus saprophyticus. J. Infect. Dis. 142: Kammer, R. B., and L. J. Short Cefaclor-summary of clinical experience. Postgrad. Med. J. 55: Martinelli, R., A. Da Silva Lopes, M. De Oliveira, and H. Rocha Amoxicillin-clavulanic acid in treatment of urinary tract infection due to gram-negative bacteria resistant to penicillin. Antimicrob. Agents Chemother. 20: Neu, H. C., and K. P. Fu Clavulanic acid: a novel inhibitor of,3-lactamases. Antimicrob. Agents Chemother. 14: Orskov, I., F. Orskov, B. John, and K. Jann Serology, chemistry, and genetics of 0 and K antigens of Escherichia coli. Bacteriol. Rev. 41: Sanders, C. C., and W. E. Sanders, Jr Emergence of resistance during therapy with the newer 1-lactam antibiotics: role of inducible P-lactamases and implications for the future. Rev. Infect. Dis. 5: Smith, P. B., K. M. Tomfohrde, D. L. Rhoden, and A. Balows API system: a multitube micromethod for identification of Enterobacteriaceae. Appl. Microbiol. 24: Sykes, R. B., and M. Matthew The 3-lactamases of gram-negative bacteria and their role in resistance to P-lactam antibiotics. J. Antimicrob. Chemother. 2: Thomas, V., A. Shelokove, and M. Foreland Antibodycoated bacteria in urine and the site of urinary tract infection. N. Engl. J. Med. 290: