Journal of Antimicrobial Chemotherapy (1991) 28, 581-586
Comparative efficacy and safety of cefprozil and cefaclor in the treatment of acute uncomplicated urinary tract infections John C. Christensoii'^, W. Manford Goocfa*^, John N. Herrod' and EHse Swensoir^ 'University of Utah School of Medicine, Department of Pediatrics; bDivision of Infectious Diseases, Salt Lake City, Utah 84132; 'Primary Children's Medical Center, Division of Clinical Pharmacology, and *Bryner Clinic, Salt Lake City, Utah, USA Ccfprozil is a new oral semi-synthetic cephalosporin with broad antibacterial spectrum and prolonged serum elimination half-life. In vitro, cefprozil demonstrates excellent activity against common urinary tract pathogens such as Escherichia coli and Klebsiella pneumoniae. Cefprozil, 500 mg once a day, was compared to cefaclor, 250 mg three times a day, in an open, randomized, comparative, clinical trial for the treatment of acute, uncomplicated, urinary tract infection. One hundred and two adult patients were eligible for safety evaluation; four patients were excluded due to side-effects (abdominal discomfort, nausea and vomiting). Ninety-eight patients were eligible for evaluation of efficacy. Clinical and bacteriological responses were comparable for both antibiotics. Leucopenia, nausea, and vaginal yeast infections were slightly more common in the cefprozil group. Cefprozi], 500 mg once daily, appears to be an appropriate alternative for the treatment of acute, uncomplicated urinary tract infections.
Introduction Cefprozil, formerly known as BMY-28100, is a new oral scmisynthetic 7-phenylglycyl cephalosporin. Its broad-spectrum antibacterial activity and stability to hydrolysis by many /Mactamase enzymes, plus a prolonged half-life when compared to other oral cephalosporins, has possible clinical benefits for the treatment of various infections, especially urinary tract infections. Cefprozil is more active in vitro against members of the Enterobacteriaceae, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, than cephalexin. Over 90% of clinical isolates of Staphylococcus spp. are inhibited by < 8-0 mg/L of cefprozil (Jones et al., 1988). In-vitro activity was found to be comparable to cefaclor against these same pathogens (Chin & Neu, 1987; Eliopoulos et al., 1987; Jones et al., 1988; Leitner et al., 1987). Serratia marcescens, Citrobacter freundii, Enterobacter spp., and Pseudomonas aeruginosa are all resistant to cefprozil (Eliopoulos et al., 1987). The average serum half-life of cefprozil is 1-2 h, in contrast to cefaclor of 0-6-0-9 h. Approximately 65% of a single dose of cefprozil is recovered in the urine within 8 h after its administration (Barbhaiya et al., 1990ft). Phase I studies have demonstrated that the incidence and types of side-effects observed with cefprozil are similar to those reported with other oral cephalosporins (Barbhaiya et al., 1990a). The purpose of this study was to compare the efficacy and safety of cefprozil administered once a day to that of cefaclor, a cephalosporin shown to be effective in the 581 0305-7453/91/100581 +06 J02.00/0
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treatment of urinary tract infections (Iravani & Richard, 1986) when administered three times a day. Methods Patients were enrolled in this open, randomized, comparative clinical study between 1987 and 1988 at the Department of Internal Medicine of the Bryner Clinic, an outpatient multispecialty clinic in the metropolitan area of Salt Lake City. Adult patients, 18 years of age or older, with documented or suspected acute uncomplicated urinary tract infections were selected. Signs and symptoms considered to be consistent with acute uncomplicated urinary tract infection were: fever, urinary difficulty (hesitancy, urgency, burning, frequency), dysuria, suprapubic pain and tenderness. Patients with asymptomatic bacteriuria were considered candidates for enrollment if they had two consecutive significant urine cultures with the same single pathogen in a 24 h period. An informed consent document was signed by all patients enrolled into study. All female patients of childbearing age had a documented negative pregnancy test before receiving the study drug. Patients surgically-sterilized by hysterectomy or tubal ligation were enrolled without satisfying this requirement. Patients were excluded from enrolment if they met any of the following criteria: history of anaphylaxis to penicillin or cephalosporins; history of allergies to cephalosporins; patients who had received a long-acting parental penicillin within two weeks before enrollment; pregnant or lactating women; patients with signs and symptoms suggestive of acute or chronic pyelonephritis; history of major renal or significant hepatic disease; history of gastrointestinal malabsorption; patients with anatomic abnormalities of the urinary tract. Before treatment, a medical history, physical examination, and laboratory studies which included a haematological analysis (white blood cell count (WBQ and differential, haemoglobin, haematocrit, platelet count, erythrocyte sedimentation rate), chemical analysis (liver enzymes, blood urea nitrogen, creatinine), urine analysis (with microscopic examination), and a clean-voided midstream urine culture were performed. A urine culture was considered significant if > 100,000 cfu/mL of a single urinary pathogen were isolated. Patients were reevaluated three to five days into therapy and five to nine days after completing therapy. Patients were randomized to receive either cefprozil (Bristol-Meyers Squibb Company), 500 mg orally once daily, or cefaclor (Eli Lilly and Company), 250 mg three times a day, using a 2 : 1 computer-generated randomization schedule provided by the sponsor. Randomization was performed by a research assistant. Each study drug was administered for a total of ten days. To document compliance with the study, the patient was asked to return all unused capsules at the completion of the study. Patients needed to receive the study drug for at least five consecutive days in order to be eligible for evaluation of efficacy. No other antimicrobial therapy was given concomitantly with the study drug. Clinical responses were classified as: satisfactory—resolution or improvement of all pre-treatment symptoms without the appearance of any new symptoms at the time of the post-treatment evaluation; unsatisfactory—pre-treatment symptoms remained unchanged or worsened at the end of study, or all pre-treatment symptoms resolved but new symptoms appeared at the time of post-treatment evaluation. Bacteriological responses were categorized as: eradicated—the original causative pathogen was eradicated and no new pathogen with a colony count of > 103 cfu/mL
Cefprozil rj cefador in UTIs
583
emerged; reinfection—the original causative pathogen was eradicated as determined by post-treatment culture and a new pathogen with a colony count of > K^cfu/mL emerged after that culture; relapse—original causative pathogen was eradicated as determined by the post-treatment culture and the same pathogen re-emerged with a colony count of > lO^cfu/mL after the five to nine day culture; persistence—the original causative pathogen persisted at a colony count of > 104 cfu/mL as determined by the on-treatment and post-treatment culture taken after completion of therapy. All bacterial isolates were tested for antimicrobial susceptibility utilizing 30/zg cefprozil and cephalothin impregnated discs, using the Kirby-Bauer method of disc diffusion on Mueller-Hinton agar (National Committee for Clinical Laboratory Standards, 1988). Organisms were considered resistant if zones of inhibition were less than 14 mm and susceptible if the zones of inhibition were > 18 mm. Patients were removed from the study if they met any of the following criteria: no pathogen isolated in pre-treatment urine culture; in-vitro susceptibility testing indicated resistance of the pathogen to either cefprozil or cefaclor, pre-treatment culture revealed causative pathogen at < K^cfu/mL (except coagulase-negative staphylococci which were considered significant at > 10,000 cfu/mL); poor clinical response after 72 h of therapy; occurrence of a serious or alarming adverse reaction related to the study drug. The study drugs were compared for their overall clinical and bacteriological response rates and incidence and severity of adverse reactions. Statistical analysis was performed utilizing Fisher's exact test. A P value equal to or less than 0-05 was considered to be significant. Results One hundred and thirty-four patients were enrolled in this clinical trial. Thirty-two patients were subsequently withdrawn because they did not meet criteria for eligibility to be evaluable: no pathogen isolated, 19; resistant pathogens, 8; no repeat cultures performed, 3; lack of compliance with study protocol, 1; one self-withdrawal. A total of 102 patients (68—cefprozil, 34—cefaclor) were eligible for safety evaluation. Four patients discontinued treatment due to adverse effects (3—cefprozil, 1—cefaclor). Ninety-eight patients were eligible for evaluation for efficacy. All patients completed ten days of therapy except for three patients in the cefprozil-treated group who completed seven to eight days of therapy.
Table L Underlying illnesses commonly observed in the cefprozil and cefaclor treatment groups Illness Diabetes mellitus Previous hysterectomy History of previous UTI' Arterial hypertension Prostate disease 'Urinary tract infection.
Cefprozil (n •= 65) Cefaclor (n = 33) no. (%) no. (%) 3 (4-6) 7 (11) 1 (1-5) 12 (18) 1 (1-5)
4(12) 1 (3) 2(6) 7 (21) 2 (6)
584
J. C. dnfatcnson et aL Table II. Bacterial pathogens of the urinary tract in 98 patients
Organism
Cefprozil no. (%)
Cefaclor no. (%)
E. coli
60 (92-3)
27 (82)
K.pneumoniae
4(6-2)
4(12)
K. oxytoca S. saprophytiau
0 1 (1-5)
1 (3) 1 (3)
The treatment groups were comparable in age, cefprozil—54-7 years (range 19-92; median 58-5), cefaclor—53-0 years (range 21-87; median 57), P = 0-67, sex, and type and severity of signs and symptoms of urinary tract infection. Mean duration of signs and symptoms of disease were similar for cefprozil and cefaclor, 5-8 and 5-6 days, respectively (P = 0-87). No invasive diagnostic procedures were performed on our patients during the study period. Table I summarizes the most common underlying illnesses per study group. Diabetes mellitus, a history of previous urinary tract infections, and prostate disease, were more common in the cefaclor-treated group. A history of previous hysterectomy was more common in the cefprozil-treated group. The predominant urinary pathogen isolated was E. coli (Table II). Other reported pathogens were: K. pneumoniae, K. oxytoca, and Staphylococcus saprophyticw. The clinical and bacteriological responses are summarized in Table III. The number of patients responding favourably, either with clinical improvement or resolution of signs and symptoms of disease, was slightly higher in those patients receiving cefprozil. This difference was not statistically significant. Clinical response could not be assessed in four patients (cefprozil, 3; cefaclor, 1) because of initially asymptomatic bacteriuria. Except for one cefaclor-treated patient, subjects who had an unsatisfactory clinical response to a study drug had a concomitant bacterial urine culture documenting persistent infection or evidence of relapse/reinfection. Urinary pathogens were eradicated at a similar percentage in both treatment groups. The percentage of bacteriological relapses/reinfections was similar for both treatment groups. Four patients with bacteriological relapse/reinfection were asymptomatic. E. coli was the causative pathoTabte
m . Clinical and bacteriological responses of the 94 patients
Response Clinical satisfactory unsatisfactory Bacteriological eradicated reinfection relapse persistence
Cefprozil no. (%)
Cefaclor no. (%)
54 (87) 8(13)
25 (78) 7(22)
52 (80) 2(3) 9 (14) 2(3)
27 (82)
1 0)
4 (12)
1 0)
Cefprozil Ff eefador in UTIs
585
Table IV. Comparative summary of most common adverse reactions observed in 102 patients Adverse event Leukoperua Vaginal yeast infection Nausea Elevated Kver enzymes Thrombocytosis
Cefprozil (n = 68) Cefador (n - 34) no. (%) no. (%) 14 7 7 5 3
(20-5) (113) (103) (7-35) (4-4)
2 (5-9) 2 (7) 0 2(5-9) 1 (2-9)
gen for all reinfections except for two patients in the cefaclor-treated group where Enterococcus spp. and K. pnewnoniae were isolated. Eleven male patients were enrolled into the study. Five patients in each treatment group demonstrated good clinical and bacteriological responses. One patient in the cefprozil-treated group was not evaluable for clinical response due to asymptomatic bacteriuria at the time of enrolment. Only five patients who failed treatment had underlying illnesses (cefprozil, 2 (rheumatoid arthritis, hypertension); cefaclor, 3 (2 patients with diabetes mellitus, 1 patient with hypertension). The incidence of adverse reactions is summarized in Table FV. These were more commonly observed in the cefprozil-treated patients. Leukopenia (defined as WBC < 5000/mm3) and nausea were more common in the cefprozil-treated group. These were not statistically significant (P = 0-08 and 0-07, respectively). Vaginal yeast infections were slightly more common in the cefprozil-treated patients. All these resolved with topical antifungal therapy. Four patients were discontinued from the study due to adverse reactions. Gastrointestinal complaints (abdominal discomfort, nausea and vomiting) were the most frequent cause for discontinuation from study; all these episodes occurred in cefprozil-treated patients. One cefaclor-treated patient experienced a generalized tingling-like sensation, with palmar itching 18 h into therapy. All sideeffects resolved after discontinuing study drugs. Other less frequently observed adverse reactions were: elevated liver enzymes (defined as alanine aminotransferase or aspartate aminotransferase > 40IU/L); thrombocytosis (platelets > 450,000/mm3); diarrhoea; eosinophilia (eosinophils > 5%). Discussion Due to the continuing emergence of resistance, mainly due to the production of /Mactamase enzymes by Gram-negative bacilli which commonly cause urinary tract infections, newer antimicrobial agents with increased stability to 0-lactamase hydrolysis are necessary. Agents with broad-spectrum antimicrobial coverage and prolonged halflife that could be orally administered would be ideal for treatment of urinary tract infections. Antimicrobial therapy requiring less frequent dosing may also increase compliance to therapy (Hussar, 1987). Cefprozil, given once a day, resulted in clinical responses similar to those of cefaclor administered three times a day. There was no difference between treatment groups with regard to the number of patients with underlying illnesses among those that failed therapy.
586
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The incidence of adverse reactions was somewhat greater in patients treated with cefprozil, with leukopenia and nausea being the most common. None of the WBC counts was less than 3900/mm3. Gastrointestinal side effects were the most common cause for discontinuation of study drugs. Vaginal yeast superinfections were slightly more common in the cefprozil-treated patients. A recently published Phase I study reported similar findings (Barbhaiya et al., 1990a). The percentage of bacteriological relapses/reinfections was similar for each treatment group. Bacterial pathogens were eradicated at a similar percentage in both treatment groups. Cefprozil 500 mg once daily appears to be an effective regimen for the treatment of acute uncomplicated urinary tract infection. This regimen compares favourably to cefaclor 250 mg administered three times a day. Further studies will be needed to evaluate the efficacy of cefprozil in shorter durationregimens(one day versus three days). Acknowledgements This study was supported by a grant from Bristol-Myers Squibb Company. References Barbhaiya, R. H., Shukla, U. A., Glcason, C. R., Shyu, W. C , Wilber, R. B., Martin, R. R. et al. (1990a). Phase I study of multiple-dose cefprozil and comparison with cefaclor. Antimicrobial Agents and Chemotherapy 34, 1198-203. Barbhaiya, R. H., Shukla, U. A., Gleason, C. R., Shyu, W. C , Wilber, R. B. & Pittman, K. A. (19906). Comparison of cefprozil and cefaclor phannacokineu'es and tissue penetration. Antimicrobial Agents and Chemotherapy 34, 1204-9. Chin, N.-X. & Neu, H. C. (1987). Comparative antibacterial activity of a new oral cephalosporin, BMY-281OO. Antimicrobial Agents and Chemotherapy 31, 480-3. Eliopoulos, G. M., Reiszner, E., Wennersten, C. & Moellering,, R. C. (1987). In vitro activity of BMY-28100, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 653-6. Hussar, D. A. (1987). Importance of patient compliance in effective antimicrobial therapy. Pediatric Infectious Disease Journal 6, 971-5. Iravani, A. & Richard, G. A. (1986). Amoxicillin-clavulanic acid versus cefaclor in the treatment of urinary tract infections and their effects on the urogenital and rectal flora. Antimicrobial Agents and Chemotherapy 29, 107-11. Jones, R. N., Barry, A. L. and the Collaborative Antimicrobial Testing Group. (1988). BMY-28100, a new oral cephalosporin: antimicrobial activity against nearly 7000 recent clinical isolates, comparative potency with other oral agents, and activity against /Mactamase producing isolates. Diagnostic Microbiology and Infectious Disease 9, 11-26. Leitner, F., Pursiano, T. A., Buck, R. E., Tsai, Y. H., Chisholm, D. R., Misiek, M. et al. (1987). BMY-28100, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 238-43. National Committee for Clinical Laboratory Standards. (1988). Performance Standards for Antimicrobial Disk Susceptibility Tests, 4th edn; Tentative Standard M2-T4. NCCLS, Villanova, PA. (Received 12 December 1990; revised version accepted 31 May 1991)
Comparative efficacy and safety of cefprozil and cefaclor in the treatment of acute uncomplicated urinary tract infections John C. Christensoii'^, W. Manford Goocfa*^, John N. Herrod' and EHse Swensoir^ 'University of Utah School of Medicine, Department of Pediatrics; bDivision of Infectious Diseases, Salt Lake City, Utah 84132; 'Primary Children's Medical Center, Division of Clinical Pharmacology, and *Bryner Clinic, Salt Lake City, Utah, USA Ccfprozil is a new oral semi-synthetic cephalosporin with broad antibacterial spectrum and prolonged serum elimination half-life. In vitro, cefprozil demonstrates excellent activity against common urinary tract pathogens such as Escherichia coli and Klebsiella pneumoniae. Cefprozil, 500 mg once a day, was compared to cefaclor, 250 mg three times a day, in an open, randomized, comparative, clinical trial for the treatment of acute, uncomplicated, urinary tract infection. One hundred and two adult patients were eligible for safety evaluation; four patients were excluded due to side-effects (abdominal discomfort, nausea and vomiting). Ninety-eight patients were eligible for evaluation of efficacy. Clinical and bacteriological responses were comparable for both antibiotics. Leucopenia, nausea, and vaginal yeast infections were slightly more common in the cefprozil group. Cefprozi], 500 mg once daily, appears to be an appropriate alternative for the treatment of acute, uncomplicated urinary tract infections.
Introduction Cefprozil, formerly known as BMY-28100, is a new oral scmisynthetic 7-phenylglycyl cephalosporin. Its broad-spectrum antibacterial activity and stability to hydrolysis by many /Mactamase enzymes, plus a prolonged half-life when compared to other oral cephalosporins, has possible clinical benefits for the treatment of various infections, especially urinary tract infections. Cefprozil is more active in vitro against members of the Enterobacteriaceae, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, than cephalexin. Over 90% of clinical isolates of Staphylococcus spp. are inhibited by < 8-0 mg/L of cefprozil (Jones et al., 1988). In-vitro activity was found to be comparable to cefaclor against these same pathogens (Chin & Neu, 1987; Eliopoulos et al., 1987; Jones et al., 1988; Leitner et al., 1987). Serratia marcescens, Citrobacter freundii, Enterobacter spp., and Pseudomonas aeruginosa are all resistant to cefprozil (Eliopoulos et al., 1987). The average serum half-life of cefprozil is 1-2 h, in contrast to cefaclor of 0-6-0-9 h. Approximately 65% of a single dose of cefprozil is recovered in the urine within 8 h after its administration (Barbhaiya et al., 1990ft). Phase I studies have demonstrated that the incidence and types of side-effects observed with cefprozil are similar to those reported with other oral cephalosporins (Barbhaiya et al., 1990a). The purpose of this study was to compare the efficacy and safety of cefprozil administered once a day to that of cefaclor, a cephalosporin shown to be effective in the 581 0305-7453/91/100581 +06 J02.00/0
© 1991 The British Society for Antimicrobial Chemotherapy
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J. C. Christenson et aL
treatment of urinary tract infections (Iravani & Richard, 1986) when administered three times a day. Methods Patients were enrolled in this open, randomized, comparative clinical study between 1987 and 1988 at the Department of Internal Medicine of the Bryner Clinic, an outpatient multispecialty clinic in the metropolitan area of Salt Lake City. Adult patients, 18 years of age or older, with documented or suspected acute uncomplicated urinary tract infections were selected. Signs and symptoms considered to be consistent with acute uncomplicated urinary tract infection were: fever, urinary difficulty (hesitancy, urgency, burning, frequency), dysuria, suprapubic pain and tenderness. Patients with asymptomatic bacteriuria were considered candidates for enrollment if they had two consecutive significant urine cultures with the same single pathogen in a 24 h period. An informed consent document was signed by all patients enrolled into study. All female patients of childbearing age had a documented negative pregnancy test before receiving the study drug. Patients surgically-sterilized by hysterectomy or tubal ligation were enrolled without satisfying this requirement. Patients were excluded from enrolment if they met any of the following criteria: history of anaphylaxis to penicillin or cephalosporins; history of allergies to cephalosporins; patients who had received a long-acting parental penicillin within two weeks before enrollment; pregnant or lactating women; patients with signs and symptoms suggestive of acute or chronic pyelonephritis; history of major renal or significant hepatic disease; history of gastrointestinal malabsorption; patients with anatomic abnormalities of the urinary tract. Before treatment, a medical history, physical examination, and laboratory studies which included a haematological analysis (white blood cell count (WBQ and differential, haemoglobin, haematocrit, platelet count, erythrocyte sedimentation rate), chemical analysis (liver enzymes, blood urea nitrogen, creatinine), urine analysis (with microscopic examination), and a clean-voided midstream urine culture were performed. A urine culture was considered significant if > 100,000 cfu/mL of a single urinary pathogen were isolated. Patients were reevaluated three to five days into therapy and five to nine days after completing therapy. Patients were randomized to receive either cefprozil (Bristol-Meyers Squibb Company), 500 mg orally once daily, or cefaclor (Eli Lilly and Company), 250 mg three times a day, using a 2 : 1 computer-generated randomization schedule provided by the sponsor. Randomization was performed by a research assistant. Each study drug was administered for a total of ten days. To document compliance with the study, the patient was asked to return all unused capsules at the completion of the study. Patients needed to receive the study drug for at least five consecutive days in order to be eligible for evaluation of efficacy. No other antimicrobial therapy was given concomitantly with the study drug. Clinical responses were classified as: satisfactory—resolution or improvement of all pre-treatment symptoms without the appearance of any new symptoms at the time of the post-treatment evaluation; unsatisfactory—pre-treatment symptoms remained unchanged or worsened at the end of study, or all pre-treatment symptoms resolved but new symptoms appeared at the time of post-treatment evaluation. Bacteriological responses were categorized as: eradicated—the original causative pathogen was eradicated and no new pathogen with a colony count of > 103 cfu/mL
Cefprozil rj cefador in UTIs
583
emerged; reinfection—the original causative pathogen was eradicated as determined by post-treatment culture and a new pathogen with a colony count of > K^cfu/mL emerged after that culture; relapse—original causative pathogen was eradicated as determined by the post-treatment culture and the same pathogen re-emerged with a colony count of > lO^cfu/mL after the five to nine day culture; persistence—the original causative pathogen persisted at a colony count of > 104 cfu/mL as determined by the on-treatment and post-treatment culture taken after completion of therapy. All bacterial isolates were tested for antimicrobial susceptibility utilizing 30/zg cefprozil and cephalothin impregnated discs, using the Kirby-Bauer method of disc diffusion on Mueller-Hinton agar (National Committee for Clinical Laboratory Standards, 1988). Organisms were considered resistant if zones of inhibition were less than 14 mm and susceptible if the zones of inhibition were > 18 mm. Patients were removed from the study if they met any of the following criteria: no pathogen isolated in pre-treatment urine culture; in-vitro susceptibility testing indicated resistance of the pathogen to either cefprozil or cefaclor, pre-treatment culture revealed causative pathogen at < K^cfu/mL (except coagulase-negative staphylococci which were considered significant at > 10,000 cfu/mL); poor clinical response after 72 h of therapy; occurrence of a serious or alarming adverse reaction related to the study drug. The study drugs were compared for their overall clinical and bacteriological response rates and incidence and severity of adverse reactions. Statistical analysis was performed utilizing Fisher's exact test. A P value equal to or less than 0-05 was considered to be significant. Results One hundred and thirty-four patients were enrolled in this clinical trial. Thirty-two patients were subsequently withdrawn because they did not meet criteria for eligibility to be evaluable: no pathogen isolated, 19; resistant pathogens, 8; no repeat cultures performed, 3; lack of compliance with study protocol, 1; one self-withdrawal. A total of 102 patients (68—cefprozil, 34—cefaclor) were eligible for safety evaluation. Four patients discontinued treatment due to adverse effects (3—cefprozil, 1—cefaclor). Ninety-eight patients were eligible for evaluation for efficacy. All patients completed ten days of therapy except for three patients in the cefprozil-treated group who completed seven to eight days of therapy.
Table L Underlying illnesses commonly observed in the cefprozil and cefaclor treatment groups Illness Diabetes mellitus Previous hysterectomy History of previous UTI' Arterial hypertension Prostate disease 'Urinary tract infection.
Cefprozil (n •= 65) Cefaclor (n = 33) no. (%) no. (%) 3 (4-6) 7 (11) 1 (1-5) 12 (18) 1 (1-5)
4(12) 1 (3) 2(6) 7 (21) 2 (6)
584
J. C. dnfatcnson et aL Table II. Bacterial pathogens of the urinary tract in 98 patients
Organism
Cefprozil no. (%)
Cefaclor no. (%)
E. coli
60 (92-3)
27 (82)
K.pneumoniae
4(6-2)
4(12)
K. oxytoca S. saprophytiau
0 1 (1-5)
1 (3) 1 (3)
The treatment groups were comparable in age, cefprozil—54-7 years (range 19-92; median 58-5), cefaclor—53-0 years (range 21-87; median 57), P = 0-67, sex, and type and severity of signs and symptoms of urinary tract infection. Mean duration of signs and symptoms of disease were similar for cefprozil and cefaclor, 5-8 and 5-6 days, respectively (P = 0-87). No invasive diagnostic procedures were performed on our patients during the study period. Table I summarizes the most common underlying illnesses per study group. Diabetes mellitus, a history of previous urinary tract infections, and prostate disease, were more common in the cefaclor-treated group. A history of previous hysterectomy was more common in the cefprozil-treated group. The predominant urinary pathogen isolated was E. coli (Table II). Other reported pathogens were: K. pneumoniae, K. oxytoca, and Staphylococcus saprophyticw. The clinical and bacteriological responses are summarized in Table III. The number of patients responding favourably, either with clinical improvement or resolution of signs and symptoms of disease, was slightly higher in those patients receiving cefprozil. This difference was not statistically significant. Clinical response could not be assessed in four patients (cefprozil, 3; cefaclor, 1) because of initially asymptomatic bacteriuria. Except for one cefaclor-treated patient, subjects who had an unsatisfactory clinical response to a study drug had a concomitant bacterial urine culture documenting persistent infection or evidence of relapse/reinfection. Urinary pathogens were eradicated at a similar percentage in both treatment groups. The percentage of bacteriological relapses/reinfections was similar for both treatment groups. Four patients with bacteriological relapse/reinfection were asymptomatic. E. coli was the causative pathoTabte
m . Clinical and bacteriological responses of the 94 patients
Response Clinical satisfactory unsatisfactory Bacteriological eradicated reinfection relapse persistence
Cefprozil no. (%)
Cefaclor no. (%)
54 (87) 8(13)
25 (78) 7(22)
52 (80) 2(3) 9 (14) 2(3)
27 (82)
1 0)
4 (12)
1 0)
Cefprozil Ff eefador in UTIs
585
Table IV. Comparative summary of most common adverse reactions observed in 102 patients Adverse event Leukoperua Vaginal yeast infection Nausea Elevated Kver enzymes Thrombocytosis
Cefprozil (n = 68) Cefador (n - 34) no. (%) no. (%) 14 7 7 5 3
(20-5) (113) (103) (7-35) (4-4)
2 (5-9) 2 (7) 0 2(5-9) 1 (2-9)
gen for all reinfections except for two patients in the cefaclor-treated group where Enterococcus spp. and K. pnewnoniae were isolated. Eleven male patients were enrolled into the study. Five patients in each treatment group demonstrated good clinical and bacteriological responses. One patient in the cefprozil-treated group was not evaluable for clinical response due to asymptomatic bacteriuria at the time of enrolment. Only five patients who failed treatment had underlying illnesses (cefprozil, 2 (rheumatoid arthritis, hypertension); cefaclor, 3 (2 patients with diabetes mellitus, 1 patient with hypertension). The incidence of adverse reactions is summarized in Table FV. These were more commonly observed in the cefprozil-treated patients. Leukopenia (defined as WBC < 5000/mm3) and nausea were more common in the cefprozil-treated group. These were not statistically significant (P = 0-08 and 0-07, respectively). Vaginal yeast infections were slightly more common in the cefprozil-treated patients. All these resolved with topical antifungal therapy. Four patients were discontinued from the study due to adverse reactions. Gastrointestinal complaints (abdominal discomfort, nausea and vomiting) were the most frequent cause for discontinuation from study; all these episodes occurred in cefprozil-treated patients. One cefaclor-treated patient experienced a generalized tingling-like sensation, with palmar itching 18 h into therapy. All sideeffects resolved after discontinuing study drugs. Other less frequently observed adverse reactions were: elevated liver enzymes (defined as alanine aminotransferase or aspartate aminotransferase > 40IU/L); thrombocytosis (platelets > 450,000/mm3); diarrhoea; eosinophilia (eosinophils > 5%). Discussion Due to the continuing emergence of resistance, mainly due to the production of /Mactamase enzymes by Gram-negative bacilli which commonly cause urinary tract infections, newer antimicrobial agents with increased stability to 0-lactamase hydrolysis are necessary. Agents with broad-spectrum antimicrobial coverage and prolonged halflife that could be orally administered would be ideal for treatment of urinary tract infections. Antimicrobial therapy requiring less frequent dosing may also increase compliance to therapy (Hussar, 1987). Cefprozil, given once a day, resulted in clinical responses similar to those of cefaclor administered three times a day. There was no difference between treatment groups with regard to the number of patients with underlying illnesses among those that failed therapy.
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J- C Chrfatenson et ML
The incidence of adverse reactions was somewhat greater in patients treated with cefprozil, with leukopenia and nausea being the most common. None of the WBC counts was less than 3900/mm3. Gastrointestinal side effects were the most common cause for discontinuation of study drugs. Vaginal yeast superinfections were slightly more common in the cefprozil-treated patients. A recently published Phase I study reported similar findings (Barbhaiya et al., 1990a). The percentage of bacteriological relapses/reinfections was similar for each treatment group. Bacterial pathogens were eradicated at a similar percentage in both treatment groups. Cefprozil 500 mg once daily appears to be an effective regimen for the treatment of acute uncomplicated urinary tract infection. This regimen compares favourably to cefaclor 250 mg administered three times a day. Further studies will be needed to evaluate the efficacy of cefprozil in shorter durationregimens(one day versus three days). Acknowledgements This study was supported by a grant from Bristol-Myers Squibb Company. References Barbhaiya, R. H., Shukla, U. A., Glcason, C. R., Shyu, W. C , Wilber, R. B., Martin, R. R. et al. (1990a). Phase I study of multiple-dose cefprozil and comparison with cefaclor. Antimicrobial Agents and Chemotherapy 34, 1198-203. Barbhaiya, R. H., Shukla, U. A., Gleason, C. R., Shyu, W. C , Wilber, R. B. & Pittman, K. A. (19906). Comparison of cefprozil and cefaclor phannacokineu'es and tissue penetration. Antimicrobial Agents and Chemotherapy 34, 1204-9. Chin, N.-X. & Neu, H. C. (1987). Comparative antibacterial activity of a new oral cephalosporin, BMY-281OO. Antimicrobial Agents and Chemotherapy 31, 480-3. Eliopoulos, G. M., Reiszner, E., Wennersten, C. & Moellering,, R. C. (1987). In vitro activity of BMY-28100, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 653-6. Hussar, D. A. (1987). Importance of patient compliance in effective antimicrobial therapy. Pediatric Infectious Disease Journal 6, 971-5. Iravani, A. & Richard, G. A. (1986). Amoxicillin-clavulanic acid versus cefaclor in the treatment of urinary tract infections and their effects on the urogenital and rectal flora. Antimicrobial Agents and Chemotherapy 29, 107-11. Jones, R. N., Barry, A. L. and the Collaborative Antimicrobial Testing Group. (1988). BMY-28100, a new oral cephalosporin: antimicrobial activity against nearly 7000 recent clinical isolates, comparative potency with other oral agents, and activity against /Mactamase producing isolates. Diagnostic Microbiology and Infectious Disease 9, 11-26. Leitner, F., Pursiano, T. A., Buck, R. E., Tsai, Y. H., Chisholm, D. R., Misiek, M. et al. (1987). BMY-28100, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 238-43. National Committee for Clinical Laboratory Standards. (1988). Performance Standards for Antimicrobial Disk Susceptibility Tests, 4th edn; Tentative Standard M2-T4. NCCLS, Villanova, PA. (Received 12 December 1990; revised version accepted 31 May 1991)
