Loracarbef (LY163892) Versus Cefaclor and Norfloxacin in the Treatment of Uncomplicated Pyelonephritis DAVID L.
HYSLOP, M.D.,
Indianapolis, Indiana, WERNER BISCHOFF, M.D., Backnang, Germany
Optimal therapy for pyelonephritis requires the immediate administration of an effective broad-spectrum antibiotic. Because conventional oral antibiotics such as the sulfonamides and the aminopenicillins are limited by the development of resistant bacteria associated with this common disease, the therapeutic effectiveness of a new oral carbacephem antibiotic was investigated. Two double-blind, randomized clinical trials of ioracarbef (LY163892) were conducted. A total of 245 patients (->18 years old) with uncomplicated pyelonephritis were enrolled in parallel studies. One study compared loracarbef with cefaclor; the other compared loracarbef with norfloxacin. In the combined patient population, 119 patients were treated with loracarbef (400 mg twice daily), 43 with cefaclor (500 mg three times daily), and 83 with norfloxacin (400 mg twice daily). All treatment regimens continued for ->14 days. A total of 68 patients in the loracarbef group, 25 in the cefaclor group, and 43 in the norfloxacin group qualified for efficacy analysis. Esch. erichia coli was the causative pathogen in 85.0% of these patients. Successful posttherapy clinical and bacteriologic responses were similar for all three study drugs: 94.1 and 86.8%, 96.0 and 80.0%, 97.7 and 88.4% for loracarbef, cefaclor, and norfloxacin, respectively. Late posttherapy clinical responses were 87.4, 83.3, and 91.7% for the loracarbef, cefaclor, and norfloxacin groups, respectively. Bacteriologic responses for the three groups were 79.6, 60.0, and 88.9%. The most frequent adverse effects (headache, diarrhea, and nausea) were experienced by three patients (2.5%) in the loracarbef group; headaches were noted in two (4.7%) cefaclor patients, diarrhea was noted in three (7.0%) patients in the cefaclor group, and nausea was noted in four (9.3%). Gastrointestinal From Lilly Research Laboratories,Indianapolis,Indiana,and the Departmentof Urology, District Hospital, Backnang, Germany. Requests for reprints should be addressed to David L. Hyslop, M.D., Lilly Laboratory for Clinical Research,Wishard Memorial Hospital,7th Floor, Myers Building, 1001 West lOth Street, Indianapolis, Indiana 46285.
6A-86S
events were noted in four patients (4.8%) in the norfloxacin group. The data demonstrate that loracarbef is comparable in efficacy and safety to both cefaclor and norfloxacin as oral therapy for uncomplicated pyelonephritis.
cute pyelonephritis is a common disease caused by bacterial infection of the kidney. Its A classic symptoms include flank pain/tenderness, fever, and chills, often in combination with dysuria, urgency, and frequency. Nausea and vomiting may also accompany these symptoms. Significant bacteriuria, defined by excessive numbers of bacteria in clean-voided urine (->105 colony-forming units [CFU]/mL), is a distinct feature [1]. Most cases of acute pyelonephritis occur after infection of the lower urinary tract, and it is widely accepted that initial fecal contamination of the lower tract is the usual primary event in the disease's pathogenesis. Escherichia coli is the predominant causative pathogen, accounting for about 85% of urinary tract infections [2]. Other common pathogens associated with pyelonephritis are Proteus species, Enterococcus faecalis, Pseudomonas species, Klebsiella species, and Staphylococcus species. After recurrent acute attacks, the latter organisms are more common and may become more resistant to antibiotic therapy [2]. The management of patients with acute pyelonephritis is controversial. At issue are the antibiotic choice, the length of treatment, and whether hospitalization and intravenous antibiotics are necessary. Because 25-35% ofE. coli have become resistant to conventional oral therapies using sulfonamides or aminopenicillins [3], these agents no longer provide optimal treatment. As a result, cephalosporins such as cefaclor, cefixime, and cephalexin and quinolones such as norfloxacin and ciprofloxacin are frequently used for the treatment of uncomplicated pyelonephritis in selected patients on an outpatient basis [1,4-8]. Although mild-tomoderate pyelonephritis responds well to oral antibiotic therapy, nausea and vomiting may preclude this approach to treatment, necessitating hospitalization and parenteral therapy.
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUM ON ANTIMICROBIALTHERAPY! HYSLOPand BISCHOFF
The present article describes the combined findings of two controlled clinical trials comparing loracarbef (LY163892) with cefaclor and norfloxacin in the treatment of uncomplicated pyelonephritis. Loracarbef, an agent of the carbacephem class of fl-lactam antibiotics, has been shown to provide in vitro activity against a broad spectrum of bacteria, including E. coli, Klebsiella pneumoniae, Proteus mirabilis, and staphylococci, and their fl-lactamase-producing strains [9-14]. In one trial, loracarbef was compared with cefaclor, a semisynthetic oral cephalosporin with proven effectiveness in the treatment of pyelonephritis [15-17]. The other trial compared loracarbef with norfloxacin, a fluorinated 4-quinolone that has shown excellent antimicrobial activity against both gram-positive and gramnegative bacteria associated with pyelonephritis [18-20].
PATIENTS AND METHODS Patients Between March 1988 and December 1989, 245 patients with uncomplicated pyelonephritis were enrolled in two double-blind, randomized clinical trials. Patients -- 18 years of age from the investigators' patient populations were candidates for the studies if they had uncomplicated upper urinary tract infections with a clinical diagnosis of pyetonephritis. Patient selections were made on the basis of a demonstrated history of therapeutic compliance; each patient signed an informed consent form. The study comparing loracarbef with cefaclor was conducted in the United States and was approved by the investigators' institutional review boards. The study comparing loracarbef with norfloxacin was conducted in Europe according to ethical committee guidelines, including the Declaration of Helsinki (1983 Venice Amendment). Pyelonephritis was defined as the presence of two or more of the following signs/symptoms: fever (>38.0°C), flank pain, or granulocyte casts in spun urinary sediment. Subsequently, the diagnosis had to be proven by the presence of significant bacteriuria, that is, urine culture showing ->105 CFU/mL in a cleanvoided or catheterized urine specimen. Pregnant or nursing women were excluded from the study, as were patients with any of the following: complicated urinary tract infections (past or present history of obstructive uropathy or nephrolithiasis), presence of indwelling Foley catheter or other urinary tract instrumentation, and/or a history of renal impairment (serum creatinine >-2.0 mg/dL or ->177 tLmol/L in the study of loracarbef vs. cefaclor, or ->1.9 mg/dL or ->170 t~mol/L in the study of loracarbef vs. norfloxacin). Other exclusionary criteria included significant underlying dis-
ease or concomitant infection that might have precluded evaluation of response, an anticipated requirement of systemic antibiotics other than the study antibiotic during the course of the study, and/ or use of successful or suppressive antimicrobial therapy within 3 days of the pretherapy evaluations. The use of other investigational agents within the previous 28 days and/or hypersensitivity to penicillins and/or cephalosporins were also grounds for exclusion.
Treatment Regimens In one study, patients were randomized to receive either loracarbef 400 mg (two 200 mg capsules) twice daily or cefaclor 500 mg (two 250 mg capsules) three times daily. Medication was packaged in blister cards and placebo was administered at midday to patients in the loracarbef group in order to maintain blinding. In the other study, patients were randomized to receive either loracarbef (two 200 mg capsules) twice daily or norfloxacin 400 mg (one capsule) twice daily along with one capsule of placebo twice daily. Both regimens in the study of loracarbef versus norfloxacin were packaged in bottles. The minimum treatment time was 14 days for patients responding to therapy, but no minimum duration was required for patients not responding to treatment.
Evaluation Criteria The experimental protocol specified four observation periods. After clinical and/or bacteriologic diagnosis confirmed the suitability of the patient for participation in the study, a complete history and physical examination were obtained within 24 hours prior to the first dose of study drug (day 0). During the second observation period, midtherapy (days 24), the patient's response was evaluated, as was adherence to the treatment regimen. A physical examination took place on days 5-9 after the conclusion of therapy to evaluate the patient's response to therapy; an additional physical examination was performed at the late-posttherapy period (4-6 weeks after the conclusion of therapy) in order to evaluate patients for possible relapse of infection. Quantitative urine cultures were required at each observation period. Susceptibility (or intermediate susceptibility) of isolated pathogens to both loracarbef and cefaclor was determined by standardized-disk methodology of the National Committee for Clinical Laboratory Standards (30 t~g disks) and/or by minimal inhibitory concentration (MIC) determination. Cefaclor susceptibility was mea-
June 22, ].992 The American Journal of Medicine Volume92 (suppl 6A)
6A-87S
SYMPOSIUM ON ANTIMICROBIALTHERAPY/HYSLOPand BISCHOFF
sured using cephalothin, a representative of the cephalosporin class. Susceptibility for loracarbef and cefaclor was defined as zone diameter ->15 mm or MIC -13 mm or MIC 105 CFU/mL); and "failure" indicated original pathogen was not eradicated (->104 CFU/mL). In addition, responses were deemed unevaluable if posttherapy cultures were not obtained or if a patient received nonstudy antibiotic therapy for an unrelated infection. Concomitant medication for treatment of underlying diseases or conditions was allowed with the exception of systemic antibiotics and phenazopyridine hydrochloride. If a systemic antibiotic other than the study agent was required for treatment of pyelonephritis, the study antibiotic was discontinued and the patient was classified as a symptomatic failure. If a systemic antibiotic was given for any other condition, the patient was classified as unable to evaluate clinically and bacteriologically. Patients' temperatures were obtained at each visit. Patients were also examined and questioned at each visit for the presence and severity of the following signs and symptoms: dysuria, urgency, urinary frequency, gross hematuria, nocturia, and flank pain. At the pretherapy visit, a numeric value was recorded for each symptom present: 1 = mild, 2 = moderate, or 3 = severe. If a particular symptom was absent at the pretherapy evaluation, it was assigned a code of 0 and was not followed further during the course of the study. If a symptom that was absent at the pretherapy visit appeared at a subsequent visit, it was recorded as a treatmentemergent event. On the basis of resolution or presence of these symptoms, a global symptomatic response was assigned by the investigator at the posttherapy and late-posttherapy assessments: cure, improvement (substantial), failure, relapse, or unable to evaluate. Laboratory testing (hematology, blood chemistry, and urinalysis) was required at both pretherapy and posttherapy visits. Panels were repeated at midtherapy and late-posttherapy visits only as 6A-88S
clinically indicated. Urine was collected at the midtherapy evaluation and assayed for presence of antimicrobial activity to assess patient compliance.
Discontinuation from Study A patient was discontinued from the study if the pathogen isolated from initial culture was resistant to either study antibiotic used in the studies. If there was obvious symptomatic failure of the study antibiotic at any time during treatment, or if there was a significant adverse event or a significant alteration in a laboratory parameter, a patient was also removed from the study. Discontinuation was also instigated if a patient wished to be withdrawn from the study, if the blinding was broken for safety reasons, or if the patient had an elevated pretherapy serum creatinine (->2.0 mg/dL). Pretherapy laboratory tests and urine cultures were repeated for patients discontinued from the study. Patients who showed a favorable clinical response to treatment but had a pretherapy urine culture negative for pathogen (3% of one or more of each treatment group by study. ; Loracarbef groups: compared with cefaclor/compared with norfloxacin/combined.
thus offer a distinct advantage over currently used oral antibiotics with more demanding dosing requirements. The present studies have shown that loracarbef exhibits comparable clinical and bacteriologic efficacy to both cefaclor and norfloxacin in patients with uncomplicated pyelonephritis. Favorable symptomatic responses (cure or improvement) at posttherapy were seen in 94.1, 96.0, and 97.7% of patients treated with loracarbef, cefaclor, and norfloxacin, respectively. Symptomatic and bacteriologic response rates were comparable when results were analyzed by causative pathogen, including E. coli and P. mirabilis. All E. coli pretherapy isolates tested with loracarbef were susceptible, as compared with a low incidence of resistance for this common pathogen noted in susceptibility testing with cefaclor (two resistant isolates) and norfloxacin (one resistant isolate). Favorable late-posttherapy clinical responses were comparable between the three groups: 87.4% for the loracarbef group, 83.3% for the cefaclor group, and 91.7% for the norfioxacin group. Loracarbef also showed a comparable safety profile. The most frequent adverse effects (headache, diarrhea, and nausea) were experienced by three patients (2.5%) in the loracarbef group; headaches were noted in two (4.7%) cefaclor patients, diarrhea was noted in three (7.0%) patients in the cefaclor group, and nausea was noted in four (9.3%). Gastrointestinal events were noted in four patients (4.8%) in the norfloxacin group. The distribution of adverse events in all three treatment groups was not statistically significant. Hypersensitivity was observed in none of the patients in the loracarbef group, whereas it was noted in two patients (4.7%) and one patient (1.2%) in the cefaclor and norfloxacin groups, respectively. Only two patients (0.8%) discontinued therapy due to adverse events presumed to be drug related (one with nausea and vomiting in the loracarbef group
and one with maculopapular rash in the cefaclor group). In summary, the data demonstrate that loracarbef is comparable in efficacy and safety to both cefaclor and norfloxacin in treating uncomplicated pyelonephritis on an outpatient basis. In addition to loracarbef's broad antimicrobial activity against urinary tract pathogens, its twice-daily dosing requirement may contribute to its therapeutic value. Loracarbef is thus an option to consider for the oral antibiotic treatment of this common medical problem.
REFERENCES 1. Sobel JD, Kaye D. Urinary tract infections. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone, 1990; 582-611. 2. Schreiner GF, Kissane JM. The urinary system. In: Kissane JM, ed. Anderson's pathology, 9th ed. St. Louis: Mosby, 1990; 804-70. 3. Johnson JR, Stamm WE. Diagnosis and treatment of acute urinary tract infections. Infect Dis Clin North Am 1987; 1: 773-91. 4. Iravani A. Advances in the understanding and treatment of urinary tract infections in young women. Urology 1991; 37: 503-11. 5. Stamm WE, McKevitt M, Counts GW. Acute renal infection in women: treatment with trimethoprim-sulfamethoxazole or ampicillin for two or six weeks: a randomized trial. Ann Intern Med 1987; 106: 341-5. 6. Scott MR, Lowenstein SR, Marx JA, Koziol-McClain J, Svoboda L, Ranniger S. Management of acute pyelonephritis in an emergency department observation unit. Ann Emerg Med 1991; 20: 253-7. 7. Ward G, Jorden RC, Severance HW. Treatment of pyelonephritis in an observation unit. Ann Emerg Med 1991; 20: 258-61. 8. Safrin S, Siegel D, Black D. Pyelonephritis in adult women: inpatient versus outpatient therapy. Am J Med 1988; 85: 793-8. 9. CaD C, Chin NX, Neu HC. In-vitro activity and/3-1actamasestability of LY163892. J Antimicrob Chemother 1988; 22: 155-65. 10. Howard AJ, Dunkin FT. Comparative in-vitro activity of a new oral carbacephem, LY163892. J Antimicrob Chemother 1988; 22: 445-56, 11. Jones RN, Barry AL. Antimicrobial activity of LY163892, an orally administered 1-carbacephem. J Antimicrob Chemother 1988; 22: 315-20. 12. Knapp CC, Washington JA II. In vitro activities of LY163892, cefaclor, and cefuroxime. Antimicrob Agents Chemother 1988; 32: 131-3. 13. Pelosi E, Fontana R. In vitro activity and/3-1actamase stability of LY163892. Eur J Clin Microbiol Infect Dis 1988; 7: 549-51. 14. Jones RN, Barry AL. B-lactamase hydrolysis and inhibition studies of the new 1-carbacephem LY163892. Eur J Clin Microbiol 1987; 6: 570-1.
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
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SYMPOSIUMON ANTIMICROBIALTHERAPY/HYSLOPand BISCHOFF 15. Iravani A, Richard GA. Amoxicillin-clavulanic acid versus cefaclor in the treatment of urinary tract infections and their effects on the urogenital and rectal flora. Antimicrob Agents Chemother 1986; 29: 107-11. 16. Iravani A, Richard GA. Single-dose cefuroxime axetil versus multiple-dose cefaclor in the treatment of acute urinary tract infections. Antimicrob Agents Chemother 1989; 33: 1212-6. 17. Verhoef J. Cefaclor in the treatment of skin, soft tissue, and urinary tract infections: a review. Clin Ther 1988; 11 (Suppl A]: 71-82. 18. Turgeon P, Dubois J, Stoffel S. In vitro activity of norfloxacin against 4003 clinical isolates: a multicentre study in Canada. Curr Ther Res 1985; 38: 169-72. 19. Appelbaum PC, Spangler SK, Sollenberger L. Susceptibility of non-fermentative gram-negative bacteria to ciprofloxacin, norfloxacin, amifloxacin, pefloxacin and cef-
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June 22, 1992 The American Journal of Medicine
pirome. J Antimicrob Chemother 1986; 18: 675-9.
20. Sabbaj J, Hoagland VL, Shih WJ. Multiclinic comparative study of norfloxacin and trimethoprim-sulfamethoxazole for treatment of urinary tract infections. Antimicrob Agents Chemother 1985; 27: 297-301. 21. Jorgensen JH, Redding JS, Maher LA. Influence of storage and susceptibility test conditions on stability and activity of LY163892 and four other cephalosporins. Antimicrob Agents Chemother 1988; 32: 1477-80. 22. Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990; 150: 1881-4. 23. Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1984; 6: 592-9.
Volume 92 (suppl 6A)
HYSLOP, M.D.,
Indianapolis, Indiana, WERNER BISCHOFF, M.D., Backnang, Germany
Optimal therapy for pyelonephritis requires the immediate administration of an effective broad-spectrum antibiotic. Because conventional oral antibiotics such as the sulfonamides and the aminopenicillins are limited by the development of resistant bacteria associated with this common disease, the therapeutic effectiveness of a new oral carbacephem antibiotic was investigated. Two double-blind, randomized clinical trials of ioracarbef (LY163892) were conducted. A total of 245 patients (->18 years old) with uncomplicated pyelonephritis were enrolled in parallel studies. One study compared loracarbef with cefaclor; the other compared loracarbef with norfloxacin. In the combined patient population, 119 patients were treated with loracarbef (400 mg twice daily), 43 with cefaclor (500 mg three times daily), and 83 with norfloxacin (400 mg twice daily). All treatment regimens continued for ->14 days. A total of 68 patients in the loracarbef group, 25 in the cefaclor group, and 43 in the norfloxacin group qualified for efficacy analysis. Esch. erichia coli was the causative pathogen in 85.0% of these patients. Successful posttherapy clinical and bacteriologic responses were similar for all three study drugs: 94.1 and 86.8%, 96.0 and 80.0%, 97.7 and 88.4% for loracarbef, cefaclor, and norfloxacin, respectively. Late posttherapy clinical responses were 87.4, 83.3, and 91.7% for the loracarbef, cefaclor, and norfloxacin groups, respectively. Bacteriologic responses for the three groups were 79.6, 60.0, and 88.9%. The most frequent adverse effects (headache, diarrhea, and nausea) were experienced by three patients (2.5%) in the loracarbef group; headaches were noted in two (4.7%) cefaclor patients, diarrhea was noted in three (7.0%) patients in the cefaclor group, and nausea was noted in four (9.3%). Gastrointestinal From Lilly Research Laboratories,Indianapolis,Indiana,and the Departmentof Urology, District Hospital, Backnang, Germany. Requests for reprints should be addressed to David L. Hyslop, M.D., Lilly Laboratory for Clinical Research,Wishard Memorial Hospital,7th Floor, Myers Building, 1001 West lOth Street, Indianapolis, Indiana 46285.
6A-86S
events were noted in four patients (4.8%) in the norfloxacin group. The data demonstrate that loracarbef is comparable in efficacy and safety to both cefaclor and norfloxacin as oral therapy for uncomplicated pyelonephritis.
cute pyelonephritis is a common disease caused by bacterial infection of the kidney. Its A classic symptoms include flank pain/tenderness, fever, and chills, often in combination with dysuria, urgency, and frequency. Nausea and vomiting may also accompany these symptoms. Significant bacteriuria, defined by excessive numbers of bacteria in clean-voided urine (->105 colony-forming units [CFU]/mL), is a distinct feature [1]. Most cases of acute pyelonephritis occur after infection of the lower urinary tract, and it is widely accepted that initial fecal contamination of the lower tract is the usual primary event in the disease's pathogenesis. Escherichia coli is the predominant causative pathogen, accounting for about 85% of urinary tract infections [2]. Other common pathogens associated with pyelonephritis are Proteus species, Enterococcus faecalis, Pseudomonas species, Klebsiella species, and Staphylococcus species. After recurrent acute attacks, the latter organisms are more common and may become more resistant to antibiotic therapy [2]. The management of patients with acute pyelonephritis is controversial. At issue are the antibiotic choice, the length of treatment, and whether hospitalization and intravenous antibiotics are necessary. Because 25-35% ofE. coli have become resistant to conventional oral therapies using sulfonamides or aminopenicillins [3], these agents no longer provide optimal treatment. As a result, cephalosporins such as cefaclor, cefixime, and cephalexin and quinolones such as norfloxacin and ciprofloxacin are frequently used for the treatment of uncomplicated pyelonephritis in selected patients on an outpatient basis [1,4-8]. Although mild-tomoderate pyelonephritis responds well to oral antibiotic therapy, nausea and vomiting may preclude this approach to treatment, necessitating hospitalization and parenteral therapy.
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUM ON ANTIMICROBIALTHERAPY! HYSLOPand BISCHOFF
The present article describes the combined findings of two controlled clinical trials comparing loracarbef (LY163892) with cefaclor and norfloxacin in the treatment of uncomplicated pyelonephritis. Loracarbef, an agent of the carbacephem class of fl-lactam antibiotics, has been shown to provide in vitro activity against a broad spectrum of bacteria, including E. coli, Klebsiella pneumoniae, Proteus mirabilis, and staphylococci, and their fl-lactamase-producing strains [9-14]. In one trial, loracarbef was compared with cefaclor, a semisynthetic oral cephalosporin with proven effectiveness in the treatment of pyelonephritis [15-17]. The other trial compared loracarbef with norfloxacin, a fluorinated 4-quinolone that has shown excellent antimicrobial activity against both gram-positive and gramnegative bacteria associated with pyelonephritis [18-20].
PATIENTS AND METHODS Patients Between March 1988 and December 1989, 245 patients with uncomplicated pyelonephritis were enrolled in two double-blind, randomized clinical trials. Patients -- 18 years of age from the investigators' patient populations were candidates for the studies if they had uncomplicated upper urinary tract infections with a clinical diagnosis of pyetonephritis. Patient selections were made on the basis of a demonstrated history of therapeutic compliance; each patient signed an informed consent form. The study comparing loracarbef with cefaclor was conducted in the United States and was approved by the investigators' institutional review boards. The study comparing loracarbef with norfloxacin was conducted in Europe according to ethical committee guidelines, including the Declaration of Helsinki (1983 Venice Amendment). Pyelonephritis was defined as the presence of two or more of the following signs/symptoms: fever (>38.0°C), flank pain, or granulocyte casts in spun urinary sediment. Subsequently, the diagnosis had to be proven by the presence of significant bacteriuria, that is, urine culture showing ->105 CFU/mL in a cleanvoided or catheterized urine specimen. Pregnant or nursing women were excluded from the study, as were patients with any of the following: complicated urinary tract infections (past or present history of obstructive uropathy or nephrolithiasis), presence of indwelling Foley catheter or other urinary tract instrumentation, and/or a history of renal impairment (serum creatinine >-2.0 mg/dL or ->177 tLmol/L in the study of loracarbef vs. cefaclor, or ->1.9 mg/dL or ->170 t~mol/L in the study of loracarbef vs. norfloxacin). Other exclusionary criteria included significant underlying dis-
ease or concomitant infection that might have precluded evaluation of response, an anticipated requirement of systemic antibiotics other than the study antibiotic during the course of the study, and/ or use of successful or suppressive antimicrobial therapy within 3 days of the pretherapy evaluations. The use of other investigational agents within the previous 28 days and/or hypersensitivity to penicillins and/or cephalosporins were also grounds for exclusion.
Treatment Regimens In one study, patients were randomized to receive either loracarbef 400 mg (two 200 mg capsules) twice daily or cefaclor 500 mg (two 250 mg capsules) three times daily. Medication was packaged in blister cards and placebo was administered at midday to patients in the loracarbef group in order to maintain blinding. In the other study, patients were randomized to receive either loracarbef (two 200 mg capsules) twice daily or norfloxacin 400 mg (one capsule) twice daily along with one capsule of placebo twice daily. Both regimens in the study of loracarbef versus norfloxacin were packaged in bottles. The minimum treatment time was 14 days for patients responding to therapy, but no minimum duration was required for patients not responding to treatment.
Evaluation Criteria The experimental protocol specified four observation periods. After clinical and/or bacteriologic diagnosis confirmed the suitability of the patient for participation in the study, a complete history and physical examination were obtained within 24 hours prior to the first dose of study drug (day 0). During the second observation period, midtherapy (days 24), the patient's response was evaluated, as was adherence to the treatment regimen. A physical examination took place on days 5-9 after the conclusion of therapy to evaluate the patient's response to therapy; an additional physical examination was performed at the late-posttherapy period (4-6 weeks after the conclusion of therapy) in order to evaluate patients for possible relapse of infection. Quantitative urine cultures were required at each observation period. Susceptibility (or intermediate susceptibility) of isolated pathogens to both loracarbef and cefaclor was determined by standardized-disk methodology of the National Committee for Clinical Laboratory Standards (30 t~g disks) and/or by minimal inhibitory concentration (MIC) determination. Cefaclor susceptibility was mea-
June 22, ].992 The American Journal of Medicine Volume92 (suppl 6A)
6A-87S
SYMPOSIUM ON ANTIMICROBIALTHERAPY/HYSLOPand BISCHOFF
sured using cephalothin, a representative of the cephalosporin class. Susceptibility for loracarbef and cefaclor was defined as zone diameter ->15 mm or MIC -13 mm or MIC 105 CFU/mL); and "failure" indicated original pathogen was not eradicated (->104 CFU/mL). In addition, responses were deemed unevaluable if posttherapy cultures were not obtained or if a patient received nonstudy antibiotic therapy for an unrelated infection. Concomitant medication for treatment of underlying diseases or conditions was allowed with the exception of systemic antibiotics and phenazopyridine hydrochloride. If a systemic antibiotic other than the study agent was required for treatment of pyelonephritis, the study antibiotic was discontinued and the patient was classified as a symptomatic failure. If a systemic antibiotic was given for any other condition, the patient was classified as unable to evaluate clinically and bacteriologically. Patients' temperatures were obtained at each visit. Patients were also examined and questioned at each visit for the presence and severity of the following signs and symptoms: dysuria, urgency, urinary frequency, gross hematuria, nocturia, and flank pain. At the pretherapy visit, a numeric value was recorded for each symptom present: 1 = mild, 2 = moderate, or 3 = severe. If a particular symptom was absent at the pretherapy evaluation, it was assigned a code of 0 and was not followed further during the course of the study. If a symptom that was absent at the pretherapy visit appeared at a subsequent visit, it was recorded as a treatmentemergent event. On the basis of resolution or presence of these symptoms, a global symptomatic response was assigned by the investigator at the posttherapy and late-posttherapy assessments: cure, improvement (substantial), failure, relapse, or unable to evaluate. Laboratory testing (hematology, blood chemistry, and urinalysis) was required at both pretherapy and posttherapy visits. Panels were repeated at midtherapy and late-posttherapy visits only as 6A-88S
clinically indicated. Urine was collected at the midtherapy evaluation and assayed for presence of antimicrobial activity to assess patient compliance.
Discontinuation from Study A patient was discontinued from the study if the pathogen isolated from initial culture was resistant to either study antibiotic used in the studies. If there was obvious symptomatic failure of the study antibiotic at any time during treatment, or if there was a significant adverse event or a significant alteration in a laboratory parameter, a patient was also removed from the study. Discontinuation was also instigated if a patient wished to be withdrawn from the study, if the blinding was broken for safety reasons, or if the patient had an elevated pretherapy serum creatinine (->2.0 mg/dL). Pretherapy laboratory tests and urine cultures were repeated for patients discontinued from the study. Patients who showed a favorable clinical response to treatment but had a pretherapy urine culture negative for pathogen (3% of one or more of each treatment group by study. ; Loracarbef groups: compared with cefaclor/compared with norfloxacin/combined.
thus offer a distinct advantage over currently used oral antibiotics with more demanding dosing requirements. The present studies have shown that loracarbef exhibits comparable clinical and bacteriologic efficacy to both cefaclor and norfloxacin in patients with uncomplicated pyelonephritis. Favorable symptomatic responses (cure or improvement) at posttherapy were seen in 94.1, 96.0, and 97.7% of patients treated with loracarbef, cefaclor, and norfloxacin, respectively. Symptomatic and bacteriologic response rates were comparable when results were analyzed by causative pathogen, including E. coli and P. mirabilis. All E. coli pretherapy isolates tested with loracarbef were susceptible, as compared with a low incidence of resistance for this common pathogen noted in susceptibility testing with cefaclor (two resistant isolates) and norfloxacin (one resistant isolate). Favorable late-posttherapy clinical responses were comparable between the three groups: 87.4% for the loracarbef group, 83.3% for the cefaclor group, and 91.7% for the norfioxacin group. Loracarbef also showed a comparable safety profile. The most frequent adverse effects (headache, diarrhea, and nausea) were experienced by three patients (2.5%) in the loracarbef group; headaches were noted in two (4.7%) cefaclor patients, diarrhea was noted in three (7.0%) patients in the cefaclor group, and nausea was noted in four (9.3%). Gastrointestinal events were noted in four patients (4.8%) in the norfloxacin group. The distribution of adverse events in all three treatment groups was not statistically significant. Hypersensitivity was observed in none of the patients in the loracarbef group, whereas it was noted in two patients (4.7%) and one patient (1.2%) in the cefaclor and norfloxacin groups, respectively. Only two patients (0.8%) discontinued therapy due to adverse events presumed to be drug related (one with nausea and vomiting in the loracarbef group
and one with maculopapular rash in the cefaclor group). In summary, the data demonstrate that loracarbef is comparable in efficacy and safety to both cefaclor and norfloxacin in treating uncomplicated pyelonephritis on an outpatient basis. In addition to loracarbef's broad antimicrobial activity against urinary tract pathogens, its twice-daily dosing requirement may contribute to its therapeutic value. Loracarbef is thus an option to consider for the oral antibiotic treatment of this common medical problem.
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SYMPOSIUMON ANTIMICROBIALTHERAPY/HYSLOPand BISCHOFF 15. Iravani A, Richard GA. Amoxicillin-clavulanic acid versus cefaclor in the treatment of urinary tract infections and their effects on the urogenital and rectal flora. Antimicrob Agents Chemother 1986; 29: 107-11. 16. Iravani A, Richard GA. Single-dose cefuroxime axetil versus multiple-dose cefaclor in the treatment of acute urinary tract infections. Antimicrob Agents Chemother 1989; 33: 1212-6. 17. Verhoef J. Cefaclor in the treatment of skin, soft tissue, and urinary tract infections: a review. Clin Ther 1988; 11 (Suppl A]: 71-82. 18. Turgeon P, Dubois J, Stoffel S. In vitro activity of norfloxacin against 4003 clinical isolates: a multicentre study in Canada. Curr Ther Res 1985; 38: 169-72. 19. Appelbaum PC, Spangler SK, Sollenberger L. Susceptibility of non-fermentative gram-negative bacteria to ciprofloxacin, norfloxacin, amifloxacin, pefloxacin and cef-
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pirome. J Antimicrob Chemother 1986; 18: 675-9.
20. Sabbaj J, Hoagland VL, Shih WJ. Multiclinic comparative study of norfloxacin and trimethoprim-sulfamethoxazole for treatment of urinary tract infections. Antimicrob Agents Chemother 1985; 27: 297-301. 21. Jorgensen JH, Redding JS, Maher LA. Influence of storage and susceptibility test conditions on stability and activity of LY163892 and four other cephalosporins. Antimicrob Agents Chemother 1988; 32: 1477-80. 22. Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990; 150: 1881-4. 23. Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1984; 6: 592-9.
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