Journal of Antimicrobial Chemotherapy (1991) 28, 577-580
Ceftibuten versus cefaclor for the treatment of bronchitis Valerie A. Chinirgi*, Howard Edelstein, Sharon E. Oster, Richard Karp, Kami B. Cassano, Stephanie Aiken, Peter Knnnpe and Robert E. McCabe
Ceftibuten is an oral third generation ccphalosporin with potent antimicrobial activity against Enterobacteriaceae, /Mactamase positive Haemophilia mfluenzae, Moraxella catarrhalts, Neisseria menmgitidis, Neisseria gonorrheae, penicillinsusceptible pneumococci, and /J-hcmolytic streptococci. To study the efficacy and safety of ceftibuten for treatment of bronchitis, 58 patients were randomized to therapy with either ceftibuten 400 mg once a day or cefaclor 250 mg every 8 h at a ratio of two to one. Of 45 clinically evaluable patients, 28 (87-5%) of the 32 ceftibuten patients and 12 (92-3%) of the 13 cefaclor patients were clinically improved or cured. Of 33 microbiologically evaluable patients, 21 (87-5%) of the 24 ceftibuten patients and eight (80%) of the ten cefaclor patients were cured. Of 56 patients evaluable for adverse effects, three (7-9%) of the 38 ceftibuten patients and one (5-6%) of the 18 cefaclor patients had adverse reactions. In this small study, once-daily ceftibuten appeared as safe and as effective as cefaclor for the treatment of bronchitis.
Introduction
Ceftibuten (SCH 39720) is an orally administered cephalosporin active against most Enterobacteriaceae, Haemophilus mfluenzae, Neisseria meningitidis, Neisseria gonorrheae, Moraxella catarrhalis, penicillin-susceptible pneumococci, and beta-haemolytic streptococci (Jones & Barry, 1988). Pharmacokinetic data (Nakashima et al., 1988) suggest administration once daily might be effective for bacterial bronchitis. We compared the safety and efficacy of ceftibuten, 400 mg administered once daily, with that of cefaclor for bronchitis. Materials and methods
After approval by the Martinez hospital ethics committee, sequential eligible outpatient and hospitalized patients with acute bronchitis, but not pneumonia, were enrolled after written informed consent. For inclusion in the study, sputum had to show a predominant organism, > 25 polymorphonuclear leukocytes, and < ten epithelial cells per low power field. Exclusion criteria included effective antibiotic treatment within 72 h, immediate type hypersensitivity to /Mactams, serum creatinine ^ 170 /imol/L, SGOT 'Correspondence: Valerie A. Chinirgi Martinez Veterans Administration Medical Center, Medical Service (11 IF), 150 Muir Road, Martinez, California 94553, USA. 577 0305-7453/91/100577 + 04 $02.00/0
© 1991 The British Society for Antimicrobul Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
Medical Service, Veterans Administration Medical Center, Martinez, California, and Department of Medicine, University of California Medical School, Davis, California, USA
578
V. A. Chirurgi et aL
or SGPT > three times normal, serum bilirubin > 34 /nnol/L, or neutropenia ( < 1-0 x 109 neutrophils/L). Patients were randomized to receive either ceftibuten capsules, 400 mg once daily, or cefaclor capsules, 250 mg every 8 h, at a 2:1 ratio. Susceptibility testing was done by standard disc diffusion and broth macrodilution methods. Inpatients were assessed daily. Outpatients kept a daily diary of signs and symptoms and were assessed every three to five days. Clinical cure, improvement, and failure as well as microbiological cure, persistence, colonization, superinfection, and reinfection were as previously stated (Oster et aJ., 1990). Routine laboratory tests were done every three days to assess safety.
The ceftibuten and cefaclor clinically evaluable groups were similar with respect to sex, age, underlying pulmonary disease (75% and 85%, respectively), and average length of treatment (8-2 ±0-5 and 8-8 ±0-8 days, respectively). Most patients had an acute exacerbation of chronic bronchitis (62-5% and 69-2%, respectively). Significantly more patients treated with cefaclor were inpatients (chi-square, P < 0-05), but the difference was not significant when all enrolled patients were analyzed. Seven (17-9%) of the 39 ceftibuten-treated patients could not be evaluated due to protocol violations, compared with six (31-6%) of the 19 cefaclor-treated patients. Twenty-eight (87-5%) of 32 patients responded to ceftibuten (Table). Of the failures, one developed fever and congestive heart failure during treatment. Sputum grew Staphylococcus aureus, which was considered to be colonizing the patient, who died 18 days later of metastatic carcinoma and congestive heart failure. A second patient, with normal flora by culture, did not improve clinically after seven days of outpatient treatment, but responded to erythromycin. A third patient, with severe chronic obstructive pulmonary disease (COPD), had bronchitis due to M. catarrhalis and Klebsiella pneumoniae. Symptoms and M. catarrhalis persisted after 14 days of treatment, with the ceftibuten MIC stable at 4 mg/L. He did not improve with subsequent co-trimoxazole. The fourth patient with bronchitis due to Streptococcus pneumoniae and /Mactamasc-positive M. catarrhalis had persistent symptoms and M. catarrhalis in
Table. Clinical and microbiological outcomes in patients treated for bronchitis Ceftibuten
Cefaclor
Clinical evaluation favourable (%) cure improvement
n = 32 28(87-5%) 19 9
n = 13 12(92-3%) 9 3
Microbiology evaluation cure (%) persistence superinfection reinfection
n =«= 24 21(87-5%) 2 I 0
n «= 10 8(80%) 2 0 0
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
Results
Ceftflmten vt cefador in bronchitis
579
Discussion This small study suggests that ceftibuten is safe and effective for the treatment of bronchitis. Adverse clinical and laboratory reactions occurred in 7-9% of patients, were transient, mild, and comparable to adverse reactions with cefaclor treatment of bronchitis in this and other studies (Beumer & Veldkamp, 1982; Hurst, 1984). The clinical response (87-5%) with ceftibuten was excellent, and similar to response rates of 62-92% seen in this and other studies of cefaclor for bronchitis (Beumer & Veldkamp, 1982; Hurst, 1984). Four patients treated with ceftibuten were clinical failures. There was no significant difference in the length of treatment between patients who were failures and those who responded (7-5 vs 8-2 days). Two clinical failures could not be evaluated microbiologically, and underlying diseases (congestive heart failure, lung carcinoma, bronchospasm) might have caused persistence of signs and symptoms that prompted judgement of clinical failure. Two other patients, both
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
his sputum after seven days of ceftibuten, but was cured with co-trimoxazole. The MIC of ceftibuten for M. catarrhalis increased from < 0-5 to 4 mg/L. Of the 13 patients treated with cefaclor, 12 (92-3%) responded clinically (Table). The patient who failed had sleep apnoea and cor pulmonale, and persistent symptoms and /Mactamase-negative H. influenzae in his sputum. He was cured with co-trimoxazole. Pathogens in the 24 microbiologically evaluable ceftibuten-treated patients were H. influenzae (12), H. parainfluenzae (8), M. catarrhalis (4), S. pneumoniae (2), N. meningitidis (1), Serratia marcescens (1), and K. pneumoniae (1), including five patients with two pathogens. The ten cefaclor-treated patients had H. influenzae (4), H. parainfluenzae (1), M. catarrhalis (2), S. pneumoniae (1), N. meningitidis (1), and Enterobacter aerogenes (1). The MIC,,, for ceftibuten of the H. influenzae and H. parainfluenzae isolates was < 0-5 mg/L. Five M. catarrhalis isolates had MICs < 0-5 mg/L and a single isolate had an MIC of 4 mg/L. Two N. meningitidis isolates, one E. aerogenes, one S. marcescens isolate, and one K. pneumoniae had MICs ^ 0-5 mg/L. The S. pneumoniae isolates had MICs of 8, 8, and 4 mg/L. Ceftibuten cured 21 (87-5%) of 24 patients by microbiological criteria. Two patients described above were both clinical and microbiological failures. Another patient with COPD due to /Mactamase negative H. influenzae became superinfected with S. aureus and S. marcescens. He improved with co-trimoxazole. Cefaclor eliminated the causative organism in eight (80%) of the ten evaluable patients. One patient with lung carcinoma had persistent /Mactamase negative H. influenzae, but was cured clinically. The second patient, mentioned above, had recurrence of symptoms and the pathogen at follow-up. Three patients treated with ceftibuten had adverse reactions. One patient who had right upper quadrant abdominal tenderness on entry, developed elevated serum transaminases on the seventh day of therapy. Ceftibuten was stopped and the abdominal tenderness and elevated transaminases resolved within 14 days. Other reactions were transient eosinophilia which resolved during therapy, and mild nausea which did not necessitate stopping therapy. One cefaclor patient had 24% atypical lymphocytes in the peripheral blood on the fourth day of therapy. Cefaclor was stopped after six days because of clinical improvement, and the atypical lymphocytosis resolved within two days.
580
V. A. Chirnrgi et «L
Acknowledgements This research was supported by a grant from Schering-Plough and by the Research Service of the Department of Veterans Affairs. References Beumer, H. M. & Veldkamp, J. (1982). Oral ccfaclor for treatment of bronchitis—a comparative double-blind study versus amoxydllin. International Journal of Clinical Pharmacology, Therapy, and Toxicology 20, 113-7. Eisen, S. A., Miller, D. IC, Woodward, R. S., Spitznagel, E. & Przybeck, T. R. (1990). The effect of prescribed daily dose frequency on patient medication compliance. Archives of Internal Medicine 150, 1881-4. Hurst, D. J. (1984). A comparison of cefaclor and tctracycline in the treatment of bacterial bronchitis. Clinical Therapeutics 6, 163-9. Jones, R. N. & Barry, A. L. (1988). Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin. Antimicrobial Agents and Chemotherapy 32, 1576-52. Nakashima, M., Uematsu, T., Talciguchi, Y., Mizuno, A., Iida, M., Yoshida, T. et al. (1988). Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. Journal of Clinical Pharmacology 28, 246-52. Ostcr, S., Edelstein, H., Cassano, K. & McCabe, R. (1990). Open trial of cefepime (BMY 28142) for infections in hospitalized patients. Antimicrobial Agents and Chemotherapy 34, 954-7. (Received 25 January 1991; revised version accepted 6 June 1991)
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
infected with M. catarrhalis, were both clinical and microbiological failures. One of these patients had severe underlying COPD that could have contributed to failure. The second patient had no obvious pulmonary disease, but poor drug absorption or decrease in susceptibility to ceftibuten might account for his poor clinical response, as the MIC increased from < 0-5 to 4 mg/L. There were relatively few isolates of 5. pnevmoniae, making conclusions about ceftibuten's use in treating pneumococcal bronchitis difficult. A distinct advantage of ceftibuten over other antimicrobials is administration once daily. A recent study showed that compliance improved from 59% on a three-times daily regimen of antihypertensives to 83-6% on a once-daily regimen of antihypertensives (Eisen et al., 1990). The pharmacokinetics of ceftibuten allowing once-daily dosing could improve effective antibiotic administration for bronchitis.
Ceftibuten versus cefaclor for the treatment of bronchitis Valerie A. Chinirgi*, Howard Edelstein, Sharon E. Oster, Richard Karp, Kami B. Cassano, Stephanie Aiken, Peter Knnnpe and Robert E. McCabe
Ceftibuten is an oral third generation ccphalosporin with potent antimicrobial activity against Enterobacteriaceae, /Mactamase positive Haemophilia mfluenzae, Moraxella catarrhalts, Neisseria menmgitidis, Neisseria gonorrheae, penicillinsusceptible pneumococci, and /J-hcmolytic streptococci. To study the efficacy and safety of ceftibuten for treatment of bronchitis, 58 patients were randomized to therapy with either ceftibuten 400 mg once a day or cefaclor 250 mg every 8 h at a ratio of two to one. Of 45 clinically evaluable patients, 28 (87-5%) of the 32 ceftibuten patients and 12 (92-3%) of the 13 cefaclor patients were clinically improved or cured. Of 33 microbiologically evaluable patients, 21 (87-5%) of the 24 ceftibuten patients and eight (80%) of the ten cefaclor patients were cured. Of 56 patients evaluable for adverse effects, three (7-9%) of the 38 ceftibuten patients and one (5-6%) of the 18 cefaclor patients had adverse reactions. In this small study, once-daily ceftibuten appeared as safe and as effective as cefaclor for the treatment of bronchitis.
Introduction
Ceftibuten (SCH 39720) is an orally administered cephalosporin active against most Enterobacteriaceae, Haemophilus mfluenzae, Neisseria meningitidis, Neisseria gonorrheae, Moraxella catarrhalis, penicillin-susceptible pneumococci, and beta-haemolytic streptococci (Jones & Barry, 1988). Pharmacokinetic data (Nakashima et al., 1988) suggest administration once daily might be effective for bacterial bronchitis. We compared the safety and efficacy of ceftibuten, 400 mg administered once daily, with that of cefaclor for bronchitis. Materials and methods
After approval by the Martinez hospital ethics committee, sequential eligible outpatient and hospitalized patients with acute bronchitis, but not pneumonia, were enrolled after written informed consent. For inclusion in the study, sputum had to show a predominant organism, > 25 polymorphonuclear leukocytes, and < ten epithelial cells per low power field. Exclusion criteria included effective antibiotic treatment within 72 h, immediate type hypersensitivity to /Mactams, serum creatinine ^ 170 /imol/L, SGOT 'Correspondence: Valerie A. Chinirgi Martinez Veterans Administration Medical Center, Medical Service (11 IF), 150 Muir Road, Martinez, California 94553, USA. 577 0305-7453/91/100577 + 04 $02.00/0
© 1991 The British Society for Antimicrobul Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
Medical Service, Veterans Administration Medical Center, Martinez, California, and Department of Medicine, University of California Medical School, Davis, California, USA
578
V. A. Chirurgi et aL
or SGPT > three times normal, serum bilirubin > 34 /nnol/L, or neutropenia ( < 1-0 x 109 neutrophils/L). Patients were randomized to receive either ceftibuten capsules, 400 mg once daily, or cefaclor capsules, 250 mg every 8 h, at a 2:1 ratio. Susceptibility testing was done by standard disc diffusion and broth macrodilution methods. Inpatients were assessed daily. Outpatients kept a daily diary of signs and symptoms and were assessed every three to five days. Clinical cure, improvement, and failure as well as microbiological cure, persistence, colonization, superinfection, and reinfection were as previously stated (Oster et aJ., 1990). Routine laboratory tests were done every three days to assess safety.
The ceftibuten and cefaclor clinically evaluable groups were similar with respect to sex, age, underlying pulmonary disease (75% and 85%, respectively), and average length of treatment (8-2 ±0-5 and 8-8 ±0-8 days, respectively). Most patients had an acute exacerbation of chronic bronchitis (62-5% and 69-2%, respectively). Significantly more patients treated with cefaclor were inpatients (chi-square, P < 0-05), but the difference was not significant when all enrolled patients were analyzed. Seven (17-9%) of the 39 ceftibuten-treated patients could not be evaluated due to protocol violations, compared with six (31-6%) of the 19 cefaclor-treated patients. Twenty-eight (87-5%) of 32 patients responded to ceftibuten (Table). Of the failures, one developed fever and congestive heart failure during treatment. Sputum grew Staphylococcus aureus, which was considered to be colonizing the patient, who died 18 days later of metastatic carcinoma and congestive heart failure. A second patient, with normal flora by culture, did not improve clinically after seven days of outpatient treatment, but responded to erythromycin. A third patient, with severe chronic obstructive pulmonary disease (COPD), had bronchitis due to M. catarrhalis and Klebsiella pneumoniae. Symptoms and M. catarrhalis persisted after 14 days of treatment, with the ceftibuten MIC stable at 4 mg/L. He did not improve with subsequent co-trimoxazole. The fourth patient with bronchitis due to Streptococcus pneumoniae and /Mactamasc-positive M. catarrhalis had persistent symptoms and M. catarrhalis in
Table. Clinical and microbiological outcomes in patients treated for bronchitis Ceftibuten
Cefaclor
Clinical evaluation favourable (%) cure improvement
n = 32 28(87-5%) 19 9
n = 13 12(92-3%) 9 3
Microbiology evaluation cure (%) persistence superinfection reinfection
n =«= 24 21(87-5%) 2 I 0
n «= 10 8(80%) 2 0 0
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
Results
Ceftflmten vt cefador in bronchitis
579
Discussion This small study suggests that ceftibuten is safe and effective for the treatment of bronchitis. Adverse clinical and laboratory reactions occurred in 7-9% of patients, were transient, mild, and comparable to adverse reactions with cefaclor treatment of bronchitis in this and other studies (Beumer & Veldkamp, 1982; Hurst, 1984). The clinical response (87-5%) with ceftibuten was excellent, and similar to response rates of 62-92% seen in this and other studies of cefaclor for bronchitis (Beumer & Veldkamp, 1982; Hurst, 1984). Four patients treated with ceftibuten were clinical failures. There was no significant difference in the length of treatment between patients who were failures and those who responded (7-5 vs 8-2 days). Two clinical failures could not be evaluated microbiologically, and underlying diseases (congestive heart failure, lung carcinoma, bronchospasm) might have caused persistence of signs and symptoms that prompted judgement of clinical failure. Two other patients, both
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
his sputum after seven days of ceftibuten, but was cured with co-trimoxazole. The MIC of ceftibuten for M. catarrhalis increased from < 0-5 to 4 mg/L. Of the 13 patients treated with cefaclor, 12 (92-3%) responded clinically (Table). The patient who failed had sleep apnoea and cor pulmonale, and persistent symptoms and /Mactamase-negative H. influenzae in his sputum. He was cured with co-trimoxazole. Pathogens in the 24 microbiologically evaluable ceftibuten-treated patients were H. influenzae (12), H. parainfluenzae (8), M. catarrhalis (4), S. pneumoniae (2), N. meningitidis (1), Serratia marcescens (1), and K. pneumoniae (1), including five patients with two pathogens. The ten cefaclor-treated patients had H. influenzae (4), H. parainfluenzae (1), M. catarrhalis (2), S. pneumoniae (1), N. meningitidis (1), and Enterobacter aerogenes (1). The MIC,,, for ceftibuten of the H. influenzae and H. parainfluenzae isolates was < 0-5 mg/L. Five M. catarrhalis isolates had MICs < 0-5 mg/L and a single isolate had an MIC of 4 mg/L. Two N. meningitidis isolates, one E. aerogenes, one S. marcescens isolate, and one K. pneumoniae had MICs ^ 0-5 mg/L. The S. pneumoniae isolates had MICs of 8, 8, and 4 mg/L. Ceftibuten cured 21 (87-5%) of 24 patients by microbiological criteria. Two patients described above were both clinical and microbiological failures. Another patient with COPD due to /Mactamase negative H. influenzae became superinfected with S. aureus and S. marcescens. He improved with co-trimoxazole. Cefaclor eliminated the causative organism in eight (80%) of the ten evaluable patients. One patient with lung carcinoma had persistent /Mactamase negative H. influenzae, but was cured clinically. The second patient, mentioned above, had recurrence of symptoms and the pathogen at follow-up. Three patients treated with ceftibuten had adverse reactions. One patient who had right upper quadrant abdominal tenderness on entry, developed elevated serum transaminases on the seventh day of therapy. Ceftibuten was stopped and the abdominal tenderness and elevated transaminases resolved within 14 days. Other reactions were transient eosinophilia which resolved during therapy, and mild nausea which did not necessitate stopping therapy. One cefaclor patient had 24% atypical lymphocytes in the peripheral blood on the fourth day of therapy. Cefaclor was stopped after six days because of clinical improvement, and the atypical lymphocytosis resolved within two days.
580
V. A. Chirnrgi et «L
Acknowledgements This research was supported by a grant from Schering-Plough and by the Research Service of the Department of Veterans Affairs. References Beumer, H. M. & Veldkamp, J. (1982). Oral ccfaclor for treatment of bronchitis—a comparative double-blind study versus amoxydllin. International Journal of Clinical Pharmacology, Therapy, and Toxicology 20, 113-7. Eisen, S. A., Miller, D. IC, Woodward, R. S., Spitznagel, E. & Przybeck, T. R. (1990). The effect of prescribed daily dose frequency on patient medication compliance. Archives of Internal Medicine 150, 1881-4. Hurst, D. J. (1984). A comparison of cefaclor and tctracycline in the treatment of bacterial bronchitis. Clinical Therapeutics 6, 163-9. Jones, R. N. & Barry, A. L. (1988). Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin. Antimicrobial Agents and Chemotherapy 32, 1576-52. Nakashima, M., Uematsu, T., Talciguchi, Y., Mizuno, A., Iida, M., Yoshida, T. et al. (1988). Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. Journal of Clinical Pharmacology 28, 246-52. Ostcr, S., Edelstein, H., Cassano, K. & McCabe, R. (1990). Open trial of cefepime (BMY 28142) for infections in hospitalized patients. Antimicrobial Agents and Chemotherapy 34, 954-7. (Received 25 January 1991; revised version accepted 6 June 1991)
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
infected with M. catarrhalis, were both clinical and microbiological failures. One of these patients had severe underlying COPD that could have contributed to failure. The second patient had no obvious pulmonary disease, but poor drug absorption or decrease in susceptibility to ceftibuten might account for his poor clinical response, as the MIC increased from < 0-5 to 4 mg/L. There were relatively few isolates of 5. pnevmoniae, making conclusions about ceftibuten's use in treating pneumococcal bronchitis difficult. A distinct advantage of ceftibuten over other antimicrobials is administration once daily. A recent study showed that compliance improved from 59% on a three-times daily regimen of antihypertensives to 83-6% on a once-daily regimen of antihypertensives (Eisen et al., 1990). The pharmacokinetics of ceftibuten allowing once-daily dosing could improve effective antibiotic administration for bronchitis.
