DIAGN MICROBIOLINFECT DIS 1991;14:101-105
Randomized Comparative Study of Ceftibuten versus Cefaclor in the Treatment of Acute Lower Respiratory Tract Infections Robert B. Kammer and Rudyard Ress
In a randomized, single-blind trial, ceftibuten in doses of 200 mg and 300 mg administered b.i.d., was compared with cefaclor 500 mg t.i.d, in acute lower respiratory tract infections. A total 545 patients were enrolled, of which 263 were evaluable for efficacy. All patients were adults with a diagnosis of either bacterial pneumonia or bronchitis. The infective organism was eliminated in 83% of the patients in the ceftibuten 200-mg b.i.d, treatment group and in 85% of patients in the 300-mg b.i.d, treatment group. The organisms were eliminated in 79% of cefaclor-treated patients. Satisfactory clinical responses were obtained in 91% of patients in the ceftibuten 200-mg b.i.d, treatment group and in 92% of patients in the
INTRODUCTION Ceftibuten (SCH39720) is a new, orally active cephalosporin antibiotic that has shown in vitro activity superior to that of cefaclor and cephalexin against a broad range of Gram-negative bacteria including the common respiratory pathogens Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. In addition, it is active against Streptococcus pneumoniae and Streptococcus pyogenes (Bragman and Casewell, 1990; Dornbusch et al., 1989; Jones and Barry, 1988ac; Mendelman et al., 1989; Shawar et al., 1989). Ceftibuten is stable in the presence of chromosomal cephalosporinases and plasmid-mediated penicillinases, except for the ~-lactamase produced by Bacteroides fragilis. In clinical pharmacology studies, mean peak plasma levels of 9.8 ~g/ml were observed - 2 hr after a single 200-mg dose (date on file, Schering Plough Research). Following a 300-mg dose of From Schering-Plough Research, Kenilworth, New Jersey.
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ceftibuten 300-rag b.i.d, group. Satisfactory clinical responses were obtained in 91% of cefaclor-treated patients. Predominant pathogens isolated were Streptococcus pneumoniae, Hae-
mophilus influenzae, Moraxella (Branhamella) catarrhalis, and strains of Enterobacteriaceae. Adverse experiences reported were similar for the ceftibuten and cefaclor treatment groups. Gastrointestinal side effects occured in 6% of patients treated with ceftibuten 200 mg BID, 9% in those treated with 300 mg BID, and 7% of cefaclor-treated patients. Ceftibuten 200 and 300 mg twice daily was as effective as cefaclor bacteriologically and clinically in the treatment of lower respiratory tract infections. ceftibuten, maximum serum concentrations averaged 15.0 ~g/ml. Elimination half-life ranged from 2.4 to 2.8 hr. In multiple-dose studies, no significant accumulation of ceftibuten was seen after doses of 100, 200, and 300 mg given twice daily for 7-14 days. Excretion of ceftibuten was primarily by the renal route with 70%-85% of administered drug recovered in the urine. The less active trans-isomer accounted for 18 years of age were eligible for entry into this study. To establish the diagnosis and determine the suitability of the patient for the study, a medical history was taken and a physical examination performed before enrolling the patient. The diagnosis of acute lower respiratory tract infection was to be culture confirmed. Symptoms of lower respiratory tract infection such as fever, productive cough, increasing sputum volume, pleuritic chest pain, and dyspnea were present. Rales, rhonchi, and signs of pulmonary consolidation were noted. Pneumonia patients had evidence of a new pulmonary infiltrate on a pretreatment chest roentgenogram. Laboratory criteria included a sputum Gram stain showing 25 polymorphonuclear neutrophils, with bacteria readily visible on high-power examination. Patients were excluded from enrollment if they had a history of hypersensitivity to a penicillin, cephalosporin, or any other ~-lactam antibiotic. Patients with known or suspected significant renal impairment, hepatic disfunction, or neutropenia were also excluded. A
summary of pooled demographic data for patients in the efficacy population is included in Table 1.
Treatment Procedures and Evaluation Prior to the start of the study, the protocol and statement of informed consent were reviewed and approved by an Institutional Review Board or ethical review committee. The investigators agreed to conduct the study in accordance with the Declaration of Helsinki or other provisions on the rights of human subjects as outlined in the protocol. Prior to the initiation of treatment procedures, appropriate informed consent was obtained. Patients were randomized to treatment using a randomization schedule provided by the sponsor. Patients meeting the entry criteria were assigned to one of the following oral regimens: ceftibuten 200 mg (b.i.d.), ceftibuten 300 mg (b.i.d.), or cefaclor 500 mg (t.i.d.). Patients were treated for a minimum of 5 consecutive days, but not for more than 14 days. Treatment was to continue for at least 48-72 h after the patient became asymptomatic. During treatment, patients were evaluated every 2-5 days or more if considered appropriate. Out patients were given a diary card on which to record daily the presence and intensity of specific signs and symptoms of infection. The clinical laboratory tests listed in Table 2 were required before treatment, repeated every 3-5 days during treatment, and at the end of treatment. If the patients pretreatment chest roentgenogram was abnormal, it was repeated until a resolution of the pathology was noted. Samples for bacteriologic culture were collected before starting treatment, at days 3-5 of treatment, 1-3 days
TABLE 1. Pooled Demographic Data for those Patients Included in the Efficacy Populationa Ceftibuten 200 mg BID Number of patients Gender (no. patients) Male Female Race (no. patients) White Black Other Median age (years) Median weight (kg) Primary diagnosis (no. patients) b Bronchitis Pneumonia
Ceftibuten 300 mg BID
Cefaclor 500 mg TID
85 3 1 58 61.6
85 6 2 55 63.2
73 6 2 58 60.2
aKruskal-Wallistest was used to compare treatmentdifferencesfor age and weight; chi-square was used to compare race, gender, and distributionof diagnosis. The three treatment groups were comparable for all demographicvariables (p > 0.3). bThe distribution of diagnosis among the three treatment groups was comparable (p > 0.4), chi-square test.
Ceftibuten vs Cefaclor in LRTI
after the end of treatment, and at 7-14 days after the end of treatment. Absence of an available culture source was interpreted as a negative culture. Susceptibility to ceftibuten and cefaclor was determined by either disk diffusion or a standard method of minimum inhibitory concentration. Testing for ~lactarnase production in strains of Moraxella and Haemophilus was performed by the chromogenic cephalosporin assay. To be considered evaluable for efficacy a patient had the following: • A pathogen susceptible to both ceftibuten and cefaclor isolated from a sputum specimen obtained within 48 hr before treatment. • If appropriate specimens were available, cultures from days 3-5 of treatment, 1-3 days after treatment, and 7-14 days after treatment. • A minimum of 5 consecutive days of treatment with the assigned study drug. • No other antibiotic treatment between the pretreatment and posttreatment cultures. The clinical response was defined as cure if there was complete resolution of signs and symptoms of infection. The response was called improvement if there was clinically significant decrease in the sign and symptoms of infection. If persistence or worsening occurred, the response was called a failure. The overall bacteriologic response to therapy was classified for each patient according to the following definitions:
Clinical Laboratory Tests
Hematology • Hemoglobin • Hematocrit • Total white blood cell count with differential • Platelet count • Prothrombin time • Direct Coombs' test Blood chemistries • SGOT (AST) • SGPT (ALT) • Alkaline phosphatase • Total bilirubin (direct if total increased) • Creatinine • Urea nitrogen (BUN) Urinalysis • pH • Specific gravity • Protein • Glucose • Hemoglobin • Microscopic examination of sediment, including presence of cells (type), casts (type), and bacteria
Causative organism(s) absent at or immediately after termination of therapy, or the complete disappearance of the culture source (e.g., sputum) so that follow-up culture is impossible. Continued presence of causative organism(s) at the end of treatment. Isolation of pathogen other than original organism(s) during treatment or within 1-3 days after treatment and associated with persisting or worsening signs and symptoms of infection. Causative organism(s) absent during or immediately after the end of treatment, but followed by the reappearance of the same organism(s) at the same site at or before the follow-up visit. Causative organism(s) absent at or immediately after termination of therapy, but appearance of a new infecting organism(s) at the same site during the follow-up period and causing the appearance of signs and symptoms. The appearance of any new potentially pathogenic organism(s) in cultures obtained after starting treatment, but without signs and symptoms of infection and not requiring specific antibiotic treatment.
Adverse experiences that occurred during the treatment were recorded on the patient's case report form and the investigator assessed the relationship of the adverse experience to treatment as being either probable, possible, or unrelated. The severity of adverse experience was graded as mild, moderate, severe or life threatening.
Patients Whose Efficacy Date Were Excluded from Analysis Of the 545 patients enrolled in the study, 282 were excluded after treatment had begun. Most (188) were excluded because no pathogen was isolated from the pretherapy sputum cultures. Another 38 patients were excluded because their pathogens were resistant to study medications (21 patients had cefaclor-resistant organisms and 17 patients had ceftibuten-resistant organisms at entry to this study).
Statistical Methods and Data Analysis For all tests, common among-group and betweengroup differences were considered to be statistically significant at p = 40.05. Between-group comparisons of observations for nominal variables, such as gender, race, and elimination rate, were performed via a chi-square test, and comparisons for ordinal
R.B. Kammer and R. Ress
Ceftibuten Bacterial Responses vs Rx by Pathogen Percent Eliminated
Haemophilus influenzae(90) Streptococcuspneumoniae(78) Moraxella spp. (21)
80 74 91
50 96 90
slightly higher clinical response rate to cefaclor than for ceftibuten: 98% versus 91%. The opposite was the case for bronchitis patients: 85% for cefaclor and 95% for ceftibuten.
variables, such as age, weight, clinical response, duration of treatment, time to resolution of signs, and symptoms, were performed with the Kruskal-Wallis test.
RESULTS Comparison of Treatment Groups The three treatment groups were comparable with regard to distribution of gender, race, age, and weight (Table 1). The average age of patients in the efficacy population was 55 years with a range of 18-99 years. Of the 263 evaluable patients in the efficacy population, 89 received ceftibuten 200 mg (b.i.d.), 93 received ceftibuten 300 mg (b.i.d.), and 81 patients received cefaclor 500 mg (t.i.d.).
Isolated Bacterial Pathogens Haemophilus influenzae, S. pneumonae, and Moraxella species were the most commonly isolated bacterial pathogens in this study and were equally distributed in the treatment groups. The bacterial responses to treatment by specific pathogen are shown in Table 3. In 80% of ceftibuten-treated patients, Haemophilus spp. were eliminated. In cefaclor-treated patients, the elimination rate was 50% for Haemophilus spp. Only 74% of ceftibuten-treated patients had S. pneumoniae eliminated from clinical specimens. Moraxella spp. were eliminated with equal frequency with both treatments.
Response to Treatment Satisfactory clinical responses were obtained in 91% of the patients treated with ceftibuten 200 mg (b.i.d.). A similar response rate (92%) was seen in those patients treated with ceftibuten at the higher dose. In cefaclor-treated patients, 91% reported a satisfactory clinical response. Patients with pneumonia had a
The types and number of adverse experiences reported were similar (gastrointestinal) for the ceftibuten and cefaclor group, and there was no significantly greater incidence of adverse experiences in the ceftibuten 300-mg b.i.d, group compared with the 200-rag b.i.d, group. In the ceftibuten groups, 3% (5 of 187) of patients in the 200-mg b.i.d, group and 3 % (5 of 187) in the 300-rag b. i. d. group reported heartburn; 2% (4 of 171) of cefaclor-treated patients reported heartburn. Three percent (5 of 171) of cefaclor-treated patients reported nausea compared with