Azithromycin for the treatment of pertussis

Abstract

A prospective, open label, noncomparative trial was conducted to assess the efficacy of a 5-day course of azithromycin in bacteriologic eradication of pertussis. Patients received azithromycin 10 mg/kg/day on Day 1 and then 5 mg/kg/day for the next 4 days. Nasopharyngeal specimens for culture and PCR testing were used to identify Bordetella pertussis at enrollment and at Day 2 to 3 and 14 to 21 after start of treatment. Of 121 subjects enrolled with clinical pertussis, 29 were culture-positive and 5 additional subjects were PCR-positive at diagnosis. Eradication of B. pertussis from the nasopharynx occurred in 33 (97%) of 34 culture/PCR-positive patients by the second to third day of azithromycin treatment; the 1 positive case was by PCR only; 100% were culture/PCR-negative at the Day 14 to 21 follow-up visit. A 14-day course of erythromycin has been the standard treatment for pertussis for five decades. 1 Erythromycin is effective in reducing transmission, decreasing disease severity and hastening clearance of Bordetella pertussis. Antibiotic therapy may also prevent or treat secondary infections, although it may not shorten the duration of coughing illness. 1 There is a paucity of data on the efficacy and safety of newer macrolides in treatment of pertussis. 2–4 The purpose of this study was to assess the microbiologic efficacy of a 5-day, once daily azithromycin regimen in children and their parents with B. pertussis infection. A second objective was to evaluate the safety of the treatment in children diagnosed with pertussis syndrome (with and without B. pertussis-microbiologically confirmed). Methods. This was a prospective, open label, noncomparative study. We enrolled children and their parents seen at the Elmwood Pediatric Group, Rochester, NY between July 1991 and July 2002. Inclusion and exclusion criteria. Subjects were eligible for inclusion if they presented with a clinical syndrome of pertussis, defined as cough lasting 7 to 14 days and one of the following: (1) paroxysmal cough; (2) cough ending in vomiting; or (3) inspiratory whoop. The patients were otherwise in good health and without obvious cause for their cough syndrome other than possible pertussis. Exclusion criteria for the study consisted of: (1) the presence of a cough for >14 days; (2) treatment with any antibiotic with known activity against B. pertussis (e.g. macrolides, trimethoprim-sulfamethoxazole) in the prior 7 days; and (3) known allergy to macrolide antibiotics. Therapy. After we obtained written informed consent to participate in the study, we provided a 5-day course of azithromycin (Zithromax; Pfizer) 10 mg/kg on Day 1 followed by 5 mg/kg/day once daily for the following 4 days (maximum dose 1000 mg on Day 1 and 500 mg on Days 2 to 5). The drugs were provided in suspension or tablet according to the preference of the subject at no charge, and all were instructed how to take the medication by the study nurse. Microbiologic adverse event and compliance evaluation. A nasopharyngeal (NP) specimen for B. pertussis culture and PCR analysis was taken from each subject at entry into the study and on Days 2 to 3 and 14 to 21. Medication compliance and adverse events were assessed during study visits. Adverse events, defined as any undesirable experience occurring in a subject during the clinical trial considered related to the investigational drug, were recorded throughout the study. Compliance was evaluated by bottle weight, pill counts and subject diary. Laboratory methods. Sampling for B. pertussis culture and PCR was obtained by a NP aspirate (Lucké aspirator) or NP swab (Calgiswab; calcium alginate); the specimen was transported to the microbiology laboratory in charcoal transport medium (Regan-Lowe). B. pertussis was identified by standard laboratory techniques. 5 PCR was performed by methods previously described. 6 Analysis. Microbiologic response was characterized as: eradication; if no B. pertussis growth or PCR reactivity in NP specimens or persistent; if B. pertussis was present in a posttreatment culture. Results. Five subjects were parents of child subjects, 12 (35%) were age 10 to 20 years and 17 (50% were age 6 months to 10 years. Pertussis vaccination status was appropriate for age in 90% of the subjects. Subjects had cough illness for a median of 7 days (mean ± sd 8 ± 6); 79% had paroxysmal cough, 24% had a cough ending in vomiting and 29% had an inspiratory whoop. Twenty-nine of the cases had a positive culture for B. pertussis, and 5 additional cases were PCR-positive at enrollment. The microbiologic eradication rate was 97% at Days 2 to 3 of treatment and 100% at the Day 14 to 21 posttreatment follow-up (Table 1); comparison with eradication rates after treatment with other antimicrobials is included in Table 1. 7–14 Subjects reported that it took a mean of 16 ± 12 days (median, 9 days; range, 2 to 45 days) before they began to improve symptomatically after initiating azithromycin therapy. A mean of 28 ± 19 days (median, 32 days; range, 5 to 90 days) elapsed after the start of treatment before full recovery was noted.TABLE 1: Microbiologic efficacyThere were no serious adverse events in any of the study patients. Overall the incidence of drug-related adverse events was low. Three (10%) of the subjects complained of nausea, gastrointestinal discomfort or loose stools. All subjects were fully compliant with the medication regimen. Discussion. In this study azithromycin was shown to be effective in eradicating B. pertussis quickly from the nasopharynx. Organisms could not be detected in nasopharyngeal cultures on Day 2 to 3 of treatment for 97% of subjects, suggesting a shorter period of contagion compared with erythromycin (Table 1). Overall there were few drug-related adverse events. The azithromycin dosage used in this study was associated with a high adherence rate. Erythromycin is the recommended antibiotic by the American Academy of Pediatrics for treatment of pertussis. 1 A principle limitation of erythromycin relates to gastrointestinal adverse effects, which are relatively common and dose-dependent. Halperin et al. 14 described 168 patients with pertussis, one-third of whom developed adverse reactions, primarily gastrointestinal with erythromycin estolate treatment. Azithromycin is active against B. pertussis, with in vitro MIC90 values identical with those of erythromycin (MIC90 0.03 μg/ml). 15 Therapeutic serum concentrations and high tissue concentrations of azithromycin result in tissue-to-serum ratios greater than that with erythromycin. Azithromycin has a lower incidence of gastrointestinal adverse effects than does erythromycin. In two earlier studies of 5 days of azithromycin treatment in children with pertussis, 100% microbiologic eradication was reported 2, 3; a 3-day regimen was less effective. 3 In summary azithromycin for treatment of patients with pertussis resulted in a high rate of bacteriologic eradication of B. pertussis organisms and rapid clearance from the nasopharynx thereby shortening contagion. Azithromycin treatment resulted in few adverse events and compliance with the 5-day regimen was excellent. Acknowledgments. This clinical trial was sponsored by an unrestricted grant from Pfizer.