L. Montero. Carrera 16# , Consultorio 303, Santafe de Bogotd, D.C., Colombia

Transcription

1 Journal of Antimicrobial Chemotherapy (1996) 37, Suppl. C, A comparative study of the efficacy, safety and tolerability of azithromycin and cefaclor in the treatment of children with acute skin and/or soft tissue infections L. Montero Carrera 16# , Consultorio 303, Santafe de Bogotd, D.C., Colombia An open, multicentre study was carried out in 200 paediatric patients between 6 months and 12 years of age with skin and/or soft tissue infections (mild-to-moderate dermatological conditions and abscesses) to compare the efficacy and safety of azithromycin and cefaclor oral suspensions. Patients were randomly assigned to receive either azithromycin (lomg/kg once daily for 3 days) or cefaclor (20mg/kg/day in three divided doses for 10 days). The clinical efficacy of both treatments was comparable: 92/98 (94%) of the evaluable azithromycin patients were cured or improved as were 93/98 (95%) of those treated with cefaclor. Before treatment, 74 pathogens were isolated from 60 of the azithromycin- and 80 pathogens from 66 of the cefaclor-treated patients. In the azithromycin group, 70/74 (95%) pathogens were eradicated, as were 79/80 (99%) pathogens in the cefaclor group. All 200 patients were evaluable for safety analyses. Both drugs were well tolerated, with a low incidence of side-effects: 3/100 (3%) in the azithromycin group and 2/100 (2%) in the cefaclor group. No patient in either treatment group withdrew from the study because of adverse events. In conclusion, azithromycin is as effective and as well tolerated as cefaclor in the treatment of children with skin and/or soft tissue infections. Introduction Skin and soft tissue infections are common, unpleasant and may become dangerous if left untreated. The most common pathogens are Staphylococcus aureus, Streptococcus pyogenes and Streptococcus agalactiae (Shanson, 1989). Many antibiotics have been used to treat these infections, but their success has been limited by drug resistance or by adverse reactions. Newer antibiotics have shown improved efficacy and safety profiles, but optimal therapy has not yet been defined. Several reports have confirmed the clinical efficacy and wide antimicrobial spectrum of the azalide azithromycin in the treatment of skin and soft tissue infections. Against Gram-positive organisms azithromycin has a spectrum of activity similar to erythromycin (Retsema et al., 1987), but it is substantially more potent in vitro against several important pathogens including /?-haemolytic streptococci of groups C, F and G (Chin et al., 1987). Against Group A and B /?-haemolytic streptococci, azithromycin is as effective as erythromycin in vitro but more effective than cephalexin or cefaclor. In a mouse model of skin infection with S. pyogenes, azithromycin proved to be more effective than clarithromycin or roxithromycin while erythromycin had no effect /96/37CI $12.00/ The British Society for Antimicrobial Chemotherapy

2 126 L. Montero (Pechere, 1994). In other animal models of infection, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and S 1. aureus (thigh muscle); erythromycin failed against both infections (Girard el al., 1987). The objectives of the present study were to determine the efficacy and safety of a 3-day course of once-daily azithromycin compared with a 10-day course of cefaclor (three times daily) in the treatment of children with acute skin and/or soft tissue infections. Study design Patients and methods Two hundred children (6 months-12 years) with acute skin and/or soft tissue infectionsincluding abscesses, furuncles, impetigo, pyoderma, cellulitis, infected wounds, scabies with secondary infection and skin ulcersentered this multicentre, open, comparative study. The study was carried out at centres in Colombia, Guatemala, Panama and South Africa. At the pretreatment assessment within 24 h of study drug administration (visit 1, day 1), informed consent was obtained from each patient's parent or legal guardian. A medical history was recorded and a physical examination was performed on each patient before starting antibiotic therapy. To facilitate comparison of signs and symptoms (fever, malaise, pain/tenderness, erythema, swelling, induration, visible pus, exudate, crusting and other specified signs or symptoms) these were graded on a four-point scale: 0 = absent; 1 = mild; 2 = moderate; and 3 = severe. Wherever possible, material was taken for microbiological examination. Blood samples were obtained for haematological and biochemical evaluation, and urinalysis was performed. Other laboratory tests were performed only when indicated. Patients were excluded from the study if they satisfied any of the exclusion criteria shown in Table I. On day 35 of the study (visit 2), patients were examined for signs and symptoms of infection compared with baseline and, in addition, compliance with drug therapy and side-effects were recorded. Where appropriate, material was obtained from the infection site for culture of pathogens and determination of their susceptibility to antibacterial drugs. The final evaluation was undertaken on day after the start of treatment (visit 3). In addition to the assessments carried out at visit 2, laboratory safety tests were repeated. Treatment Patients were randomly assigned in a 1:1 ratio to receive either azithromycin (cherryor banana-flavoured suspension containing 200 mg azithromycin/5 ml) or cefaclor (250 mg/5 ml) oral suspension. Azithromycin was administered once daily at a dose of 10 mg/kg for 3 days 1 h before or 2 h after a meal. Cefaclor was administered at a total daily dosage of 20 mg/kg in divided doses 8 hourly, for 10 days, irrespective of meal times.

3 Azithromycin in skin infections 127 Evaluations Clinical efficacy was classified as: 'cure' (disappearance of all pretreatment signs and symptoms of infection); 'improvement' (improvement in, or partial disappearance of, pretreatment signs and symptoms; or 'failure' (no change in, or worsening of, signs and symptoms). Bacteriological efficacy was categorized as 'eradication' (complete elimination of pretreatment pathogens or unavailability of culturable material); 'partial eradication' (eradication of some, but not all, of the pretreatment pathogens if multiple pathogens were initially isolated); 'persistence' (persistence of pretreatment pathogen(s)) or 'superinfection' (appearance of one or more new pathogen(s) requiring treatment with another antibiotic and the presence of signs and symptoms of infection, irrespective of whether the pretreatment pathogen(s) were eradicated). Any adverse events occurring during the study were recorded and classified as mild, moderate, or severe. The investigator was also requested to record the relationship between adverse events and drug therapy as 'yes', 'no', or 'uncertain/unknown'. All results outside the range of normal values in laboratory parameters were recorded. Whenever possible, tests showing abnormal values were repeated and patients demonstrating clinically meaningful abnormalities or changes in laboratory parameters were monitored until reversion to pretreatment values or resolution of the problem. Data analysis Demographic characteristics and predisposing factors were compared between treatment groups using the y} test for categorical data, Student's /-test for continuous variables, or non-parametric statistical techniques as appropriate. Results There were no significant differences between the two treatment groups in any of the demographic characteristics (Table II). Clinical efficacy Of the 100 children enrolled in each treatment group, 98 were evaluable for clinical efficacy in the azithromycin group and 98 in the cefaclor group. The reason for the Table I. Patient exclusion criteria Treatment with another antibiotic within 72 h before enrolment unless there was documented failure of the other antimicrobial therapy Previous treatment with azithromycin Terminal illness or other condition precluding completion and evaluation of study drug therapy Known hypersensitivity to azithromycin, macrolides, or penicillins/cephalosporins Treatment with any investigational drug within one month before enrolment Infections requiring treatment with another antimicrobial agent in addition to the study drug Concurrent treatment with ergotamine or digitalis glycosides Chronic diarrhoeal disease or other gastrointestinal condition potentially affecting study drug absorption. Isolation of pathogen(s) resistant to the study drug

4 128 L. Montero Table II. Demographic data of 200 children with acute skin and/or soft tissue infections Gender male female Age (years) mean ± S.D. range Weight (kg) mean ± S.D. range Height (cm) mean ± S.D. range Ethnic origin white black other* Azithromycin (n = 100) 49 (49%) 51 (51%) 5.5 ± ± ± (36%) 19(19%) 45 (45%) Cefaclor (n = 100) 57 (57%) 43 (43%) 5.7 ± ± ± (33%) 20 (20%) 47 (47%) "Comprises azithromycin: mestizo 19, mixed 12, other 14 Cefaclor: mestizo 20, mixed 13, other 14. exclusion of all four of these patients from clinical evaluation was loss to follow-up. There were no significant between-group differences in clinical efficacy: at visit 3, 92/98 (94%) of the azithromycin patients were considered cured or improved, as were 93/98 (95%) of those treated with cefaclor (Table III). Considering individual conditions, cefaclor failed in 1/13 (8%) cases of pyoderma, 2/51 (4%) cases of impetigo and 2/18 (11%) cases of cellulitis, whereas in the azithromycin group, treatment failures were observed in 3/44 (7%) of cases of impetigo and 3/16 (19%) of cases of cellutitis (Table III). Table III. Paediatric patients cured/improved or failing with azithromicin or cefaclor therapy Primary diagnosis Abscess Cellulitis Furuncle Impetigo Infected wound Pyoderma Scabies- Skin ulcer Total No. of patients (%) azithromycin cefaclor cured/improved failed cured/improved 7/7(100%) 13/16(81%) 4/4(100%) 41/44(93%) 2/2 (100%) 21/2 2/2(100%) 2/2 (100%) 92/98 (94%) 0/7 (0%) 3/16(19%) 0/4 (0%) 3/44 (7%) 0/21 (14%) 6/98 (6%) 7/7 (100%) 16/18(89%) 7/7 (100%) 49/51 (96%) 12/13(92%) 2/2 (100%) 93/98 (95%) failed 0/7 (0%) 2/18(11%) 0/7 (0%) 2/51 (4%) 1/13(8%) 5/98 (5%) With secondary bacterial infection.

5 Azithromycin in skin infections 129 Table IV. Bacteriological efficacy of azithromycin and cefaclor in children with skin/soft tissue infections Treatment/organism No. of isolates No. ( eradicated %) persisted' Azithromycin S. aureus S. pyogenes Viridans streptococci Staphylococcus epidermidis Streptococci group G E. agglomerans E. cloacae Total (98%) 18(95%) 70 (95%) 1 (2%) 1 (5%) 4 (5%) Cefaclor S. aureus S. pyogenes Viridans streptococci Total (98%) 20(100%) 79 (99%) 1 (2%) 1(1%) 'All; pathogens isolated at baseline were susceptible to azithromycin (disc diffusion zone >18mm; MIC <2mg/L). Bacteriological efficacy Seventy-four pathogens were isolated from 60 of the azithromycin-treated patients and 80 pathogens from 66 of the cefaclor-treated patients. In the azithromycin group, 70/74 (95%) pathogens were eradicated, as were 79/80 (99%) pathogens in the cefaclor group (Table IV). The four failures in the azithromycin group were in patients with impetigo infected with 5. aureus, S. pyogenes, Enterobacter agglomerans and Enterobacter cloacae. The one failure in the cefaclor group was in a patient with pyoderma infected with S. aureus. Safety All 200 patients were evaluable for safety analyses. Both drugs were well tolerated, with a low incidence of side-effects: 3/100 (3%) in the azithromycin group and 2/100 (2%) in the cefaclor group. The side-effects reported in this study were all mild dermatological conditions (pruritus, rash or urticaria) and abscess, except for one patient who experienced a moderate papular rash that was only possibly due to azithromycin. No patient in either treatment group withdrew from the study because of side-effects. Discussion Azithromycin has been compared with several antibiotics, including erythromycin, cloxacillin and cephalexin, in the treatment of infections of the skin and soft tissues in adults (Kiani, 1994). All studies reported to date have shown that azithromycin is at least equivalent to these antimicrobial agents in terms of clinical cure and improvement rates and also in the eradication of pathogenic bacteria (Kiani, 1994). However,

6 130 L. Montero azithromycin has the advantages of a simpler dosage regimen (once daily) compared with antibiotics such as cephalosporins (most of which have to be taken twice or three-times daily) and also a shorter duration of therapy (3-5 days with azithromycin compared with 7-10 days for cephalosporins, Kiani, 1994). Initial comparative clinical trials in adult patients with infections of the skin and soft tissues studied azithromycin at a dosage of 500 mg on day 1, followed by 250 mg once daily for the next 4 days. These studies confirmed that azithromycin was as effective as 500 mg cloxacillin administered four times daily for 7 days (Daniel et al., 1991), 500 mg cephalexin given twice daily for 10 days (Herbert, 1990; Treadway, 1990; Kiani, 1991; Mallory, 1991), or 500 mg erythromycin taken four times daily for 7 days (Daniel et al., 1991). The high incidences of satisfactory clinical response and bacteriological eradication were similar for azithromycin and the comparative agents. Later studies showed that azithromycin could be administered for only 3 days, at a dosage of 500 mg once daily, and still produce the same high efficacy rates in patients with skin and soft tissue infections. Two prospective randomized studies (one in adults and the other in both adults and children) with skin and skin structure infections showed that once-daily azithromycin at a dosage of 500 mg (10 mg/kg in children) for 3 days was as effective as dicloxacillin at a dosage of 250 mg ( mg/kg/day in children) administered four times daily for 7 days (Arias-Orozco et al., 1991; Amaya-Tapia et al., 1993). An open, randomized, multicentre trial in 110 children (2-12 years old) with clinically diagnosed acute skin and soft tissue infections showed that oral azithromycin (10 mg/kg/day) administered once daily for only 3 days was as effective as dicloxacillin ( mg/kg/day) or flucloxacillin ( mg/day) four times daily for 7 days (Rodriguez-Solares et al., 1993). In common with other investigations, the present study has shown that azithromycin is as effective as comparative antibiotics in eradicating the bacteria causing skin and soft tissue infections and in achieving clinical cure or improvement. The most common pathogens isolated from our patients were S. pyogenes and 5. aureus, as in other studies, and both azithromycin and cefaclor were equally effective against these and the other pathogens isolated. Both drugs were very well tolerated, with few adverse events. There were, however, significant differences in the treatment regimens of both antibiotics, with advantages in favour of azithromycin. The once-daily dosing of azithromycin and the short (3-day) duration of treatment are likely to be associated with better patient compliance than three-times-daily treatment with cefaclor and the longer (10-day) dosing duration. In conclusion, azithromycin is as effective and as well tolerated as cefaclor for the treatment of infections of skin or soft tissues in children, and has the advantage of a shorter, simpler therapeutic regimen. References Amaya-Tapia, G., Aguirre-Avalos, G., Andrade-Villanueva, J., Peredo-Gonzalez, G., Morfin-Otero, R., Esparza-Ahumada, S. et al. (1993). Once-daily azithromycin in the treatment of adult skin and skin-structure infections. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Arias-Orozoco, M., Andrade-Villanueva, J., Amaya-Tapia, G., Plasccncia-Hernandez, A. & Rodriguez-Noriega, E. (1991). Safety and efficacy of azithromycin (AZI) and dicloxacillin (DICLO) in the treatment of skin and skin structure infections (SSSI). In Program and

7 Azithromycin in skin infections 131 Abstracts of the Thirty-First Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, American Society for Microbiology, Washington, DC. Chin, N. X., Saha, G., Labthavikul, P. & Neu, H. C. (1987). The in vitro activity of CP-62,993, a new 15-membered ring macrolide compared with that of other oral antibiotics. In Program and Abstracts of the Twenty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, American Society for Microbiology, Washington, DC. Daniel, R. & the European Azithromycin Study Group. (1991). Azkhiomycin, erythromycin and cloxacillin in the treatment of infections of skin and associated soft tissues. Journal of International Medical Research 19, Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella, J. A. et al. (1987). Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrobial Agents and Chemotherapy 31, Herbert, A. (1990). Azithromycin in the treatment of skin and skin structure infections: a multicenter, double-blind, double-dummy trial employing cephalexin (Reflex) as a comparative agent. Clinical Research 38, 929A. Kiani, R. (1991). Double-blind, double-dummy comparison of azithromycin and cephalexin in the treatment of skin and skin structure infections. European Journal of Clinical Microbiology and Infectious Diseases 10, Kiani, R. (1994). Azithromycin in the treatment of infections of skin and associated tissues. Reviews of Contemporary Pharmacotherapeutics 5, Mallory, S. B. (1991). Azithromycin compared with cephalexin in the treatment of skin and skin structure infections. American Journal of Medicine 91, Suppl. 3A, Pechere, J.-C. (Ed.) (1994). Comparative activity of antibiotics against group A streptococci in experimental infections. In Acute Bacterial Pharyngitis, pp Cambridge Medical Publications, Worthing. Retsema, J., Girard, A., Schelkly, W., Manousos, M., Anderson, M., Bright, G. et al. (1987). Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against Gram-negative organisms. Antimicrobial Agents and Chemotherapy 31, 1939-^7. Rodriguez-Solares, A., Perez-Gutierrez, F., Prosperi, J., Milgram, E. & Martin, A. (1993). A comparative study of the efficacy, safety and tolerance of azithromycin, dicloxacillin and flucloxacillin in the treatment of children with acute skin and skin-structure infections. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Shanson, D. C. (1989). Microbiology in Clinical Practice, 2nd edn, pp Wright, London.