Multicenter Evaluation of Azithromycin and Cefaclor in Acute Lower Respiratory Tract Infections DIANA

DARK,

M.D.,

Kansas City, ~issoun

This was a randomized, third-party-blinded, multicenter study that compared once-daily azithromycin (500 mg on day 1, followed by 250 mg on days 2-5) to cefaclor (500 mg three times daily for 10 days) in the treatment of patients with acute bronchitis or pneumonia. A total of 546 patients were entered into the study and 272 patients were evaluable for efficacy analysis. Of these, 249 (176 azithromycin, 73 cefaclor) had bronchitis and 23 (15 azithromycin, 8 cefaclor) had pneumonia. The combined clinical cure and improvement rate, as determined by the investigator, was 96% for azithromycin and 94% for cefaclor, with 88% bacteriologic eradication in both treatment groups. The elimination of Haemophilus influenzae was significantly better with azithromycin (94.5%) than with cefaclor (61.1%) (p CO.001; Fisher’s exact two-tail test). The two antibiotics were well tolerated during this study; the incidence of side effects reported was similar for azithromycin and cefaclor. Approximately two thirds of the side effects were mild. Only minor abnormalities in the screening laboratory tests were noted. This study shows that a 5-day course of once-daily azithromycin is as effective as a lo-day three times daily course of cefaclor in the treatment of patients with acute lower respiratory tract infections.

From the Veterans Administration This iork

was supported

Medical Center, Medical Services Office, Kan-

by a research grant from Pfizer Central Research,

Requests for reprints should be addressed to Diana Dark, M.D., Veterans Administration Medical Center, Medical Services Office, 4801 Linwood Boulevard, Kansas City, Missouri 64128.

September

A

zithromycin is an azalide, a new class of antibiotics, now undergoing evaluation as a treatment for a wide range of bacterial infections [l]. Azithromycin is similar in chemical structure to the widely used macrolide antibiotic erythromycin, but has a methyl-substituted nitrogen in the macrolide ring. This modification is responsible for marked alterations of in vitro antibacterial activity, especially against Gram-negative organisms [2]. The antibacterial spectrum of azithromycin is similar to that of erythromycin against Gram-positive bacteria; however, there is increased activity against many Gram-negative organisms. Azithromycin also demonstrates significant in vitro activity against the pathogens causing atypical respiratory disease, such as Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae [2,3]. In addition, azithromycin has a pharmacokinetic profile distinct from erythromycin, with superior stability in an acid environment such as the stomach. Studies in animals and humans have also demonstrated a uniformly long elimination half-life and have shown high concentrations in many tissues and body fluids, most notably lung tissue [41. Macrolide antibiotics such as erythromycin are often prescribed for treatment of upper and lower respiratory tract infections (URTIs, LRTIs) both in children and adults. The clinical usefulness of erythromycin is often limited, however, by gastrointestinal intolerance and its inconsistent effectiveness against many organisms common in LRTIs, notably Haemophilus influenxae. Other antibiotics commonly prescribed for acute LRTIs include cephalosporins, many of which require relatively short dosing intervals but demonstrate extended antibacterial spectra. However, the cephalosporins do not have activity against the aforementioned pathogens of atypical respiratory tract infections. Several studies have examined the effectiveness of short-course azithromycin in the treatment of acute bronchitis [5,6] and acute bacterial pneumonia [71. The purpose of this multicenter trial was to evaluate prospectively the efficacy and safety of a new orally administered antibiotic, azithromycin, compared with a commonly prescribed cephalosporin, cefaclor, in the treatment of acute LRTIs. 12, 1991

The American Journal of Medrcine

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PATIENTPOPULATIONAND METHODS This third-party-blinded, randomizedtrial, conducted at 26 centers, was designedto comparethe safety and efficacy of azithromycin and cefaclor in the treatment of acute LRTIs. Both inpatients and outpatients aged 16 years or older with a clinical diagnosisof acutebronchitis or pneumoniawere eligible to enter the study. Patients with acute exacerbations of chronic bronchitis or chronic obstructive pulmonary diseasewere included. Female patients of childbearingage, unlesslactating or pregnant, were enrolled providing they used adequate contraceptionduring and after the trial. Informed written consentwas obtainedfrom all patients. The study was conducted in compliance with institutional review board and informed consentregulations of eachcenter. Exclusion criteria for enrollment were: known hypersensitivity or intolerance to macrolide or cephalosporinantibiotics; the presence of active peptic ulcer diseaseor any condition affecting drug absorption (e.g., gastrectomy, pancreatic insufficiency); treatment with another antibiotic during the 72 hours prior to enrollment; the presenceof co-existing chronic bronchitis, bronchiectasis, or chronic obstructive pulmonary diseasenot accompaniedby acute infection; cystic fibrosis. Patients were evaluatedby a number of clinical, laboratory, and radiographictests, looking particularly for evidenceof fever, cough,purulent sputum, rales/rhonchi,leukocytosis,andinfiltration on chest radiographs.This initial assessmentwas substantiated by a bacteriologic diagnosisbasedon culture demonstrationof a likely etiologic organism in sputum obtainedwithin 48 hours beforestarting treatment. Sputum sampleswith more than 25 polymorphonuclearleukocytes and less than 10 squamous epithelial cells per low-power field of Gram-stained sputum were cultured. If a specimen of expectorated sputum could not be obtained, induction of sputum with nebulized saline, tracheal aspiration, or fiberoptic bronchoscopywas carried out. Criteria for determining the presence of acute bacterial LRTI were: (a) purulent sputum with Gram-staincharacteristicsasjust outlined; (b)clinical evidenceof acute infection with at least one of the following: fever (~38°C); true rigors; leukocytosis (white cell count ~12,000);(c) localfindings suggestive of LRTI @ales,rhonchi, wheezes,or evidenceof consolidation). Disease definitions include the above criteria plus: (a) for pneumonia:an acute pulmonary infiltrate, apparent on chest radiographs upon study entry or during the courseof therapy, which could not be attributed to someother etiology (e.g., con3A-32s

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gestive heart failure); (b) for acute purulent bronchitis: the absenceof an acute infiltrate on any chestradiographtaken immediately prior to or during the courseof therapy; (c) for acuteexacerbation of chronicobstructive pulmonary disease(COPD):a significant increasein the amount of sputum production (80% more than the usual daily sputum quantity) and an increase in purulence compared with that of the sputum usually produced by the patient, plus a clinically established diagnosis of chronic bronchitis, emphysema, asthma, or asthmatic bronchitis, and the presenceor absenceof an acute infiltrate on chest radiographs defined an acute bacterial exacerbationof COPD with pneumonia or with purulent bronchitis, respectively. Patient responseto treatment was monitored by assessingclinical signs and symptoms (fever, dyspnea, sputum production, cough, and chest sounds) at baselineand on study days 6 (-+l day), 11 (between days 10 and 13), 18 (21 day), 30 (?l day), and at any other time, as clinically indicated. Clinical responsewas classifiedas satisfactory or unsatisfactory: Satisfactory indicated a patient was cured if signs and symptoms of infection resolved during the study with no evidenceof infection at day 11 (days 10-13). A patient was judged to be improved if signs and symptoms had subsidedduring the study but there was incomplete resolution by day 11 (days 10-13). Unsatisfactory indicated failure of therapy with no apparent clinical responseat day 11. Bacterial eradication was defined as elimination of the initial causative pathogen by day 11 (days 10-13). Culture and susceptibility studies were performed on sputum,samples at baselineand on study days 6 and 11 and repeated when clinically indicated. Patients with positive radiologicfindings at baselinehad follow-up chest radiographsat the end of therapy (day 11 visit), and on study completion if infiltrates were not resolved at the day 11 visit. Susceptibility of all causative organisms to the study drugs was determinedusing the Kirby-Bauer method (disk-diffusion or broth dilution methods). For the purposesof this study, the criteria for determining susceptibility to azithromycin (15 pg disks) were: zone-inhibition diameters of ~18 mm for susceptiblecategory; 14-17 mm for intermediate category; and 513 mm for resistant organisms. The correspondingminimum inhibitory concentrations were 52 mg/L, 4 mg/L, and 28 mg/L, respectively. If treatment randomization was delayed until the results of the bacteriologytesting and antibiotic susceptibilities were available, the causative organism had to be susceptibleto both drugs. However, if patients were randomizedto treatment

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beforethe bacteriologicresults were reported, then [ TABLEI the pathogenhad to be susceptibleto the assigned Investigators’Assessmentof Clinical Responseat the End of drug. Therapy in the 272 EvaluablePatients Patients were evaluated for side effects at each Treatment Group follow-up visit; screeninglaboratory tests, including urinalysis, hematology, and chemistry profiles, Azithromycin Cefaclor were performed at baseline and on all scheduled Clinical Response No. % No. % follow-up visits. Cured 1;: 36.1 :: 30.9 A total of 552 patients were randomizedin a 2:l Improved 60.2 64.2 ratio by a third party to prevent the investigator Failed 3.7 4.9 19: 100.0 8: 100.0 knowing the patient’s study medication. Six pa- Total evaluable tients did not take any study medication and were excluded from analysis. In the remaining 546 patients, 367 patients (189males, 178females)were TABLEII treated with azithromycin (500mg as two 250 mg OrganismsIsolated from Sputum on Entryto Study capsuleson day 1, followed by 250mg on days 2-5 Treatment Group as a singledaily dose)and 179patients (87males,92 females)were treated with cefaclor (500mg three Aziiromycin Cefaclor times daily for 10 days). The majority of patients % Organism No. No. % were diagnosedas having acute bronchitis: 93% of Moraxella (Lkanhame//a)catarMs 10.1 azithromycin patients and 92%of cefaclorpatients. Haemophibs influenzae 18.2 The remaining patients in eachgroup had a diagno- Haemophiilusparahaemo@cus 4.0 Haemophlus parainfluenzae 17.2 sis of acute pneumonia.The mean age was similar K/ebsie//apneumoniae 5.1 0 in each group: 51.4 years (range, 16-91) in the Staphylococcus aureus 13.8 1i.l 11.8 :: 22.2 Stre$xoccus pneumomae azithromycin group and 51.0 years (17-87) in the * 23.6 14.1 cefaclor group. Total isolated lM1 i 100

213:: ii 2: 1’:

L

RESULTS Total enrollment was 552patients, 546 of whom actually took the assignedantibiotic (azithromycin 367,cefaclor 179).Excluded from the efficacy analysis were 274 patients, 176 in the azithromycin group and 98 in the cefaclorgroup. The presenceof a resistant pathogenwas the reasonfor exclusionin 26 azithromycin patients (7.1%) and in 14 cefaclor patients (7.8%). Other reasonsfor exclusionwere: no baseline pathogen (118 azithromycin, 63 cefaclor); no end of therapy assessment (24 azithromycin, 13 cefaclor);no susceptibility results (3 azithromycin, 3 cefaclor);inadequateduration of therapy (1 azithromycin, 4 cefaclor); concomitant systemic antibiotic therapy (3 azithromycin, 1 cefaclor); inapplicable baseline diagnosis (1 azithromycin, 0 cefaclor). The efficacy data were therefore based on 272 evaluable patients, 191 azithromycin patients (52%of those entered)and 81 cefaclor patients (45%). Of these evaluable patients, 249(176azithromycin, 73 cefaclor)had bronchitis and 23 (15azithromycin, 8 cefaclor)had pneumonia as their primary diagnosis. The clinical responsefor each evaluablepatient, as judged by the investigator at the end of the study, is shown in Table I. The overall response (cured and improved) at the end of therapy was very good in each treatment group: 96.3% with azithromycin and 95.1%with cefaclor. The clinical September

*Other organisms: Acinetobacter calcoaceticus anifratus, Acinetobacfer calcoaceficus Iwofi, Aeromonas hydrophila, Citrobacter freundii, Escherichia co/i, Enterobacter aerogenes, Enterobacter agg/omerans, Enterobacfer cloacae, Enterobacter sakazakii, Enterobatter spp., Enterococcus spp., Haemophilus spp., Klebsiella oxyfoca, Moraxella osloenSE, Moraxella spp., Neisseria meningndis, Neisseria (acfamica, Streptococcus pyogenes, Streptococcus anginosus, .Sfreptococcus sanguis, Streptococcus agalacticae, Streptococcus group G, Streptococcus mitis.

cure rate was 36.1% in patients treated with azithromycin compared with 30.9% in patients treated with cefaclor.In addition, 60.2%and64.2% of patients, respectively, were clinically improved. Thirty different organismswere identified in the 272 evaluablepatients, someof which were causative pathogens.The most commonorganismsin the azithromycin group were H. influenzae (21.7%), Staphylococcus aureus (13.8%), Streptococcus pneumoniae (ll.S%), H. parainfluenxae (9.1%), and Branhamella catarrhulis (8.7%)(Table II). In the cefaclor group, S. pneumoniae accountedfor 22.2% of the causative pathogens;H. influenxae (18.2%),H. parainfluenxae (17.2%),and S. aureus (14.1%)were the next most commonisolates. The overall bacteriologiccure rate for the evaluablepatients in this study was similar for both antibiotics: 88.2% in the azithromycin group and 87.9%in the cefaclor group. The bacteriologiccure, as judged by eradication in the sputum culture of the initial causativeorganism in patients with pneumonia, was 100%in patients treated with cefaclor and 94.1% in patients treated with azithromycin (Table III). 12,

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illnesses were respiratory tract infections other than bronchitis or pneumonia.

TABLEIII BacteriologicResponseby PrimaryDiagnosis Primary Diagnosis Treatment Group Azithromycin Total no. organisms Total eradicated % organisms eradicated Cefaclor Total no. organisms Total eradicated %organisms eradicated

Bronchiis

Pneumonia

237

17

208 81.8% ;;

86.2%

;i.l% ;;

100.0%

Onepatient with pneumoniacausedby S. aureus had a persistent pathogen. Azithromycin and cefaclorwere equally effective bacteriologically in the patients with bronchitis (87.3%and 86.2%,respectively). The bacteriologic results revealed some notable differencesin the responseof individual pathogens to azithromycin and cefaclor(Table IV). The elimination of H. influenzae was significantly better with the azalide (94.5%) than with the cephalosporin (61.1%) (p

Multicenter evaluation of azithromycin and cefaclor in acute lower respiratory tract infections.

This was a randomized, third-party-blinded, multicenter study that compared once-daily azithromycin (500 mg on day 1, followed by 250 mg on days 2-5) ...
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