DIAGN MICROB1OLINFECT DIS 1992;15:97S-101S
97S
A Randomized Double-Blind Controlled Trial of Roxithromycin and Cefaclor in the Treatment of Acute Lower Respiratory Tract Infections in General Practice Murray W. Tilyard and Susan M. Dovey
A multicenter, randomized, double-blind, single-dummy placebo-controUed study is being undertaken by the Research Unit of the Royal New Zealand College of General Practitioners to compare the efficacy and tolerance of 150 rag twice daily roxithromycin with 250 mg three times daily cefaclor in the treatment of 250 8eneral practice patients with acute lower respiratory tract infections (LRTIs). Interim analysis of 200 patients reveals no statistically significant differences in the study parameters. Of the patients on roxithromycin and cefaclor, 83% and 67%, respectively, had a moderate or severe illness. Based on efficacy criteria, 96% of roxithromycin recipients and 99%
of cefaclor recipients had a satisfactory or improved response. On an intention-to-treat basis, this was reduced to 95% for both treatment groups. Sputum grading and semiquantitative culturing was performed according to NCCLS standards. The mas! common isolates in order were Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Efficacy for bacteriologically evaluable cases was 87.5% for roxithromycin and 57% for cefaclor. Four patients on roxithromycin (3.9%) and 11 patients on cefaclor (11.3%) withdrew because of side effects probably or possibly related to the study treatment. The study is ongoing.
INTRODUCTION
cephalosporin cefaclor, which is frequently used as treatment of lower respiratory tract infection (LRTI). Both medications have a well-established tolerance and efficacy profile. This study design was based on the normal general practice treatment for lower respiratory tract infections, with emphasis on clinical assessment of cause and outcome.
Roxithromycin is an oral macrolide antibiotic with an improved pharmacokinetic profile over earlier macrolides (Periti et al., 1989). The long half-life of 10-12 hr permits convenient twice-daily administration while maintaining activity against common respiratory tract pathogens as well as the increasingly recognized atypical pathogens such as Mycoplasma pneumoniae, Legionella pneumoniae, and Chlamydia spp. This twice-daily regimen for roxithromycin also makes it an ideal medication in the primary care setting where compliance can be a problem causing suboptimal treatment of infections. No previous comparative work has been performed against the oral From the Royal New Zealand Collegeof General Practitioners, ResearchUnit, Dunedin, New Zealand. Additional copies of this supplement are availablefrom Roussel UCLAF, DomaineTh~rapeutiqueAntibioth~rapie,35 Boulevard des Invalides, 75007Paris, France. Received 8 October 1991;revised and accepted 15 November 1991. © 1992ElsevierSciencePublishers Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
METHODS Patients General practitioners in eight locations throughout New Zealand enrolled 200 patients presenting with lower respiratory tract infections. Eligible patients were aged 18 years or older and presented with a cough and signs consistent with bacterial lower respiratory tract infection. The diagnosis was based primarily on clinical assessment, supported by serology, bacteriology of sputum (if obtained), and chest radiographs if clinically indicated. Patients with signs and symptoms solely suggestive of viral upper respiratory tract infections were not enrolled.
985
Study Design The protocol was reviewed and approved by the ethics committee of the Otago Area Health Board and the New Zealand Department of Health. Written informed consent was given by each participant. The study design was parallel, randomized, doubleblind, and single-dummy placebo controlled. Randomization was in blocks of four to ensure that half of the study participants would receive roxithromycin and half cefaclor, and that individual doctors would assign equal numbers of patients to each treatment.
Drugs and Dosage Following initial assessment and entry into ti',e trial, the first week of study medication was dispe,sed. Medication was packaged in predispensed Webster blister packs with 21 doses (7 days of treatment) provided at visit 1. Each dose contained either a roxithromycin 150-mg tablet or a cefaclor 250-mg capsule as active treatment, with an accompanying dummy placebo (except where randomization was to roxithromycin, when both tablets in the midday do~e were dummy). Patients were instructed to take one dose three times a day before meals. If clinically indicated at the end of 7 days' therapy, then a further 7 days of medication was dispensed. Follow-up assessment of clinical and bacteriologic status was made at the end of therapy.
Assessments Patients were assessed for eligibility by their general practitioner. They had to have cough and signs consistent with lower respiratory tract infection. At the initial visit, details were recorded relating to patients' clinical status, demography, general health, concomitant medication, and underlying diseases and conditions. A chest radiograph was obtained if clinically indicated. Sputum was obtained where possible for microbiologic testing and culture techniques performed to NCCLS standards. Blood samples for hematology, biochemistry, and serology were taken at commencement and end of therapy. Clinical efficacy was evaluated by the general practitioner. Efficacy was deemed satisfactorywhere the infection had completely cleared with the resolution of clinical signs and symptoms, improved if there was an improvement in signs and symptoms without complete resolution, and unsatisfactoryif the infection remained the same or had worsened. Follow-up chest radiographs were undertaken if clinically indicated. Bacteriologic efficacy was deemed satisfactory if the pathogen was eradicated on post-
M.W. Tilyard and S.M. Dovey
TABLE 1 Underlying Conditions or Risk Factors Roxithromycin 80 Patients
Cefaclor 64 Patients
Smokers CORD Asthma Bronchiectasis Diabetes Immunodeficiency Cardiovascular Renal disease Alcoholism Other
33 37 17 2 3 1 27 1 2 12
32 15 13 0
Total risk factors
135
89
1 17 0 5 5
CORD, chronicobstructiverespiratory disease. treatment culture, or if there was improvement to such an extent that posttreatment culture was not possible, or in the event that a new organism was identified without any local or systemic signs of infection (colonization). An ,msatisfactory bacteriologic outcome was defined where the pathogen remained on posttreatment culture or where a new organism appeared with evidence of a new infection. To facilitate identification of the responsible pathogen, we performed complement fixation and immunofluorescence tests for M. pneumoniae, Chlamydia spp., LegioneUaspp., and viral agents [influenza A and B, respiratory syncitial virus (RSV), and adenovirus] on paired sera at one central reference laboratory. A fourfold rise in titer or a single titer of >256 was taken to represent recent infection. Adverse events were noted on the case report form at follow-up visits. The type of reaction, severity, duration, action taken, and the outcome were noted as well as the general practitioner's opinion on the causal relationship between the adverse reaction and study medication.
Statistical Analysis The statistical analysis comprised chi-squared tests (with Yates' correction) for treatment comparisons. RESULTS
Patients A total of 200 patients were included in the analysis. The mean age of patients was 51.2 years (median, 53 years; and range, 18-90 years). There were 98 women and 102 men enrolled. The underlying conditions or risk factors are shown in Table 1. More
Roxithromycin versus Cefaclor in LRTI
995
patients randomized to treatment with roxithromycin had underlying conditions or risk factors than those randomized to receive cefaclor (77.7% vs 66.0%) Underlying chest disease was reported for 56 patients randomized to roxithromycin and 28 patients randomized to cefaclor. C l i n i c a l Efficacy A diagnosis of acute isolated bronchitis was made in 160 cases, acute exacerbation of chronic bronchitis in 32 cases, typical pneumonia in six cases, and atypical pneumonia in two cases. Severity was described as moderate or severe in 75% (1~9) of cases. Of the patients on roxithromycin, 83% had moderate or severe illness compared with 67% of those on cefaclor. This difference was not statistically significant. Of the 103 cases assigned 5o treatment with roxithromycin, 91 were evaluable for efficacy. Fewer than 12 doses were taken in three cases, five cases were not evaluable because serologic tests indicated infection attributable to a viral cause, and in four cases a resistant pathogen was isolated on pretreatment culture. A satisfactory or improved outcome was achieved in 96% of evaluable cases. On intention-to-treat analysis, this was reduced to 95% of cases. Of the 97 cases assigned to cefaclor, 88 (90%) were evaluable. Fewer than 12 doses were taken in four cases, a viral infection was indicated in two cases, in two cases a resistant pathogen was isolated on pretreatment culture or identified by serology, and
one case was lost to follow-up. For evaluable cases, 99% achieved a satisfactory or improved outcome. On intention-to-treat analysis, this reduced to 95%. There were no s~.atistically significant differences in outcom~ between the treatments. Tables 2 and 3 detail clinical efficacy, both for evaluable cases only and on intention to txeat. The mean duration of therapy was 8.7 days in the roxithromycin group and 9.2 days in the cefaclor group. In the roxithromycin group, 28 patients (27%) required an extension of therapy beyond 7 days, and 35 patients (36%) on cefaclor required more than 7 days' therapy. Bacteriologic Efficacy Sputum was obtained from 140 patients (70%). Of sputum specimens, 40% grew a potential pathogen. Assessment of the bacteriologic efficacy per protocol was possible in 15 cases (7%). The most common isolates in order were Haemophilus influenzae, M. catarrhalis, and Streptococcus pneumoniae. Of the bacteriologically evaluable cases, seven (87.5%) of eight were successfully eradicated by roxithromycin compared with five (57%) of seven for cefaclor. Because of the small numbers involved, significance cannot be established. Seven cases of viral infectio~ were detected by serology: three cases of RSV and four of imluenza A. A satisfactory or improved clinical response was reported in all cases. One case of Chlamydia spp. infection (probable C. pneumoniae-TWAR strain) was
TABLE 2 Clinical Efficacy--Intention to Treat
Roxithromycin Acute isolated bronchitis Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage Cefaclor Acute isolated bronchitis Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage
Total Number
Satisfactory Outcome
Improved Outcome
Unsatisfactory Outcome
76 22
49 11
24 9
3 2
3 2
0 1
3 1
0 0
103 100
61 59
37 36
5 5
84 10
40 5
40 5
4 0
3 0
2 0
1 0
0 0
97 100
47 48
46 47
4 5
100S
M.W. Tilyard and S.M. Dovey
TABLE 3 Clinical Efficacy--Evaluable Cases Only Total Number
Satisfactory Outcome
Improved Outcome
Unsatisfactory Outcome
Roxithromycin Acute isolated bronchitis Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage (%)
64 22
43 II
19 9
2 2
3 2 91 91
0 1 55 81
3 1 32 35
0 0 4 4
Cefaclr,r Acute isolated bronchitis
76
39
36
1
10
5
5
0
3 0
2 0
1 0
0 0
89 100
46 52
42 47
1 1
Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage (%)
detected in a patient with a clinical diagnosis of severe acute bronchitis. In this case an improved clinical outcome was reported after a 14-day course of treatment with cefaclor.
Tolerance Twenty-two patients (11%) withdrew from treatment Lecause of side effects, failure to improve on therapy, or exclusion criteria; 10 were patients randomized to treatment with roxithromycin, and 12 were patients randomized to cefaclor. Four patients in the roxithromycin group (3.9%) and 11 patients in the cefaclor group (11.3%) withdrew because of side effects probably or possibly related to treatment. Adverse events of probable, possible, or doubtful relationship to treatment were reported in 19 patients (18.4%) on roxithromycin and 22 patients (22.7%) on cefaclor (Table 4). For 10 patients (9.7%) on roxithromycin and 19 patients (19.6%) on cefaclor, these were deemed to have a probable or possible causal relationship to the study treatment. Adverse events were predominantly gastrointestinal and generally mild. No report was made of any significant laboratory abnormalities which could be attributed to treatment with either antibiotic. DISCUSSION In New Zealand, as in Europe and the United States, lower respiratory tract infection is among the 10 most
common reasons for consultation in general practice (Ridley-Smith, 1973; Marsland et al., 1976; Rosenblatt et al., 1982). Although some maintain that prescribing antibiotics for these conditions is inappropriate as they may often have a viral etiology (Koster, 19o°2), the standard clinical response when a patient presents with a lower respiratory tract infection is antibiotic therapy. Examination of sputum is often of little use in identifying responsible bacterial pathogens, and a viral cause is difficult to establish. To accommodate the possibilities that the infections of the participants in this study may have a viral etiology, or be caused by an atypical pathogen, we incorporated techniques into the study design to establish etiology wherever possible. A definite bacterial pathogen was identified in only 21 cases and a probable viral cause in seven cases, leaving 86% of patients with an illness of unconfirmed cause. These results are similar to those reported from other studies (Marsland et al., 1976) and demonstrate the dilemma facing general practitioners. The pragmatic response has been to prescribe an antibiotic, taking into consideration spectrum of activity, side-effect profile, and frequency of administration. The results of this study indicate that roxithromycin compares favorably with cefaclor. It is well tolerated and can be taken under a twice-daily regimen. Pharmacologic studies (Anderson et al., 1987; Cuffini et al., 1989) have demonstrated that roxithromycin accumulates in phagocytes at high concentrations, enhancing bactericidal activity against intracellular respiratory pathogens. As an antibiotic
Roxithromycin versus Cefaclor in LRTI
TABLE 4
101S
Distribution of Side Effects and Their Relationship to the Test Treatment Total Reported
Probably Related
Possibly Related
Unlikely/ Unassessable
Rox
Cef
Rox
Cef
Rox
Cef
Rox
Cef
GI CNS Skin GU Others
13 3 0 6 2
19 9 2 2 1
4 0 0 2 0
12 5 2 2 0
4 1 0 1 0
6 2 0 0 0
5 2 0 3 2
1 2 0 0 1
Total events Number of patients
24 20
33 22
6 5
21 12
6 5
8 7
12 10
4 3
Rox, roxithromycin;Cef, cefaclor;GI, gastrointestinal system; CNS, central nervous system; and GU, genitourinary system. that is synergistic with phagocytes, roxithromycin has advantages in the empiric treatment of c o m m o n respiratory infections (McDonald, 1990). A n enrollment of 250 patients in this study is p l a n n e d to ensure that sufficient n u m b e r s are analyzed to detect a statistically significant difference with sufficient p o w e r (8 0.15 a n d 13 0.80, two-tailed
hypothesis). At this stage n o statistically significant differences in efficacy a n d tolerance b e t w e e n the t w o ~ e a t m e n t s have b e e n d e m o n s t r a t e d . There is a t r e n d for better tolerance in those treated with roxithromycin, w h i c h is likely to provide an effective a n d well-tolerated treatment for general practice patients with lower respiratory tract infections.
REFERENCES Anderson R, Van Rensburg CEJ, Joone G, Lukey PT (1987) An in vitro comparison of the intraphagocytic bioactivity of erythromycin and roxithromycin, l Antimicrob Chemother 20(Suppl B):57-68. Cuffini AM, Carlone NA, Tullio V, Borsotto M (1989) Comparative effects of roxithromycin and erythromycin on cellular immune functions in vitro. 3. Killing of intracellular Staphylococcus aureus by human macrophages. Microbios 58:27-33. Koster F (1982) Acute bronchitis. In Ambulatory Medicine. Eds, LR Barker, JR Burton, and PD Zieve. Baltimore: Williams and Wilkins, pp 227-228. Marsland DW, Wood M, Mayo F (1976) Content of family practice: I. Rank order of diagnosis by frequency. J Faro Pract 3:37-68.
McDonald P (1990) New approaches to the management of community acquired pneumonia. JAMA SEA Suppl 6(3):14-19. Periti P, Mazzei T, Mini E, Novelli A (1989) Clinical pharmacokinetic properties of the macrolide antibiotics. 2. Effects of age and various pathophysiological states. Clin Pharmacokinet 16:261-281. Ridley-Smith RM (1973) Why the patients came. NZ Med J 78:240-246. Rosenblatt RA, Cherkin IX:, Schneeweiss R, Hart LG, Greenwald H, Kirkwood CR, Perkoff GT (1982) The structure and content of family practice: current status and future trends. ~ Fam Pract 15:681-722.
97S
A Randomized Double-Blind Controlled Trial of Roxithromycin and Cefaclor in the Treatment of Acute Lower Respiratory Tract Infections in General Practice Murray W. Tilyard and Susan M. Dovey
A multicenter, randomized, double-blind, single-dummy placebo-controUed study is being undertaken by the Research Unit of the Royal New Zealand College of General Practitioners to compare the efficacy and tolerance of 150 rag twice daily roxithromycin with 250 mg three times daily cefaclor in the treatment of 250 8eneral practice patients with acute lower respiratory tract infections (LRTIs). Interim analysis of 200 patients reveals no statistically significant differences in the study parameters. Of the patients on roxithromycin and cefaclor, 83% and 67%, respectively, had a moderate or severe illness. Based on efficacy criteria, 96% of roxithromycin recipients and 99%
of cefaclor recipients had a satisfactory or improved response. On an intention-to-treat basis, this was reduced to 95% for both treatment groups. Sputum grading and semiquantitative culturing was performed according to NCCLS standards. The mas! common isolates in order were Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Efficacy for bacteriologically evaluable cases was 87.5% for roxithromycin and 57% for cefaclor. Four patients on roxithromycin (3.9%) and 11 patients on cefaclor (11.3%) withdrew because of side effects probably or possibly related to the study treatment. The study is ongoing.
INTRODUCTION
cephalosporin cefaclor, which is frequently used as treatment of lower respiratory tract infection (LRTI). Both medications have a well-established tolerance and efficacy profile. This study design was based on the normal general practice treatment for lower respiratory tract infections, with emphasis on clinical assessment of cause and outcome.
Roxithromycin is an oral macrolide antibiotic with an improved pharmacokinetic profile over earlier macrolides (Periti et al., 1989). The long half-life of 10-12 hr permits convenient twice-daily administration while maintaining activity against common respiratory tract pathogens as well as the increasingly recognized atypical pathogens such as Mycoplasma pneumoniae, Legionella pneumoniae, and Chlamydia spp. This twice-daily regimen for roxithromycin also makes it an ideal medication in the primary care setting where compliance can be a problem causing suboptimal treatment of infections. No previous comparative work has been performed against the oral From the Royal New Zealand Collegeof General Practitioners, ResearchUnit, Dunedin, New Zealand. Additional copies of this supplement are availablefrom Roussel UCLAF, DomaineTh~rapeutiqueAntibioth~rapie,35 Boulevard des Invalides, 75007Paris, France. Received 8 October 1991;revised and accepted 15 November 1991. © 1992ElsevierSciencePublishers Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
METHODS Patients General practitioners in eight locations throughout New Zealand enrolled 200 patients presenting with lower respiratory tract infections. Eligible patients were aged 18 years or older and presented with a cough and signs consistent with bacterial lower respiratory tract infection. The diagnosis was based primarily on clinical assessment, supported by serology, bacteriology of sputum (if obtained), and chest radiographs if clinically indicated. Patients with signs and symptoms solely suggestive of viral upper respiratory tract infections were not enrolled.
985
Study Design The protocol was reviewed and approved by the ethics committee of the Otago Area Health Board and the New Zealand Department of Health. Written informed consent was given by each participant. The study design was parallel, randomized, doubleblind, and single-dummy placebo controlled. Randomization was in blocks of four to ensure that half of the study participants would receive roxithromycin and half cefaclor, and that individual doctors would assign equal numbers of patients to each treatment.
Drugs and Dosage Following initial assessment and entry into ti',e trial, the first week of study medication was dispe,sed. Medication was packaged in predispensed Webster blister packs with 21 doses (7 days of treatment) provided at visit 1. Each dose contained either a roxithromycin 150-mg tablet or a cefaclor 250-mg capsule as active treatment, with an accompanying dummy placebo (except where randomization was to roxithromycin, when both tablets in the midday do~e were dummy). Patients were instructed to take one dose three times a day before meals. If clinically indicated at the end of 7 days' therapy, then a further 7 days of medication was dispensed. Follow-up assessment of clinical and bacteriologic status was made at the end of therapy.
Assessments Patients were assessed for eligibility by their general practitioner. They had to have cough and signs consistent with lower respiratory tract infection. At the initial visit, details were recorded relating to patients' clinical status, demography, general health, concomitant medication, and underlying diseases and conditions. A chest radiograph was obtained if clinically indicated. Sputum was obtained where possible for microbiologic testing and culture techniques performed to NCCLS standards. Blood samples for hematology, biochemistry, and serology were taken at commencement and end of therapy. Clinical efficacy was evaluated by the general practitioner. Efficacy was deemed satisfactorywhere the infection had completely cleared with the resolution of clinical signs and symptoms, improved if there was an improvement in signs and symptoms without complete resolution, and unsatisfactoryif the infection remained the same or had worsened. Follow-up chest radiographs were undertaken if clinically indicated. Bacteriologic efficacy was deemed satisfactory if the pathogen was eradicated on post-
M.W. Tilyard and S.M. Dovey
TABLE 1 Underlying Conditions or Risk Factors Roxithromycin 80 Patients
Cefaclor 64 Patients
Smokers CORD Asthma Bronchiectasis Diabetes Immunodeficiency Cardiovascular Renal disease Alcoholism Other
33 37 17 2 3 1 27 1 2 12
32 15 13 0
Total risk factors
135
89
1 17 0 5 5
CORD, chronicobstructiverespiratory disease. treatment culture, or if there was improvement to such an extent that posttreatment culture was not possible, or in the event that a new organism was identified without any local or systemic signs of infection (colonization). An ,msatisfactory bacteriologic outcome was defined where the pathogen remained on posttreatment culture or where a new organism appeared with evidence of a new infection. To facilitate identification of the responsible pathogen, we performed complement fixation and immunofluorescence tests for M. pneumoniae, Chlamydia spp., LegioneUaspp., and viral agents [influenza A and B, respiratory syncitial virus (RSV), and adenovirus] on paired sera at one central reference laboratory. A fourfold rise in titer or a single titer of >256 was taken to represent recent infection. Adverse events were noted on the case report form at follow-up visits. The type of reaction, severity, duration, action taken, and the outcome were noted as well as the general practitioner's opinion on the causal relationship between the adverse reaction and study medication.
Statistical Analysis The statistical analysis comprised chi-squared tests (with Yates' correction) for treatment comparisons. RESULTS
Patients A total of 200 patients were included in the analysis. The mean age of patients was 51.2 years (median, 53 years; and range, 18-90 years). There were 98 women and 102 men enrolled. The underlying conditions or risk factors are shown in Table 1. More
Roxithromycin versus Cefaclor in LRTI
995
patients randomized to treatment with roxithromycin had underlying conditions or risk factors than those randomized to receive cefaclor (77.7% vs 66.0%) Underlying chest disease was reported for 56 patients randomized to roxithromycin and 28 patients randomized to cefaclor. C l i n i c a l Efficacy A diagnosis of acute isolated bronchitis was made in 160 cases, acute exacerbation of chronic bronchitis in 32 cases, typical pneumonia in six cases, and atypical pneumonia in two cases. Severity was described as moderate or severe in 75% (1~9) of cases. Of the patients on roxithromycin, 83% had moderate or severe illness compared with 67% of those on cefaclor. This difference was not statistically significant. Of the 103 cases assigned 5o treatment with roxithromycin, 91 were evaluable for efficacy. Fewer than 12 doses were taken in three cases, five cases were not evaluable because serologic tests indicated infection attributable to a viral cause, and in four cases a resistant pathogen was isolated on pretreatment culture. A satisfactory or improved outcome was achieved in 96% of evaluable cases. On intention-to-treat analysis, this was reduced to 95% of cases. Of the 97 cases assigned to cefaclor, 88 (90%) were evaluable. Fewer than 12 doses were taken in four cases, a viral infection was indicated in two cases, in two cases a resistant pathogen was isolated on pretreatment culture or identified by serology, and
one case was lost to follow-up. For evaluable cases, 99% achieved a satisfactory or improved outcome. On intention-to-treat analysis, this reduced to 95%. There were no s~.atistically significant differences in outcom~ between the treatments. Tables 2 and 3 detail clinical efficacy, both for evaluable cases only and on intention to txeat. The mean duration of therapy was 8.7 days in the roxithromycin group and 9.2 days in the cefaclor group. In the roxithromycin group, 28 patients (27%) required an extension of therapy beyond 7 days, and 35 patients (36%) on cefaclor required more than 7 days' therapy. Bacteriologic Efficacy Sputum was obtained from 140 patients (70%). Of sputum specimens, 40% grew a potential pathogen. Assessment of the bacteriologic efficacy per protocol was possible in 15 cases (7%). The most common isolates in order were Haemophilus influenzae, M. catarrhalis, and Streptococcus pneumoniae. Of the bacteriologically evaluable cases, seven (87.5%) of eight were successfully eradicated by roxithromycin compared with five (57%) of seven for cefaclor. Because of the small numbers involved, significance cannot be established. Seven cases of viral infectio~ were detected by serology: three cases of RSV and four of imluenza A. A satisfactory or improved clinical response was reported in all cases. One case of Chlamydia spp. infection (probable C. pneumoniae-TWAR strain) was
TABLE 2 Clinical Efficacy--Intention to Treat
Roxithromycin Acute isolated bronchitis Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage Cefaclor Acute isolated bronchitis Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage
Total Number
Satisfactory Outcome
Improved Outcome
Unsatisfactory Outcome
76 22
49 11
24 9
3 2
3 2
0 1
3 1
0 0
103 100
61 59
37 36
5 5
84 10
40 5
40 5
4 0
3 0
2 0
1 0
0 0
97 100
47 48
46 47
4 5
100S
M.W. Tilyard and S.M. Dovey
TABLE 3 Clinical Efficacy--Evaluable Cases Only Total Number
Satisfactory Outcome
Improved Outcome
Unsatisfactory Outcome
Roxithromycin Acute isolated bronchitis Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage (%)
64 22
43 II
19 9
2 2
3 2 91 91
0 1 55 81
3 1 32 35
0 0 4 4
Cefaclr,r Acute isolated bronchitis
76
39
36
1
10
5
5
0
3 0
2 0
1 0
0 0
89 100
46 52
42 47
1 1
Acute on chronic bronchitis Typical pneumonia Atypical pneumonia Total Percentage (%)
detected in a patient with a clinical diagnosis of severe acute bronchitis. In this case an improved clinical outcome was reported after a 14-day course of treatment with cefaclor.
Tolerance Twenty-two patients (11%) withdrew from treatment Lecause of side effects, failure to improve on therapy, or exclusion criteria; 10 were patients randomized to treatment with roxithromycin, and 12 were patients randomized to cefaclor. Four patients in the roxithromycin group (3.9%) and 11 patients in the cefaclor group (11.3%) withdrew because of side effects probably or possibly related to treatment. Adverse events of probable, possible, or doubtful relationship to treatment were reported in 19 patients (18.4%) on roxithromycin and 22 patients (22.7%) on cefaclor (Table 4). For 10 patients (9.7%) on roxithromycin and 19 patients (19.6%) on cefaclor, these were deemed to have a probable or possible causal relationship to the study treatment. Adverse events were predominantly gastrointestinal and generally mild. No report was made of any significant laboratory abnormalities which could be attributed to treatment with either antibiotic. DISCUSSION In New Zealand, as in Europe and the United States, lower respiratory tract infection is among the 10 most
common reasons for consultation in general practice (Ridley-Smith, 1973; Marsland et al., 1976; Rosenblatt et al., 1982). Although some maintain that prescribing antibiotics for these conditions is inappropriate as they may often have a viral etiology (Koster, 19o°2), the standard clinical response when a patient presents with a lower respiratory tract infection is antibiotic therapy. Examination of sputum is often of little use in identifying responsible bacterial pathogens, and a viral cause is difficult to establish. To accommodate the possibilities that the infections of the participants in this study may have a viral etiology, or be caused by an atypical pathogen, we incorporated techniques into the study design to establish etiology wherever possible. A definite bacterial pathogen was identified in only 21 cases and a probable viral cause in seven cases, leaving 86% of patients with an illness of unconfirmed cause. These results are similar to those reported from other studies (Marsland et al., 1976) and demonstrate the dilemma facing general practitioners. The pragmatic response has been to prescribe an antibiotic, taking into consideration spectrum of activity, side-effect profile, and frequency of administration. The results of this study indicate that roxithromycin compares favorably with cefaclor. It is well tolerated and can be taken under a twice-daily regimen. Pharmacologic studies (Anderson et al., 1987; Cuffini et al., 1989) have demonstrated that roxithromycin accumulates in phagocytes at high concentrations, enhancing bactericidal activity against intracellular respiratory pathogens. As an antibiotic
Roxithromycin versus Cefaclor in LRTI
TABLE 4
101S
Distribution of Side Effects and Their Relationship to the Test Treatment Total Reported
Probably Related
Possibly Related
Unlikely/ Unassessable
Rox
Cef
Rox
Cef
Rox
Cef
Rox
Cef
GI CNS Skin GU Others
13 3 0 6 2
19 9 2 2 1
4 0 0 2 0
12 5 2 2 0
4 1 0 1 0
6 2 0 0 0
5 2 0 3 2
1 2 0 0 1
Total events Number of patients
24 20
33 22
6 5
21 12
6 5
8 7
12 10
4 3
Rox, roxithromycin;Cef, cefaclor;GI, gastrointestinal system; CNS, central nervous system; and GU, genitourinary system. that is synergistic with phagocytes, roxithromycin has advantages in the empiric treatment of c o m m o n respiratory infections (McDonald, 1990). A n enrollment of 250 patients in this study is p l a n n e d to ensure that sufficient n u m b e r s are analyzed to detect a statistically significant difference with sufficient p o w e r (8 0.15 a n d 13 0.80, two-tailed
hypothesis). At this stage n o statistically significant differences in efficacy a n d tolerance b e t w e e n the t w o ~ e a t m e n t s have b e e n d e m o n s t r a t e d . There is a t r e n d for better tolerance in those treated with roxithromycin, w h i c h is likely to provide an effective a n d well-tolerated treatment for general practice patients with lower respiratory tract infections.
REFERENCES Anderson R, Van Rensburg CEJ, Joone G, Lukey PT (1987) An in vitro comparison of the intraphagocytic bioactivity of erythromycin and roxithromycin, l Antimicrob Chemother 20(Suppl B):57-68. Cuffini AM, Carlone NA, Tullio V, Borsotto M (1989) Comparative effects of roxithromycin and erythromycin on cellular immune functions in vitro. 3. Killing of intracellular Staphylococcus aureus by human macrophages. Microbios 58:27-33. Koster F (1982) Acute bronchitis. In Ambulatory Medicine. Eds, LR Barker, JR Burton, and PD Zieve. Baltimore: Williams and Wilkins, pp 227-228. Marsland DW, Wood M, Mayo F (1976) Content of family practice: I. Rank order of diagnosis by frequency. J Faro Pract 3:37-68.
McDonald P (1990) New approaches to the management of community acquired pneumonia. JAMA SEA Suppl 6(3):14-19. Periti P, Mazzei T, Mini E, Novelli A (1989) Clinical pharmacokinetic properties of the macrolide antibiotics. 2. Effects of age and various pathophysiological states. Clin Pharmacokinet 16:261-281. Ridley-Smith RM (1973) Why the patients came. NZ Med J 78:240-246. Rosenblatt RA, Cherkin IX:, Schneeweiss R, Hart LG, Greenwald H, Kirkwood CR, Perkoff GT (1982) The structure and content of family practice: current status and future trends. ~ Fam Pract 15:681-722.
