Tolerability of Roxithromycin vs Erythromycin in Comparative Clinical Trials in Patients with Lower Respiratory Tract Infections

PHARMACOVIGILANCE Clin. Drug Invest. 1997 Nov; 14 (5): 405-417 11 73-2563/97/0011-0405/$0650/0

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Tolerability of Roxithromycin vs Erythromycin in Comparative Clinical Trials in Patients with Lower Respiratory Tract Infections

Richard f. Milne, l Roger W. Olney, 1 Gregory D. Gamble2 and John Turnidge 3

1 Adis International Ltd, Auckland, New Zealand

2 Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand

3 Women and Childrens Hospital, Adelaide, South Australia, Australia

Summary The comparative tolerability and rate of withdrawal from clinical trials was established from a pooled analysis of comparative clinical studies of roxithromycin and/or erythromycin in patients with lower respiratory tract infections. Where stated, 65 % of patients were managed in the community and some as inpatients. 942 patients in 13 studies received roxithromycin 300 mg/day and 1253 patients in 15 studies received erythromycin in various formulations and dosages. 47% of patients had an initial diagnosis of community-acquired pneumonia, 20% had an acute infectious exacerbation of chronic bronchitis, 30% had acute bronchitis, and a further 4% had unspecified lower respiratory tract infection. The incidence of adverse events that were definitely or probably associated with antibacterial therapy (excluding laboratory abnormalities) was 25-fold higher for patients receiving erythromycin compared with roxithromycin (24 .8 vs 10. I %), and the rate of withdrawal from clinical trials due to adverse events was 3.6-fold higher (7 .1 vs 2.0%). Most of the adverse events associated with erythromycin were gastrointestinal in nature. Since adverse events and withdrawals help determine the compliance rate and the clinical value of an antibacterial agent in routine clinical practice, they should be taken into account when prescribing a macrolide for a respiratory tract infection.

Along with ~-lactams, tetracyclines and cepha

losporins, macrolides are commonly used as em

pirical first-line antibacterial therapy for patients

with acute bronchitis and acute exacerbations of

chronic bronchitis, and they are recommended for

patients with community-acquired pneumonia (CAP) .[1 -3] In pneumonia, macrolides are effica

cious against both 'typical' and 'atypical' patho-

gens. However, the clinical efficacy of an anti

bacterial agent, as measured in a clinical trial,

can overestimate the effectiveness of the drug in

routine clinical practice because of the rigidly con

trolled nature of the trial and the close monitoring

and follow-up of patients that is usually demanded

by the protocol. It is the effectiveness in routine clinical practice

406

rather than the efficacy determined in a clinical trial that determines both the clinical value of a drug and also the overall cost of managing an infectious episode, including the cost of reconsultations for the same infective episode. The effectiveness of antibacterial drugs in routine community practice depends on the specific indication and the severity of the disease, the efficacy of the drugs against the causative pathogens and, importantly, patient compliance, which hinges on tolerability and convenience of administration.

The first macrolide to become available was erythromycin, which is available in various formulations, all of which are generally administered 3 or 4 times daily. Roxithromycin was the first of the 'second generation' of macrolides with an improved pharmacokinetic profile allowing a onceor twice-daily dosage regimen. 14,5] Its antibacterial spectrum encompasses both' typical' and ' atypical' respiratory pathogens and it penetrates well into respiratory tissues and secretionsJ6] Roxithromycin is at least as efficacious as erythromycin for a given patient population and mix of causative pathogens.f7,8] Although some macrolides, including erythromycin, are considered to have only intermediate or borderline in vitro activity against Haemophilus injluenzae,l31 roxithromycin has been shown to confer good clinical and bacteriological responses in patients with upper and lower respiratory tract infection who are infected with this pathogen.f9]

The adverse gastrointestinal effects of erythromycin, such as pain, cramping, nausea, vomiting and diarrhoea, are well known!3] and have been shown to reduce compliance and the clinical outcome oftherapy (e.g. Anastasio et al.[ 10]). Evidence from animal studies shows that erythromycin is a motilin agonist that has a prokinetic effect on the gut. f II] There is evidence that roxithromycin causes fewer and/or less severe gastrointestinal effects than erythromycin,[12] but this has not been studied systematically over a large range of patients. Paulsen and colleaguesfl2 ] found that 19 erythromycin stearate is tolerated significantly less well than roxithromycin 300mg daily (adverse events

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Millleetal.

were 51.3% for erythromycin versus 17.5% for roxithromycin; p = 0.003).

Poor tolerance of drug therapy is more than simply a matter of patient discomfort because it reduces compliance and may therefore reduce the effectiveness of therapy and the reconsultation rate, and hence the total cost of managing an infective episode.

The purpose of this study was to determine from a comprehensive review of published comparative clinical trials of roxithromycin and erythromycin in patients with lower respiratory tract infections (LRTIs) the following: • The proportions of patients who experienced

adverse events during the course of antibacterial therapy.

• The proportions of patients who withdrew from the trials as a result of adverse events associated with antibacterial drug therapy. Only LRTI studies were chosen rather than all

indications because it may not be assumed that adverse events occur independent of indication.

Methods

Literature Searches

A complete review was undertaken of all clinical studies of roxithromycin or erythromycin vs any comparator antibacterial drug in the treatment of LRTI. Relevant studies were identified by a systematic search of both Medline® (1987 to 1996) and a commercial database (Adisbase; Adis International Ltd) covering the period 1989 to 1996 inclusive. The review was limited to comparative clinical studies published in the English language (or with an English language Summary) involving the use of either roxithromycin or erythromycin, or both drugs, in the treatment of LRTI.

Further comparative studies of roxithromycin published over this time period were identified by examining the reference lists of all retrieved articles and that of a major recent review of roxithromycin.[7] The 10-year search period was deemed adequate for the collection of sufficient data to demonstrate any trends , but sufficiently

elin . Drug Invest. 1997 Nov; 14 (5)

Roxithromycin vs Erythromycin Tolerability in LRTIs

short to ensure that studies collected for analysis were of a similar scientific standard.

Analysis of Adverse Events

Adverse events for roxithromycin and erythromycin were tabulated on a per patient basis rather than on a per event basis. We excluded laboratory abnormalities because these were not reported in many of the studies and because they are unlikely in clinical practice to cause a patient to stop taking a short course of either drug without a clinical adverse event being captured.

Adverse events data that were considered possibly or probably related to the study drug, were included whenever this information was reported in individual studies. In those studies that did not state whether adverse events were considered possibly or probably related to the study drug, the overall incidence of adverse events (excluding laboratory abnormalities) was reported. All withdrawals that the investigators stated were probably due to adverse events of roxithromycin or erythromycin were included. Where investigators stated that withdrawals were due to adverse events or lack of efficacy (without specifying numbers of each), or adverse events and lack of efficacy, these figures were also included.

Statistical Analysis

Data were examined and analysed within the statistical analysis system SAS (SAS Institute Inc., SAS/STAT Guide for personal computers, Cary, NC, SAS Institute Inc., 1987). All tests were twotailed, and a 5% significance level was maintained throughout these analyses . A nonparametric approach (Wilcoxon test for independent groups) was taken to compare continuous covariates, while categorical covariates were compared with X2 test without continuity correction. Adjustment to the main effects for potential important confounders was provided using categorical modelling techniques.

Inspection of the data suggests that one study[13] may represent an outlier so analyses were performed both with and without this study. However,

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407

a formal test of heterogeneity of the studies within each of the drug groups suggested that they were homogeneous and could be treated as a whole (X2,

p > 0.05), so this study was included in the final analyses. Where a range of values was provided, the mid-point was adopted as a measure of central tendency (e.g. duration of the course of therapy) . If appropriate this was weighted by the sample size of each condition.

Relevance of Erythromycin Dosage to Incidence of Adverse Events

Similar search procedures were used to identify all of the published respiratory tract infection studies (upper and lower) on erythromycin. From this, the adverse events were noted against drug dosage; the aim was to determine whether adverse events occurred to a similar or greater extent as the dose of erythromycin was increased.

Results

Studies Reviewed

Twenty-three trials involving the use of roxithromycin in the treatment of LRTI in comparative clinical studies were identified. Six of these studies were discarded because their results were reported more fully in other papers and a further three because the trials also included patients with upper respiratory tract infections (URTI) and data could not be separated. One head-to-head comparative study with erythromycin was excluded because the data were incompleteJl4] A total of 15 studies of erythromycin were analysed, including three that compared erythromycin with roxithromycin, and the total number of different studies analysed was 25.

Thirty-one trials involving the use of erythromycin in the treatment of LRTI in comparative clinical studies were identified. Eight of these studies were excluded because they included patients with URTI, five because the data presented in these studies were incomplete (with respect to dosage regimens used, adverse events, withdrawal rates, etc.), one because subjects in the study received

Clin. Drug Invest. 1997 Nov; 14 (5)

408 Milneet al.

Table I. Numbers of patients in each treatment group with community-acquired pneumonia. AECB or acute bronchitis

Community-acquired AECB Acute bronchitis LRTI or other" pneumonia (%) (%) (%) (%)

Roxithromycin (n = 942) 279 (30) 234 (25) 389 (41) 40 (4)

Erythromycin (n = 1253) 758 (60) 192 (15) 260 (21) 43 (3)

Total (n = 2195) 1037 (47) 426 (20) 649 (30) 83 (4)

a Two patients had a diagnosis of bronchiectasis.

Abbreviations: AECB = acute exacerbation of chronic bronchitis or chronic obstructive pulmonary disease; LRTI = lower respiratory tract infection.

erythromycin in combination with another antibiotic, one because the study included only paediatric patients , and one because erythromycin was given as long-term prophylaxis to patients with acute infective exacerbation of chronic bronchitis (AECB) or chronic obstructive respiratory disease (AB/CORD).

Three of the studies selected for review were head-to-head comparisons of roxithromycin vs

erythromycin that have a high degree of internal validity because of the randomisation process. One other study compared two different formulations of erythromycin. The remainder compared either roxithromycin or erythromycin with another macrolide or another agent commonly used as first-line therapy for patients with LRTI.

Indications

Many patients were diagnosed as having CAP, others with AECB and some with isolated acute bronchitis . A few suffered from bronchiectasis. In one study,1121 the general diagnosis of 'LRTI' was applied to all patients without further specification.

Table I shows the distribution of indications across all the studies. It is clear that a higher proportion of patients receiving erythromycin was initially diagnosed with pneumonia. This finding reflects mostly one large study.IIS] Roughly equivalent proportions of patients receiving roxithromycin were diagnosed with pneumonia, AECB or acute bronchitis .

Hospitalisation

Many studies were conducted in the community and the remainder were' conducted in a hospital set-

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Table II. Adverse event rates and withdrawal rates for patients treated in hospital or in the community' in relation to the numbers of patients evaluated for tolerability in each setting

Roxithromycin (%) Erythromycin (%)

Adverse events

Inpatient 34/305 (11) 521225 (23)

Outpatient or community 51 /501 (10) 149/455 (33)

Withdrawals

Inpatient 4/305 (1.3) 13/225 (6)

Outpatient or community 12/501 (2 .4) 61 /455 (13)

a All studies in which the setting was identified and patients remained in that setting for the duration of therapy.

ting. Table II shows the incidence of adverse events and withdrawals for patients who were treated in the community or in hospital, excluding studies in which patients were discharged from hospital during the trial. The proportions of adverse events reported were higher for patients treated as outpatients with erythromycin than for inpatients, but similar for patients treated with roxithromycin. Withdrawal rates were 2-fold higher for patients treated with erythromycin compared with roxithromycin in both settings, and were also 2-fold higher in the community than in hospital.

Drug Formulations and Dosage Regimens

Roxithromycin was administered at dosages of 150mg twice daily or 300mg once daily. Various oral formulations of erythromycin were used, the dosages used ranging from 1 to 2 g/day either in 4 divided doses or 3 divided doses (two studies) or 2 divided doses (four studies). In many of these studies the formulation was listed as 'erythromycin'


Roxithromycin us Erythromycin Tolerability in LRTIs

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Incidences of Adverse Events and Withdrawals

Table III shows the comparative incidence of reported adverse events and numbers of patients who withdrew from therapy because of adverse events in direct comparative clinical trials of roxithromycin vs erythromycin as first-line therapy for LRTIs.

Table IV shows the comparative incidence of reported adverse events and the numbers of patients who withdrew from therapy because of adverse events in comparative clinical trials of roxithromycin as first-line therapy for LRTI (excluding direct comparisons of roxithromycin vs erythromycin).

Table V shows the comparative incidence of reported adverse events and numbers of patients who withdrew from therapy because of adverse events in comparative clinical trials of erythromycin as first-line therapy for LRTI , excluding direct comparisons of roxithromycin vs erythromycin. Table VI summarises the statistical analysis of the data derived from tables III to V.

The study populations within each drug group were surprisingly comparable. Although potentially important covariates were not uniformly reported in all the studies, there were no statistically significant differences between the groups in the following:

• Clinical efficacy of roxithromycin vs erythromycin in patients who were evaluable for efficacy (88% vs 88%; p = 0.99)

• Age of the patient (p = 0.62)

• Percentage of male patients (p = 0.72)

• Clinical setting (hospital or community; p=0.53)

• Duration of the course of treatment (p = 0.17)



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(presumably the base formulation) or stearate. Ethylsuccinate, base and acistrate (2-acetate stearate) formulations were also administered in some studies. The estolate formulation , which has been associated with cholestatic hepatitis,l3] was not used in the studies that we analysed .

Incidences of Adverse Events and Withdrawals

Table III shows the comparative incidence of reported adverse events and numbers of patients who withdrew from therapy because of adverse events in direct comparative clinical trials of roxithromycin vs erythromycin as first-line therapy for LRTIs.

Table IV shows the comparative incidence of reported adverse events and the numbers of patients who withdrew from therapy because of adverse events in comparative clinical trials of roxithromycin as first-line therapy for LRTI (excluding direct comparisons of roxithromycin vs erythromycin).

Table V shows the comparati ve incidence of reported adverse events and numbers of patients who withdrew from therapy because of adverse events in comparative clinical trials of erythromycin as first-line therapy for LRTI, excluding direct comparisons of roxithromycin vs erythromycin . Table VI summarises the statistical analysis of. the data derived from tables III to V.

The study populations within each drug group were surprisingly comparable. Although potentially important covariates were not uniformly reported in all the studies, there were no statistically significant differences between the groups in the following:

• Clinical efficacy of roxithromycin vs erythromycin in patients who were evaluable for efficacy (88% vs 88%; p = 0.99)

• Age of the patient (p = 0.62)

• Percentage of male patients (p = 0.72)

• Clinical setting (hospital or community; p = 0.53)

• Duration of the course of treatment (p = 0.17)


6> Table IV. Incidence of adverse events probably or possibly associated with therapy and numbers of patients who withdrew from therapy because of adverse events in comparative ... » ...... D. clinical trials of roxithromycin as first-line therapy for lower respiratory tract infection (excluding direct comparisons of roxithromycin vs erythromycin; see table III) 0 u; 3" Reference Indication Dosage Comparator agent No. of pts evaluated No. of pts receiving Withdrawals due to it 3 (no. of pts evaluated for tolerance to roxithromycin who reported adverse events in pts 0 g for efficacy) roxithromycin adverse events' (%) receiving roxithromycin (%) :J

Biselli et a1.116] Bronchitis (17) 150mg bid Q. Clarithromycin 50 3 (6) 0(0)

~ AECB (29) ~ Pneumonia (4) D.

~ <6' Dautzenberg et a1. 11 9] Acute bronchitis (188) 150mg bid Amoxicillin + clavulanic acid 235 25 (10.6) 3 (1.3) ::r or

AECB (32) ro a; Pneumonia (15) ;( CD D.

de Vlieger et a1.12O] AECB 300mg od Doxycyline 41 4(9.8) 0(0)

Laurentl21 ] Acute bronchitis (25) 150mg bid Azithromycin 100 8 (8) 2 (2)

AECB (46)

Pneumonia (23)

Morandini et al.l22] AECB (22) 150mg bid Azithromycin 24 2 (8.3) 2 (8.3)

Pneumonia (2)

Poirierl23] Pneumonia 150mg bid Clarithromycin 37 5 (13.5) 1 (2.7)

Schbnwald et al.l24] Atypical pneumonia 150mg bid Azithromycin 53 3 (5.7) 0(0)

Karalus et a1.125] and Acute bronchitis (84) 150mg bid Amoxicillin + clavulanic acid 122 12 (9.8) 5 (4.1) SCOII et al.l26] AECB (16)

Pneumonia (15)

Others (2)b

Q Tilyard & Dovey [27] Acute bronchitis (76) 150mg bid Cefaclor 103 10 (9.7) 4 (3.9)

~. and Scoll et al.1281 AECB (22) 0 Pneumonia (5) C co 3" <

Zeluff et al. [29] Pneumococcal 150mg bid Cefradine 80 9 (11.3) 0(0) CD

'" -0

pneumonia -0 a Number of patients with adverse events considered 'possibly or 'probably related to drug therapy, excluding laboratory abnormalities. ~ '-J

Z Infective exacerbation of bronchiectasis. 0 b ;;-

.< Abbreviations: AECB = acute exacerbation of chronic bronchitis; bid = twice dail;t; od = once dail;t. " ,;: ~

2J ==-

Table V. Incidence of adverse events probably or possibly associated with therapy and numbers of patients who withdrew from therapy because of adverse events in comparative :N » 0 Cl clinical trials of erythromycin as first·line therapy for lower respiratory tract infection, excluding direct comparisons of erythromycin vs roxithromycin (see table III) ~. v;. g:. 5" Reference Indication (no. of pts Formulation and Comparator No. of pts evaluated for No. of pts reporting Withdrawals due to (j)

..., 0

3 evaluated for efficacy) dosage regimena tolerance to erythromycinb adverse eventsC (%) adverse events (%) :3 8- Anderson et al[301 Pneumonia Stearate 0.5g qid Clarithromycin 112 37 (33) 21 (19) '< o· f")

:J S· Q.

'" ~ Bohte et al.[31 ] Non-pneumococca[ Base 0.5g qid Benzylpenicillin, 21 4 (19) 2 (9.5) 'J,

tTl ~ pneumonia azithromycin

..., Cl '< g:. ~ ,..,

Chien et al. [13] Pneumonia Stearate 0.5g qid Clarithromycin 134 76 (57) 37 (28) 0 <0 3 ::r '< ur f")

~ Daniel & European Bronchitis (24) Stearate 0.5g qid Azithromycin 88 16 (18) 1 (1 .1) 5'

<' Azithromycin Study AECB (42) ol <1> Group[32] iii' Cl Pneumonia (21) ,..,

PJ Other (1) ~

--< de Cock & Poels[33] Bronchitis (47) Ig bid Spiramycin 99 41 (41) 11 (11.1) S·

AECB (32) r-'

Pneumonia (22) ~ <f>

Forsen et al. [34] AECB Acistrate O.4g tid Erythromycin base 57 15 (26) 5 (8.8) Base 0.5g tid vs acistrate

Jang et al. [35] Pneumonia NSO.5g qid Clarithromycin 20 6(30) 2 (10)

Liippo et al.[15] Pneumonia (293) NS 0.25g qid Dirithromycin 296 46 (15.5) 2 (0.7)

Others (3)

Moretti et al.[36] Acute bronchitis (34) NS 0.6g tid Brodimoprim 69 12 (17.4) 2 (2.9)

AECB(35)

Peugeot et al. [37] Bronchitis (7) NS O.4g qid Ofloxacin 28 4 (14.3) 0(0)

AECB (7)

Q Pneumonia (13)

~.

0 C

Schbnwald et al.[38] Atypical pneumonia NS 0.5g qid Azithromycin 44 6(13.6) 0(0)

<D 5" Wiesner et al.[39] Bronchitis (135) Acistrate O.4g bid Doxycycline 148 20(13.5) 3 (2.0) < <1> "l. AECB (2)

:s Pneumonia (11)

z a 1.39g of erythromycin stearate is equivalent to 1 9 of erythromycin. 0 b May be greater than the number of patients evaluated for efficacy. :<;

"- c Number of patients reporting adverse events considered to be possibly or probably drug related , excluding laboratory abnormalities. "'" 9 Abbreviations: AECB - acute exacerbation of chronic bronchitis; bid = twice daily; NS = not stated; gid = 4 times daily; tid = 3 times daily. .... ....

412

• Indications: CAP (p = 0.64), AECB (p = 0.43), acute bronchitis (p = 0.61), other (p = O. IS), LRTI generally (p = 0.S7)

• Year of publication of the study (p = 0.S7).

The proportions of patients reporting adverse events in the roxithromycin- and erythromycintreated groups were 10.1 % (95% CI S to 12%) and 24.S% (95% CI 22 to 27%), respectively. Thus, the difference between the groups was 14%. An implication of this finding was that using roxithromycin instead of erythromycin in LRTIs could result in a decrease in adverse events of between IS and 12% in 95 out of 100 cases (p = 0.000 I). This result was not affected by omitting one study that appeared to be an outlier[13] or by consideration of potential covariate differences in a categorical model.

Table VI also shows that, in general, patients treated with roxithromycin withdrew from studies less frequently than patients treated with erythromycin. The proportion of patients who withdrew from the roxithromycin- and erythromycin-treated groups was 2.0% (95% CI I to 3%) and 7.1 % (95% CI 6 to 9%), respectively. Thus, the difference between the groups was 5%. An implication of this observation is that using roxithromycin instead of erythromycin in LRTIs could result in a reduction of withdrawals of between 7 and 4% in 95 out of 100 cases (p = 0.02).

In summary, adverse events that were possibly or probably related to therapy were reported for 2.5-fold more patients receiving erythromycin compared with roxithromycin, and withdrawals due to adverse events were 3.6-fold higher for patients receiving erythromycin compared with roxithromycin.

To provide an impression of the types of adverse events reported, we analysed all three of the head-

Milne el al.

to-head comparative studies of roxithromycin vs erythromycin (table III).

Figure I shows the percentages of patients reporting various types of adverse events. Most of the adverse events that were possibly or probably attributable to therapy with either drug were gastrointestinal upsets. These events were almost 2-fold more prevalent in the patient group receiving erythromycin. However, there were no events classified as 'other' in the erythromycin-treated group. Gastrointestinal adverse events for either drug included nausea, vomiting, abdominal pain and diarrhoea.

Relevance of Erythromycin Dosage to Incidence of Adverse Events

Table V shows that the majority of LRTI studies used doses of erythromycin greater than I g daily. Our search of all upper and lower respiratory tract infection studies of erythromycin showed that the dosage of erythromycin ranged from O.S to 2g daily. The Ig daily dosage was investigated in IS studiesI12,15,17,34,39-5Ij and the 2g daily dosage was investigated in 16 studies. [13, I 6.30-33,35,38.48,50,52,53-561

Other dosages of various salt forms were investigated in only a small number of studies (O.Sg, n= I; 1.2g,n= 1; 1.5g,n= I; 1.6g,n=2; I.Sg,n=2).

Overall, 2403 patients evaluated for adverse events received erythromycin Ig and IS16 patients received erythromycin 2g. The reported incidence of adverse events varied considerably between studies and did not appear to be dose related but rather appeared to be related to the formulation of erythromycin under investigation. High incidences of adverse events were reported with erythromycin stearate Ig (35.9%), erythromycin enteric-coated base I g (33.S%), erythromycin ethylsuccinate

Table VI. Reported adverse events and withdrawals from therapy for all studies reported in tables III , IV and V

Roxithromycin (range, 95% GI) Erythromycin (range, 95% GI) Difference (SE)

Adverse events possibly or probably related to therapy

Withdrawal due to adverse events

10.1% (8 to 12%)

2.0% (1 to 3%)

Abbreviations: GI = confidence interval; SE = standard error.

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24.8% (22 to 27%) 14% (1.5%)

7.1% (6 to 9%) 5% (0.045%)



16

e: 12 '0 Q) 1:: 8 0 0-~

4 0 z 0

GastroIntestinal Skin

Type of event

o Roxithromycin • Erythromycin

Others

Fig. 1. Incidence of adverse events reported in head-to-head comparative trials of roxithromycin vs ery1hromycin.

1600mg (37.9%), erythromycin (unspecified) entericcoated Ig (45.8%) and erythromycin particles in tablets Ig (52%). Interestingly, the percentage of patients reporting adverse effects among all those treated with either the 1 or 2g dosage was 35.9% for erythromycin Ig and 24.9% for erythromycin 2g.

Discussion

Our analysis of comparative trials of roxithromycin and/or erythromycin demonstrated that 2.5-fold more patients receiving erythromycin (24.8 vs 10.1 %) experienced adverse events, mostly gastrointestinal in nature, and 3.6-fold more (7.1 vs 2.0%) withdrew from clinical trials because of adverse events associated with drug therapy. Others have shown that 17% of patients administered a 10-day course of erythromycin for a variety of acute infections took less than 80% of their drug , and almost half of these withdrew voluntarily from therapy because of adverse gastrointestinal effects. Furthermore, there was a clear relationship between noncompliance and treatment failure. IIO]

Our study did not set out to evaluate the clinical or bacteriological efficacy of either drug. Nevertheless, the analysis of patients evaluable for efficacy showed an overall good or satisfactory clinical response for evaluable patients of 88% for both agents, which was comparable with that achieved in a recent meta-analysis of roxithromycin in patients with confirmed H. inJluenzae infection (87 ± 5%[9]), but lower than that achieved in a large study in general practice (94% for AECB; 95% for CAPIS7]).

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413

Despite the similarity in efficacy in evaluable patients, 7% of patients receiving erythromycin vs 2% receiving roxithromycin withdrew from the trials and therefore could not be evaluated for efficacy. The drugs therefore would be expected to differ in their effecti veness in routine clinical practice, in contrast to their efficacy in clinical trials, and more patients receiving erythromycin compared with roxithromycin would be expected to reconsult their GP.

Most of the studies included in our analysis compared roxithromycin or erythromycin with another macrolide or another class of antibacterial agent, and three studies compared roxithromycin directly with erythromycin. It is theoretically possible that a retrospective analysis of two groups of studies pools dissimilar patient groups and/or introduces systematic bias (confounding). However, our analysis showed remarkable homogeneity within studies of roxithromycin and within studies of erythromycin. Furthermore, the differences between studies of roxithromycin vs erythromycin could not be attributed to differences in the patient age or gender, indication, proportions of patients hospitalised, duration of therapy, clinical efficacy or year of publication of the study.

For both drugs, both the adverse event rates and the withdrawal rates were similar or higher in patients treated in the community than in the hospital. However, these differences could not account for the differences between groups of patients treated with either of the two drugs . Thus, our analysis provides clear evidence that standard courses of roxithromycin are better tolerated than standard courses of erythromycin in various formulations in patients with LRTls, regardless of the clinical setting.

Most of the studies of roxithromycin used dosages of 150mg twice daily, although two studies (7.3% of patients receiving roxithromycin) used dosages of 300mg once daily (table II). PecherelS8]

reported a randomised controlled comparison of these two dosage regimens in a study of 1588 patients with URTl (about 40%) and LRTl (about 50%), plus a few patients with skin and soft tissue

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414

infections. The overall proportions of patients with one or more adverse events were similar for the two dosage regimens (7.2% for twice-daily dosages and 8.5% for once-daily dosages; p = 0.33). These proportions were similar to those in our study (8 to 12%, table VI). Pechere[58] also showed a higher frequency of gastrointestinal events (7.0 vs 4.4%; P = 0.03) with the once-daily regimen.

Our analysis included studies of erythromycin in which various formulations and dosage regimens were used (tables III and V). However, a formal test of heterogeneity of the studies within each of the drug groups suggested that each group was homogeneous, and could therefore be treated as a whole. The sample size was not large enough to draw conclusions as to whether the proportions of patients with adverse events differed across these studies, so we were unable to determine whether any formulation was better or worse tolerated than any other. It has been suggested that using small regular doses of erythromycin can minimise adverse events.[591 Although this method could be useful in hospitalised patients, it is not clear whether it would provide any advantage in community practice because of its probable adverse consequences for compliance rates.

We noted that the majority of LRTI studies used doses of erythromycin greater than Ig daily. Therefore, it could be concluded that the reason for the apparently superior tolerability of roxithromycin was because the dosage of erythromycin was greater than is usually employed in clinical practice. However, our analysis of the adverse events reported in studies including patients with URTI and/or LRTI showed that the reported incidence of adverse events was not dosage related but appeared to be related to the formulation of erythromycin under investigation. In fact, the incidence of adverse events was lower for erythromycin 2g than for erythromycin I g. Therefore, there appears to be no evidence that erythromycin Ig is better tolerated than erythromycin 2g daily.

It is important to measure adverse events and withdrawals in routine clinical settings because the outcome of therapy will depend partly on compli-

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Milneetal.

ance, but also because the average cost of managing an infective episode will depend partially on reconsultation rates (RJM, unpublished model). Most of the studies were conducted in community practice, where information on adverse events and voluntary cessation of therapy in unselected patients is not collected routinely.

Clinical trials provide an estimate in a controlled environment with high internal validity. However, it is possible that the percentage of adverse events reported in clinical trials overestimates that experienced in usual community practice. For example, in a clinical trial, all patients are asked specific questions about adverse events and most patients would undergo routine review. Conversely, clinical trials are likely to underestimate the percentage of patients withdrawing from therapy because of the demands that the protocol places on both the physician investigators and the participating patients.

The place of antibacterial therapy in patients with CAP is well established.!I .3] However, an early study cast doubt on the usefulness of antibacterial therapy in acute bronchitis in otherwise healthy individuals,[60] and the debate continues[6I,62 1. It is arguable, therefore, whether antibacterial therapy is appropriate for a subset of the patients included in our analysis. Nevertheless, about one-third of the patients included in the trials that we reviewed had an initial diagnosis of acute bronchitis (table I), Moreover, a survey of general practitioners in New Zealand indicated that about three-quarters of patients with an initial diagnosis of acute bronchitis receive empirical antibiotic therapy, presumably for prophylaxis (RJM, manuscript in preparation),

Roxithromycin is to be preferred over erythromycin because of its more convenient dosage regimen and more favourable tolerability. Meanwhile, the place of antibacterial therapy in patients with acute bronchitis requires further review and possibly more education of prescribers, taking into account the complex nature of the doctor-patient interaction.!631



Conclusions

This pooled analysis of clinical trials showed that roxithromycin was considerably better tolerated than erythromycin, and fewer patients withdrew from therapy because of adverse events related to drug therapy. Most of these events were gastrointestinal in nature. Roxithromycin is, therefore, likely to be more effective than erythromycin in community practice because of higher compliance rates, in addition to causing fewer intolerable adverse effects for the patient with an LRTI. As a consequence, it is also likely to be associated with lower reconsultation rates for treatment failure and for management of troublesome gastrointestinal events.

Further research is needed on the role of antibacterial therapy in patients with acute isolated bronchitis, rates of withdrawal from therapy and reconsultation rates in community practice, and also on the tolerability of other first-line drug therapies for LRTIs.

Acknowledgements

The authors thank Trevor Speight for helpful comments. and Kerry Dechant and Anne Parrent for project management. Hoechst Marion Roussel provided funding for this study. The study selection, analysis, interpretation of results and manuscript were entirely under the control of the authors.

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Correspondence and reprints: Dr Richard 1. Milne, PO Box 60315, Titirangi, Auckland, New Zealand.


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Tolerability of Roxithromycin vs Erythromycin in Comparative Clinical Trials in Patients with Lower Respiratory Tract Infections