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Journal of Antimicrobial Chemotherapy (2000) 46, 255–262
Comparative efficacy of 5 days of dirithromycin and 7 days of
erythromycin in skin and soft tissue infections
Margaret M. Wasilewski*, Michael G. Wilson, Gregory D. Sides and Jennifer L. Stotka
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
We investigated the comparative efficacy and safety of dirithromycin and erythromycin in the
treatment of skin and soft tissue infections in this double-blind, randomized, multicentre study,
in which 439 patients were randomized to treatment with dirithromycin (500 mg daily for 5 days)
or erythromycin (250 mg every 6 h for 7 days). All randomized patients were included in the
termination analysis, which showed that 187 of 220 (85.0%) dirithromycin recipients and 177 of
219 (80.8%) erythromycin recipients were clinically cured or improved (95% confidence interval
(CI) 3.0% to 11.4%). In the termination analysis of the 211 bacteriologically evaluable
patients, clinical cure or improvement occurred in 83 of 100 (83%) dirithromycin recipients and
in 89 of 111 (80.2%) erythromycin recipients (95% CI 7.8% to 13.4%), and bacteriological
eradication occurred in 85 of 100 (85%) and 89 of 111 (80.2%), respectively. Adverse events
were similar in incidence and nature between the two groups, except that there was less nausea
with dirithromycin (3.6% versus 8.2%; P 0.042). Ten of 220 (4.5%) dirithromycin recipients and
27 of 219 (12.3%) erythromycin recipients returned >20% of their prescribed medication (P 0.033). In the treatment of skin and soft tissue infections, dirithromycin (500 mg daily for 5 days)
was comparable in efficacy to, and caused significantly less nausea than, erythromycin
(250 mg every 6 h for 7 days). Compliance with the dirithromycin regimen was superior to that
with the erythromycin regimen.
Introduction
Most common skin and soft tissue infections, including
impetigo, cellulitis, folliculitis, furuncles and carbuncles,
are caused by Staphylococcus aureus and group A streptococci.1–3 The penicillins, first-generation cephalosporins,
and macrolides are commonly used to treat uncomplicated
community-acquired skin and soft tissue infections because
of their historic activity against staphylococci and streptococci. However, resistant strains of staphylococci (β-lactamase-producing and/or non-β-lactamase-producing) are
now widespread.4
In the last decade, the fluoroquinolones emerged as
alternatives to the β-lactams for the treatment of skin and
soft tissue infections. However, factors limiting use of fluoroquinolones include: gastrointestinal and central nervous
system toxicity and the potential for arthropathy, which
precludes routine use in children and adolescents;5 high
cost relative to other orally administered alternatives; and
an unnecessarily broad spectrum of activity for most common community-acquired skin and soft tissue infections.6
Traditionally, erythromycin has been both a first-line
therapy and an alternative antibacterial agent for the treatment of patients who were sensitive to, or intolerant of,
β-lactams. However, adverse gastrointestinal effects, poor
absorption resulting in unpredictable serum and tissue
concentrations, and clinically significant drug interactions
are limiting factors.
Dirithromycin is a 14-membered ring macrolide antibacterial agent, which is rapidly converted to its active
form, erythromycylamine, by non-enzymatic hydrolysis
during absorption. The antimicrobial spectra of dirithromycin and erythromycylamine are similar to that of erythromycin in vitro, with a reported potency ranging from
two- to four-fold less active7 to two-fold more active8 against
Gram-positive bacteria. Dirithromycin is highly active
against streptococci, with an MIC90 of 0.25 mg/L being
reported for Streptococcus pyogenes.9 Dirithromycin is also
active against S. aureus, with an MIC90 of 4.0 mg/L, and
Staphylococcus epidermidis, with an MIC90 of 1.0 mg/L.9
Dirithromycin has more favourable pharmacokinetics
than erythromycin, and therefore has potential clinical
*Corresponding author. Tel: 1-317-276-6291; Fax: 1-317-276-9666; E-mail: [email protected]
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© 2000 The British Society for Antimicrobial Chemotherapy
M. M. Wasilewski et al.
advantages.10 Dirithromycin has a terminal half-life of 44 h
(range 16–65 h) following a 500 mg oral dose,11 allowing for
once-daily administration. The volume of distribution of
dirithromycin at steady state is 5 L/kg. Tissue concentrations peak between 5 and 10 h after a dose and gradually
redistribute into serum, resulting in a tissue half-life of
20 h. Thus, tissue concentrations are maintained well in
the range of the MICs for susceptible organisms for at least
24 h after a single oral dose.12,13 Additionally, dirithromycin
is not a competitor of the cytochrome P450 system, and
thus has low propensity for drug interactions.14 Dirithromycin for 7 days has been shown to be effective in the treatment of skin and soft tissue infections.10
The objective of this study was to compare the efficacy
and safety of dirithromycin 500 mg daily for 5 days with
erythromycin 250 mg every 6 h for 7 days in the treatment
of skin and soft tissue infections. Patient compliance with
the once-daily dirithromycin regimen as compared with the
four-times-daily erythromycin regimen was also assessed.
Materials and methods
Study design
This was a double-blind, double-dummy, randomized, multicentre study with two parallel arms. Thirty-one physicians,
who specialized in family practice, dermatology and internal medicine, participated in this study. Patients were randomized to receive either dirithromycin or erythromycin.
Patients in the dirithromycin treatment group received a
total daily dose of 500 mg, given as a single dose of two 250
mg tablets per day for five consecutive days. These patients
also received dummy tablets resembling erythromycin,
given as one tablet every 6 h for seven consecutive days.
Patients in the erythromycin treatment group received a
total daily dose of 1000 mg of erythromycin base, given as
one 250 mg tablet every 6 h for seven consecutive days.
These patients also received dummy tablets resembling
dirithromycin, given as a single dose of two tablets per day
for five consecutive days. Dirithromycin or its dummy was
taken orally with, or immediately after, a meal. Erythromycin or its dummy was taken orally 1 h before meals
and at bedtime. Almedica Drug Labeling System (ADLS)
labels were used to identify the medication kits and bottles.
All bottles with any remaining tablets were returned by the
patient at the post-therapy visit, and the remaining tablets
were counted. Patients were defined as compliant if they
took 80% of tablets dispensed.
A complete history, physical examination and culture of
the infected site were performed at a pretherapy visit
(within 24 h before the first dose of study medication).
Patients with abscesses received surgical treatment as
deemed necessary by the investigator. Physical examination and follow-up history were performed on days 3–5
of study medication, 3–5 days after the end of study
medication (post-therapy visit) to evaluate clinical response
to therapy, and 10–14 days after the end of study medication (late post-therapy visit) to evaluate recurrence of
infection. Repeat skin or tissue cultures were performed at
these visits, if clinically indicated.
Patient population
Patients aged 12 years, weighing at least 37 kg, and with a
culturable bacterial infection of the skin and/or soft tissue
were eligible for inclusion. Eligible bacterial infections
included subcutaneous abscess, impetigo, pyoderma, skin
ulcer (excluding decubitus and venous stasis ulcers, and
ulcers below the knees in diabetic patients), post-surgical
or traumatic wound infections, cellulitis or erysipelas and
lymphangitis. Postpartum, nursing and pregnant women
were excluded, and women of childbearing potential must
have used a reliable method of birth control during, and for
30 days following completion of therapy. Other exclusion
criteria included: the presence of any condition that could
have precluded evaluation of response; any known or
anticipated use of systemic or topical antimicrobials (other
than as prescribed in the study) from 7 days before enrolment until the post-therapy evaluation; hypersensitivity to
macrolide antibiotics; and use of oral or intravenous corticosteroids. Informed consent, approved by the institutional
review board, was signed by each patient or their legal
guardian.
Clinical efficacy analysis
All data were collected at the investigational site and
analysed by Eli Lilly. Patients were considered clinically
evaluable if they met enrolment criteria, had appropriate
examinations before and after therapy and met standards
for minimum compliance (no minimum compliance was
required for a clinical response of relapse or failure, or for
safety evaluation). Clinical response was assessed by the
investigator based on signs and symptoms. Response
definitions were as follows: (i) cure, elimination of all signs
and symptoms of infection with no recurrence within the
follow-up period; (ii) improvement, significant, but incomplete, resolution of signs or symptoms of infection; (iii)
relapse, worsening of signs and symptoms of infection
following initial improvement; relapse must have been
preceded by at least one clinical assessment (either during
or following therapy) of cure or improvement; (iv) failure,
signs and symptoms did not subside or improve with therapy; a patient requiring the addition of another antibiotic
for the study indication during the expected period of study
drug administration was classified as a clinical failure; (v)
unable to evaluate, unable to evaluate a clinical response
because of premature discontinuation, lack of post-therapy
evaluation, poor compliance or other extenuating circumstance; this response disqualified a patient for efficacy
analysis but not for safety analysis.
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Dirithromycin and erythromycin in SSTI
Bacteriological efficacy analysis
To qualify for the bacteriological evaluation, a patient must
have met all qualifications for clinical evaluation, and the
patient’s pretherapy culture had to be positive for a pathogen. While susceptibility to the study medication(s) was not
a criterion for bacteriological evaluability, sensitivities15,16
were determined. Bacteriological response was assessed by
the investigator based on culture results.17
Safety analysis
All patients who gave consent to participate and were
randomized to a treatment group were included in the
safety analysis. At each visit, patients and/or guardians
were asked open-ended questions regarding the occurrence and nature of any clinical adverse event and were
instructed to contact the investigator should an adverse
event occur. Haematology, blood chemistry and urine tests
were performed at the visits before and after therapy, and
at the late post-therapy visit, if clinically indicated. Adverse
events were classified using the US Food and Drug Administration Coding Symbol Thesaurus for Adverse Reaction
Terms (COSTART) and categorized by body system.
Statistical analysis
Statistical analyses were performed at two time points:
after therapy and at termination. The termination analysis
was based on the results of the late post-therapy visit
(10–14 days after the end of study medication). However,
if a patient had a clinical response of failure at the posttherapy visit (3–5 days after the end of study medication),
or discontinued before the post-therapy visit, a late posttherapy response was not obtained. In this case, the
response for that patient at the earlier visit was used in the
termination analysis. All eligible patients were included in
the clinical and bacteriological analyses.
2 tests and confidence intervals were used to compare
clinical and bacteriological response rates between treatment groups. 2 tests also were used to compare adverse
event frequencies between treatment groups. Appropriate
continuous data procedures, such as t-tests, were used for
the analysis of laboratory-monitoring data to test for
significant changes from baseline values both within and
between treatment groups.
The general association Cochran–Mantel–Haenszel
statistic was used to compare differences between treatment groups across investigators. Investigators who enrolled
fewer than eight patients were pooled.
Results
Patient population
Two hundred and twenty patients were randomized to the
dirithromycin group and 219 to the erythromycin group.
Approximately half of all patients had a diagnosis of
subcutaneous abscess. The other most frequent diagnoses
were traumatic wound infection, cellulitis and pyoderma.
The two groups were well matched with respect to demographics and baseline clinical parameters (Table I).
Of the 220 dirithromycin recipients, 187 were clinically
evaluable; 100 of the latter were also bacteriologically
evaluable. Of the 219 erythromycin recipients, 184 were
clinically evaluable; 111 of the latter were also bacteriologically evaluable. The main reasons for clinical unevaluability were premature discontinuation because of lack
of susceptibility of the pretreatment isolate to the study
drug (before a protocol amendment negating this criterion)
and loss to follow-up. The main reason for bacteriological
unevaluability was failure to identify a pathogen.
One hundred and sixty-eight of 220 dirithromycin recipients and 175 of 219 erythromycin recipients completed the
protocol. Of patients who did not complete the protocol,
19 of 52 dirithromycin recipients and 15 of 44 erythromycin
recipients discontinued because of lack of efficacy.
Termination efficacy analyses
Termination analysis of all patients. In the termination
analysis, a favourable clinical response (cure or improvement) was seen in 187 of 220 (85.0%) dirithromycin recipients and in 177 of 219 (80.8%) erythromycin recipients
(95% confidence interval (CI) for the difference between
proportions 3.0% to 11.4%) (Table II). A statistically
significant advantage for dirithromycin was demonstrated
between treatment groups in the distribution of clinical
responses (Pearson 2 10.933, four degrees of freedom
(DF), P 0.027). A favourable bacteriological response
(eradication or presumptive eradication) was seen in 146
of 220 (66.4%) dirithromycin recipients and 139 of 219
(63.5%) erythromycin recipients (95% CI 6.2% to
12.0%). There was no statistically significant difference
between the treatment groups in the distribution of bacteriological responses in all patients at termination (Pearson
2 7.593, 4 DF, P 0.108).
Termination analysis of bacteriologically evaluable patients.
In the termination analysis of bacteriologically evaluable
patients, a favourable clinical response (cure or improvement) was seen in 83 of 100 (83.0%) dirithromycin recipients and in 89 of 111 (80.2%) erythromycin recipients (95%
CI 7.8% to 13.4% (Table III), but this was not statistically significant (Pearson 2 6.783, 3 DF, P 0.079). A
favourable bacteriological response (eradication or presumed eradication) was seen in 85 of 100 (85%) dirithromycin recipients and 89 of 111 (80.2%) erythromycin
recipients (95% CI 5.6% to 15.2%), but this difference
also was not statistically significant. (Pearson 2 5.511,
3 DF, P 0.138), and results determined for the clinically
evaluable population were comparable to those for the
bacteriologically evaluable population.
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M. M. Wasilewski et al.
Table I. Demographic and baseline characteristics of the dirithromycin and erythromycin
treatment groups
Parameter
Gender
male
female
Mean age (years)
Race
Caucasian
Black
Hispanic
Native American
Asian
other
Mean height (cm)
Mean weight (kg)
Presenting diagnosis
subcutaneous abscess
traumatic wound infection
cellulitis
pyoderma
impetigo
post-operative wound infection
infected skin ulcer
lymphangitis
erysipelas
Dirithromycin (n 220)
Erythromycin (n 219)
123 (55.9%)
97 (44.1%)
42.2 (range 13–92)
113 (51.6%)
106 (48.4%)
41.5 (range 12–86)
176 (80.0%)
26 (11.8%
16 (7.3%)
1 (0.5%)
1 (0.5%)
0
170.6
78.6
168 (76.7%)
20 (9.1%)
25 (11.4%)
3 (1.4%)
2 (0.9%)
1 (0.5%)
171.0
79.5
110 (50.0%)
24 (10.9%)
28 (12.7%)
30 (13.6%)
11 (5.0%)
14 (6.4%)
2 (0.9%)
1 (0.5%)
0
114 (52.1%)
31 (14.2%)
26 (11.9%)
15 (6.8%)
15 (6.8%)
9 (4.1%)
6 (2.7%)
2 (0.9%)
1.(0.5%)
Correlation of clinical and bacteriological responses
revealed that 82 of 100 (82%) dirithromycin recipients and
89 of 111 (80.2%) erythromycin recipients had both a
favourable clinical and a favourable bacteriological
response. Fourteen of 17 dirithromycin recipients and all
22 erythromycin recipients who had unfavourable clinical
responses also had persistence or presumed persistence of
the pathogen.
Post-therapy efficacy analyses
Results of efficacy analyses of data from the post-therapy
evaluations (performed 3–5 days after the end of study
medication) were similar to those for the termination
analyses.
There was no statistically significant difference between
the treatment groups in the distribution of clinical
responses (Pearson 2 3.171, 4 DF, P 0.530) or bacteriological responses (Pearson 2 4.807, 6 DF, P 0.569) for all
patients at the post-therapy visit.
In addition, the general association Cochran–Mantel–
Haenszel statistic across investigators showed no statistically significant difference between treatment groups in the
distribution of clinical responses (2 3.554, 4 DF, P 0.470)
or bacteriological responses (2 5.847, 6 DF, P 0.441) for
all patients at the post-therapy visit.
Post-therapy analysis of bacteriologically evaluable patients
by diagnostic subgroup. Post-therapy clinical and bacteriological results were analysed by diagnostic subgroup and
were broadly similar between the two treatment groups. Of
the patients with subcutaneous abscesses, who accounted
for more than half of all bacteriologically evaluable patients,
48 of 54 (88.9%) dirithromycin recipients and 57 of 61
(93.4%) erythromycin recipients had a favourable clinical
outcome. Thirty-nine of 54 dirithromycin recipients and 47
of 61 erythromycin recipients with abscesses underwent
incision and drainage. There was no statistically significant
difference in the proportions of favourable clinical responses
between treatment groups after controlling for the effects
of incision and drainage of subcutaneous abscess (Cochran–
Mantel–Haenszel general association 2 0.536, 1 DF, P 0.464).
Bacteriological eradication
S. aureus was isolated from most infections before treatment and was eradicated or presumed eradicated from 44
of 56 (78.6%) dirithromycin recipients and from 48 of 59
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Table II. Termination analysis: clinical and bacteriological responses in all patients
Number of patients (%)
Response
Clinical
favourable
cure
improvement
total
unfavourable
relapse
failure
total
Bacteriological
favourable
eradication
presumed eradication
total
unfavourable
presumed persistent
persistence
total
dirithromycin (n 220)
erythromycin (n 219)
95% CIa
141 (64.1%)
46 (20.9%)
187 (85.0%)
151 (68.9%)
26 (11.9%)
177 (80.8%)
13.9% to 4.1%
3.0% to 11.4%
13 (5.9%)
16 (7.3%)
29 (13.2%)
23 (10.5%)
11 (5.0%)
34 (15.5%)
2.3% to 6.8%
9.0% to 4.4%
5 (2.3%
141 (64.1%)
146 (66.4%)
0
139 (63.5%)
139 (63.5%)
6.2% to 12.0%
14 (6.4%)
8 (3.6%)
22 (10.0%)
17 (7.8%)
15 (6.8%)
32 (14.6%)
a
These are the lower and upper bounds for the 95% CIs for the true differences between treatment groups, percentage of dirithromycintreated patients minus percentage of erythromycin-treated patients. Since these confidence intervals contain 0, there are no statistically
significant differences.
Table III. Termination analysis: clinical and bacteriological responses in bacteriologically evaluable patients
Number of patients (%)
Response
Clinical
favourable
cure
improvement
total
unfavourable
relapse
failure
total
Bacteriological
favourable
eradication
presumed eradication
total
unfavourable
presumed persistent
persistence
total
dirithromycin (n 100)
erythromycin (n 111)
95% CIa
74 (74.0%)
9 (9.0%)
83 (83.0%)
86 (77.5%)
3 (2.7%)
89 (80.2%)
15.3% to 8.3%
7 (7.0%)
10 (10.0%)
17 (17.0%)
15 (13.5%)
7 (6.3%)
22 (19.8%)
3.9% to 11.3%
13.40% to 7.8%
4 (4.0%)
81 (81.0%)
85 (85.0%)
0
89 (80.2%)
89 (80.2%)
5.6% to 15.2%
11 (11.0%)
4 (4.0%)
15 (15.0%)
14 (12.6%)
8 (7.2%)
22 (19.8%)
a
7.8% to 13.4%
These are the lower and upper bounds for the 95% CIs for the true differences between treatment groups, percentage of dirithromycin
recipients minus percentage of erythromycin recipients. Since these confidence intervals contain 0, there are no statistically significant differences.
259
M. M. Wasilewski et al.
Table IV. Bacteriological eradication rates (proven or presumed)
Number eradicated/total isolated
Pathogens
dirithromycin
erythromycin
44/56
8/8
5/5
3/3
2/2
1/1
1/1
5/6
16/18b
48/59
12/13
5/5
2/3
1/1
2/2
–
0/1
19/27c
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus group A
Enterococcus
Streptococcus group G
Streptococcus group B
Streptococcus group C
Gram-negative organismsa
Multiple organisms
a
Pseudomonas aeruginosa, Enterobacter agglomerans, Klebsiella pneumoniae, Proteus
mirabilis, Serratia marcescens, Haemophilus influenzae.
b
Multiple pathogens persisted or were presumed to have persisted in two patients:
S. aureus, K. pneumoniae and Morganella morganii in one patient, and S. aureus and
Citrobacter sp. in the other patient. Both patients were clinical failures.
c
Multiple pathogens persisted or were presumed to have persisted in six patients,
all of whom had unfavourable clinical responses: S. aureus and streptococcus group
G; S. aureus and S. epidermidis; S. epidermidis and Enterobacter cloacae; S. aureus and
streptococcus group B; S. aureus and streptococcus group A; and streptococcus group B
and enterococcus, plus P. mirabilis. In two patients, one of two pathogens was eradicated
while the other (S. aureus and P. mirabilis, respectively) persisted; both patients had
unfavourable clinical responses.
Table V. Adverse events reported by at least 2% of
patients during the period of study drug administration,
regardless of relationship to treatment
(81.3%) erythromycin recipients infected with a single
pathogen (Table IV).
Safety analysis
A total of 167 adverse events were reported by 92 of 220
(41.8%) dirithromycin recipients, and 182 events were
reported by 96 of 219 (43.8%) erythromycin recipients
(P 0.669). The events reported most frequently in both
groups were headache and symptoms associated with the
digestive system (abdominal pain, diarrhoea, dyspepsia
and nausea). Nausea was reported by a significantly lower
proportion of dirithromycin recipients (3.6%) than of
erythromycin recipients (8.2%) (P 0.042). Adverse events
reported in at least 2% of patients, regardless of relationship to study drug, are listed in Table V.
No deaths were reported during the course of the study.
Four serious adverse events occurred, none of which was
related to study drug administration. In dirithromycin recipients, one case each of cellulitis and apnoea secondary to
congestive heart failure occurred, and in erythromycin recipients, one case each of cellulitis and myocardial infarction
occurred. Four patients in each treatment group discontinued treatment early because of adverse events considered
to be related to the study drug. In the dirithromycin group,
these events were diarrhoea, stomach pain, nausea and rash.
In the erythromycin group, these events were vomiting,
nausea (two patients) and gastrointestinal discomfort.
Number of patients (%)
Event
Abdominal pain
Diarrhoea
Headache
Dyspepsia
Nausea
Pain
dirithromycin
(n 220)
18 (8.2%)
14 (6.4%)
12 (5.5%)
11 (5.0%)
8 (3.6%)
4 (1.8%)
erythromycin
(n 219)
17 (7.8%)
20 (9.1%)
13 (5.9%)
4 (1.8%)
18 (8.2%)
9 (4.1%)
P
0.871
0.278
0.828
0.067
0.042
0.157
Analysis of clinical laboratory data revealed no statistically significant differences between the treatment populations in mean values and no clinically significant alterations
in laboratory parameters that were attributed to study
drug.
Compliance
Ten of 220 patients (4.5%) in the dirithromycin group and
27 of 219 (12.3%) patients in the erythromycin group
returned 20% of their prescribed medication. Comparison
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Dirithromycin and erythromycin in SSTI
of treatment groups, using active therapy as the denominator, revealed a statistically significant difference in the distribution of percentage of drug returned (Pearson 2 12.12,
5 DF, P 0.033). However, when treatment groups were
compared with respect to percentage of drug returned
using total number of tablets (active and placebo) dispensed as the denominator, similar results were seen
between groups.
Discussion
In this double-blind, randomized, multicentre study, dirithromycin (500 mg daily for 5 days) was as effective as
erythromycin (250 mg q 6h for 7 days) for skin and soft
tissue infections. Thus, a shorter course of once-daily
therapy with dirithromycin demonstrated efficacy similar
to conventional therapy with erythromycin.
These results support the findings of Derriennic &
Escande,18 who reported no statistically significant differences in clinical or bacteriological efficacy between
dirithromycin 500 mg daily for 7 days and erythromycin
250 mg q 6h for 7 days in two large double-blind, randomized, multicentre studies of skin and soft tissue infections.
The first study, conducted in North America, evaluated 156
patients treated with dirithromycin and 127 patients
treated with erythromycin. Post-therapy responses were
identical between the two treatment groups, with 94% of
patients clinically cured or improved and 87% of infecting
pathogens eradicated. At the late post-therapy evaluation,
132 of 135 (97.8%) dirithromycin recipients and 104 of 114
(91.2%) erythromycin recipients were clinically cured or
improved, while the pathogen was eradicated from 126
(93.3%) and 99 (86.8%) patients, respectively. The second
study, conducted in Europe, evaluated a total of 100
dirithromycin recipients and 99 erythromycin recipients.
More than 95% of patients in each group had a favourable
clinical response at both the post-therapy and late posttherapy evaluations. Favourable bacteriological responses
were achieved by 87 of 100 (87%) dirithromycin recipients
and 88 of 99 (89%) erythromycin recipients post-therapy,
and by 87 of 91 (95.6%) and 84 of 92 (91.3%) recipients,
respectively, at the late post-therapy evaluation.
In the present study, headache and gastrointestinal
symptoms were reported by a lower proportion of dirithromycin recipients (3.6%) than erythromycin recipients
(8.2%) (P 0.042). In the two studies reported by
Derriennic & Escande,18 nausea was also less common with
dirithromycin therapy (1.6% and 5.6%) than with erythromycin therapy (2.0% and 7.3%), although this difference
was not statistically significant.
Failure to comply with the prescribed treatment regimen
is a common cause of treatment failure and represents a
significant cost to healthcare systems by leading to recurrence of illness, additional physician and pharmacy visits,
and hospital admission.19 The present study shows an
improvement in patient compliance with dirithromycin.
Studies have reported that compliance decreases with
increased frequency of administration and that as many as
60% of patients do not comply with four-times-daily
administration regimens.20,21 To improve patient compliance, Feldman & DeTullio19 recommend selecting treatments that have the least likelihood of causing adverse
effects and that can be administered once daily. Thus, the
less frequent dosing of dirithromycin may explain some of
the increased compliance in dirithromycin recipients. In
this study, in which the patients took the same number of
pills over a 7 day period, dirithromycin recipients had a
higher compliance than erythromycin recipients. Also, the
higher compliance in dirithromycin recipients may be
explained by the lower incidence of nausea (3.6% versus
8.2%; P 0.042).
For patients with skin and soft tissue infections not
requiring hospitalization, cephalosporins, macrolides and
β-lactam penicillins provide coverage for the usual pathogens, S. aureus and S. pyogenes. When clinical and bacteriological efficacy are equivalent, few side effects and ease of
administration are attractive to physicians and patients
because they should enhance compliance and diminish
adverse events. Thus, in the treatment of skin and soft
tissue infections, dirithromycin 500 mg daily for 5 days is at
least therapeutically equivalent in efficacy to, and causes
significantly less nausea than, erythromycin 250 mg every
6 h for 7 days. In addition, dirithromycin’s once-daily
dosing may enhance patient compliance.
Acknowledgements
The authors wish to thank Karen Burkey, Sarah Nehrt and
Michael Benton, PhD for preparation of the manuscript.
This work was supported by Eli Lilly and Company,
Indianapolis, IN, USA.
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Received 13 August 1999; returned 22 October 1999; revised
28 February 2000; accepted 20 March 2000
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