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Abstract
Macrolides are not used exclusively for the treatment of community-acquired respiratory tract infections. Their ability to
penetrate cells makes them highly suitable for the treatment of diseases caused by intracellular pathogens, such as non-gonococcal
urethritis and trachoma. Azithromycin is approved for these indications. Clinical studies have also been conducted, or are
currently being carried out, to assess the use of macrolides in the treatment of atherosclerosis, eradication of Helicobacter pylori
and the management of life-threatening gastrointestinal diseases, cystic fibrosis and malaria. 2001 Published by Elsevier Science
B.V. on behalf of the International Society for Chemotherapy.
Keywords: Macrolides; Azithromycin; Non-gonoccoccal urethritis; Trachoma; Atherosclerosis; Peptic ulcer; Helicobacter pylori; Malaria; Cystic
fibrosis; Shigellosis; Typhoid
1. Introduction
3. Trachoma
Trachoma is one of worlds leading causes of blindness in developing countries. Childrens eyelids become
infected with C. trachomatis at an early age and are
repeatedly reinfected. Infections are often passed from
one child to another on the hands when the eyes are
rubbed, or the microorganism is transported by flies.
Gradually, the conjunctiva and eyelids becomes scarred
after successive infections and turn in, leading to damage of the cornea. The continued abrasion of the cornea
eventually results in loss of sight.
Until recently, the treatment of trachoma was inconvenient, and in many cases impractical. An oily suspension of oxytetracycline needed to be applied to the eyes
for prolonged periods of time. To achieve correct application of the ointment, it should ideally be administered
by trained personnel. Also, the ointment needs to be
refrigerated between applications to avoid loss of potency; such facilities are often not available in countries
where trachoma is endemic. Also, if the ointment from
a tube is applied to the eyes of more than one patient,
there is the possibility of further transmission of the
infection.
The first report of the effective treatment of trachoma using a single oral dosing regimen was an
important advance in the prevention of blindness [5]. In
a randomised single-blind study, azithromycin at a dose
2. Non-gonococcal urethritis
Using azithromycin, urethritis caused by Chlamydia
trachomatis can be effectively treated with a single oral
dose. Clinical studies have shown that a 1 g
azithromycin dose is as effective as a 7-day course of
doxycycline 100 mg administered twice daily [1 4]. The
oral single-dose regimen eliminates any problem of
patient compliance and is more satisfactory than an
intramuscular injection of ceftriaxone, the alternative
single-dose therapy.
0924-8579/01/$20 2001 Published by Elsevier Science B.V. on behalf of the International Society for Chemotherapy.
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of 20 mg/kg was compared with conventional treatment involving 6 weeks of topical tetracycline (with
the addition of erythromycin for severe cases) in children living in two villages in The Gambia where trachoma was endemic. By the 6 months follow-up,
trachoma had been resolved in 78% of the subjects
treated with azithromycin and 72% of those who had
received conventional treatment were cured. Other
randomised, controlled studies confirmed the efficacy
of single-dose oral azithromycin [6,7]. The significance
of these findings has been recognised by the World
Health Organisation, and azithromycin is now being
used as part of the SAFE strategy worldwide in order
to eradicate blinding trachoma [8].
4. Atherosclerosis
Based on the findings of over 20 studies, there is
epidemiological evidence for serological link between
Chlamydia pneumoniae and atherosclerosis [9]. Vascular cells and macrophages have been shown to be
infected with viable C. pneumoniae in samples obtained from patients with progressive coronary artery
disease [10,11]. In rabbits infected with C. pneumoniae
and reinfected 3 weeks later, inflammatory changes in
their aortas have been detected [12]. In the following
2 4 weeks, intima media thickening or fibroid
plaques resembling atherosclerosis were observed. In
rabbits infected with C. pneumoniae, the administration of azithromycin soon after the infection prevented the formation of aortic lesions [13]. There
have also been numerous studies that have detected
C. pneumoniae in atherosclerotic lesions of patients,
whereas the microorganism was infrequently detected
in non-atheromatous arteries [14].
Meier et al. speculated that, if a causal relationship
exists between C. pneumoniae and cardiovascular
events, individuals who used antibiotics that were effective against this organism should be at lower risk
of developing acute myocardial infarctions than nonusers [15]. They conducted a retrospective study in
3315 patients aged 75 years or younger with a diagnosis of first-time acute myocardial infarction between
1992 and 1997, and in 13 139 controls without myocardial infarction matched to cases according to age,
sex, general practice attended and calendar time.
Their study found that the myocardial infarction patients were significantly less likely than the control
subjects to have received treatment using agents that
were effective against C. pneumoniae (specifically tetracyclines or quinolones). Previous use of erythromycin,
sulphonamides,
penicillins,
or
cephalosporins was not associated with any reduction
in the incidence of myocardial infarction.
A pilot clinical study has been conducted to compare the effect of roxithromycin and placebo on the
incidence of recurrent major ischaemic events in patients with unstable angina or non-Q-wave myocardial
infarction [16]. Patients were randomised to receive
twice-daily oral treatment with roxithromycin 150 mg
or placebo for 30 days and were followed up for 6
months. It was found that roxithromycin use resulted
in a statistically significant reduction in the primary
composite triple endpoint rates, the incidences of
severe recurrent ischaemia; myocardial infarction and
ischaemic death, respectively, were 5.4, 2.2 and 2.2%
in the placebo group, and 1.1, 0 and 0% in the roxithromycin group. From these observations, the authors concluded that, in addition to standard
cardiovascular medication, antichlamydial antibiotics
may be useful in therapeutic intervention for patients
with coronary artery disease. The study, however, had
many design faults, the main one being that positive
serology in the patients was not determined.
A second, more carefully designed study conducted
by Gupta and coworkers examined the relationship
between antibodies against C. pneumoniae and future
cardiovascular events in male survivors of myocardial
infarction [17]. In a subgroup of these patients, the
effect of azithromycin on further cardiovascular
events was also evaluated. The study confirmed that
the incidence of adverse cardiovascular events occurring over a mean follow-up period of 189 4 months
increased with an increasing anti-C. pneumoniae titre.
The study also established that the odds ratio for a
cardiovascular event in seropositive (] 1/64 titre) patients who had received azithromycin 500 mg once
daily for 3 or 6 days was the same as that in patients
who were seronegative.
Further large-scale clinical studies using macrolides
are currently being carried out. Additional studies are
also required to confirm the eradication of the organism from within the arterial wall.
5. Peptic ulcers
In vitro studies have shown that the macrolides are
effective against Helicobacter pylori [18]. Clinical trials
have also demonstrated that clarithromycin can eradicate the organism from patients with peptic ulcers
when used in association with another active antimicrobial agent and a proton-pump inhibitor [1921].
However, this therapy is of no benefit in the management of non-ulcer dyspepsia [22]. Macrolide resistance
is uncommon in H. pylori, but may have a significant
impact in individual patients receiving triple therapy
[23].
MIC90 (mg/l)
Campylobacter species
E. coli
Shigella species
Salmonella species
Salmonella typhii
0.125
2
1
4
1
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authors suggested that azithromycin may provide alternative treatment for typhoid when resistance to ampicillin, chloramphenicol and trimethoprim/sulphamethoxazole is suspected.
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8. Malaria
Extensive chloroquine resistance in Plasmodium falciparum has complicated the treatment of this form of
malaria. In vitro studies and animal models have shown
that azithromycin is active against P. falciparum, including chloroquine-resistant strains [43,44].
When azithromycin was administered to children in
The Gambia for the control of trachoma [5], a favourable effect was observed in children with concurrent malaria. Azithromycin 20 mg/kg given once weekly
for 3 weeks reduced the proportion of parasites [45].
Also, fever subsided and spleen size was reduced in
azithromycin-treated children. The preliminary data
demonstrating the efficacy of azithromycin need to be
confirmed by conducting large-scale studies.
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