International Journal of Antimicrobial Agents 18 (2001) S93 S97

www.ischemo.org

New perspectives on macrolide antibiotics

J.-C. Peche`re *
Department of Genetics and Microbiology, Uni6ersity Medical Centre, CMU, 1 Rue Michel Ser6et, CH-1211 Gene6a 4, Switzerland

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

The broad spectrum of activity of macrolides against

the Gram-positive and Gram-negative respiratory
pathogens has lead to their widespread acceptance for
the treatment of community-acquired respiratory
pathogens. Activity against other pathogens, and in
particular against intracellular microorganisms, means
that they have alternative uses.

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.

* Tel.: +41-22-702-5656; fax: +41-22-346-7237.

E-mail address: pechere@cmu.unige.ch (J.-C. Peche`re).

0924-8579/01/$20 2001 Published by Elsevier Science B.V. on behalf of the International Society for Chemotherapy.
PII: S 0 9 2 4 - 8 5 7 9 ( 0 1 ) 0 0 3 9 3 - 4

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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].

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6. Gastrointestinal infectious diseases

There are three features of azithromycin that suggest
it may be effective against certain serious gastrointestinal infectious diseases. Firstly, azithromycin displays a
degree of activity against Enterobacteriaceae, including
enterotoxigenic, enterohaemorrhagic, enteroinvasive
and enteropathogenic strains of Escherichia coli and
Shigella species (Table 1) [24]. Secondly, the primary
route of excretion of azithromycin is in faeces [25].
Thirdly, azithromycin achieves good cell penetration
with high intracellular levels [26]. Thus, azithromycin
may be a suitable agent for the treatment of gastrointestinal infectious diseases caused by pathogens,
such as Shigella and Salmonella species, that display a
significant intracellular step in their pathogenicity.
In a double-blind clinical trial conducted in
Bangladesh, the efficacy of azithromycin was compared
with that of ciprofloxacin [27]. The dosing regimen for
azithromycin was 500 mg on study day 1, followed by
250 mg once daily for the 4 subsequent days, and the
patients assigned to ciprofloxacin treatment received
500 mg once every 12 h for 5 days. The clinical success
rates for azithromycin and ciprofloxacin were 82 and
89%, respectively. Bacteriological eradication was
achieved in 94% of patients treated with azithromycin
compared with 100% in the ciprofloxacin treatment
group. Because of the increasing incidence of
quinolone-resistant strains of Shigella, the availability
of alternative therapy for a potentially life-threatening
disease may be very important in the future.
Azithromycin has also been shown, in a study conducted in Egypt, to be highly effective against typhoid
fever [28]. Multiple-drug-resistant isolates were obtained prior to treatment in over 30% of the patients
included in this open-label study. Patients in the
azithromycin treatment group received a single oral
dose of 1 g on the first day, followed by 500 mg given
orally once daily on the next 6 days. Ciprofloxacin was
administered orally as a 500-mg dose, given twice daily,
for 7 days. All patients responded favourably to treatment. Defervescence occurred 3.891.0 days after the
start of azithromycin therapy and 3.39 1.0 days after
the first dose of ciprofloxacin. Cultures of blood and
stools after therapy were negative in all patients. The
Table 1
In vitro activity of azithromycin against enteric pathogens [23]
Species

MIC90 (mg/l)

Campylobacter species
E. coli
Shigella species
Salmonella species
Salmonella typhii

0.125
2
1
4
1

S95

authors suggested that azithromycin may provide alternative treatment for typhoid when resistance to ampicillin, chloramphenicol and trimethoprim/sulphamethoxazole is suspected.

7. Pseudomonas aeruginosa, diffuse panbronchiolitis

and cystic fibrosis
Prolonged treatment at low doses with 14- or 15membered-ring macrolides has been shown to be beneficial to patients with diffuse panbronchiolitis (DPB), a
lethal disease in which lung chronic superinfections
with P. aeruginosa significantly reduce life expectancy
[29]. It has been postulated that the beneficial effects of
macrolides in DPB could be related to the anti-inflammatory activity of these compounds [29]. In particular,
azithromycin produced modest, but significant reductions in markers of inflammation in patients with
chronic coronary artery diseases [30]. Macrolides also
inhibited nitric oxide generation by rat pulmonary alveolar macrophages [31]. The 14- and 15-membered-ring
macrolides also exert anti-pseudomonal activity [32].
Tateda and coworkers showed that, after exposure to
clinically achievable concentrations of azithromycin for
48 h, there was significant reduction in P. aeruginosa
viability in mucoid and non-mucoid strains [33]. They
also found that 4 mg/l azithromycin inhibited protein
synthesis after as little as 12 h and that protein synthesis continued to decrease in a time-dependent manner.
Other studies have shown that the macrolides depressed
the production of virulence exoproducts, including lactase, protease, haemagglutinins, lecithinase, DNase, exotoxin A and pyocyanin [3436]. At subinhibitory
concentrations where the growth rate and protein synthesis of the organism did not seem to be affected, the
production of biofilm was suppressed by macrolides
[3739]. Reduced biofilm production is associated with
enhanced serum sensitivity [32] and phagocytosis by
polymorphonuclear leucocytes [40]. The beneficial effects of adjunctive azithromycin have been demonstrated in a mouse model by Nicolau et al. [41].
Although timekill methodology noted no appreciable
improvement in bactericidal activity of ceftazidime
when azithromycin was added, the mouse model
showed that the addition of azithromycin significantly
improved survival compared with treatment with ceftazidime alone.
All these observations have prompted investigators
to test the impact of prolonged macrolide therapy in
patients with cystic fibrosis and lung superinfection
with P. aeruginosa. At present, there are three published open-label studies (but no randomised controlled
trials) that have evaluated the use of macrolide antibiotics in the treatment of chest infection in patients with
cystic fibrosis [42]. Randomised trials, with clear out-

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come measures, are needed to evaluate properly this

potentially useful treatment of cystic fibrosis.

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.

9. Future use of macrolides and resistance

If current studies evaluating the effectiveness of
macrolides in reducing the incidence of cardiovascular
events prove successful, there will be an inevitable
expanded use of macrolides. It would be unethical to
restrict the use of a drug that significantly improved a
patients prognosis. Under these circumstances, there is
theoretically the potential for resistance to develop.
A study conducted in children found that, when
erythromycin or clarithromycin was used to treat community-acquired pneumonia, eradication of C. pneumoniae from the nasopharynx was 86 and 79%,
respectively. In vitro testing of the persistent organisms
showed that there was no development of resistance
[46]. However, another study showed a four-fold increase in the minimum inhibitory concentration in isolates of two of the seven patients with persistent C.
pneumoniae after the administration of azithromycin for
community-acquired pneumonia [47]. Use of a highly
effective agent should ensure that the microorganism is
eradicated before resistance can develop.
Similarly, the extensive use of antibiotics for longer
durations, as in the treatment of peptic ulcers, could
result in increased resistance. Megraud reported overall
resistance to clarithromycin in 3% of isolates, whereas
resistance to metronidazole, another agent frequently
employed for the eradication of H. pylori, is about 24%
[48]. Reduced susceptibility inevitably means ineffective
eradication and clinical failure. In patients infected with
metronidazole-resistant strains, the clinical efficacy falls
from 95 to 75% [49].

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