4.2 – Clinical data
All available evidence on the use of azithromycin in the treatment of
COVID-19 was summarized in Table 2.
In March, Gautret et al. showed that the early treatment either
with hydroxychloroquine presented superior virological clearance
compared to standard of care[8]. Moreover, the addition of
azithromycin further improved the activity of hydroxychloroquine alone.
However, only 6 patients were treated with hydroxychloroquine and
azithromycin.
Based on this study and in vitro data showing synergic activity,
some hospitals started to spread the use of this combination.
Nevertheless, the International Society of Antimicrobial Chemotherapy
raised concerns as they believed that did not meet the society’s
expected standard[71].
These authors subsequently expanded the number of included patients
evaluating this combination[72,73]. They included those admitted to
the infectious disease ward or treated in day-care hospital, so disease
presentation was mild. Overall, clinical and viral outcome was positive.
On the contrary, Molina et al. challenged these results in sicker
patients as this strategy was not associated with any clinical benefit
or antiviral activity[74]. In all these studies, unfortunately, a
control group was lacking.
Mahevas et al. assessed the efficacy of hydroxychloroquine in 173
hospitalized patients showing no effect in any outcomes[75].
Patients with organ failure, ARDS or ICU at admission and those treated
with other experimental therapies (remdesivir, tocilizumab or
lopinavir/ritonavir) were excluded. Given that the objective of the
study was the evaluation of the efficacy of hydroxychloroquine, the
outcomes of azithromycin alone or in combination were not analyzed.
Azithromycin was administered in 15 (18 %) patients in the treatment
group and 26 (29 %) in the control group. Among those treated with
azithromycin alone, 5 (19.2 %) died and 6 (23.1 %) were transferred to
the ICU. These patients, however, were not further analyzed nor included
in the propensity-score analysis and no data about their baseline and
clinical demographics were detailed.
In patients hospitalized at Veterans Health Administration medical
centers, Magagnoli et al. demonstrated a higher risk of mortality
in hospitalized patients treated with hydroxychloroquine alone after
propensity-score adjustment [76]. However, this finding was not
observed with combination therapy. The risk of mechanical ventilation
was similar among hydroxychloroquine alone (aHR 1.19 [95% CI
0.78-1.82]) and hydroxychloroquine/azithromycin groups (aHR 1.09
[95% CI 0.72-1.66]) when compared to the no-hydroxychloroquine
group. The use of other therapies was not assessed and no information
about ICU status at admission was reported.
Geleris et al. included 1,085 hospitalized patients in a
propensity-score matched analysis in New York[77]. Patients who died
or were intubated within 24 hours after presentation were excluded.
Azithromycin was used in both groups (59.9 % in the treatment group and
37.2 % in the control group). Other agents as tocilizumab/sarilumab or
remdesivir were allowed (data on corticosteroids was not shown). In the
multivariate analysis hydroxychloroquine or azithromycin use was not
associated with the composite primary endpoint.
Rosenberg et al. showed a trend towards reduced mortality in the
azithromycin alone group, after adjusting for multiple factors[78].
Unlike other studies, patients admitted to the ICU were not excluded. In
the estimated direct-adjusted model, 21-day mortality was 22.5 % (95%
CI 19.7-25.1) in the combination group, 18.9 % (95% CI 14.3-23.2) in
the hydroxychloroquine alone group, 10.9 % (95% CI 5.8-15.6) in the
azithromycin group and 17.8 % (95% CI, 11.1-23.9) in the control
group. When hydroxychloroquine and azithromycin monotherapy groups were
compared, no differences were observed in mortality (aHR 1.92 [95% CI
0.99-3.74]), although it was in the limit of significance.
Another pre-print study showed potential benefits of azithromycin alone,
but unfortunately was withdrawn.
Recently, Guérin et al. assessed the time to clinical recovery of
azithromycin and its combination with hydroxychloroquine compared to
standard of care in outpatients[79]. Both treatments accelerated
recovery both in the global cohort and after adjusting in a case-control
analysis. No significant differences were found when azithromycin
monotherapy and combination therapy were compared (P=0.26).
Barbosa et al . evaluated the combination therapy in the need for
hospitalization in outpatients[80]. Patients with flu-like symptoms
were referred to telemedicine service, where combination therapy was
offered. Those who refused to initiate this treatment were considered
the control group. The treatment group was associated with a reduction
in the need for hospitalization of 3.5 %. Moreover, among those in the
treatment group, patients treated before day 7 of symptoms onset
required less hospitalization (1.17 % vs. 3.2 %, P<0.001).
To date, 36 clinical trials are recruiting patients to evaluate
azithromycin in a wide variety of scenarios (outpatients, combined with
hydroxychloroquine or other drugs, ICU…).