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International Journal of Antimicrobial Agents 56 (2020) 106 143
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents
journal homepage: www.elsevier.com/locate/ijantimicag
Safety and effectiveness of azithromycin in patients with COVID-19:
An open-label randomised trial
Ehsan Sekhavati
a
, Fatemeh Jafari
b , c
, SeyedAhmad SeyedAlinaghi
d
,
Saeidreza Jamalimoghadamsiahkali
e
, Sara Sadr
b
, Mohammad Tabarestani
f
,
Mohammad Pirhayati
c
, Abolfazl Zendehdel
g
, Navid Manafic
, Mahboubeh Hajiabdolbaghi
h
,
Zahra Ahmadinejad
i
, Hamid Emadi Kouchak
h
, Sirous Jafari
h
, Hosein Khalili
j
,
Mohamadreza Salehi
h
, Arash Seifih
, Fereshteh Shahmari Golestank
, Fereshteh Ghiasvandi , ∗
a
Department of Cardiology, Ziayian Hospital, Tehra n University of Medical Sciences, Tehra n, Iran
b
Mazandaran University of Medical Sciences, School of Medicine, Sari, Iran
c
Iran University of Medical Sciences, School of Medicine, Tehr an, Iran
d
Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk Behaviors, Teh ran University of Medical Sciences, Tehran , Iran
e
Department of Infectious Diseases, Ziayian Hospital, Teh ran University of Medical Sciences, Teh ran , Iran
f
Medical Students Research Committee, Mazandaran University of Medical Sciences, School of Medicine, Sari, Iran
g
Geriatric Department, Ziayian Hospital, Teh ran University of Medical Sciences, Teh ran , Iran
h
Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Teh ran , Iran
i
Liver Transplantation Research Center, Department of Infectious Diseases, Imam Khomeini Hospital Complex, Keshavarz Boulevard, Tehran University of
Medical Sciences, Teh ran 14197 -3 3141, Iran
j
Department of Pharmacotherapy, Faculty of Pharmacy, Tehr an University of Medical Sciences, Tehra n, Iran
k
Department of Infectious Diseases, Teh ran University of Medical Sciences, Tehran , Iran
a r t i c l e i n f o
Keywo rds:
COVID-19
SARS-CoV-2
Azithromycin
Hydroxychloroquine
Lopinavir
Ritonavir
a b s t r a c t
As no specific pharmacological treatment has been validate d for use in coronavirus disease 2019 (COVID-
19) , we aimed to assess the effectiveness of azithromycin (AZM) in these patients at a referral cen-
tre in Iran. An open-label, randomised controlled trial was conducted on patients with laboratory-
confirmed COVID-19. A total of 55 patients in the control group receiving hydroxychloroquine (HCQ) and
lopinavir/ritonavir (LPV/r) were compared with 56 patients in the case group who in addition to the
same regimen also received AZM. Patients with prior cardiac disease were excluded from the study. Fur-
thermore, patients from the case group were assessed for cardiac arrythmia risk based on the American
College of Cardiology (ACC) risk assessment for use of AZM and HCQ. The main outcome measures were
vital signs, SpO
2
levels, duration of hospitalisation, need for and length of intensive care unit admission,
mortality rate and results of 30-day follow-up after discharge. Initially, there was no significant difference
between the general conditions and vital signs of the two groups. The SpO
2
levels at discharge were sig-
nificantly higher, the respiratory rate was lower and the duration of admission was shorter in the case
group. There was no significant difference in the mortality rate between the two groups. Patients who
received AZM in addition to HCQ and LPV/r had a better general condition. HCQ + AZM combination may
be beneficial for individuals who are known to have a very low underlying risk for cardiac arrhythmia
based on the ACC criteria.
©2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.
1. Introduction
In late December 2019, an outbreak of an emerging disease
with a remarkably high virulence in Wuhan, China, soon became
∗Corresponding author. Tel .: + 98 21 6119 2659; fax: + 98 21 6658 1657.
E-mail addresses: fatemejafari72@gmail.com (F. Jafari), ghiasvand_62@yahoo.com
(F. Ghiasvand).
a global concern. Disease symptoms resemble a viral pneumonia
and genetic analysis of lower respiratory tract samples of early
infected patients showed an infection caused by the novel coro-
navirus 2019-nCoV, subsequently named severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus
disease 2019 (COVID-19). The disease rapidly spread throughout
China and infected multiple other countries [1 , 2] . On 12 March
2020, the Wo rld Health Organization (WHO) declared the epidemic
https://doi.org/10.1016/j.ijantimicag.2020.106143
0924-8579/© 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.
2 E. Sekhavati, F. Jafari and S. SeyedAlinaghi et al. / International Journal of Antimicrobial Agents 56 (2020) 10614 3
of COVID-19 as a global pandemic. In addition to primary respira-
tory involvement, reports show other organ systems, including the
gastrointestinal, neurological and haematopoietic systems, can also
be considerably affected by this virus [3 , 4] . Coronavirus infections
in humans are mostly mild; a meta-analysis of epidemiologic stud-
ies conducted in China showed that 12.6–23.5% of patients experi-
ence a severe form of COVID-19 with an overall mortality rate of
2.0–4.4% [5] . There are no specific pharmacological treatments for
the novel coronavirus as yet [6] . Repositioning of well-known med-
ications as antiviral treatment is preferred in circumstances where
there is little time for standard randomised controlled trials and
preliminary laboratory investigations into a new medication. Com-
plete knowledge of the possible side effects and safety profile of
old medications lays the groundwork for better monitoring of the
treatment effect and outcome [7] .
Multiple medications have been used in clinical trials against
COVID-19. Chloroquine (CQ), an immunomodulatory drug, is
widely used as an antimalarial agent and was discovered to have
broad-spectrum antiviral effects in 2006 [8] . Hydroxychloroquine
(HCQ), an analogue of CQ, has a better clinical safety profile and
allows for a higher daily dose compared with CQ [9 , 10] . The com-
bination lopinavir/ritonavir (LPV/r) has been approved and used for
human immunodeficiency virus (HIV) infection across the world;
both substances are protease inhibitors, but ritonavir also enhances
the pharmacokinetic and pharmacodynamic properties of lopinavir
[11] . These antiviral agents have been used in the treatment of
Middle East respiratory syndrome (MERS) [12] . Lopinavir has also
been proven to have in vitro activity against SARS-CoV infec-
tion in humans [13–15] . Azithromycin (AZM), a macrolide antibi-
otic, has shown efficacy in preventing severe respiratory infections
in patients suffering from viral pneumonia [16] . In vitro studies
have demonstrated that it is active against Zika and Ebola viruses
[17] and it has a high affinity for the binding interaction site of
the SARS-CoV-2 spike protein and angiotensin-converting enzyme
2 (ACE2) [18] , which is the critical human cell receptor for the
SARS-CoV-2 virus, and it is believed that blocking this interaction
can potentially prevent the infection [19] .
The combination of HCQ and AZM has been very well received
among physicians and, according to an online international survey
of 5500 physicians over 13–15 April 2020, these medications are
the most commonly used medication in the treatment of COVID-
19 [20] . However, there are a considerable cardiac risks associated
with the concomitant use of AZM and HCQ, and cardiac arrhyth-
mias caused by QT interval prolongation can potentially increase
the mortality rate in patients who are treated with this combina-
tion [21 , 22] .
In this clinical trial, we evaluated the potential treatment bene-
fits of this combination in patients with low risk for QT prolonga-
tion and arrhythmia. We used the scoring system proposed by the
American College of Cardiology (ACC) [23] to exclude patients with
a moderate to high risk of cardiac arrhythmias from the study.
2. Materials and methods
2.1. Participants
Between 24 April and 8 May 2020, a total of 202 patients with
compelling clinical symptoms for a diagnosis of COVID-19 were ad-
mitted to Ziaeian Hospital in Tehra n (Iran). All patients underwent
reverse transcriptase PCR (RT-PCR) testing and a lung computed to-
mography (CT) scan. Inclusion criteria were a positive RT-PCR test
and significant findings compatible with radiographic imaging of
COVID-19 pulmonary involvement. Exclusion criteria were age < 18
years, pregnancy or nursing during the time of admission, past his-
tory or concurrent cardiac disease, recent history of antiviral ther-
apy, and contraindications for use of HCQ, AZM or LPV/r (Kaletra
R ;
AbbVie Inc., Chicago, IL, USA), such as retinopathy or glucose-6-
phosphate dehydrogenase deficiency, or a history of allergic reac-
tions to these medicines.
2.2. Study arms and treatment plans
Patients were randomly divided into two treatment groups, a
case group comprising 56 patients and a control group comprising
55 patients. On the first day of admission, laboratory studies in-
cluding complete blood count and erythrocyte sedimentation rate
(ESR) were performed. The case group received oral AZM 500 mg
daily, oral LPV/r 40 0/10 0 mg twice daily and oral HCQ 400 mg
daily. The control group received oral LPV/r 40 0/10 0 mg twice daily
and oral HCQ 400 mg daily; for both treatment groups, all medi-
cations were administered for 5 days.
On the first day of admission, for patients assigned to the case
treatment group, the risk for ventricular arrhythmia in concurrent
treatment with HCQ and AZM was calculated based on the pro-
posed guideline by the ACC [23] , and patients with a score of ≥7
were excluded from the study.
Patients were assessed by daily measurements of core body
temperature, respiratory rate, heart rate and peripheral capillary
oxygen saturation (SpO
2
). Daily electrocardiogram (ECG) studies
were also conducted to monitor possible evolution of heart rate-
corrected QT (QTc) interval prolongation, in which case, treatment
with AZM and HCQ would have been stopped. For correction of
the QT interval, Bazett’s formula (QTc = QT/
√
RR) was used [24] .
In case of deterioration in general and/or pulmonary condition,
methylprednisolone was prescribed [25] . Patients were discharged
when they achieved a stable SpO
2
> 92%, had no respiratory dis-
tress and were afebrile for 3 consecutive days. The primary end-
points in this trial were a decrease in mortality, duration of hos-
pitalisation and need for intensive care unit (ICU) admission. Sec-
ondary endpoints were determined as improvements in SpO
2
and
vital signs as well as the general wellbeing of the patient.
Sample size calculation was performed for non-inferiority tests
of difference between two group proportions. We assumed an ef-
fectiveness of 65% for the intervention group and effectiveness of
50% for the control group. We also assumed a margin of non-
inferiority of at least 10% between the two groups. With these as-
sumptions, a sample size of 48 cases in each group was calculated.
After consideration of a dropout rate of 10%, the total sample size
of 110 cases was calculated. The power of the study was deter-
mined as 90% (G
∗Power, Erdfelder, Faul, & Buchner, 1996).
2.3. Ethical considerations
In accordance with the Declaration of Helsinki, written in-
formed consent was obtained from all participants before inclu-
sion in the study. Patients were assured that declining to partici-
pate or leaving the study at any point would not affect the quality
of their treatment and that they would thereafter receive standard
care. The study protocol was approved by the Institutional Review
Board of Teh ran University of Medical Sciences.
2.4. Measurements and statistical analysis
Distribution of age, sex, initial clinical symptoms and vital signs
measured on the first day of admission were compared between
the two groups. The vital signs including core body temperature,
respiratory rate, heart rate and SpO
2
were also compared on the
third and last days of treatment between the two groups as an out-
come measure. Differences in duration of hospitalisation, number
of patients whose condition deteriorated and required ICU admis-
sion, length of ICU stay, mortality rate and results of 30-day follow-
up after discharge were also evaluated as outcome measures.
E. Sekhavati, F. Jafari and S. SeyedAlinaghi et al. / International Journal of Antimicrobial Agents 56 (2020) 10614 3 3
Analysis was performed using IBM SPSS Statistics for Windows
v.22.0 (IBM Corp., Armonk, NY, USA). Quantitative variables were
reported as the mean ±standard deviation and qualitative vari-
ables as the frequency and percentage. Because of the normal dis-
tribution of the data, the independent t -test was used to assess the
difference in means. The χ2 test and Fisher’s exact test were used
to assess the statistical relationships between categorical variables.
The level of significance was set at a P -value of < 0.05 for all analy-
ses. The number needed to treat with a confidence interval (CI) of
95% was reported for requirement for ICU admission, need for intu-
bation and mortality rate. We also evaluated the effect size based
on Hedges’ g because of the difference in the number of partici-
pants in each group.
2.5. Safety
Since a stepwise plan was practiced in our study, patients with
any prior cardiac disease were excluded from the study. Further-
more, the ACC criteria for risk assessment of simultaneous use of
AZM and HCQ were assessed for each person to make sure no pa-
tient has an increased risk of ventricular arrythmia. All patients
were also monitored closely for any signs of ECG rhythm abnor-
mality or clinical features of cardiac arrhythmia.
3. Results
3.1. Demographic characteristics
Based on the inclusion criteria and after excluding 91 cases, 111
cases were included in the study, which were randomised and al-
located between the two treatment groups of case ( n = 56) and
control ( n = 55) patients ( Fig. 1 ). All patients completed their 5-
day required treatment duration.
In the case treatment group, the ventricular arrhythmia risk
score was three in 12 patients (21.4%), four in 32 patients (57.1%)
and five in 12 patients (21.4%). The mean age and demographic fac-
tors such as sex were not significantly different between the two
treatment arms ( P = 0.700 and 0.387, respectively) ( Table 1 ).
3.2. Clinical and laboratory findings
Table 1 gives the clinical features and laboratory test results
of patients in both groups. Fever, dyspnoea, chills, cough, pro-
duction of sputum, haemoptysis and chest pain were not sig-
nificantly different between the two groups ( P > 0.05). Myalgia,
headache and vomiting were initially reported more by control pa-
tients ( P = 0.0 0 0, 0.0 05 and 0.031, respectively). Weakness was
found significantly more frequently in patients in the case group
( P = 0.042) . The mean SpO
2
levels upon admission and on the
third day of admission were not significantly different between the
two groups ( P = 0.920 and 0.610, respectively) ( Fig. 2 ). Laboratory
test results did not show a significant difference between the two
groups ( P > 0.05).
3.3. Treatment outcomes
Table 1 shows treatment outcomes in both treatment groups.
Core temperature was not significantly different between the case
and control groups (36.88 °C vs. 36.77 °C, respectively; P = 0.190).
At discharge, SpO
2
levels were significantly higher in the case
group (93.95% vs. 92.40%; P = 0.030) and the respiratory rate
was significantly lower (15.85 breaths/min vs. 17.4 2 breaths/min;
P = 0.010). The duration of hospitalisation in the case group was
significantly shorter than the control group (4.61 days vs. 5.96
days; P = 0.02) ( Fig. 3 ). The calculated effect size for SpO
2
lev-
els, respiratory rate at discharge and duration of hospitalisation
were –0.461, 0.721 and 0.618 (all medium effect sizes), respectively
( Table 2 ). Two patients in the case group and seven patients in
the control group required ICU admission, which did not show sta-
tistical significance (3.6% vs. 12.7%, respectively; P = 0.070). Three
patients in the control group were intubated during the course of
admission versus no patients in the case group, which was statis-
tically insignificant ( P = 0.118) ( Fig. 4 ). The difference between the
mean duration of ICU admission was not significant between the
groups (5.00 days vs. 4.43 days; P = 0.157). There was one death
in the control group and none in the case group; this difference
was insignificant ( P = 0.495). No patient in either group experi-
enced cardiac arrhythmia or QTc prolongation.
4. Discussion
During the rapidly spreading global pandemic of COVID-19, it
is important to have an effective and safe treatment plan. There
are several reports on the effectiveness of various medications, but
as yet none of them have been proven to be significantly effec-
tive. Recently, combination therapy with HCQ and AZM has be-
come one of the most favoured treatment regimens among med-
ical professionals [26–28] . Studies have shown that the combina-
tion of HCQ and AZM can reinforce the efficacy of HCQ [28 , 29] .
Gautret et al. conducted a non-randomised open-label clinical trial
that has shown promising results for the combination of HCQ and
AZM [27] . In their study, they reported that the HCQ + AZM combi-
nation had a significant effect on viral load reduction within only
3–6 days of treatment in COVID-19 patients [27] , but a number
of reviews have questioned the randomisation technique used in
this study and pointed out that the small study patient popula-
tion and other methodological pitfalls question the certainty with
which the results of this study are to be received [30–33] . Million
et al. published an article that was an extension to the previous
study by Gautret et al. in which they conducted a retrospective
analysis of 1061 cases in France and reported that HCQ + AZM com-
bination therapy is beneficial and significantly lowers the mortality
rate of COVID-19 [34] .
In the current study, which was an open-label, blocked, ran-
domised clinical trial, we found that patients who received AZM
in addition to HCQ had a shorter duration of hospitalisation in
comparison with the control group, with a medium effect size
( P = 0.020, Hedges’ g = 0.618). In their multicentre, randomised,
open-label, three-group, controlled trial, Calvalcanti et al. evaluated
the safety and efficacy of HCQ and AZM in hospitalised patients
with suspected or confirmed COVID-19 [35] . They reported that the
duration of hospital stay was longer in patients who were treated
with both HCQ and AZM compared with those who were only
treated with HCQ, but this difference was non-significant [10.3
days vs. 9.6 days; odds ratio (OR) = 0.7, 95% CI –0.6 to 1.9] [35] .
In our study, there were two patients in the case group (3.6%)
and seven patients in the control group (12.7%) who required ICU
admission, which does not show statistical significance. In their
retrospective multicentre cohort study, Rosenberg et al. evaluated
1438 patients with a confirmed diagnosis of COVID-19. They re-
ported a higher frequency of ICU admission in patients receiving
HCQ and AZM (30.7%) or HCQ alone (19.2%) compared with those
receiving only AZM (10.9%) [36] .
In our study, there was one death in the control group and none
in the case group; this difference was insignificant ( P = 0.495).
However, in their multicentre retrospective observational study
in hospitalised patients positive for COVID-19, Arshad et al. re-
ported that treatment with AZM alone significantly decreased
the mortality hazard ratio by 66% and combination therapy with
HCQ + AZM decreased the mortality hazard ratio by 71% [37] . They
also performed a multivariate Cox regression model and found
that combination therapy had no significant effect on the mor-
4 E. Sekhavati, F. Jafari and S. SeyedAlinaghi et al. / International Journal of Antimicrobial Agents 56 (2020) 10614 3
Fig. 1. Randomisation and treatment protocols of the patients.
Fig. 2. Comparison of SpO
2 (%) changes between the two treatment groups. The
control group received oral lopinavir/ritonavir 40 0/10 0 mg twice daily and oral hy-
droxychloroquine 400 mg daily; the case group in addition to the same regimen
also received oral azithromycin 500 mg daily.
tality rate [37] . Rosenberg et al. reported that the probability of
death for patients who were receiving treatment with HCQ + AZM
was 25.7% (95% CI 22.3–28.9%) [36] . They compared patients who
were treated with HCQ, AZM and HCQ + AZM with patients who re-
ceived no treatment and reported that there was no significant as-
Fig. 3. Comparison of the mean duration of hospitalisation (days) between the two
treatment groups. The control group received oral lopinavir/ritonavir 40 0/10 0 mg
twice daily and oral hydroxychloroquine 400 mg daily; the case group in addition
to the same regimen also receive d oral azithromycin 50 0 mg daily.
sociation between treatment with these medications—alone or in
combination—and the in-hospital mortality rate [36] . However, the
observational design of their study may limit definite interpreta-
tions of their findings. Despite the results of other studies that re-
port an effective virucidal potency for the combination of HCQ and
E. Sekhavati, F. Jafari and S. SeyedAlinaghi et al. / International Journal of Antimicrobial Agents 56 (2020) 10614 3 5
Tabl e 1
Demographic, clinical and laboratory findings in the two treatment groups
a
.
Variable Case group ( n = 56) Control group ( n = 55) P -value
Age (years) 54.38 ±15.92 59.89 ±15.55 0.700
Body temperature on admission ( °C) 38.07 ±0.69 37.72 ±0.91 0.020
White blood cell count ( ×10
9
/L) 6.94 ±2.65 6.28 ±2.30 0.160
Haemoglobin (g/dL) 13.65 ±1.97 12.80 ±1.94 0.200
Platelet count ( ×10
9
/L) 230.45 ±111.77 238.46 ±99.56 0.690
ESR (mm/h) 64.86 ±29.12 70.71 ±32.05 0.320
RR on admission (breaths/min) 23.75 ±5.19 22.62 ±5.72 0.280
SpO
2
on admission (%) 89.61 ±2.98 89.51 ±6.84 0.920
Day 3 SpO
2
(%) 89.36 ±4.59 88.75 ±7.67 0.610
Sex
Female 28 (50.00) 32 (58.18) 0.387
Male 28 (50.00) 23 (41.82)
Fever 38 (67.86) 33 (60.00) 0.389
Dyspnoea 41 (73.21) 43 (78.18) 0.542
Myalgia 18 (32.14) 22 (74.55) 0.000
Chills 18 (32.14) 25 (45.45) 0.150
Weakness 10 (17.86) 3 (5.45) 0.042
Cough 34 (60.71) 41 (74.55) 0.120
Sputum production 3 (5.36) 8 (14.55) 0.105
Haemoptysis 3 (5.36) 0 (0.00) 0.243
Headache 6 (10.71) 18 (32.7) 0.005
Vomiting 7 (12.50) 16 (29.09) 0.031
Chest pain 10 (17.86) 12 (21.82) 0.601
Primary endpoints
Hospital stay (days) 4.61 ±2.59 5.96 ±3.21 0.020
Need for ICU admission 2 (3.57) 7 (12.73) 0.070
Death 0 (0.00) 1 (1.82) 0.495
Secondary endpoints
Discharge body temperature ( °C) 36.88 ±0.33 36.77 ±0.53 0.190
ICU length of stay (days) 5.00 ±0.01 4.43 ±2.99 0.157
RR at discharge (breaths/min) 15.85 ±1.99 17.42 ±2.42 0.010
SpO
2
at discharge (%) 93.95 ±2.14 92.40 ±4.58 0.030
Need for intubation 0 (0.00) 3 (5.45) 0.118
ESR, erythrocyte sedimentation rate; RR, respiratory rate; SpO
2
, peripheral capillary oxygen saturation;
ICU, intensive care unit.
NOTE: The control group received oral lopinavir/ritonavir 40 0/10 0 mg twice daily and oral hydrox-
ychloroquine 400 mg daily; the case group in addition to the same regimen also received oral
azithromycin 50 0 mg daily.
a Data are the mean ±standard deviation or n (%).
Tabl e 2
Effect sizes for outcome of patients in the case and control treat-
ment groups.
Variable Hedges’ g 95% CI
SpO
2
at discharge –0.461 –0.838, –0.084
RR at discharge 0.721 0.337, 1.105
Length of hospital stay 0.618 0.103, 0.858
CI, confidence interval; SpO
2
, peripheral capillary oxygen satura-
tion; RR, respiratory rate.
NOTE: The control group rece ived oral lopinavir/ritonavir 40 0/10 0
mg twice daily and oral hydroxychloroquine 400 mg daily; the
case group in addition to the same regimen also received oral
azithromycin 50 0 mg daily.
AZM [34 , 36 , 38] , Molina et al. did not find any evidence to support
the efficacy of this combination in viral clearance or improvement
of clinical status of their patients [33] .
Our study also showed that patients in the case treatment
group who were treated with AZM in addition to the main treat-
ment regimen had significantly higher SpO
2
levels ( P = 0.030) and
a lower respiratory rate at the time of discharge ( P = 0.010). The
effect sizes showed the differences between two groups in these
variables were considerable (Hedges’ g = –0.461 and 0.721, respec-
tively). Calvalcanti et al. reported that patients receiving HCQ + AZM
compared with patients who received AZM alone had a non-
significant lower rate of need for oxygenation with a high-flow
nasal cannula or non-invasive ventilation during treatment (9.3%
vs. 10.7%; OR = 0.92, 95% CI 0.5–1.7) [35] .
Fig. 4. Requirement for intensive care unit (ICU) admission and intubation in the
two treatment group. The control group received oral lopinavir/ritonavir 40 0/10 0
mg twice daily and oral hydroxychloroquine 400 mg daily; the case group in addi-
tion to the same regimen also received oral azithromycin 500 mg daily. The number
of patients is given on the y -axis, with percentage above the bars.
Possible side effects of a treatment are determining factors in
evaluating the suitability of a medication regimen. CQ or HCQ as
monotherapy have some common adverse effects such as pruri-
tus, nausea and headache as well as some uncommon but seri-
ous adverse effects such as arrhythmias due to QT interval prolon-
gation, hypoglycaemia, idiosyncratic hypersensitivity reactions and
neuropsychiatric effects [39] . Prolongation of the QTc interval and
torsade de pointes are the most important side effects of separate
6 E. Sekhavati, F. Jafari and S. SeyedAlinaghi et al. / International Journal of Antimicrobial Agents 56 (2020) 10614 3
Tabl e 3
Calculation of risk score for QTc interval prolongation.
Risk factor Score
Age ≥68 years 1
Female sex 1
Loop diuretic 1
Serum K
+
≤3.5 mEq/L 2
Admission QTc ≥450 ms 2
Acute MI 2
≥2 QTc-prolonging drugs 3
Sepsis 3
Heart failure 3
One QTc-prolonging drug 3
Maximum risk score 21
K
+
, potassium; MI, myocardial infarction.
and, especially, concomitant treatment with HCQ and macrolides
such as AZM that can negatively affect the survival rate [35 , 37] .
Lane et al. evaluated the safety of HCQ alone and in combination
with AZM. They studied 323 122 patients who were treated with
this combination and concluded that a short-term treatment with
HCQ is safe, but long-term treatment or addition of AZM to the
treatment (even in the short-term) may increase the risk of heart
failure or cardiovascular mortality rate, which can be caused by
their synergetic effects on the QTc interval, leading to a lethal ar-
rhythmia [40] . Considering the possible side effects of this com-
bination therapy, clinicians should consider having a baseline QTc
interval and monitoring of QTc interval, heart rate and serum elec-
trolytes during administration of these drugs [38] . A scoring sys-
tem to predict the risk of QT interval prolongation in hospitalised
patients has been designed ( Table 3 ). Scores of < 7, 7–10 and ≥11,
respectively, correlate with a low, medium and high risk of QT in-
terval prolongation in hospitalised patients [23] . In our study, all
patients had a risk score of < 6, all patients were monitored during
treatment and none of them experienced QTc interval prolonga-
tion, which would have warranted a halt in treatment with HCQ
and AZM.
The small sample size and open-label design are limitations of
our study. Because of the shortage in our resources, we could not
test the viral loads of the patients at daily intervals.
5. Conclusion
Patients in the group receiving the experimental treatment reg-
imen that included AZM had a significantly shorter hospital stay
as well as significantly higher SpO
2
and lower respiratory rate at
discharge. However, a risk scoring system should be utilised be-
fore initiating treatment to prevent QTc prolongation, especially for
high-risk patients.
Funding: This study was supported by the Te hr an University of
Medical Sciences research centre [grant no. 47493].
Competing interests: None declared.
Ethical approval: This project was approved by the Institu-
tional Review Board of Te hran University of Medical Sciences
[IR.TUMS.VCR.REC.1399.165].
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