A Case Series of 100 COVID-19 Positive Patients Treated with Combination of Ivermectin and Doxycycline

Abstract

Background: A definitive treatment of SARS CoV-2 is yet to arrive and the human death toll rises exponentially globally. In this health emergency, it might be useful to look into the old therapies which could be effective against the virus. In vitro research showed Ivermectin could decrease the concentration of coronavirus 4000 to 5000 folds in living lung tissue.
Aim: In this prospective study a combination of Ivermectin and Doxycycline will be evaluated therapeutically to treat COVID-19 patients.
Methods: 100 COVID-19 patients were enrolled in this study with a predefined inclusion and exclusion criteria. RT- PCR of the SERS-CoV-2 will be done at designated government hospitals. The clinical features and response to treatment were noted according to a dedicated protocol.
Results: In this study male and female were 64 and 36 respectively, the age ranged between 8 to 84 years. Retesting was done between 4 and 18 days of starting medication. All patients tested negative and their symptoms improved within 72 hours. There were no noticeable side effects.
Conclusion: Combination of Ivermectin and doxycycline was found to be very effective in viral clearance in mild and moderately sick COVID-19 patients. Medical societies and institutions should undertake larger multi center studies to validate and recommend this combination therapy to include in national guidelines

Full text

p-ISSN 1015-0870
e-ISSN 2309-6365
Supplement 2020
COVID-19
Journal of
Bangladesh College of Physicians and Surgeons
Official Journal of
The Bangladesh College of Physicians and Surgeons
www.bcpsbd.org & www.banglajol.info/index.php/JBCPS
Enlisted in DOAJ/HINARI/AsiaJOL/BanglaJOL
Indexed in: IndexCopernicus,Ulrichsweb,Google Scholar,ProQuest,CrossRef,EBSCO
Vol. 38, COVID-19
Supplement 2020

Abstract:
Background: A definitive treatment of SARS CoV-2 is yet to
arrive and the human death toll rises exponentially globally.
In this health emergency, it might be useful to look into the
old therapies which could be effective against the virus. In
vitro research showed Ivermectin could decrease the
concentration of coronavirus 4000 to 5000 folds in living
lung tissue.
Aim: In this prospective study a combination of Ivermectin
and Doxycycline will be evaluated therapeutically to treat
COVID-19 patients.
Methods: 100 COVID-19 patients were enrolled in this study
with a predefined inclusion and exclusion criteria. RT- PCR
of the SERS-CoV-2 will be done at designated government
hospitals. The clinical features and response to treatment
were noted according to a dedicated protocol.
Results: In this study male and female were 64 and 36
respectively, the age ranged between 8 to 84 years. Retesting
was done between 4 and 18 days of starting medication. All
patients tested negative and their symptoms improved within
72 hours. There were no noticeable side effects.
Conclusion: Combination of Ivermectin and doxycycline
was found to be very effective in viral clearance in mild and
moderately sick COVID-19 patients. Medical societies and
institutions should undertake larger multi center studies to
validate and recommend this combination therapy to include
in national guidelines.
Keywords: Covid-19, Doxycycline, Ivermectin
Bangladesh Coll Phys Surg 2020; 38: 10-15)
DOI: https://doi.org/10.3329/jbcps.v38i0.47512
a. Prof. Mohammed Tarek Alam, Professor and Head of
Department of Medicine, Bangladesh Medical College,
House # 34, Road # 14/A, R/A, Dhaka-1209, Bangladesh
b. Rubaiul Murshed, Chairperson, Shomman Foundation,
House # 71/1, Road # 15/A, Dhanmondi R/A, Dhaka-1209,
Bangladesh & Chief Consultant, Central Police Hospital, 2
DIT Ave, Dhaka 1000, Bangladesh
c. Dr. Elias Bhiuyan, Assistant Professor, Department of
Medicine, Bangladesh Medical College, House # 34, Road #
14/A, R/A, Dhaka-1209, Bangladesh
d. Dr. Sadia Saber, Assistant Professor, Department of
Medicine, Bangladesh Medical College, House # 34, Road #
14/A, R/A, Dhaka-1209, Bangladesh
e. Rafa Faaria Alam, Medical Officer, Department of Medicine,
Bangladesh Medical College, House # 34, Road # 14/A, R/
A, Dhaka-1209, Bangladesh
f. Rishad Choudhury Robin, Associate Project Lead, Shomman
Foundation, House # 71/1, Road # 15/A, Dhanmondi R/A,
Dhaka-1209, Bangladesh and Faculty Member, School of
Public Health and Life Science, University of South Asia,
Dhaka-1212, Bangladesh
Address of Correspondence: Dr. Mohammed Tarek Alam,
Professor and Head of Department of Medicine, Bangladesh Medical
College, House # 34, Road # 14/A, R/A, Dhaka-1209, Bangladesh.
E-mail: mtarekalam16@gmail.com, Phone: +8801819-185449
A Case Series of 100 COVID-19 Positive Patients Treated
with Combination of Ivermectin and Doxycycline
MT ALAMa, R MURSHEDb , E BHIUYANc, S SABERd, RF ALAMe, RC ROBINf
Background:
One hundred years after the Spanish flu pandemic in
1918-20, the whole world is again facing devastation
due to the Covid-19 (SARS CoV-2) pandemic. This
virulent virus SARS CoV-2 has high infectivity, morbidity
and remarkable fatality rate. No specific treatment or
vaccine has been invented to save mankind yet.
Scientists, physicians and concerned multidisciplinary
professional including political leaders are united to
explore a quick effective treatment and vaccine before it
is too late. Empirical applications of some drugs have
been assumed to work with success, but without having
a clinical trial, they cannot be validated. Until anything
comes up, it might be useful to repurpose old therapies
which could be effective against the virus.
In the beginning of April 2020, Caly et al. from Monash
University, Australia published their research article
stating that a single dose of Ivermectin (an anti-
parasitic drug) could decrease the concentration of
coronavirus in vitro. In the lab, Caly et al. bathed Vero-
hSLAM cells with Ivermectin at a concentration of
5µM from 2 hours post-infection SARS-CoV-2 isolate
Australia/VIC01/2020 until the conclusion of the
experiment. SARS-CoV-2 RNA was determined by RT-
PCR at days 0-3 in both supernatant and cell pellet
experiments. The authors noted 93-99.8% reduction in
viral RNA for Ivermection versus DMSO control at
24h in the supernatant (released virions) and cell
associated viral RNA (total virus) respectively. They
also describe by 48 hours about 5000 fold reduction of
viral RNA and maintenance of effect at 72 hours.1
They concluded that the human dose needed to be
ascertained in further studies. In the current SARS-CoV-
2 pandemic, this news was a ray of hope.
Journal of Bangladesh College of Physicians and Surgeons
Vol. 38, COVID-19 (Supplement Issue), July 2020

Methodology:
Study design
Observational /Cross-sectional study
Study Population
All RT-PCR SARS- CoV-2 positive patients fulfilling the
selection criteria. Mild and moderate cases purposively
selected from Bangladesh Medical College.
Selection criteria
Inclusion Criteria
•Subjects within age group 5 years and above
•With either sex, male or female
•Confirmed cases of Covid-19 by RT-PCR test
•Patients who are classified as asymptomatic,
•Mild and moderate cases with typical symptoms
•Patients who are not already treated with any other
antiviral drugs
Exclusion criteria
•Patients who are severe and critically ill.
•Patients with chronic liver diseases
•Patients with pregnancy and on lactation
•Children less than 5 years of age or less than 15kg
weight.
Procedure
100 patients RT-PCR confirmed cases of SARS CoV-2
met the selection criteria and was enrolled in the study.
They were given a combination treatment of Tab
Ivermectin and Cap Doxycycline along with
supportive treatment. The dose of ivermectin was 0.2
mg/kg single dose. Doxycycline 100 mg daily was given
to patients aged 8 years and above for 10 days. Patients
were given the choice to go to a COVID 19 designated
hospital but they went home and continued treatment.
Follow up was done every day for all symptomatic
patients over telephone about remission of
symptoms. RT-PCR test was repeated with sample of
nasal swab for all patients according to availability
of testing centers between 4 to 18 days. Six weeks
after testing negative, we plan to follow up on the
patient about their health conditions.
Result:
This observational study, consisting of 64 males and
36 females was conducted from April to May 2020
(Figure 2) in Bangladesh Medical College. The oldest
patient was 84 years and the youngest one was 8 years
with most patients between the ages of 21 to 40 years
(Figure 3). Patients were divided in 3 groups: Mild (73),
Moderate (20) and Severe (7), based on their symptoms.
From the severe patients, three had fever more than
103 Fahrenheit for seven days with severe cough and
lung infiltrates , three had severe loose motion and
one had uncontrolled diabetes. Out of the rest, 20
patients had moderate symptoms of mild fever (100
Fahrenheit) and mild cough. Moreover, 73 had mild
symptoms of malaise, sore throat, loss of smell, loss of
taste, and body ache. Fifty percent symptomatic
improvement of mild to moderate patients was seen
between 3rd to 5th day after starting treatment. All 7
severe patients’ symptoms subsided by 50 percent by
7th day of treatment. Retesting was done between 4 to
18 days of starting medication (Figure 4). Twenty five
patients underwent retesting between 4th to 8th days,
51 between 9th to 13th days and 24 between 14th to 18th
days from starting medication. All of the patients tested
negative. None needed intensive care admission and
no deaths were reported.
Fig 1: Schematic of Ivermectin’s proposed antiviral
action on coronavirus .
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.
11

Discussion:
An elderly female colleague with co-morbidities, who
tested positive for SARS-CoV2, was referred to the
Medicine Out Patient Department. As she was
asymptomatic, she was advised isolation but she wanted
to be treated without Hydroxychloroquine and
Azythromycin fearing cardiac toxicity.
Fig.-2: Gender of Covid-19 Positive patients (N=100)
64
36
Male
Female
Fig.- 3: Male and female ratio in different age groups
of Covid-19 positive patients (N=100)
18
22
12 11
11
16
10
432
0
5
10
15
20
25
<20 21-30 31-40 41-50 51-60 >60
Male Female
Fig.-4: Number of Patients testing Negative on Days
after Starting Treatment (N=100)
0
10
20
30
40
50
60
4th to 8th Day 9th to13th Day 14th to 18th Days
She was informed about the recent findings on
Ivermectin and agreed to take an oral combination of
200mcg/kg single dose of Ivermectin along with
Doxycycline 100mg orally daily for 10 days. She tested
negative in seven days.
This observation correlates with the findings of Caly et
al.1 We had given the standard single dose of Ivermectin
that is normally given for the treatment of scabies and
head lice although a very high dose was used in vitro.
Doxycycline, a trusted antibiotic, anti-malarial, anti-
typhus, and anti-viral which also decreases cytokine
production without any cardiac toxicity has been a good
combination in our small observational study2. We only
treated asymptomatic and mostly mildly symptomatic
patients.
Ivermectin was discovered in 1975 and came into medical
use in 1981.3,4 It is on the World Health Organization’s
List of Essential Medicines.5 Ivermectin is a FDA
approved drug, it is used for prevention, treatment, and
control of river blindness (onchocerciasis) in
populations where the disease is common. It is also
used for treatment of Strongyloidosis, enterobiasis,
Trichuris trichura, Loa Loa, Scabies, human lice, malaria
and is also known to have wide-spectrum antiviral
activity against number of viruses under in-vitro
conditions. 6,7,8,9 SARS-CoV-2 is a single stranded RNA
virus which is closely related to SARS coronavirus
(SARS-CoV). Recent study on Ivermectin against SARS-
CoV-2 under in-vitro conditions revealed that it can
inhibit the viral replication. The single treatment of this
drug was able to reduce the virus up to 5000-fold in
Vero-hSLAM cells bathed with Ivermectin within 48
hours. However, no further reduction was reported with
further increase in time period i.e up to 72 hours.
Moreover, no toxicity was seen with the drug at any
point of time10. Mechanism by which Ivermectin
responded against the SARS CoV-2 virus is not known
and was believed to be working similarly as it acted on
other viruses. It was known to inhibit the nuclear import
of viral and host proteins. Integrase protein of viruses
and the importin IMPα/β1 heterodimer was responsible
for IN nuclear import which further increases the
infection. As most of the RNA viruses are dependent
Journal of Bangladesh College of Physicians and Surgeons Vol. 38, COVID-19 (Supplement Issue), July 2020
12

upon IMPα/β1 during infection, Ivermectin acts on it
and inhibits the import with the increase in antiviral
response 1,10.
Fig 1 shows a schematic of Ivermectin’s proposed
antiviral action on coronavirus. IMPα/β1 binds to the
coronavirus cargo protein in the cytoplasm (top) and
translocates it through the nuclear pore complex (NPC)
into the nucleus where the complex falls apart and the
viral cargo can reduce the host cell’s antiviral response,
leading to enhanced infection. Ivermectin binds to and
destabilizes the IMPα/β1 heterodimer thereby
preventing IMPα/β1 from binding to the viral protein
(bottom) and preventing it from entering the nucleus.
This, likely, results in reduced inhibition of the antiviral
responses, leading to a normal, more efficient antiviral
response1.
Ivermectin is well tolerated by uninfected humans. It is
primarily metabolized in the liver by CYP450-3A47 and
has a plasma half-life of 16 hours and is almost
exclusively excreted in faeces with minimal clearance by
the kidneys. Therefore, it does not require dose
adjustment for people with renal failure. There have been
some reports of a mild anticoagulation effect. However,
this is usually not significant enough to alter coagulation
parameters such as the prothrombin ratio.
Side effects of oral Ivermectin are rare and usually
minor. These include transient tachycardia, flushing,
nausea and lightheadedness. More severe
neurological side effects are theoretically possible in
rare susceptible individuals. Moreover, FDA
describes some of the side-effects that may be
associated with Ivermectin include skin rash,
vomiting, diarrhea, stomach pain, facial or limb
swelling, neurologic adverse events (dizziness,
seizures, confusion), sudden drop in blood pressure,
severe skin rash potentially requiring hospitalization
and liver injury (hepatitis) 11. The safety of Ivermectin
in pregnant women has not been studied and such
use is not recommended. Studies in animals have
shown an increase in birth defects. Safety and
effectiveness in children below 5 years and under 15
kg and pregnant women have not been established.
Ivermectin passes into breast milk and use during
breast feeding is not recommended12. No significant
drug interactions with Ivermectin are recognized.
In vitro studies showed Doxycycline to exert anti
inflammatory effects at low (20 - 40mg/day) and high
(100 or 200mg/day) doses with inhibitory action on
metalloproteases and modulating effects of pro
inflammatory cytokines IL 6, IL 8 and tumor necrosis
factor alpha. The anti inflammatory properties of
Doxycycline and other components of tetracycline
has been demonstrated for several inflammatory
airway diseases, including, acute respiratory distress
syndrome. Thereby, low Doxycycline doses have
been shown to be more effective than high doses to
prevent induction of pro inflammatory cytokines (such
as IL 6) in inflammatory diseases13. Doxycycline is
rapidly and almost completely absorbed after oral
administration and has half life of 16-18 hours. Based
on the available evidence, we believe Tetracyclines
may be effective agents in the treatment of Covid-19
due to their ability to chelate Zinc compounds on
matrix metalloprotienases (MMP) on which corona-
viruses rely heavily for survival, cell infiltration, cell
to cell adhesion and replication, many of which has
Zinc as part of their MMP complex.14 It is a safe and
inexpensive drug with a minimal toxicity14.
Doxycycline is largely excreted unchanged both in
the bile and urine and the dose does not require
adjustment in patients with renal failure, because of
their enterohepatic circulation this drug may remain
in the body for a long time after cessation of therapy.
Doxycycline can produce GI irritation most commonly
after oral administration. Tolerability can be improved
by administering it with food. Doxycycline can be
safely used in children aged 8 years and above15.
Currently global scenario is not stable as there is no
effective drugs could be prescribed under sufficient
evidence based clinical trials. Already efficacy and
effectiveness of Hydroxychloroquine is
questionable16,17,18. As Doxycycline is safe to use in
treatment of ARDS it alone could be a better option
for Covid-19 treatment.
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.
13

Conclusion:
It is too early in this pandemic to claim major successes
of the effectivity of our combination therapy (Ivermectin
and Doxycycline) as our number is small and there is no
control group. Nevertheless, the results encourage us
to continue the clinical study for people of the world in
this improbable crisis as each and every life counts.
We urge the different medical societies and International
organizations to take up this unique observation and
quickly give it a trial and clearance because these drugs
are FDA approved for many years with excellent safety
and efficacy reviews. At the very least, using them in
the first few days of being positive with or without
symptoms may save the admissions of those 20% who
suffer and the unnecessary deaths on ventilators. We
can also stop the community transmission by
asymptomatic carriers by treating the asymptomatic
COVID-19 positive patients. Above all it is a very cheap
combination, and if fast tracked by a quick trial would
cost pennies and save a lot of lives, specifically designed
for resource-poor settings.
References:
1. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff
K.M. The FDA-approved Drug Ivermectin inhibits the
replication of SARS-CoV-2 in vitro. Antivir Res. 3 April
2020:104787. [PMC free article] [PubMed] [Google
Scholar]
2. Holmes NE, Charles PGP. Safety and Efficacy Review of
Doxycycline. Clinical Medicine Therapeutics.
2009;1:CMT.S2035.
3. Mehlhorn H (2008). Encyclopedia of parasitology (3rd
ed.). Berlin: Springer. p. 646. ISBN 978-3-540-48994-8.
4. Vercruysse J, Rew RS, eds. (2002). Macrocyclic lactones in
antiparasitic therapy. Oxon, UK: CABI Pub. p. Preface.
ISBN 978-0-85199-840-4.
5. World Health Organization (2019). World Health
Organization model list of essential medicines: 21st list
2019. Geneva: World Health Organization. hdl:10665/
325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-
NC-SA 3.0 IGO.
6. Azeem S., Ashraf M., Rasheed M.A., Anjum A.A., Hameed
R. Evaluation of cytotoxicity and antiviral activity of
ivermectin against Newcastle disease virus. Pak J Pharm
Sci. 2015;28(2):597–602. [PubMed] [Google Scholar]
7. Mastrangelo E., Pezzullo M., De Burghgraeve T., Kaptein
S., Pastorino B., Dallmeier K. Ivermectin is a potent
inhibitor of flavivirus replication specifically targeting NS3
helicase activity: new prospects for an old drug. J
Antimicrob Chemother. 2012;67(8):1884–1894. doi:
10.1093/jac/dks147. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
8. Götz V., Magar L., Dornfeld D., Giese S., Pohlmann A.,
Höper D. Influenza A viruses escape from MxA restriction
at the expense of efficient nuclear vRNP import. Sci Rep.
2016;6:23138. doi: 10.1038/srep23138. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]
9. Lundberg L., Pinkham C., Baer A., Amaya M., Narayanan
A., Wagstaff K.M. Nuclear import and export inhibitors
alter capsid protein distribution in mammalian cells and
reduce Venezuelan Equine Encephalitis Virus replication.
Antivir Res. 2013;100(3):662–672. [PubMed] [Google
Scholar]
10. R. Choudharyand A.K. Sharma. Potential use of
hydroxychloroquine, ivermectin and azithromycin drugs
in fighting COVID-19: trends, scope and relevance. New
Microbes New Infect. 2020 May; 35: 100684. Published
online 2020 Apr 22 doi: 10.1016/j.nmni.2020.100684
11. FDA. FAQ: COVID-19 and Ivermectin Intended for Animals
2020 [cited 2020 17 June]. Available from: https://
www.fda.gov/animal-veterinary/product-safety-
information/faq-covid-19-and-ivermectin-intended-
animals https://www.fda.gov/animal-veterinary/product-
safety-information/faq-covid-19-and-ivermectin-intended-
animals
12. McCarthy J., Laukas A., Hotez P.J. Chemotherapy of
Helminth infections (Chapter 51). Goodman Gilman’s
The Pharmacological Basis of Therapeutics, 12 ed. New
York: McGraw-Hill Companies, Inc; 2011. pg- 1456
Goodman and Gilman’s The Pharmacological Basis of
Therapeutics 12th edition, pg-1456
13. Claudio Conforti, Roberta Giuffrida, Iris Zalaudek, and Nicola
Di Meo. Doxycycline, a widely used antibiotic in dermatology
with a possible anti inflammatory action against IL 6 in
COVID 19 outbreak. Dermatol Ther. 2020 May 15: e13437.
doi: 10.1111/dth.13437 [Epub ahead of print]
14. Sodhi, M. and Etminan, M., 2020. Therapeutic Potential
for Tetracyclines in the Treatment of COVID 19.
Pharmacotherapy: The Journal of Human Pharmacology
and Drug Therapy, 40(5), pp.487-488.
Journal of Bangladesh College of Physicians and Surgeons Vol. 38, COVID-19 (Supplement Issue), July 2020
14

15. MacDougall C., Chambers H. F. Protein Synthesis Inhabitors
and Miscellaneous Antibectorial Agents (Chapter 55).
Goodman Gilman’s The Pharmacological Basis of
Therapeutics, 12 ed. New York: McGraw-Hill Companies,
Inc; 2011. pg- 1524Goodman and Gilman’s The
Pharmacological Basis of Therapeutics 12th edition,
pg-1524
16. Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy
of hydroxychloroquine in patients with COVID-19
pneumonia who require oxygen: observational comparative
study using routine care data. BMJ. 2020;369:m1844.
17. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in
patients with mainly mild to moderate Coronavirus Disease
2019: open label, randomised controlled trial. BMJ.
2020;369:m1849.
18. Rosenberg ES, Dufort EM, M Udo T, et al. Treatment with
hydroxychloroquine or azithromycin and in-hospital
mortality in patients with COVID-19. JAMA. 2020; Epub
ahead of print
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.
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