Doxycycline - Rationale for Use in COVID-19

The pandemic of coronavirus disease (COVID-19) has massively spread across 210 countries & territories around the globe. The agent causing the infection identified to be a beta coronavirus; was first named as Novel coronavirus (2019-nCoV). The International Committee of taxonomy of viruses then changed the name to SARS-CoV-2, connoting the coronavirus causing severe acute respiratory syndrome-2 (1)

Several generations have been exposed to COVID-19 at different stages of life. Moreover, most of the best available anti-viral agents have been of limited help in the treatment of COVID-19.(2)

Managing COVID-19 – Evolving Therapy Expectations & Repurposing of Existing Drugs

Respiratory failure had been certainly the major cause of death in previous viral pandemics, from the Spanish flu in 1918 to the MERS-CoV in 2012, likewise is the case in the new COVID-19.(3) While our understanding of the complex disease pathways continues to move forward; broadly, key medications' targets are repurposed antiviral, other anti-infective, or immunomodulatory agents, in addition to drugs that act on host cell receptors.(1)

Doxycycline – Promising Partner in COVID-19 Care

Antimicrobial with Multimodal Action

Doxycycline - semisynthetic derivative of tetracycline, has well-defined anti-bacterial effects. In vitro studies have indicated doxycycline to be possessing anti-inflammatory effects at low (20-40 mg/day) and high (100 or 200 mg/day) doses, along with inhibitory action on metalloproteases and modulating effects on pro-inflammatory cytokines IL-6, IL-8, and tumor necrosis factor-alpha (4)

Antiviral Activity – To Multiple Viruses & Through Multiple Pathways

In-vitro studies have indicated the antiviral activity of Doxycycline against SARS-CoV-2 (5). The mechanism of the antiviral effects of tetracycline derivatives seems to be secondary to transcriptional upregulation of intracellular zinc-finger antiviral protein (ZAP), an encoding gene in host cells (6). ZAP can also bind to specific target viral mRNAs and represses the RNAs translation (7). Experimental studies have used tetracyclines to induce the overexpression of host ZAP in HEK293 (Human Embryonic Kidney cells 293), rats and monkeys cell lines (Vero cells), which contributed to the inhibition of RNA viruses such as the Dengue, Ebola, Human Immunodeficiency Virus, Zika, and Influenza A viruses(6)

Doxycycline is a highly lipophilic agent that chelates zinc compounds on matrix metalloproteinases (MMPs) of mammalian cells (8) - an in vitro study suggesting that murine coronaviruses rely on MMPs for cell fusion and viral replication. Other plausible pathways of viral fusion and replication by coronaviruses utilize host proteases (9), also could be a possible target to doxycycline.

Anti-inflammatory – Inhibiting the Key Mediators of Cytokine Storm

In COVID-19, global evidential experiences indicate elevated levels of blood interleukin (IL)-6 have been more commonly associated with severe COVID-19 illness and among non-survivors, suggesting that mortality might be due to virus-driven hyper inflammation and to cytokine storm. (10)

Intense proinflammatory states had also been implicated to have a key role in the pathogenesis of dengue and haemorrhagic fever, leading to cytokine storm. Of valuable importance is to note that, doxycycline reduced pro-inflammatory cytokines, including IL-6 and tumour necrosis factor (TNF)-α, in patients with dengue haemorrhagic fever, and mortality rates were found to be 46 % lower in doxycycline-treated patients(11).

Global Recommendations for Doxycycline

NICE UK guideline - Antibiotics for pneumonia in adults in the hospital during COVID-19(12):

• Doxycycline is considered one of the empirical choices of oral antibiotics:
• For moderate to severe pneumonia in adults (>18 years) with suspected Community-Acquired Pneumonia (CAP)
  
• For non-severe pneumonia in adults (>18 years) with suspected Hospital Acquired Pneumonia (HAP)

Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance(13)

If empirical antibiotics are indicated, the recommendation is for:

• Doxycycline 100 mg PO BID x 5 days or Azithromycin 500 mg PO x 1 then 250 mg PO daily for 4 days along with Ceftriaxone 1 gm IV daily.
• For nonpregnant patients, doxycycline is preferred over azithromycin.
  

Coronavirus disease 2019 (COVID-19) continues to remain a significant public health challenge, and the current antiviral arsenal for its treatment is limited, with questionable efficacy. While efforts are underway for the discovery of new effective agents, validation of their actual potential may take quite some time

Therefore, the repurposing of existing drugs for new indications is the need of the hour, as we see it happening globally. Along with this endeavor, Doxycycline emerges as an antimicrobial agent possessing antiviral and anti-inflammatory activities; which by dampening the critical cytokine storm has the potential to prevent lung damage.(14) Along with its cost-effectiveness, acceptable tolerance (15) and ease of availability, Doxycycline, as a prominent consideration in patients with COVID-19 seem a rational as well as a realistic one.

References

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2. Saghazadeh A, Rezaei N. Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids. Int Immunopharmacol. 2020;84:106560. doi:10.1016/j.intimp.2020.106560
3. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on ananalysis of data of 150 patients from Wuhan, China. Intensive Care Med [Internet]. 2020 Mar 3;1–3. Available from: http://link.springer.com/10.1007/s00134-020-05991-x
4. Di Caprio R, Lembo S, Di Costanzo L, Balato A, Monfrecola G. Anti-inflammatory properties of low and high doxycycline doses: an in vitro study. Mediators Inflamm. 2015;2015:329418. https://doi.org/10.1155/2015/329418
5. In vitro antiviral activity of doxycycline against SARS-CoV-2 – IHU. [cited 2020 Apr 23]. Available from: https://www.mediterranee-infection.com/invitro- antiviral-activity-of-doxycycline-against-sars-cov-2
6. Tang Q, Wang X, Gao G. The short form of the zinc finger antiviral protein inhibits Influenza A virus protein expression and is antagonized by the virus encoded NS1. J Virol 2017, doi:http://dx.doi.org/10.1128/jvi.01909-16.
7. Guo X, Carroll J-WN, MacDonald MR, Goff SP, Gao G. The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs. J Virol 2004, doi:http://dx.doi.org/10.1128/jvi.78.23.12781-12787.2004.
8. Vanlaere I, Libert C. Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock. Clin Microbiol Rev 2009, doi:http://dx.doi.org/10.1128/CMR.00047-08
9. Phillips JM, Gallagher T, Weiss SR. Neurovirulent Murine Coronavirus JHM.SD uses cellular zinc metalloproteases for virus entry and cell-cell fusion. J Virol 2017, doi:http://dx.doi.org/10.1128/jvi.01564-16.
10. Zhou F, Yu T, Du R, et al. Clinical course, and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020, doi:http://dx.doi.org/10.1016/S0140-6736(20)30566-3.
11. Fredeking T, Zavala-Castro J, Gonzalez-Martinez P, et al. Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF Levels. Recent Pat Antiinfect Drug Discov 2015, doi:http://dx.doi.org/10.2174/1574891x10666150410153839
12. COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital, NICE guideline Published: 1 May 2020 www.nice.org.uk/guidance/ng173
13. Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance, July 2020, Version 6.1 7/1/2020
14. Malek AE, Granwehr BP, Kontoyiannis DP. Doxycycline as a potential partner of COVID-19 therapies. IDCases. 2020;21:e00864. Published 2020 Jun 6. doi:10.1016/j.idcr.2020.e00864
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