Doxycycline in COVID-19: How a Veteran Antibiotic Stands Out?!!

A significant proportion of patients with COVID-19 present with fever and cough. Those requiring hospitalization due to dyspnoea usually have bilateral radiological infiltrates. (3) Despite the viral origin of COVID-19, a standard reflex by physicians is to start treatment with antibiotics, since cough, fever and radiological infiltrates are hallmarks of bacterial community-acquired pneumonia which requires antibiotic treatment.

The anxiety and uncertainty surrounding the pandemic and the absence of globally recognised antiviral agents with proven efficacy are probably other contributors to widespread and excessive use of antibiotics.

Though the exact incidence of bacterial superinfection in CoVID-19 is unknown, the rationale and fair argument for antibiotic treatment in patients with COVID-19 seem to be based on past experience with bacterial superinfection in influenza, where most studies report initial co-infection or secondary bacterial pneumonia in up to 35% of cases in hospitalized patients.

While several unmet research needs are awaited to categorically define & rationalise use of antibiotics in patients with COVID-19, the following approach may be considered:

1. Antibiotics should be reserved for patients with the most severe presentations (e.g. those with high oxygen demands and rapidly progressing respiratory failure). Biomarkers (C-reactive protein, procalcitonin) may have a role in determining for which patients' antibiotics can be withheld.

2. If antibiotics are started, microbiological tests should ideally be obtained beforehand, whenever permissible

3. Antibiotic treatment should be continuously re-evaluated and stopped as soon as possible if the possibility of bacterial superinfection is considered low (e.g. persistently low inflammatory biomarkers, negative bacteriological tests, CT scan non-compatible with COVID).

4. If antibiotic treatment is continued, switch to oral agent needs to considered rapidly, if the patient is able to take oral medications, and absence of fever should not be required as a criterion for such switch; since patients with COVID-19 often show persistent fever over several days.

5. Antibiotic treatment duration should not exceed 5 days in most cases, as generally recommended in most guidelines for community-acquired pneumonia 6

6. If during COVID-19 treatment a secondary respiratory worsening occurs, use of antibiotics should be re-considered after taking adequate respiratory samples and performing radiological diagnostics. It is, however, important to realize that secondary worsening commonly seen between days 7 and 9 and in most cases is probably attributable to the hyperinflammatory phase which is an adaptive immune reaction rather than to a bacterial superinfection (7)

Doxycycline is a broad-spectrum tetracycline antimicrobial agent; it exhibits anti-inflammatory effects along with in vitro antiviral activity against several RNA viruses.

Tetracycline derivatives such as doxycycline are highly lipophilic antimicrobial agents that chelate zinc compounds on matrix metalloproteinases (MMPs) of mammalian cells (8) , and an in vitro study showed that murine coronaviruses rely on MMPs for cell fusion and viral replication. Other mechanisms of viral fusion and replication by coronaviruses utilize host proteases (9) , which could be a possible target to doxycycline.

In COVID-19, elevated levels of blood interleukin (IL)-6 have been more commonly observed in severe COVID-19 illness and among non-survivors, suggesting that mortality might be due to virus driven hyperinflammation and to cytokine storm. (10)

This acute reaction is similar to the intense proinflammatory state that has a central role in the pathogenesis of dengue and haemorrhagic fever, leading to cytokine storm and its complications' sequel. (11)

It is important to note that doxycycline decreased pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF)-α, in patients with dengue haemorrhagic fever, leading to a mortality rate that was 46 % lower in the doxycycline-treated group (11.2 %) than in the untreated group (20.9 %). Doxycycline was found to be more effective than tetracycline in the reduction of these proinflammatory cytokines. 

Severe acute respiratory syndrome–related coronavirus (SARS-CoV) encompasses a papain-like protease that significantly triggers an Early growth response protein 1 (Egr-1)– dependent activation of Transforming Growth Factor Beta 1 (TGF-β1), resulting in upregulation of pro-fibrotic responses in vitro and in vivo in the lungs (13) Recent computational method studies have identified doxycycline among the drugs that could potentially be used to inhibit this SARS-CoV-2 papain-like protease (14)

While the treatment options for pandemic continues to evolve, we have fairly established till date that patients with COVID-19 need both antiviral and anti-inflammatory treatment as well as protection against lung damage. Use of antibiotic needs to judicious and justified – but in the real- world practice settings, best remains a discretion of clinicians' judgement of patient assessment

While selecting an antibiotic, Doxycycline has been cited as a potential partner (15) of COVID-19 treatment armamentarium because of its anti-viral and anti-inflammatory effects, microbiological coverage against atypical bacterial pneumonia, and alleviating the lung sequel complications associated with COVID-19. Equally important practical advantages for Indian patients - it is widely available, cost-effective and safe.

While choosing Doxycycline for COVID-19, the clinician may be like consider it as an agent – not just antibiotic, but as an antimicrobial and beyond prospective.

1 WHO. Novel coronavirus—China. Jan 12 2020. https://www.who, (accessed I- 2020-novel-coronavirus- china/en/, Feb 12 2020)

2 Shi Y, Wang Y, Shao C, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 2020, doi:http://dx.doi.org/10.1038/s41418-020- 0530-3.

3 Rodriguez-Morales AJ, Cardona-Ospina JA, Gutierrez-Ocampo E, Villamizar- Pena R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis 2020:101623.

4 Klein EY, Monteforte B, Gupta A, Jiang W, May L, Hsieh YH, et al. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Virus. 2016; 10:394e40

5 Claessens YE, Debray MP, Tubach F, Brun AL, Rammaert B, Hausfater P, et al. Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia. Am J Respir Crit Care Med 2015;192:974e82.

6 Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019;200: e45e67

7 Xiong Y, Sun D, Liu Y, Fan Y, Zhao L, Li X, et al. Clinical and high-resolution CT features of the COVID-19 infection: comparison of the initial and follow-up changes. Invest Radiol 2020;55(6):332e9. https://doi.org/10.1097/RLI.0000000000000674

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 Fredeking TM, Castro JEZ, Vado-Solis I, Perez-Osorio C. Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever. Clin Dev Immunol 2011, doi:http://dx.doi.org/10.1155/2011/370872.

13 Barretto N, Jukneliene D, Ratia K, Chen Z, Mesecar AD, Baker SC. The papain like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol 2005, doi:http://dx.doi.org/10.1128/ jvi.79.24.15189-15198.2005.

14 Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B 2020, doi:http://dx.doi.org/10.1016/j.apsb.2020.02.008.

15 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