An overview on the current available treatment for COVID-19 and the impact of antibiotic administration during the pandemic

Paula, H.S.C.; Santiago, S.B.; Araújo, L.A.; Pedroso, C.F.; Marinho, T.A.; Gonçalves, I.A.J.; Santos, T.A.P.; Pinheiro, R.S.; Oliveira, G.A.; Batista, K.A.

doi:10.1590/1414-431X2021e11631

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Review • Braz. J. Med. Biol. Res. 55 • 2022 • https://doi.org/10.1590/1414-431X2021e11631 copy

An overview on the current available treatment for COVID-19 and the impact of antibiotic administration during the pandemic

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused several problems in healthcare systems around the world, as to date, there is no effective and specific treatment against all forms of COVID-19. Currently, drugs with therapeutic potential are being tested, including antiviral, anti-inflammatory, anti-malarial, immunotherapy, and antibiotics. Although antibiotics have no direct effect on viral infections, they are often used against secondary bacterial infections, or even as empiric treatment to reduce viral load, infection, and replication of coronaviruses. However, there are many concerns about this therapeutic approach as it may accelerate and/or increase the long-term rates of antimicrobial resistance (AMR). We focused this overview on exploring candidate drugs for COVID-19 therapy, including antibiotics, considering the lack of specific treatment and that it is unclear whether the widespread use of antibiotics in the treatment of COVID-19 has implications for the emergence and transmission of multidrug-resistant bacteria.

COVID-19; SARS-CoV-2; Antimicrobial resistance; Multidrug-resistant bacteria

Therapy	Mechanism of action	Approval for COVID-19 use	Recommendations	Reference
Colchicine	Anti-mitotic, anti-inflammatory activities. It interferes with secretion of inflammatory cytokines.	Not approved	There is insufficient evidence to recommend the use for the treatment of COVID-19.	(14,15)
Chloroquine and Hydroxychloroquine	The drugs seem to interfere with the activity of ACE2, making it unable to interact with the SARS-CoV-2 spike protein, preventing the virus from entering the cells. The drugs interfere with the endosomal pH, which may affect the ability of the virus to fuse and enter cells.	Not approved	Not recommended for prophylactic use nor for treatment of COVID-19 infected individuals independent of illness severity.	(37,39)
Dexamethasone	Blockade of inflammation pathways; vasodilation and immune cell migration.	FDA ANVISA	Recommended for hospitalized patients requiring supplemental oxygen or mechanical ventilation.	(18)
Remdesivir	Inhibitor of viral RNA polymerase.	FDA ANVISA	Recommended for hospitalized patients requiring supplemental oxygen, but not recommended for routine use in patients who require mechanical ventilation.	(34)
Convalescent plasma	Passive immunity in the form of neutralizing antibodies obtained using apheresis in survivors with prior infection of SARS-CoV-2.	FDA ANVISA	Recommended only in the context of a clinical trial.	(22,25)
Monoclonal antibodies
Bamlanivimab and Etesevimab	Bamlanivimab and etesevimab bind to different but overlapping sites on the receptor binding domain of the spike protein of SARS-CoV-2 blocking its attachment to the human ACE2 receptor.	FDA ANVISA	Recommended for the treatment of mild to moderate COVID-19 in adults and children over 12 years old and weighing at least 40 kg.	(30,31)
Tocilizumab	Tocilizumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that inhibits the binding of IL-6 to both membrane and soluble IL-6 receptors, blocking IL-6 signaling and reducing inflammation.	FDA	Suggested use on hospitalized with severe or critical disease receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation.	(32)
Casirivimab and Imdevimab	Casirivimab and imdevimab bind to different sites on the receptor binding domain of the spike protein of SARS-CoV-2, blocking its attachment to the human ACE2 receptor.	FDA ANVISA	Patients with mild to moderate COVID-19 at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19.	(33)

Antibiotic	Antiviral mechanism	Compliance with WHO guidelines (46)	Reference
Fluoroquinolones		WHO does not recommend the use of antibiotics in mild-to-moderate COVID-19 patients. WHO does not encourage the use of broad-spectrum antibiotics for COVID-19 management, especially those from the Watch and Reserve list. WHO recommends the use of antibiotic therapy for patients with suspected or confirmed severe COVID-19 presenting highly suspected pneumonia based on clinical signs.	(81)
Levofloxacin	Membrane fusion inhibition; replication inhibition; immunomodulatory effects
Moxifloxacin	Inhibition of SARS-CoV-2 replication; immunomodulatory activity
Ciprofloxacin	Inhibition of viral replication; immunomodulatory activity.
Cephalosporines		WHO does not recommend antibiotics for therapy and/or prophylaxis in suspected or confirmed mild-to-moderate COVID-19 patients unless a bacterial infection is confirmed. WHO does not encourage the use of broad-spectrum antibiotics for COVID-19 management, especially second-to-fourth generation cephalosporins, which are listed as Watch and Reserve antibiotics.	(54,55)
First- to fourth-generation	Viral replication inhibition; inhibition of the interaction between the viral spike protein and ACE2 receptors.
Macrolides		WHO does not recommend antibiotics for therapy and/or prophylaxis in suspected or confirmed mild-to-moderate COVID-19 patients unless a bacterial infection is confirmed; WHO does not recommend the therapeutic and/or prophylactic use of azithromycin alone or with hydroxychloroquine/chloroquine for COVID-19; WHO does not encourage the use of broad-spectrum antibiotics for COVID-19 management, especially those from the Watch and Reserve list.	(57,59,64-67)
Azithromycin	Attenuation of viral infection by (i) increasing endosomal/lysosomal pH; (ii) membrane fusion inhibition; and (iii) amplifying the interferon-mediated antiviral responses; Decreases the production of cytokines, reducing the occurrence of a “cytokine storm”.
Clarithromycin	Immunomodulatory effects by (i) suppressing the infection-related inflammation and (ii) reducing the vascular hyper-permeability.
Tetracyclines		WHO recommends the use of antibiotic therapy for patients with suspected or confirmed severe COVID-19 presenting highly suspected pneumonia based on clinical signs. WHO recommends against the use of antibiotic therapy or prophylaxis for patients with suspected or confirmed mild-to-moderate COVID-19 without a presence of a bacterial co-infection. WHO does not encourage the use of broad-spectrum antibiotics for COVID-19 management, especially those from the Watch and Reserve list.	(56)
Doxycycline	Inhibition of viral replication; interference with protein synthesis; immunomodulatory effects.
Minocycline	Inhibition of protein synthesis; Inhibition of RNA replication; immunomodulatory effects.

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[1] Correspondence: K.A. Batista: <karla.batista@ifg.edu.br>