Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Repurposing of older drugs such as chloroquine or hydroxychloroquine (HC) and more recently, azithromycin (AZ), has received much attention recently in the treatment of Covid-19. Both HC and AZ have immune modulating and antiviral activity that may potentially be effective in our fight against Covid-19.

 
Chloroquine/HC: Chloroquine is an old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. It is active in mice against a variety of viruses, including some enteroviruses, Zika virus, and influenza A H5N1 (1). Both chloroquine and HC are active in vitro against Covid-19, though HC appears to be more active (2).

 
Azithromycin: A macrolide often used for treatment of bacterial respiratory tract infections but also with anti-inflammatory and antiviral activity. Azithromycin has been shown to augment interferon response in rhinovirus-infected bronchial epithelial cells as well as in an experimental mouse model of asthma exacerbation (3,4). It also has activity against Zika virus (5). As recently as 2016, some authors opined that macrolides may be useful in pandemic influenza characterized by excessive inflammatory cytokine production because of their anti-inflammatory and interferon-boosting potential (6).

 
March 2020 French clinical trial: A small non-randomized clinical trial involving 36 confirmed Covid-19 patients (mean age 45 y) reported that HC (200 mg 3x/day x 10 days) was associated with rapid viral clearance from nasopharynx, often within 3-6 days (7). The effect was even more pronounced when AZ (500 mg 1st day, followed by 250 mg daily x 4 days) was added in 6 patients.

It’s worth emphasizing that most subjects in this study were either asymptomatic (17%) or had mild disease with upper respiratory tract infection symptoms only (61%). Pneumonia was diagnosed in only 6 patients.  A significant number of patients in the treatment arm also dropped out of the study, some due to ICU transfer.

 
Although such preliminary reports appear promising, the proof of the efficacy and safety of HC and/or AZ in the treatment of Covid-19 awaits larger properly designed clinical studies. Stay tuned!

 

 

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References
1. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.ncbi.nlm.nih.gov/pubmed/32147496
2. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respirartory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020, March 9. https://www.ncbi.nlm.nih.gov/pubmed/32150618
3. Menzel M, Akbarshai H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Scientific Reports 2016;6:28698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923851/
4. Menzel M, Akbarshai H, Uller L. Azithromycin exhibits interferon-inducing properties in an experimental mouse model of asthma exacerbation. Eur Resp J 2015;46:PA5095. https://erj.ersjournas.com/content/46/suppl_59/PA5095
5. Retallack H, Di Lullo E, Knopp AC, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Nat Acad Sci USA 2016;113:14408-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167169/
6. Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III-IFN-augmenting activity in airway epithelium. J Antimicrob Chemother 2016;71:2767-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031920/
7. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19:results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents—In Press 17 March 2020-DOI: 10.1016/j.ijantimicag.2020.105949 . https://www.sciencedirect.com/science/article/pii/S0924857920300996

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

What changes should I consider in my treatment of hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic society (ATS) and Infectious Diseases Society of America (IDSA)?

Compared to 2007,1 the 2019 ATS/IDSA guidelines2 propose changes in at least 4 major areas of CAP treatment in inpatients, with 2 “Do’s” and 2 “Dont’s”:

  • Do select empiric antibiotics based on severity of CAP and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (see related pearl on P4P)
  • Do routinely treat CAP patients who test positive for influenza with standard CAP antibiotics
  • Don’t routinely provide anaerobic coverage in aspiration pneumonia (limit it to empyema and lung abscess) (see related pearl on P4P)
  • Don’t routinely treat CAP with adjunctive corticosteroids in the absence of refractory shock

β-lactam plus macrolide is recommended for both non-severe and severe CAP.  β-lactam plus respiratory fluoroquinolone is an alternative regime in severe CAP, though not endorsed as strongly as β-lactam plus macrolide therapy (low quality of evidence).  Management per CAP severity summarized below:

  • Non-severe CAP
    • β-lactam (eg, ceftriaxone, cefotaxime, ampicillin-sulbactam and newly-added ceftaroline) plus macrolide (eg, azithromycin, clarithromycin) OR respiratory fluoroquinolone (eg, levofloxacin, moxifloxacin)
    • In patients at risk of MRSA or P. aeruginosa infection (eg, prior isolation of respective pathogens, hospitalization and parenteral antibiotics in the last 90 days or locally validated risk factors—HCAP has been retired), obtain cultures/PCR
    • Hold off on MRSA or P. aeruginosa coverage unless culture/PCR results return positive.
  • Severe CAP
    • β-lactam plus macrolide OR β-lactam plus respiratory fluoroquinolone (see above)
    • In patients at risk of MRSA or P. aeruginosa infection (see above), obtain cultures/PCR
    • Add MRSA coverage (eg, vancomycin or linezolid) and/or P. aeruginosa coverage (eg, cefepime, ceftazidime, piperacillin-tazobactam, meropenem, imipenem) if deemed at risk (see above) while waiting for culture/PCR results

Duration of antibiotics is for a minimum of 5 days for commonly-targeted pathogens and a minimum of 7 days for MRSA or P. aeruginosa infections, irrespective of severity or rapidity in achieving clinical stability.

For patients who test positive for influenza and have CAP, standard antibacterial regimen should be routinely added to antiinfluenza treatment.

For patients suspected of aspiration pneumonia, anaerobic coverage (eg, clindamycin, ampicillin-sulbactam, piperacillin-tazobactam) is NOT routinely recommended in the absence of lung abscess or empyema.

Corticosteroids are NOT routinely recommended for non-severe (high quality of evidence) or severe (moderate quality of evidence) CAP in the absence of refractory septic shock.

Related pearls on P4P:

2019 CAP guidelines on diagnostics:                                        https://pearls4peers.com/2020/02/14/what-changes-should-i-consider-in-my-diagnostic-approach-to-hospitalized-patients-with-community-acquired-pneumonia-cap-in-light-of-the-2019-guidelines-of-the-american-thoracic-society-ats-and-inf/ 

Anerobic coverage of aspiration pneumonia: https://pearls4peers.com/2019/07/31/should-i-routinely-select-antibiotics-with-activity-against-anaerobes-in-my-patients-with-presumed-aspiration-pneumonia/

References

  1. Mandell LA, Wunderink RG, Anzueto A. Infectious Disease Society of America/American Thoracic Society Consensus Guidelines on the Management guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72. https://www.ncbi.nlm.nih.gov/pubmed/17278083
  2. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2019;200:e45-e67. https://www.ncbi.nlm.nih.gov/pubmed/31573350

 

What changes should I consider in my treatment of hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic society (ATS) and Infectious Diseases Society of America (IDSA)?

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Assuming no recent changes in the dose of warfarin, one potential culprit may be her recent antibiotic exposure. Of the long list of antibiotics associated with elevated INR, quinolones (e.g. ciprofloxacin, levofloxacin), trimethoprim-sulfamethoxazole, macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are generally thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk. 1-3

Other drugs such as amiodarone (Did she have atrial fibrillation during her recent hospitalization?), acetaminophen (Has she been receiving at least 2 g/day for several consecutive days?), and increasing dose of levothyroxine (Was she thought to be hypothyroid recently?) should also be considered.3,4

Also remember to ask about herbal supplements (eg, boldo-fenugreek, dong quai, danshen) that may potentiate the effect of warfarin. 3 Of course, poor nutrition in the setting of recent illness might have also played a role.5

As far as the mechanisms for drug interaction with warfarin, some drugs act as cytochrome p450 inhibitors (thus reducing the metabolism of warfarin), while others influence the pharmacodynamics of warfarin by inhibiting the synthesis or increasing the clearance of vitamin K-2 dependent coagulation factors.3

Antibiotics may increase the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Check out a related pearl on P4P: https://pearls4peers.com/2015/06/25/is-there-anyway-to-predict-a-significant-rise-in-inr-from-antibiotic-use-in-patients-who-are-also-on-warfarin  

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References

  1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
  2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf
  3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292.  https://www.ncbi.nlm.nih.gov/pubmed/22315269
  4. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011;31:591-7. https://www.ncbi.nlm.nih.gov/pubmed/21923443
  5. Kumar S, Gupta D, Rau SS. Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. Clin Pract. 2011;1:e21. doi:10.4081/cp.2011.e21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981245

 

Contributed by Rachel Weitzman, Medical Student, Harvard Medical School, Boston, MA.

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

AZ is a macrolide antibiotic which interferes with bacterial protein synthesis by binding to the 50S ribosomal subunit. It is often used to treat acute respiratory tract infections due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as Mycoplasma, Chlamydia, and Legionella sp1. Although it has no in vitro activity against many aerobic gram-negative bacilli such as Pseudomonas aeruginosa, its chronic use has often been associated with a significant reduction in the frequency of disease exacerbations in patients with chronic bronchiectasis and colonization due to this organism, including patients with COPD or CF1-3.

Because P. aeruginosa is invariably macrolide-resistant, the beneficial effect of AZ in chronically infected or colonized patients must be due to factors other than its direct effect on bacterial replication.  Several mechanisms have been invoked including: 1. Inhibition of quorum-sensing dependent virulence factor and biofilm production 2.Blunting of host inflammatory response (eg, ↑IL-10, and ↓ IL-1ß, IL-6, IL-8, TNF-α, and ↓ chemotaxis); and 3. Enhanced antiviral response1.

The latter finding is quite unexpected but AZ appears to augment interferon response to rhinovirus in bronchial cells of COPD patients3.  With respiratory viruses (including rhinoviruses) causing 20-55% of all COPD exacerbations, perhaps this is another way AZ may help the host! Who would have thought!!

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References

  1. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation 2012;94:101-109.
  2. Cochrane review. Treatment with macrolide antibiotics for people with cystic fibrosis and chronic chest infection. Nov 14, 2012. http://www.cochrane.org/CD002203/CF_treatment-with-macrolide-antibiotics-for-people-with-cystic-fibrosis-and-chronic-chest-infection
  3. Menzel M, Akbarshahi H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD. Scientific Reports 2016; 6:28698. DOI:10.1038/srep 28698.

 

 

How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

Is there anyway to predict a significant rise in INR from antibiotic use in patients who are also on warfarin?

Not really!  Many of the commonly used antibiotics have the potential for increasing the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Although there may be some inconsistencies in the reports, generally quinolones (e.g. ciprofloxacin, levofloxacin), sulonamides (e.g. trimethoprim-sulfamethoxazole), macrolides  (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk (1,2).  Metronidazole can also be a culprit (2).

References

1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622

2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf

Is there anyway to predict a significant rise in INR from antibiotic use in patients who are also on warfarin?