Researchers Warn That Azithromycin Should Not Be Used For COVID-19

Azithromycin: In a new study published in the Oxford Journal: Open Forum Infectious Disease, researchers Dr Jeniffer Lighter and Dr Vanessa Raabe from New York University School of Medicine warn against the use of the antibiotic azithromycin to treat COVID-19. https://academic.oup.com/ofid/article/7/6/ofaa207/5849083


 
In the mad scramble to find drugs to treat COVId-19 and the testing of various drugs, many detrimental mistakes are being made. There is currently a paucity of evidence to recommend any specific regimen. Decisions are being made by regulatory bodies based on flimsy evidence and by lobbying of pharma giants with vested interest.
 
The usage of azithromycin was started by the publication in the  International Journal of Antimicrobial Agents of a ‘half-baked study’ by French researchers. https://www.sciencedirect.com/science/article/pii/S0924857920300996#!
It must be note noted that many French studies are conducted in substandard manners and also many have a notoriety for manipulating research findings.
 
In reality recommending azithromycin for COVID-19 treatment is careless. A close examination of this journal article and its treatment recommendation that has many experts questioning its credibility and revealing its poor methodology and lack of evidence to support this variation of treatment in COVID-19-positive patients. The investigators did not enroll their minimum predicted number of patients to reach 85% confidence for analysis, so outcome end points in the final manuscript were modified from the original intended analysis. Only 14 patients were treated with HCQ, 6 with HCQ and azithromycin, and 16 in a control group selected from a different hospital.
 
As differences between treatment groups rely on small numbers of patients, and statistical analysis for the risk of error in concluding that these groups were different was not performed. Treatment effectiveness was measured by percentage of individuals with negative nasopharyngeal (NP) polymerase chain reaction (PCR) swabs each day. Yet, the cumulative number of patients with negative swabs was missing, and in postanalysis, 1 patient in the HCQ + azithromycin group became positive again. The PCR NP test has moderate sensitivity, and with sample error, it shows day-to-day shifts in positivity. Standard measures of drug effectiveness were not evaluated, such as quantitative viral load using cycle thresholds, replicating virus such as viral culture, or clinical end points such as hospitalization length or morbidity and mortality. The study ended after day 6 of illness, and as has been well described for COVID-19 patients, many develop moderate or severe symptoms after the first week of symptoms. Ending the study so early missed an opportunity for more concrete validation. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
 
Yet despite the poor methodology and lack of evidence to support clinical benefit from the combination regimen, thousands of clinicians throughout the world are using th is regimen to treat COVID-19 patients.
 
Most significantly, there are currently no in vitro or animal data to suggest that azithromycin alone has antiviral activity against betacoronaviruses. The fact that it was even recommended for patient treatment trials remains a mystery.
 
Preliminary evidence from microbiology shows that azithromycin does not, in fact, inhibit SARS-CoV-2 replication in vitro in Vero cells (Kenneth Stapleford, PhD, email communication, April 2020..please refer to actual published study for all references). Moreover, there is no reported evidence that azithromycin has any anti-inflammatory effect against COVID-19 disease, as is suggested by other disease states.
 
Furthermore there is also recent evidence of higher mortality rates in COVID patients treated with both HCQ and azithromycin compared with HCQ alone. A large cohort of drug dispensation data is available through Agilum Healthcare intelligence, a pharmaceutical analytics group. https://covid19.agilum.com/agilum-releases-nationwide
-covid-19-real-world-data-rwd-survival-rate-analytics/
 
Agilum Healthcare examined inpatient dispensations of select drugs from March 1 to May 11, 2020, from hospitals nationwide, leveraging a current, near real-time data stream in order to improve timeliness and accuracy. An analysis of COVID-19 treatment regimens by age and gender on each regimen was performed, describing average hospital lengths of stay and survival rates. A total of 33 936 patients thus far have been analyzed, including 20 219 who have received HCQ (or chloroquine) plus azithromycin and 12 708 HCQ (or chloroquine) alone. The survival rate in the HCQ alone group was greater in the cohort with and without comorbidities, 88.6% and 88.1% respectively, compared with the HCQ plus azithromycin group, where survival was 86.4% and 85.5% in patients with and without underlying medical comorbidities. The length of hospital stay was 2 days less for the HCQ group in both the cohorts with and without comorbidities, compared with the HCQ plus azithromycin groups.
 
Lastly it has been proven that HCQ and azithromycin independently can induce QT interval prolongation, torsades de pointes, and drug-induced sudden cardiac death. Therefore, combining these medications poses a substantial safety risk https://jamanetwork.com/journals/jamacardiology/fullarticle/2765633 and https://pubmed.ncbi.nlm.nih.gov/32356863/ .
 
 A past international cohort study comprising 956 374 HCQ users, in which 323 122 used both HCQ and azithromycin, observed an increased risk of 30-day cardiovascular mortality, chest pain/angina, and heart failure among the patients taking HCQ plus azithromycin compared with HCQ use alone. https://www.medrxiv.org/content/10.1101/2020.04.08.20054551v2
 
The new coronavirus that causes COVID-19  can directly infect the heart, which may independently further predispose COVID-19 patients to arrhythmia development aside from the risks conveyed by pro-arrhythmogenic drug combinations . https://www.sciencedirect.com/science/article/pii/S0022282820301218
 
The Infectious Diseases Society of America, Centers for Disease Control and Prevention, and National Institutes of Health recommend that combination therapy with HCQ and azithromycin only be prescribed in the context of clinical trial use due to the potential for toxicity. https://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32338708
 
The researchers write in, “In summation, that there is no justifiable preclinical or clinical evidence to suggest that the benefits of azithromycin for COVID-19 outweigh the risks of treatment. Patients have lower mortality and length of stay rates with HCQ alone compared with combination treatment with azithromycin, and the cardiac side effects of combination therapy may be contributing to increased morbidity and mortality. The Hippocratic Oath states that physicians should ‘first, do no harm’ to patients; therefore, clinicians should stop prescribing azithromycin for COVID-19 treatment. Until more data from randomized controlled trials become available, physicians must resist sensationalized remedies and instead rely on the methodical skills developed in medical school and training to evaluate possible therapeutics. We must keep our astute skepticism of articles that have not gone through the due diligence of a peer-reviewed process. And we should not be swayed by the desperate and emotional public overtones to prescribe the ‘remedy of the day’.”
 
Interestingly enough, another study published only a few days ago warns that the use of azithromycin is associated with increased cardiovascular deaths. 
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767245#:~:
text=Azithromycin%20was%20associated%20with%20a%20significantly
%20increased%20hazard%20of%20cardiovascular,to%2010%20days%20after%20exposure.

The antibiotic azithromycin is one of the most commonly prescribed antibiotics in the US. A safety concern was raised following a study that associated azithromycin use with sudden cardiac death. Prompted by the concern over its safety issues, Dr Jonathan G. Zaroff, Division head of Research, Kaiser Permanente Northern California, and colleagues conducted the study to estimate the relative and absolute risks of cardiovascular and sudden cardiac death after an outpatient azithromycin prescription compared with amoxicillin.

The researchers retrospectively compared outcomes in some 3 million patients prescribed either azithromycin or amoxicillin -- an antibiotic not known to increase cardiovascular events. Data were analyzed from December 1, 2016, to March 30, 2020. The primary outcomes were cardiovascular death and sudden cardiac death. The study included 7 824 681 antibiotic exposures, including 1 736 976 azithromycin exposures (22.2%) and 6 087 705 amoxicillin exposures (77.8%), among 2 929 008 unique individuals (mean [SD] age, 50.7 [12.3] years; 1 810 127 [61.8%] women).

Significant key findings of the study include: Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio [HR], 1.82) but not sudden cardiac death (HR, 1.59) within 5 days of exposure. No increases in risk were found 6 to 10 days after exposure. Similar results were observed in patients within the top decile of cardiovascular risk (HR, 1.71). Azithromycin was also associated with an increased risk of noncardiovascular death (HR, 2.17) and all-cause mortality (HR, 2.00) within 5 days of exposure.

Dr Zaroff told Thailand Medical News, "There was an approximately 2-fold increased risk of cardiovascular death and noncardiovascular death after outpatient azithromycin use compared with the use of amoxicillin within a 5-day window after dispensing. Although these analyses cannot establish causality, prescribers should be aware of this potential association."

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