Azithromycin Should Not Be Used to Treat COVID-19.

As daily death tolls from COVID-19 continue to increase, there is a mad rush for therapeutic solutions that may improve patient outcomes. However, there is currently a paucity of evidence to recommend any specific regimen. Recently an article published in International Journal of Antimicrobial Agents suggested a decreased time to SARS-CoV-2 viral clearance in COVID-19-infected patients [1]. Since the release of this article, providers around the world have prescribed hydroxychloroquine (HCQ) with azithromycin. Its mythic effectiveness has even been claimed by the President of the United States as one of the “biggest game changers in the history of medicine” [2].

Truth be told, recommending azithromycin for COVID-19 treatment is careless. A close examination of this journal article and its treatment recommendation that has many shouting from the mountaintops actually reveals 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 [1]. 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 [1]. 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 [3]. Ending the study so early missed an opportunity for more concrete validation. 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 this regimen to treat COVID-19 patients.

Unfortunately, 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). Moreover, there is no reported evidence that azithromycin has any anti-inflammatory effect against COVID-19 disease, as is suggested by other disease states.

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 [4]. Agilum 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 [4]. 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 [4]. 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 [4].

Finally, 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 [5, 6]. An 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 [7]. SARS-CoV-2 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 [8]. 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 [9].

In summation, 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.”