Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells

Vojo Deretic; Graham S Timmins

The novel SARS-CoV-like virus, 2019-nCoV (CoV2), related to SARS-CoV but distinct form it, was identified as the causative agent of the current, 2019-2020 outbreak of viral pneumonia that started in Wuhan, China, which spread to all permanently inhabited continents. The human-to-human spread of CoV2 has resulted in a runaway global pandemic, causing a disease termed COVID-19 (coronavirus disease-2019) by the World Health Organization. COVID-19 pandemics is escalating at an alarming rate with 649,904 infected, as of this writing, and 15,835 deaths just in Italy and Spain with a combined 9.6% mortality rate in these disproportionately affected countries away from the epicenter of the initial epidemic 6,7 . COVID-19 threatens worldwide populations based on its pernicious combination of long incubation times coupled with exceptional spreading potential, and significantly high morbidity and mortality. The reproductive number R0 initially estimated to be 2.2-2.7 8, 9 according to some estimates may possibly reach 4.7-6.6 10 . There is an urgent public health need to understand CoV2 as a virus, COVID-19 as a disease, and COVID-19 as a frightening epidemiological phenomenon. The world is literally scrambling to develop countermeasures, including therapeutics aiming to lessen disease severity and to come up with prophylaxes including vaccines. Recently, two FDA approved drugs, chloroquine (CQ) and azithromycin (AZT), have shown therapeutic effects in in COVID-19, using viral loads as endpoints in compassionate use/initial clinical trials associated with life-threatening pulmonary complications 11 . This work began at the time when a major progress has been made in understanding the key properties of the anomalous ion conductances across cystic fibrosis (CF) respiratory epithelia, with defects in chloride transport via the cystic fibrosis transmembrane conductance regulator CFTR, and in sodium transport via the epithelial sodium channel ENaC 12 . Certain drugs have proven useful in treating pulmonary disease in CF, such as AZT, an antibiotic that has been a staple of clinical management of CF 13, 14 . CF patients treated with AZT benefit 14 in several aspects of lung function, have decreased rate of exacerbations, and experience improved quality of life [15] [16] [17] [18] [19] , albeit the magnitude of these benefits may vary 20 . As an antibiotic, the mechanism of AZT in CF might be expected to be killing of bacteria, yet the tissue levels of this macrolide do not reach the necessary anti-pseudomonal concentrations in the lungs to provide an easy explanation for its benefits. Whereas several studies propose effects of AZT on bacterial biofilms 21 , there is compelling evidence that host-mediated effects of this macrolide are just as important since: (i) AZT has beneficial effects in CF, even before 19 Pseudomonas aeruginosa colonization 22 occurs; and (ii) AZT protects the bronchial epithelium during P. aeruginosa infection independently of its antimicrobial activity 23 . Thus, AZT confers a previously undefined and antibioticindependent benefit that is both documented in CF clinical trials [15] [16] [17] [18] [19] and routinely observed in CF management. However, a subsequent study provided a cautionary note for prolonged AZT's use in CF since it, like chloroquine, inhibits autophagy 24 , which is involved in control of mycobacteria 25 .