Question normal

Roman T. Pachulski, MD
Nathan Rothman, MD
Kenneth Roistacher, MD

Covid 19 preliminary clinical reports suggest significant acute therapeutic efficacy for the combination of AZ and HC(1) above that of HC alone(2). The putative mechanism might be prevention of secondary bacterial infection in cytokine-insulted alveoli however it may be due to macrolide CYA-3A4 inhibition with elevation of hydroxychloroquine levels, perhaps unpredictably.

Case Report: 52 M with no prior medical condition presenting 3/27/20 with fever and dyspnea negative for influenza A and B and RSV but positive for COVID 19. Patient in moderate respiratory distress with bilateral crackles. Lab values: WBC 20.7k/L with neutrophilic predominance (92%) and lymphopenia (2.8%). Lab values: PaO2 44 on FiO2 100%. Serum K (5.0mg/dL, normal 3.5–5.1 mg/dL) and Mg (1.9 mg/dL, normal 1.6–2.3 mg/dL). Serum Ca was low (7.7 mg/dL, normal 8.4-10.4 mg/dL) and phosphate high (9.0 mg/dL, normal < 4.5 mg/dL) in keeping with acute renal failure with Cr rising from 2.4 to 6.5mg/dl (normal < 1.1 mg/dL) within 24h of admission. AST (166 U/L, normal <59 U/L) and LDH (3546 U/L, normal <618 U/L) and PT/ INR 14.6s/1.3 (normal <12.9s/<1.16) but normal ALT. Imaging: CXR revealed bilateral peripheral focal consolidation and right pleural effusion. Baseline EKG sinus rhythm QT/QTc 298/403 msec figure 1a). Treatment & Outcome: Patient was admitted to ICU telemetry, intubated and started on hydroxychloroquine 400 mg BID day one then 200mg BID and azithromycin 500 mg day one then 250mg daily. Day 2 EKG revealed repeated torsades de pointes though QT/QTc remained normal (250/427 msec fig 1b). Six hours later patient experienced cardiac arrest. Resuscitation efforts were unsuccessful, despite defibrillation.

Discussion: Both HC and AZ are capable of prolonging QT(3,4) and macrolide (AZ) is a well-known CYA-3A4 inhibitor which may decrease HC metabolism raising the potential for cardiotoxic accumulation and arrhythmia. Doses of HC as high as 1200mg are being suggested(1). In view of the beneficial results with HC alone(2) perhaps the initial loading dose of AZ might be omitted particularly in patients with multiorgan failure. Prophylactic mexiletine might also be considered based on the prior efficacy of quinidine mexiletine combinations(5). Notably, there was no premonitory QT prolongation documented prior to or concurrent with torsades.
References
1. Gautret et al. (2020) 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

2. YaoX,YeF,ZhangM,CuiC,HuangB,NiuP,LiuX,ZhaoL,DongE,SongC,ZhanS,LuR,LiH,TanW,LiuD.InVitroAntiviralActi and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. [Epub ahead of print]

3. Hancox JC, Hasnain M, Vieweg WV, Crouse EL, Baranchuk A. Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports. Ther Adv Infect Dis. 2013 Oct;1(5):155-65. doi: 10.1177/2049936113501816. PMID: 25165550; PMCID: PMC4040726.

4. Chun-Yu Chen, Feng-Lin Wang & Chih-Chuan Lin (2006) Chronic Hydroxychloroquine Use Associated with QT Prolongation and Refractory Ventricular Arrhythmia, Clinical Toxicology, 44:2, 173-175, DOI: 10.1080/15563650500514558

5. Mexiletine/quinidine combination therapy: electrophysiologic correlates of anti-arrhythmic efficacy. Duff HJ, Mitchell LB, Wyse DG, Gillis AM, Sheldon RS.Clin Invest Med. 1991 Oct;14(5):476-83.