Ghiasvand, F.

Manafi, N.

eprints Iran University of Medical Sciences

International Journal of Antimicrobial Agents 57 (2021) 106279 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents journal homepage: www.elsevier.com/locate/ijantimicag Reply to the letter to the editor “Azithromycin, treatment in COVID-19”Editor: J.-M. Rolain Dt“1fadsaiefcC(iowessinsrmtoitippitofisiwT(poz6n  TAowtpHmehawohmtoqbicwpdtcuaootsdv  tisth0ear Editor We thank the authors of the letter to the editor, “Azithromycin, reatment in COVID-19” for their careful reading of our paper Safety and effectiveness of azithromycin in patients with COVID- 9: An open-label randomised trial” [1] and their precise and help- ul comments. We would like to discuss the issues raised by the uthors of the letter and to provide further information and an up- ate on our paper. Regarding the questions on the severity of COVID-19 at admis- ion, all patients in the study were hospitalized based on the avail- ble national criteria and approved guidelines at that time. Dur- ng the pandemic, guidelines have changed in response to rapidly volving evidence either crediting or discrediting certain options or COVID-19 management. In accordance with our study proto- ols, patients were included based on clinical criteria suggestive of OVID-19, including oxygen saturation < 93%, respiratory distress rate > 30), and positive computed tomography (CT) scan findings ndicative of COVID-19. As COVID-19 cannot be differentiated from ther infective diseases by clinical manifestation only, any patients ith clinical characteristics of COVID-19 were tested for this dis- ase and treated accordingly. The patients included in the study howed clinical signs of COVID-19 from 7 to 10 days before admis- ion (details of clinical signs suggestive of COVID-19 can be found n our paper). The quality and rate of hemoptysis and cough were ot assessed as these were not defined as separate variables in our tudy. All patients included in our study fulfilled the admission crite- ia and had severe disease; hence we could not withhold treat- ent. As mentioned in the letter to the editor, care was taken hat all included patients were in the active phase of disease. In ur paper, we refrained from elaborating on certain points includ- ng which findings are suggestive of COVID-19 on CT scan because hese points have been explained in detail elsewhere [7] . All scans n our study were reviewed by trained radiologists who were ex- erienced in COVID-19 because of the high patient load in our hos- ital. We also understood that the increased severity of pulmonary nvolvement does not necessarily imply more severe clinical condi- ion, or vice versa. As stated in our paper, the primary set point of ur study was based on clinical condition, and not on severity of ndings on imaging. The authors of the letter criticized the randomization in our tudy. We respectfully disagree with their criticisms for the follow- ng reasons. Despite the random allocation used in our study, there ere very small differences between the two groups, as expected. DOI of original article: 10.1016/j.ijantimicag.2021.106280 pttps://doi.org/10.1016/j.ijantimicag.2021.106279 924-8579/© 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. he mean difference between oxygen saturation of patients was 0.1  P = 0.920), which was statistically insignificant and clinically unim- ortant. Also, regarding the 5-year difference between the mean f ages in the two groups, we refer to the World Health Organi- ation (WHO) guideline for COVID-19 complications, in which age 0 years is a threshold for increasing complications [2] . In the Ira- ian national guidelines, this threshold is set at 65 years of age [3] .herefore, both guidelines relate to patients aged over 60 years. ssessing the impact of treatment in patients below that age was utside the scope of our study. The authors of the letter mentioned that some of the patients ere discharged with the lower oxygen saturation goal (92%) of he study. This observation is correct, with the reason being these atients were unwilling to continue treatment in the hospital. owever, all these patients continued treatment at home with re- ote monitoring and under close follow-up. Regarding the differ- nces between the two groups in baseline characteristics, such as istory of chronic diseases, we emphasize that random allocation nd elimination of confounders was the correct approach; there ere no statistically significant differences between the groups in ur study. Patient safety was of paramount importance in our study; ence care was taken to ensure all patients received the required edications. All patients enrolled in the study had severe disease; herefore, according to the current national guidelines, initiation f hydroxychloroquine and ritonavir/lopinavir treatment was re- uired. Notably, at the time of our study, ritonavir/lopinavir had een associated with potential benefits in patients with COVID-19 n several studies [ 4 , 5 ]. Although later studies discredited the effi- acy of ritonavir/lopinavir for COVID-19 [6] , use of this treatment as included in our national guidelines at that time. As stated in our paper, the most likely serious treatment com- lication was anticipated to be heart arrhythmias, particularly ue to QT-prolongation by hydroxychloroquine and azithromycin; herefore, patients at high risk of cardiac complications were ex- luded from the study. All study patients were monitored daily sing electrocardiography (ECG) to assess cardiac health and en- ble any signs of arrhythmia or cardiac dysfunction as a side effect f treatment to be identified immediately. No adverse events were bserved that required further discussion. The authors of the letter critiqued the use of some the papers o which we referred in our discussion. In response, we empha- ize that no false claim was made in our discussion. The paper emonstrating effectiveness of azithromycin against Zika and Ebola iruses has been cited to be based on an in vitro study [1,8] . Al-hough we agree that effectiveness in human models based on n vitro studies cannot be assumed, in vitro studies are a crucial tep before progression to in vivo studies and clinical trials. We ook care to include only credible and authentic references in our aper. We emphasize that even if the validity of certain references All rights reserved. N. Manafi and F. Ghiasvand International Journal of Antimicrobial Agents 57 (2021) 106279 wbcisbtLsCcilDR[[[[[[[[as doubted, we made no definite conclusions or treatment plans ased on those papers. We thank the authors of this letter for pointing out that the orrect proportion of patients with myalgia was 40%. However, mportantly, despite this error, the statistical calculations for the tudy were completed correctly. A requested statistic was the num- er of patients receiving methylprednisolone: there were two pa- ients in the case group and seven patients in the control group. astly, we note that no study is perfect; however, we believe our tudy provided useful information. All treatment modalities for OVID-19 need to be further tested and assessed in multiple large linical trials at other sites. Again, we appreciate the careful read- ng of our paper and keen insights provided by the authors of this etter. eclarations Funding : None Competing Interests : None Ethical Approval : N/A eferences 1] Sekhavati E, Jafari F, SeyedAlinaghi SA, Jamalimoghadamsiahkali S, Sadr S, Tabarestani M, et al. Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial. Int J Antimicrob Agents 2020;56. doi: 10.1016/j.ijantimicag.2020.106143 . 2] Clinical management of COVID-19; WHO Reference Number: WHO/2019- nCoV/clinical/2020.5 2020. https://www.who.int/publications/i/item/ clinical- management- of- covid- 19 (accessed December 27, 2020). 3] Iran’s ministry of health therapeutics and clinical guidelines for COVID-19 2020. http://corona.behdasht.gov.ir/page/66/1 ’ GFE ’ G ’ Ì- ( ’ DÌFÌ- H- / 1E ’ FÌ. 4] Owa AB, Owa OT. Lopinavir/ritonavir use in Covid-19 infection: is it completely non-beneficial? J Microbiol Immunol Infect 2020;53:674–5. doi: 10.1016/j.jmii. 2020.05.014 . 2 5] Meini S, Pagotto A, Longo B, Vendramin I, Pecori D, Tascini C. Role of Lopinavir/Ritonavir in the Treatment of Covid-19: A Review of Current Evi- dence, Guideline Recommendations, and Perspectives. J Clin Med 2020;9:2050. doi: 10.3390/jcm9072050 . 6] Horby PW, Mafham M, Bell JL, Linsell L, Staplin N, Emberson J, et al. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2020;396:1345–52. doi: 10.1016/S0140-6736(20)32013-4 . 7] Kwee T, Kwee R. Chest CT in COVID-19: What the radiologist needs to know. RadioGraphics 2020;40(7) In this issue. doi: 10.1148/rg.2020200159 . 8] Bosseboeuf E, Aubry M, Nhan T, et al. Azithromycin inhibits the replication of zika virus. JAA 2018;10(1):6–11 In this issue. doi: 10.4172/1948-5964.10 0 0173 . Navid Manafi, M.D. Iran University of Medical Sciences, school of Medicine, Tehran, 1449614535, Iran. Fereshteh Ghiasvand, M.D. ∗Liver Transplantation Research Center, Department of Infectious Diseases, Imam Khomeini Hospital Complex, Keshavarz Boulevard, Tehran University of Medical Sciences, Tehran 14197-33141, Iran ∗Correspondence to , Fereshteh Ghiasvand, M.D., Liver Transplantation Research Center, Department of Infectious Diseases, Imam Khomeini Hospital Complex, Keshavarz Boulevard, Tehran University of Medical Sciences, Tehran 14197-33141, Iran. Tel.: + 98 21 6119 2659; fax: + 98 21 6658 1657. E-mail address: ghiasvand_62@yahoo.com (F. Ghiasvand) 

Reply to the letter to the editor â��Azithromycin, treatment in COVID-19â��

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Reply to the letter to the editor â��Azithromycin, treatment in COVID-19â��

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