key: cord-0944171-0lynr0w8
authors: Clancy, Cornelius J; Nguyen, M Hong
title: A first draft of the history of treating coronavirus disease 2019 (COVID-19): Use of repurposed medications in United States hospitals
date: 2020-12-15
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofaa617
sha: 7712a0d420943b68aa500bd449c166c982cc172f
doc_id: 944171
cord_uid: 0lynr0w8

nan

M a n u s c r i p t during the chaotic initial months of the pandemic. [4, 5] Using the Premier Healthcare database, which covers ~20% of US hospitalizations, Kadri found that ~60% and ~75% of adults with COVID-19 were treated with hydroxychloroquine and azithromycin in March 2020, respectively [Table] . Over the next 2 months, the proportion of COVID-19 inpatients receiving the respective agents decreased by ~80% and ~50%. By May, only ~12% of inpatients were treated with hydroxychloroquine, [3] and much residual in-hospital azithromycin use in COVID-19 patients was likely as an empiric anti-bacterial. A c c e p t e d M a n u s c r i p t 3 states, and that the proportion of hydroxychloroquine-treated inpatients fell further in June. [4] Other investigators using the IQVIA National Prescription Audit database determined that outpatient hydroxychloroquine prescriptions also decreased by ~80% between March and June. [5] In contrast, estimated percentages of hospitalized COVID-19 patients treated with remdesivir in COVID-NET increased from ~2% and ~4% in March and April, respectively, to ~30% in May and ~34% in June. By Kadri's assessment, corticosteroids were administered to 21.5% of inpatients with COVID-19 from March through May, during which time the proportion of inpatients receiving these agents increased by >80%; almost two-thirds of mechanically ventilated patients received corticosteroids over this period.

Tocilizumab use was documented in only ~5-6% of SARS-CoV-2-infected inpatients over the 3 months. [3] In June, the percentage of hospitalized patients treated with tocilizumab dropped. [4] Corticosteroids and tocilizumab were administered a median 2 hospital days earlier in May versus March. [3] Databases and methodologies employed in the studies above had relative strengths, weaknesses and potential biases that were acknowledged by the authors.

Percentages of adult inpatients treated with various agents were higher each month in Kadri's analysis, which identified cases by diagnosis codes, than in COVID-NET, which relied upon medical chart reviews of patients with laboratory-confirmed SARS- Table] .

As generally recognized at the time, [7, 8] use. [13, 14] Use of tocilizumab, a more expensive drug than dexamethasone, was low in March-May, and decreased thereafter as RECOVERY results appeared in absence of evidence for benefit of interleukin-6 inhibitors. Taken together, the data paint a mixed picture. Of concern, widespread in-hospital use of hydroxychloroquine, azithromycin and corticosteroids occurred early in the pandemic despite a lack of rigorous clinical data. However, clinicians adapted practices quickly as data were reported, unlike the often languid pace at which antibiotic prescribing responds to new clinical information. [15] [16] [17] What were the consequences of these behaviors? On balance, treated patients were likely neither helped nor harmed by hydroxychloroquine and azithromycin. Widespread corticosteroid use in mechanically ventilated patients may have fortuitously saved some lives early in the pandemic, particularly since clinicians moved to more timely treatment. [3] At the same time, misdirected corticosteroid administration may have had untoward effects. On a societal level, use of unproven medications or refusals to consider hydroxychloroquine due to unvalidated claims of excess toxicity delayed enrollment of clinical trials that might definitively identify beneficial or harmful regimens. [8, 9] Furthermore, demand for hydroxychloroquine may have reduced access for patients taking the drug for rheumatologic diseases, [18] and excess azithromycin prescribing ran risk of promoting bacterial resistance. [19, 20] The net impact of events on COVID-19 clinical outcomes, public health and global economies requires further study.

Ultimately, impact may be mitigated by the likelihood that no COVID-19 treatment is a magic bullet. In the end, we may have gotten lucky that extensive use of repurposed medications did not cause more harm. including several randomized trials with adaptive platform designs, may prove to be among the most positive scientific legacies of the pandemic. [12, 22, 23] Clinical trials that exploit international collaboration, social media, cloud computing and electronic health records, simultaneously randomize to several treatment options, quickly discontinue poorly performing therapies, and leverage common enrollment and data management systems can spare clinicians untenable choices between "doing" or "learning", offering instead opportunities to "learn while doing." [2] Building upon lessons of COVID-19, priority should be given to proactively supporting global networks that can expeditiously design, co-ordinate and conduct clinical trials during future pandemics.

A c c e p t e d M a n u s c r i p t 7

Dr. Clancy has been awarded investigator-initiated research grants from Astellas, A c c e p t e d M a n u s c r i p t 8 [24, 25] 15 June: EUA revoked. Further 65% reduction in use from May to June. [4] 

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Languid Uptake of Ceftazidime-Avibactam for Carbapenem-Resistant Gram-Negative Infections and Continued Reliance on Polymyxins

Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know

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Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Azithromycin for COVID-19: More Than Just an Antimicrobial?

Azithro postulated to decrease viral entry into cells and enhance antiviral immune responses. [26] March: Azithro reported to decrease viral load in combination with HCQ; no alternative validated treatment options. May: Reports of no improvements in mortality or intubation rates with azithro. June: Azithro use still reduced compared to March-April, but not significantly changed compared to May. [4] Residual use was likely to be largely as empiric treatment of bacterial respiratory tract infections. [6] Remdesivir N/A 2%** 30%** +1,150%** Remdesivir, an RNA-dependent, RNA polymerase inhibitor with in vitro activity against SARS-CoV-1 and Middle East respiratory syndrome coronavirus, shown to also inhibit SARS-CoV-2 in vitro. [10] March: Guidelines did not endorse routine corticosteroid treatment. April: IDSA guidelines conditionally suggested corticosteroids for severe COVID-19. 16 June: RECOVERY trial press release reported mortality benefit of dexamethasone in patients requiring respiratory support. [12] A c c e p t e d M a n u s c r i p t 9 12%26% +116% A c c e p t e d M a n u s c r i p t 10 A c c e p t e d M a n u s c r i p t