All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: A real-world observational study

Abstract

The aim of our study was to evaluate all-cause mortality risk in patients with laboratory-confirmed COVID-19 in Mexico City treated with repurposed antivirals and antibiotics. This real-world retrospective cohort study contemplated 395,343 patients evaluated for suspected COVID-19 between February 24 and September 14, 2020 in 688 primary-to-tertiary medical units in Mexico City. Patients were included with a positive RT-PCR for SARS-CoV-2; those receiving unspecified antivirals, excluded; and groups of antivirals prescribed in < 30 patients, eliminated. Survival and mortality risks were determined for patients receiving antivirals, antibiotics, both, or none. We assessed the effect of early (<2 days) versus late (>2 days) use of antivirals on mortality in a sub-cohort of patients. Multivariable adjustment, propensity score matching, generalized estimating equations, and calculation of E-values were performed to limit confounding. 136,855 patients were analyzed; mean age 44.2 (SD:16.8) years; 51.3 % were men. 16.6 % received antivirals (3 %), antibiotics (10 %), or both (3.6 %). Antivirals studied were Oseltamivir (n=8414), Amantadine (n=319), Lopinavir-Ritonavir (n=100), Rimantadine (n=61), Zanamivir (n=39), and Acyclovir (n=36). Survival with antivirals (73.7 %, p<0.0001) and antibiotics (85.8 %, p<0.0001) was lower than no antiviral/antibiotic (93.6 %). After multivariable adjustment, increased risk of death occurred with antivirals (HR=1.72, 95 % CI: 1.61-1.84) in ambulatory (HR=4.7, 95 % CI: 3.94-5.62) and non-critical (HR=2.03, 95 % CI: 1.86-2.21) patients. Oseltamivir increased mortality risk in the general population (HR=1.72, 95 % CI: 1.61-1.84), ambulatory (HR=4.79, 95 % CI: 4.01-5.75), non-critical (HR=2.05, 95 % CI: 1.88-2.23), and pregnancy (HR=8.35, 95 % CI: 1.77-39.30); as well as hospitalized (HR=1.13, 95 % CI: 1.01-1.26) and critical patients (HR=1.22, 95 % CI: 1.05-1.43) after propensity score-matching. Early versus late oseltamivir did not modify the risk. Antibiotics were a risk factor in general population (HR=1.13, 95 % CI: 1.08-1.19) and pediatrics (HR=4.22, 95 % CI: 2.01-8.86), but a protective factor in hospitalized (HR=0.81, 95 % CI: 0.77-0.86) and critical patients (HR=0.67, 95 % CI: 0.63-0.72). No significant benefit for repurposed antivirals was observed; oseltamivir was associated with increased mortality. Antibiotics increased mortality risk in the general population but may increase survival in hospitalized and critical patients.

Keywords: COVID-19; SARS-CoV-2; antibiotics; oseltamivir; pharmacoepidemiology.

Table 1. Baseline characteristics of patients with laboratory confirmed COVID-19 who were treated with or without antivirals/antibiotics, in 688 accredited COVID-19 medical units in Mexico City

Table 2. Adjusted mortality risk in laboratory-confirmed COVID-19 patients receiving antivirals, antibiotics, both, or none in 688 accredited COVID-19 medical units in Mexico City

Table 3. Adjusted mortality risk in laboratory-confirmed COVID-19 patients receiving antivirals, oseltamivir, or antibiotics after propensity score matching

Figure 1. Flow diagram of patients assessed for eligibility

Figure 2. Survival of patients (general population, ambulatory, and hospitalized) treated with antivirals and/or antibiotics.

Survival curves are shown according to treatment modality in the general population (a), ambulatory (b), and hospitalized (c) patients. Survival in patients receiving specific antivirals, antibiotics, , or none in the general population (d), ambulatory (e), and hospitalization (f) settings.

Figure 3. Survival of patients (non-critical and critical) treated with antivirals and/or antibiotics.

Survival curves of non-critical patients according to modality of treatment (a) and those receiving specific antivirals, antibiotics, or none (b). Survival curves of critical patients according to modality of treatment (c) and those receiving specific antivirals, antibiotics, or none (d).

Figure 4. Weekly prescription of oseltamivir and newly diagnosed patients with influenza (A) and COVID-19 (B) during the COVID-19 pandemic in Mexico City.

*Data of prescription of oseltamivir for patients tested only for influenza was not collected.