All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: A Real-World Observational Study

Aim

To evaluate all-cause mortality risk in patients with laboratory-confirmed COVID-19 in Mexico City treated with repurposed antivirals and antibiotics.

Methods

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 antivirals prescribed in <30 patients, eliminated. Survival and mortality risks were determined for patients receiving antivirals, antibiotics, both, or none.

Results

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. 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).

Conclusions

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.

WHAT IS ALREADY KNOWN

• Current recommendations for using repurposed antivirals and antibiotics for COVID-19 are conflicting.

• Few antivirals (i.e. lopinavir-ritonavir) have been shown to provide no additional benefit for COVID-19 in clinical trials; other antivirals may be having widespread use in real-world settings without formal assessment in clinical trials.

• Real-world use of repurposed antivirals and antibiotics for COVID-19 in population-based studies have not been performed; important populations have been left largely understudied (ambulatory patients, pregnant women, and pediatrics).

WHAT THIS STUDY ADDS

• This is the first real-world observational study evaluating amantadine, rimantadine, zanamivir, and acyclovir for COVID-19; no registered studies to evaluate these drugs exist. Only one study has evaluated risk of death for oseltamivir. Lopinavir-ritonavir have been previously evaluated in clinical trials.

• Repurposed antivirals and antibiotics were commonly prescribed in 688 ambulatory units and hospitals of Mexico City despite unclear recommendations for their use out of clinical trials.

• Oseltamivir was associated with increased mortality risk; other repurposed antivirals (zanamivir, amantadine, rimantadine, and acyclovir) had no significant and consistent impact on mortality. Antibiotics were associated with increased mortality risk in the general population but may increase survival in hospitalized and critical patients.