Clinical use of antiviral, antibiotic and immunomodulatory drugs in hospitalized COVID-19 patients: a retrospective study in Bandung, Indonesia

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused at least 240 million cases of coronavirus disease 2019 (COVID-19) and more than 4.8 million deaths worldwide until 18 October 2021.¹ At that time, Indonesia has reported 4.2 million confirmed COVID-19 cases with over 140 thousand deaths.² The management of COVID-19 using repurposed drugs has been authorized since the beginning of the pandemic³ to rapidly control the mortality and morbidity of this new disease in the absence of evidence of clinical trial results.

Exploration on the effectiveness of repurposed drugs for COVID-19 in the first year of pandemic remains inconclusive. For example, a clinical trial on the most promising antiviral remdesivir showed its benefit on the clinical improvement at day 15.⁴ However, the interim report of the World Health Organization’s (WHO) Solidarity trial showed the lack of benefit of remdesivir on the reduction of mortality and hospitalization duration.⁵ Similarly, the Indonesian national guideline for COVID-19^6,7 recommends the antiviral favipiravir. However, this drug is not part of the recommendation from the WHO guideline based on the evidence from clinical trials evaluating remdesivir and favipiravir for COVID-19 therapy.⁸ The latest version of the WHO guidelines for COVID-19 therapy provides strong recommendation for systemic corticosteroid in severe and critical COVID-19, and conditional recommendation against remdesivir in hospitalized COVID-19.⁹ Corticosteroid and tocilizumab are drugs modulating the immune response that plays a critical role in the pathogenesis of severe COVID-19. As pneumonia is the main clinical manifestation of COVID-19, the use of antibiotics for COVID-19 patients regardless of the evidence of bacterial infection is concerning.¹⁰

The report on the pharmacological therapy of COVID-19 in Indonesia is not as extensive as that in other Asian countries with high cases of COVID-19, such as China and India. This retrospective study aimed to investigate the clinical use of antiviral, antibiotic and immunomodulatory agents in hospitalized COVID-19 patients during the first year of the pandemic. The treatment using these drugs were considered common based on the pathogenesis of infection and inflammation on COVID-19 disease. These drugs are also listed in the Indonesian national guideline for COVID-19.^6,7 We also evaluated the length of stay (LOS) and the outcome following hospitalization to understand the benefit of pharmacological therapy of antiviral, antibiotic and immunomodulators.

Methods

Results

Drug regimens indicated by baseline peripheral oxygen saturation

Peripheral oxygen saturation is one of the indications of drug therapy in the Indonesian guideline of COVID-19 management. We evaluated whether different combinations of antiviral and antibiotic drugs or immunomodulatory therapy were associated with the baseline of SpO₂ recorded at admission (Figure 1). The level of SpO₂ in the group of patients receiving the double combination of remedisivir and favipiravir or other antivirals (lopinavir/ritonavir and isoprinosine) was significantly lower than that when receiving oseltamivir alone (p = 0.01 or p = 0.034, respectively) (Figure 1A). Among the antibiotic drug regimens, Figure 1B shows that patients receiving the combination of levofloxacin and ceftriaxone had higher levels of SpO₂ than those receiving combination of azithromycin and levofloxacin (p = 0.019). However, few patients with a very low level of SpO₂ were found in both of groups as shown by plots below 80% of SpO₂ in Figure 1B. In contrast, the treatment of immunomodulatory drugs was very likely indicated by the level of SpO₂ as shown by Figure 1C that the patients receiving immune-modulators were strongly associated with the lower level of SpO₂ (p = 0.001) compared to those not treated with immune-modulators (Figure 1C).

Figure 1. Peripheral oxygen saturation (SpO₂) at the initial pharmacological therapy.

(A) Baseline SpO₂ and the antiviral therapy using remdesivir, favipiravir, and oseltamivir in the various drug combinations. (B) Initial SpO₂ and antibiotic combination of relevant azithromycin, levofloxacin, and ceftriaxone. (C) Immunomodulatory therapy using methylprednisolone, dexamethasone, and tocilizumab. Data are presented as median and interquartile range (IQR). Statistical differences were analyzed by Kruskal-Wallis and Dunn’s multiple comparisons (A, B) or Mann-Whitney test (C).

Discussion

Our study evaluated the clinical use of antiviral, antibiotic and immunomodulatory drugs for hospitalized patients confirmed with COVID-19. We found that antivirals and antibiotics were the standard treatment delivered to almost all the patients, whereas the immunomodulator treatment was an additional therapy. We assessed the clinical use of these drugs with SpO₂ for the indication of therapy, and with LOS and death for the outcome of therapy.

The results showed that remdesivir is the primary drug composing various antiviral regimens. Remdesivir was recommended conditionally for COVID-19 patients who required oxygen supplementation¹⁶ and severe COVID-19 patients defined by a low level of SpO₂.⁸ However, treatment with remdesivir alone in our study did not correlate significantly with the level of SpO₂ compared to favipiravir or oseltamivir. Patients with more severe COVID-19 were more likely to receive the combination of remdesivir and favipiravir or other antiviral drugs (lopinavir/ritonavir or isoprinosine). On the other hand, oseltamivir seems to be the first antiviral choice for the non-severe COVID-19. The initial SpO₂ was not the main indication for the choice of the rest antiviral regimens.

Remdesivir in this study was used intravenously with a loading dose of 200 mg followed by 100 mg/day for a mean duration of 7 days. This dose provides an effective conversion of its metabolite into intracellular adenosine triphosphate analogue that selectively inhibits viral RNA polymerase.¹⁷ The same dose of remdesivir was used in other studies,^5,18,19 however, some studies used remdesivir for 5 days^18,20 or 10 days.^18,19 The 5-day remdesivir was associated with better outcome at day 11,¹⁸ but another study found no differences.²⁰ A meta-analysis revealed that the 5-day remdesivir provided similar benefit but fewer adverse events than the 10 day.²¹ Favipiravir in our study was given with a loading dose of 1200 mg and a daily dose of 600 mg. This dose was half of that used in several studies on COVID-19,¹⁶ but the same dose as a recent study evaluating favipiravir in recurrent COVID-19.²² Favipiravir (Avigan^®) selectively inhibits viral RNA polymerases of influenza viruses and has a broad-spectrum antiviral activity for neglected and emerging RNA viruses.^23,24 Treatment with favipiravir alone was considered safe and effective to shorten viral shedding in recurrent positive COVID-19 patients.²² Few studies showed the benefit of combined therapy of favipiravir with methylprednisolone.¹⁶ Combination of remdesivir and favipiravir was the most common antiviral regimen in our study, however, this was not available on the list of drug therapy used in clinical trials of COVID-19.^16,25 Therefore, the safety and the efficacy of the combination of remdesivir and favipiravir is unknown. Indeed, clinical judgement to guide management decisions is part of WHO’s conditional recommendation.⁹ Further studies should evaluate clinical symptoms for comprehensive evidence for clinical judgement.

The empiric antimicrobial therapy for COVID-19 patients in our study was very high (98.2%). This proportion is higher than that reported in the United Kingdom (UK) (85.2%),²⁶ Netherland (60.1%),¹⁰ and Surabaya Indonesia (75.3%).²⁷ In fact, microbiological testing showed that the bacterial infection and co-infection among hospitalized COVID-19 patients was infrequent.¹⁰ Several studies reported 1.25 % of 925 patients,¹⁰ 19.7% of 218 patients,²⁷ 1107 of 48902 patients were confirmed bacterial co-infection. In COVID-19 patients in the UK, the most frequent etiology of respiratory co-infection was Staphylococcus aureus and Haemophilus influenza, of secondary respiratory infection was Enterobacteriaceae and S aureus, and in bloodstream infection was Escherichia coli and S aureus.²⁶ In the Indonesian setting, Gram-negative was the common causative agents of bacterial infection in COVID-19 patients.²⁷ These findings suggested that the choice for empirical antimicrobial should be treated for Gram-negative bacteria and S aureus until the results of culture available.

Our study showed that IV levofloxacin (500/750 mg), IV ceftriaxone (200 mg), and oral azithromycin (500 mg) were the common antibiotic therapy used in COVID-19 patients. The combination of intravenous levofloxacin and ceftriaxone was the most frequent antibiotic regimen prescribed. The choice of levofloxacin for COVID-19 patients is probably because fluoroquinolone antibiotic has a broad-spectrum activity. Fluoroquinolone antibiotic is used in severe CAP, and has the potency of antiviral and immune-modulator.²⁸ Ceftriaxone is a broad-spectrum beta-lactam antibiotic that has been one of the choices for treating community-onset pneumonia (COP). The dose of 1000 mg has a similar cure rate to 2000 mg.²⁹ Azithromycin is a macrolide antibiotic that is effective against Gram-positive, Gram-negative, and atypical bacteria. It has primarily been used as a treatment for upper and lower respiratory infection with its potential application for COVID-19 due to its effect of antiviral and immune-modulator.³⁰ A systematic review and meta-analysis study reported the prevalence of antibiotic use in COVID-19 patients was 24.5% azithromycin, 10% fluoroquinolone, and 9% ceftriaxone.³¹ However, the study found the lack of data on the specific indication and specific name antibacterial agents. The standard broad-spectrum antibiotics in our study were not supported by the type of bacteria found in most studies.^26,27,31 However, our study has added value in providing the name of antibacterial agents used.

The latest version of living WHO guideline recommends both corticosteroid and IL-6 receptor blocker (tocilizumab) for severe and critical COVID-19 patients.⁹ Our study found that patients who were treated with immunomodulatory drugs (methylprednisolone, dexamethasone, and tocilizumab) had a significantly lower level of SpO₂ compared to those who were untreated with these drugs (p = 0.001). Systemic corticosteroid such as 6 mg of oral or intravenous dexamethasone or 50 mg of intravenous hydrocortisone was strongly recommended for severe and critical COVID-19, but not for the non-severe COVID-19 because of the low certainty evidence on the increased risk of death.³² Similarly, the RECOVERY clinical trial showed the efficacy of dexamethasone on reducing the incidence of death was for the severe and critical, but not on the non-severe COVID-19.³³ Interestingly, in our study, the use of immunomodulators was associated with prolonged LOS (p = 0.0043) and a higher number of deaths (p < 0.0001) compared to the non-immunomodulatory drug user. Thus, the treatment of more severe COVID-19 patients with immunomodulatory drugs did not improve the outcome.

Our study evaluated the LOS and death as the outcome for clinical use of antiviral, antibiotic, and immunomodulatory therapy. Our study found that remdesivir alone was associated with shorter LOS than therapy using other antiviral drugs (lopinavir/ritonavir or isoprinosine). This is in line with a recent review updating the results of randomized clinical trials (RCT) on antiviral agents which showed that remdesivir could increase clinical improvement but lacked benefit on preventing death.²⁵ A study in Surabaya reported that COVID-19 patients confirmed with bacterial infection had longer LOS and higher mortality than those without bacterial infection.²⁷ However, the study did not evaluate the outcome of antibiotic therapy as we did. Multivariable analysis in our study found concerning safety issues for two regimen therapies. Patients who were treated with the combination of remdesivir and favipiravir had a four times higher risk of death compared to those receiving antiviral drugs other than this regimen. Similarly, patients treated with immunomodulatory drugs had a six times higher risk of death compared to those untreated with immune-modulators. However, several baseline clinical characteristics including age, gender, sex, comorbid condition, SpO₂ level, and lymphocyte contributed to this risk and became confounding factors. It has been known from the beginning of COVID-19 pandemic that older age and comorbid disease, in particular hypertension and diabetes mellitus, were associated with higher death rate.³⁴ Lower lymphocyte count was also associated with the severity of COVID-19.^27,35 Further confirmation studies should control the baseline clinical characteristics of COVID-19 patients to validate the increased risk of death following the treatment with the combination of remdesivir and favipiravir or immunomodulatory drugs.

This study has several limitations. The non-probability sampling may affect the ability to generalize of the result to a broader population. Our study did not include data on the clinical symptoms of COVID-19 patients and the microbiological testing that would provide more comprehensive clinical judgment for antiviral and antibiotic therapy. However, to our understanding, this is among the first retrospective study reporting the details on the specific name of drugs and drug combination of antiviral and antibiotic for COVID-19 patients. Further prospective study to ensure the drug interaction and safety profile of combination drug regimens is warranted.

Conclusions

Clinical use of antiviral drugs and antibiotics in our study were very likely the standard therapy applied to almost all hospitalized COVID-19 patients. On the other hand, the treatment of COVID-19 patients using the immunomodulatory drugs was an additional therapy. The most common antiviral regimen was the combination of remdesivir and favipiravir, whereas the most frequent antibiotic regimen was the combination of levofloxacin and ceftriaxone. Treatment of hospitalized COVID-19 with remdesivir alone, the combination of favipiravir and oseltamivir, and the combination of levofloxacin and ceftriaxone was associated with short LOS. There was increased risk of death in patients treated with the combination of remdesivir and favipiravir and the immunomodulatory drugs. However, clinical characteristics at admission including age, sex, comorbid condition, SpO₂ level, and lymphocyte count contributed to this risk.

Data availability