Remdesivir use in COVID-19 patients might predispose bacteremia, matched case-control analysis.

Dear Editor,

We have read with great interest the paper by Yoon et al. (1) reporting infectious SARS-CoV-2 samples were not detected after the third dose of remdesivir despite concomitant dexamethasone treatment. Remdesivir is a nucleoside prodrug of an adenosine analogue that was approved for the treatment of COVID-19 based on reduced hospitalization duration and trend of reduced mortality in a randomized setting (2). Besides renal and liver toxicities, remdesivir has been shown to be associated with bradycardia (3), a favorable side-effect (4) of unknown mechanism that is potentially related to similarity of its metabolites to adenosine (5). Adenosine levels have an important role in control of inflammation and might dampen the hosts anti-microbial response (6) and consequently promote bacterial superinfections. Despite this potential association, there are no published data on occurrence of bacterial infections during remdesivir treatment in COVID-19 patients. In this paper we aim to investigate occurrence of bacteremia in a large real-life cohort of remdesivir-treated in comparison to matched control COVID-19 patients from our institution.

Among a total of 5959 consecutively hospitalized COVID-19 patients treated at our institution from 3/2020 to 6/2021, we retrospectively evaluated 876 consecutive remdesivir-treated patients. They were compared to a matched case-control cohort of 876 patients. Matching was based on age, sex, Charlson comorbidity index, WHO severity of COVID-19 at presentation and maximal level of oxygen requirement at the time of remdesivir application (to account for the fact that remdesivir was given to respiratory deteriorating patients). All patients were tested positive by either PCR or antigen test and had presence of COVID-19 symptoms. All patients were adults and Caucasian. Patients were treated according to the contemporary guidelines with majority receiving LMWH thromboprophylaxis and corticosteroids. Analyzed blood cultures were sampled during the whole hospitalization, and at least 48 h after initiation of remdesivir in remdesivir-treated patients. Clinically significant bacteremia was considered in the case of positive blood cultures which were sampled based on clinical reasoning of treating physicians, with exclusion of single blood cultures with isolates of contaminants such as coagulase-negative Staphylococcus (CoNS) or Corynebacterium spp, or more than one positive blood culture with same isolates but without clinical course consistent with blood-stream infection. MedCalc statistical program ver 20.104 (MedCalc Software Ltd, Ostend, Belgium) was used for all statistical procedures. The Mann-Whitney-U test, the Χ2-test, the log-rank test and the Cox-regression were used. P values <0.05 were considered statistically significant.

A total of 1752 COVID-19 patients were evaluated (876 remdesivir-treated and 876 matched controls). In comparison of remdesivir vs control patients there were no significant differences in neither age (65 vs 66 years, P = 0.109), Charlson comorbidity index (3 vs 3 points, P = 0.115), male sex (61.8% vs 61.8%, P = 1.000), severe or critical COVID-19 at the time of admission (97.9% vs 97.9%, P = 1.000) nor in requirement for high-flow oxygen therapy (HFOT, 36.5% vs 37.2%, P = 0.766) or mechanical ventilation (MV, 28.4% vs 27.9%, P = 0.791), as per matching procedure. A total of 552 (31.5%) patients died during hospitalization with remdesivir-treated patients experiencing lower mortality rate (29.2% vs 33.8%, P = 0.039).

Bacteremia was detected in 193 (11%) patients, more frequently in remdesivir-treated patients (12.6% vs 9.5%, P = 0.039). As shown in Fig. 1 A, a trend of bacteremia was more pronounced with remdesivir treatment irrespectively of the level of oxygen demand at the time of remdesivir application (regardless whether remdesivir was given prior to or during requirement for HFOT and MV), although no significant difference could be shown for particular subgroups. There was a statistically significant interaction between remdesivir use, bacteremia and death (P<0.001), with patients without bacteremia during hospitalization experiencing significantly improved survival (HR=0.70, 95% CI (0.58–0.85), P<0.001, Fig. 1B) and no evident benefit of remdesivir use present in patients experiencing bacteremia (HR=0.92, 95% CI (0.66–1.27), P = 0.634, Fig. 1C). Frequencies of specific pathogens isolated from blood cultures in remdesivir-treated and matched control patients are shown in Table 1 . Remdesivir use was significantly associated with a higher occurrence of bacteremia due to Gram-positive bacteria (P = 0.019), especially Enterococcus faecalis (P = 0.019). In addition, a nearly significant result was observable for bacteremia due to Acinetobacter baumannii (P = 0.093).

Fig. 1

A) Frequency of positive bacterial blood cultures in remdesivir-treated and matched control COVID-19 patients depending on the level of oxygen demand at the time of remdesivir application. B) Overall survival from hospital admission stratified by remdesivir use in patients without and C) with bacterial sepsis during hospitalization.

Table 1

Frequency of bacterial sepsis and specific pathogens isolated from blood cultures in remdesivir treated and matched control group of COVID-19 patients.

	Remdesivir treated (N = 876)	Matched controls (N = 876)	P value
Positive blood cultures	110 (12.6%)	83 (9.5%)	P = 0.039 *
Gram negative bacteria	81 (9.2%)	64 (7.3%)	P = 0.141
Gram positive bacteria	68 (7.8%)	44 (5%)	P = 0.019 *
Both Gram positive and negative bacteria (polymicrobial)	39 (4.5%)	25 (2.9%)	P = 0.075
Acinetobacter baumannii	63 (7.2%)	46 (5.3%)	P = 0.093
Staphylococcus aureus	21 (2.4%)	17 (1.9%)	P = 0.512
Enterococcus faecalis	22 (2.5%)	9 (1%)	P = 0.019 *
Enterococcus faecium	10 (1.1%)	8 (0.9%)	P = 0.636
Coagulase negative Staphylococcus	26 (3.0%)	18 (2.1%)	P = 0.222
Klebsiella pneumoniae	15 (1.7%)	14 (1.6%)	P = 0.852
Pseudomonas aeruginosa	5 (0.6%)	7 (0.8%)	P = 0.562
Corynebacterium species	6 (0.7%)	2 (0.2%)	P = 0.157
Escherichia coli	4 (0.5%)	8 (0.9%)	P = 0.247
Klebsiella aerogenes	0 (0%)	2 (0.2%)	P = 0.157
Proteus mirabilis	1 (0.1%)	4 (0.5%)	P = 0.179
Stenotrophomonas maltophilia	1 (0.1%)	0 (0%)	P = 0.317
Enterobacter cloacae	2 (0.2%)	1 (0.1%)	P = 0.563
Staphylococcus haemolyticus	1 (0.1%)	1 (0.1%)	P = 1.000
Serratia marcescens	1 (0.1%)	1 (0.1%)	P = 1.000
Providencia stuartii	1 (0.1%)	1 (0.1%)	P = 1.000
Staphylococcus epidermidis	1 (0.1%)	0%	P = 0.317
Beta hemolytic streptococcus	0 (0%)	1 (0.1%)	P = 0.317
Streptococcus pneumoniae	2 (0.2%)	0 (0%)	P = 0.157
Bactroides species	1 (0.1%)	0 (0%)	P = 0.317
Haemophilus parainfluenzae	0 (0%)	1 (0.1%)	P = 0.317
Providencia rettgeri	1 (0.1%)	0 (0%)	P = 0.317

*Statistically significant at level P<0.05.

To the best of our knowledge, this is the first report on higher frequency of bacteremia in COVID-19 patients treated with remdesivir. Bacteremia occurs in a substantial proportion of severe and critical COVID-19 patients who are candidates for remdesivir and the drug might especially predispose Gram-positive bacteremia, particularly with Enterococcus faecalis. Mechanisms behind these observations remain uncertain. It can be speculated that remdesivir metabolites that are adenosine analogues alter innate and specific immunity in the same fashion as adenosine does (7). Thus, remdesivir use might attenuate inflammation and promote bacterial virulency resulting in higher frequency of sepsis. Since remdesivir is given intravenously, this might also facilitate bacteremia, especially in the context of personal protective equipment that might affect dexterity of health-care workers and impose difficulties in delivering health-care (8). Importantly, no increase in bacteremia due to CoNS or Corynebacterium spp. was observed. Thus, higher frequency of bacteremia is not driven by pathogens that could be associated with contamination of blood cultures. Also, since patients were matched based on the level of oxygen demand at the time of remdesivir application, two groups were balanced regarding HFOT and MV requirement and higher frequency of bacteremia is not likely to be driven by differences in intensive level of care. Our data show that occurrence of bacteremia significantly moderates the relationship of remdesivir use with survival and attenuates potential beneficial effects of remdesivir, implying that this phenomenon has important clinical consequences. Bacterial co-infections substantially affect in-hospital mortality of COVID-19 patients (9) and special considerations should be given to patients with bacterial co-infections who are candidates for remdesivir, carefully weighting risks and benefits on an individual basis, implementing measures of increased surveillance or completely avoiding the drug.

Limitations of our work are retrospective study design and single center experience. Our results are representative of a tertiary-level institution and treatment of severe or critical COVID-19 patients and might not be generalized to other clinical contexts. Nevertheless, our data based on a large real-life cohort of remdesivir-treated and matched control patients imply that remdesivir use might be associated with higher frequency of bacteremia and this might affect prognosis of remdesivir treated patients. Future studies on this very important subject are needed.

Funding

None.

Ethical approval

The study was approved by the University Hospital Dubrava Review Board (nm. 2021/2503–04).

Declaration of Competing Interest

None.