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Association between Early Antibiotic Therapy and In-Hospital Mortality among Older Patients with SARS-CoV-2 Pneumonia

Abstract Background It is uncertain whether antibiotic therapy should be started in SARS CoV-2 pneumonia. We aimed to investigate the association between early antibiotic therapy and the risk of in-hospital mortality in older patients. Methods We performed a retrospective international cohort study (ANTIBIOVID) in five COVID-19 geriatric units in France and Switzerland. Among 1,357 consecutive patients aged 75 or more hospitalised and testing positive for SARS-CoV-2, 1072 had a radiologically confirmed pneumonia, of which 914 patients were still alive and hospitalized at 48 hours. To adjust for confounders, a propensity score for treatment was created, and stabilized inverse probability of treatment weighting (SIPTW) was applied. To assess the association between early antibiotic therapy and in-hospital 30-day mortality, SIPTW-adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed. Results Of the 914 patients with SARS-CoV-2 pneumonia, median age of 86, 428 (46.8%) received antibiotics in the first 48 hours after diagnosis. Among these patients, 147 (34.3%) died in hospital within one month vs 118 patients (24.3%) with no early antibiotic treatment. After SIPTW, early antibiotic treatment was not significantly associated with mortality (adjusted hazard ratio, 1.23; 95% CI, 0.92-1.63; P = .160). Microbiologically confirmed superinfections occurred rarely in both groups (bacterial pneumonia: 2.5% vs 1.5%, P = .220; blood stream infection: 8.2% vs 5.2%, P = .120; Clostridioides difficile colitis: 2.4% vs 1.0%, P = .222). Conclusions In a large multicentre cohort of older inpatients with SARS-CoV-2 pneumonia, early antibiotic treatment did not appear to be associated with an improved prognosis.


INTRODUCTION
The COVID-19 pandemic is the most deadly outbreak worldwide since the Spanish influenza pandemic in 1918, and its burden has been particularly heavy in the older population. Nearly one third of older patients hospitalized with SARS-CoV2 pneumonia died in hospital (1)(2)(3). Most deaths are the result of respiratory failure linked to viral pneumonia, for which therapeutic management is still a matter of debate. However, the distinction between bacterial and viral pneumonia remains particularly difficult in practice, and influenza experience has shown that coinfections are not rare in viral pneumonia, especially in older individuals (4). Despite recent advances in this field (5), there is currently no distinctive tool to conclusively distinguish SARS-CoV-2 pneumonia from bacterial pneumonia. Because delayed antibiotic treatment has been associated with worse outcomes in bacterial pneumonia (6), empirical antibiotic treatment was initially recommended for COVID -19 pneumonia in many guidelines (7). Since then, increasing data have highlighted a very low frequency of documented bacterial co-or superinfection in COVID-19 (8)(9)(10)(11)(12)(13)(14). Moreover, the widespread use of empirical antibiotics during the current pandemic appears to have contributed to the development of multidrug-resistant microorganisms (15)(16)(17). Thus, the most recent guidelines consensually suggest a restrictive use of antibacterial drugs in patients with COVID-19 (10,(18)(19)(20). However, the level of evidence for such recommendations remains very low and reposes on small-scale observational data (3,(21)(22)(23). Interventional studies only focused on azithromycin and failed to demonstrate any benefit compared with usual care (24)(25)(26). Antibiotics remain still widely prescribed in practice (8,9,15), especially in frail older individuals (3,27).
To our knowledge, whether systemic antibiotic therapy should be prescribed in older patients with acute pneumonia and testing positive for COVID- 19 has not yet been evaluated on a large scale. In a pilot study of older comorbid inpatients presenting with a SARS-CoV-2 pneumonia, we showed that one-month mortality did not differ whether patients received antibiotic treatment or not (3). We aimed to confirm this result in a larger multicenter cohort study.
A c c e p t e d M a n u s c r i p t

Data Source and Design
We performed a retrospective, multicenter cohort study using hospital records data from acute geriatric care units from four university hospitals and one regional hospital in France and Switzerland, during the first two waves of COVID-19 pandemic in Europe, from March 1, 2020, to December 31, 2020. Data were extracted from medical records in each hospital and anonymized before release to investigators.
This observational study was conducted in accordance with the Declaration of Helsinki and national standards. Geneva's committee for research ethics was consulted and approved the study. Each participant or his/her referee received an information letter and was invited to express his/her opposition to participation in the study.

Patients
We included all consecutive patients aged 75 years or older presenting with acute, radiologicallyconfirmed pneumonia and testing positive for SARS-CoV-2 with real-time polymerase chain reaction (RT-PCR). Acute pneumonia was defined according to the American guidelines (28), in the acute presence of 2 or more of the following signs: new cough, sputum production, dyspnea, pleuritic pain, abnormal temperature (<35.6°C or >37.8°C), or altered breathing sounds on auscultation, and a new infiltrate on chest imaging.
We excluded patients who were discharged or died within 48 hours after admission or for whom a bacterial co-infection requiring antibiotics was documented at admission (i.e. positive culture results in the presence of suggestive clinical features).
A c c e p t e d M a n u s c r i p t Based on our previous studies (36% in-hospital mortality rate, 2/1 exposed/non exposed ratio) (2,3) and considering a 0.7 relative hazard as clinically significant, a total sample size of 847 patients was estimated to provide 80% power, using a 2-tailed hypothesis at an α level of .05.

Exposure and Primary Outcome Measure
We compared patients who received early systemic antibiotic treatment, i.e. within the first 48 hours after diagnosis, with those who did not receive any antibiotic in these first 48 hours. The primary outcome was in-hospital 30-day mortality.
In-hospital management, including acute treatments (corticosteroid therapy with a daily dose ≥ 6mg of dexamethasone or equivalent (35), tocilizumab, remdesivir, lopinavir/ritonavir, chloroquine), antibiotic treatment (class: cephalosporins, penicillin with betalactamase inhibitors, macrolides, fluoroquinolones, and duration of first-line treatment) and palliative treatment (morphine, Vital status at discharge, hospital length of stay, transfer to intensive care unit, and palliative care requirement were also recorded. To avoid excluding patients with missing values for several of the potential confounders, multiple imputation was used to handle missing data (< 10% for all covariates) that were assumed to be missing at random for all covariates. Missing values were imputed 10 times, by sampling from their posterior predictive distribution, conditional on the observed data. In all subsequent analyses, Rubin's rules were applied to summarize the effect estimates and variances from the 10 different analyses across multiple imputed data sets (36).

Statistical Analysis
Continuous variables were described using medians and interquartile ranges, and categorical variables were described using frequencies and percentages. Wilcoxon rank sum, χ2, and log-rank tests were used to evaluate the statistical significance of unadjusted continuous, categorical, and time-to-event data, respectively. All tests were 2-tailed, and a P value of less than .05 was considered statistically significant. Statistical analyses were performed using SPSS 21.0 (IBM Corp, Armonk, NY) and  Older patients who receive antibiotic treatment often have a more severe presentation than those who do not. To account for potential confounding in the association of antibiotic use and mortality, we created a propensity score for each patient and applied inverse probability weighting. The propensity score represented the predicted probability of receiving antibiotic treatment and was determined using a logistic regression model with 48-hour antibiotic use as the dependent variable and the aforementioned potential confounders at admission (listed in table 1) as the independent variables.
Each patient's propensity score was then used to create an inverse probability weight for that patient.
Stabilized inverse probability of treatment weight (SIPTW) was then obtained by multiplying the inverse probability weight by the marginal probability of receiving the actual treatment received (i.e. early antibiotic treatment or not) (37). After adjusting for these weights, a propensity-weighted sample was thus created that was more balanced with respect to potential confounders included in the regression model.
Before assessing the outcome, we confirmed that the weighted sample was balanced using the following parameters: standardized difference, -0.15 to 0.15; and variance ratio, 0.5 to 2.0 (38). We examined overlap plots of the propensity scores by treatment group to ensure that the area of common support was adequate.
Outcomes SIPTW-adjusted Kaplan-Meier curves were calculated to compare overall in-hospital 30-day survival between patients who received early antibiotic treatment and those who did not. We further fitted an SIPTW-adjusted Cox proportional hazards regression model to compute the corresponding hazard ratio (HR). To avoid informative censoring, patients discharged from hospital were regarded as surviving to 30 days. A total of 428 patients (46.8%) received antibiotic treatment in the first 48 hours. There was wide variability in early antibiotic prescription rate among the 5 centers, ranging from 11.2% to 74.9%.
After SIPTW, the differences in the baseline covariates that were apparent in the overall sample were no longer present (Table 1 and eFigure in the Supplement).

Treatments in Hospital
The acute treatments used for SARS-CoV-2 pneumonia during the hospital stay are presented in Table 2. After SIPTW, they did not significantly differ between the two groups, except for antibiotics.
Median duration of first line of antibiotics was 6 [5][6][7][8] days in the early treatment group. Two thirds of the patients without early antibiotic treatment received antibiotics later during their hospital stay.

DISCUSSION
Antibiotics are undoubtedly one of the most important advances in medicine, even though the inappropriate use of these drugs threatens their effectiveness. There has been considerable concern about the widespread use of antibiotics since the beginning of the COVID-19 pandemic. Many authors have detected an increase in highly resistant pathogens and plead for raised antimicrobial stewardship efforts (14)(15)(16)(17). However, the clinical presentation of severe COVID-19 is frequently indistinguishable from bacterial or fungal sepsis. Given the paucity of active therapeutics, physicians are often tempted to prescribe antibiotics in frail older patients with a severe presentation. Thus, there is a need for a higher level of evidence to support recent guidelines (10,(18)(19)(20) against systematic antibiotic treatment in SARS-CoV-2 pneumonia, especially in the geriatric setting.
Few interventional studies have assessed the usefulness of antibiotic treatment in COVID-19. All trials comparing azithromycin to usual care failed to demonstrate any benefit of this antibiotic treatment (24)(25)(26). To the best of our knowledge, there is to date no interventional data concerning other antibiotic treatments. In particular, recommended empirical antibiotics for acute pneumonia (34,39), which are widely used in SARS-CoV-2 pneumonia (9), have not been evaluated in interventional studies nor in large observational studies.
The main results of this large multicenter cohort are as follows: 1) the in-hospital mortality rate for older patients hospitalized with SARS-CoV-2 pneumonia was nearly 30% at 30 days; 2) half of patients received early antibiotic treatment at admission; 3) bacterial superinfection during hospital A c c e p t e d M a n u s c r i p t stay was seldom documented in patients with or without early antibiotic therapy; and 4) early antibiotic treatment was not associated with a better in-hospital prognosis.
Our results are consistent with the literature, highlighting that more than 70% of patients with SARS-CoV-2 infection receive antibiotics, but less than 10% experience bacterial and fungal coinfection (8,11,12). However, antibiotic use varies considerably from one center to another (8,9,40), as highlighted in our study (from 11.2% to 74.9% of patients), stressing the need for stronger evidence on this issue. Broad-spectrum therapies, mainly beta-lactams, were frequently prescribed, as recommended in recent guidelines for bacterial pneumonia (34,39). Contrary to other reports (9,11), macrolides were a minority of antibiotic prescriptions. As in other reports, we found that the likelihood of early antibiotic prescription was correlated with the initial severity of pneumonia, rather than with comorbidities (21). In this elderly population, age was no longer a criterion for early antibiotic prescription.
Here, one interesting result is the relatively high frequency of bloodstream infections compared with previous reports in younger patients (12,41), although they may have been slightly overestimated by blood culture contaminations (DNAse negative staphylococci) (41). Our study population was expected to be at higher risk for severe superinfections for several reasons. First, older patients have already shown to be more prompt to develop superinfections during COVID-19 (42). Second, COVID-19 could particularly predispose to bacterial infection since bacteremia was found to be more frequent in COVID-19 than non-COVID-19 critically ill patients (43). This risk may be higher than in other infections: patients with COVID-19 were 2.5 times more likely to develop bacteremia than patients with influenza (44). The reasons for such a high frequency are not elucidated. However, the high frequency of Enterobacteriaceae, Enterococci and Candida, already documented by others in COVID-19 (9,11,14,45,46), suggest a potential digestive translocation (47), as already described at the acute phase of bacterial pneumonia (48). Digestive involvement is frequent in COVID-19 patients, especially in the older population (49), and could be due to ischemic damage in the gastrointestinal tract rather than direct viral damage (47). Interestingly, C. difficile colitis was rare, as also already reported by others. Even if antibiotic treatment remains a major risk factor for C. difficile infection in A c c e p t e d M a n u s c r i p t COVID-19 inpatients (50), this low rate could be due to COVID-19-linked reinforced cleaning procedures and reduced patient mobility (51).
Whether systematic early antibiotic treatment should be introduced in the early phase of SARS-CoV2 pneumonia remains a current issue. In a recent single-center study, authors showed that early administered antibiotics did not impact mortality in critically ill patients with COVID-19 (22), confirming similar results in non-critically ill units (3,21). However these previous results did not have sufficient power to adequately assess this question. We believe that our large multicenter data further reinforce previous findings and strongly discourage systematic antibiotic treatment. Further research is needed to define the patients for whom antibiotics should be indicated and in which settings. Our results also show that documented bacterial superinfections often develop a week or more after COVID-19 diagnosis (median of 8 days) in patients without early antibiotic treatment, further mitigating the benefit of a systematic strategy. Some authors suggest that antibiotic therapy should be reserved for the patients with the most severe presentations (10,52), but no data to date support this position. Biomarkers (C-reactive protein, procalcitonin) may play a role in deciding when antibiotics can be withheld (5,46). Also, the ability of thoracic computed tomography to distinguish alveolar infiltrates associated with bacterial pneumonia as opposed to the typical glass ground opacities seen in COVID-19 remains to be evaluated (10). This study has some limitations. First, only patients with COVID-19 hospitalized in a medical ward were included, and those initially hospitalized in the ICU were not considered. These results cannot be extrapolated to more severe patients, especially those under mechanical ventilation. Second, because no systematic sampling procedure was performed in these wards (screening was based on clinical judgment), microbiological documentation was often missing in this retrospective study. Thus, we probably underestimated bacterial infection occurrence. However, we believe that this study represents the real-world situation in most hospitals. Third, most of patients in the group without early antibiotic treatment during the first 48 hours did receive antibiotics later during their hospital stay.
A c c e p t e d M a n u s c r i p t This could have potentially mitigated any antibiotic benefit effect in the early treatment group. Again, this situation was expected in a very elderly hospital population with comorbidities. However, patients without any antibiotic treatment during hospital stay had a crude lower mortality rate (19.5%) than patients with early (34.4%) and delayed antibiotic treatment (28.0%), suggesting no benefit of such treatment. Fourth, even with an adjustment on comorbidities and clinical parameters at admission, including usual prognostic criteria in COVID-19, the results could be biased by unmeasured confounding due to factors such as frailty, which might not be well captured in routinely collected data. This study remains observational and only a randomized clinical trial could support a definite statement.
In this large multicenter study, half of older patients hospitalized with SARS-CoV-2 pneumonia received early antibiotic treatment after diagnosis even though no bacterial co-infection was documented. The likelihood of early antibiotic prescription was correlated with pneumonia severity rather than comorbidities. After adjustment for confounders, early antibiotic treatment was not associated with a decrease in in-hospital mortality or with superinfection occurrence. According to these data, antibiotic therapy should not be prescribed systematically for older patients with SARS-CoV2. Further investigations are required to target patients most at risk of bacterial superinfection, and interventional studies are needed to confirm these observational findings.  M a n u s c r i p t A c c e p t e d M a n u s c r i p t