Introduction—Background

In late December 2019, a series of pneumonia cases of an unknown etiology were diagnosed in Wuhan, Hubei province (China). One week later, a new betacoronavirus was identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) [1, 2]. In March 2020, this new disease was declared a pandemic by the World Health Organization (WHO) and as of May 31st, 2021, more than 169 million cases of COVID-19 and more than 3,500,000 deaths from it had been reported globally. Spain in particular has been one of the countries most affected by the COVID-19 pandemic, with more than 3,500,000 cases and 79,000 deaths as of that date [3,4,5]. Other most hitted countries by COVID-19 are India, United States and Brazil [6, 7].

Currently, in spring 2021, the available knowledge on how to manage patients with COVID-19 is incomplete and highly fragmented [8]. The U.S. Food and Drug Administration (FDA) has approved few drugs for treating the disease as Remdesivir. Nevertheless, physicians are using drugs approved for other indications while others are being studied. In this context, this work reflects on how to approach the challenge of treating this illness, particularly in regard to the use of antibiotics [9, 10].

The etiology of community-acquired pneumonia among hospitalized adults is unknown in 62% of cases, viral in 27% of cases, and bacterial in 14% of cases. Prior to December 2019, coronaviruses were responsible for 10% of viral pneumonias (2.7% of all etiologies) [11]. In lower respiratory tract infections, viruses can induce structural changes as reduction of ciliary function and decrease epithelial barrier function that can favor bacterial infections. It is not clear if antibiotics are necessary for these viral pneumonias [12,13,14]. Treatment guidelines for community-acquired pneumonia recommend initial empiric antibiotic therapy for possible bacterial infection or co-infection, given that they often coexist and there are no clear diagnostic tests for determining if the pneumonia is solely due to a virus at the time of onset [15, 16]. On the other hand, treatment decisions must be weighed taking into consideration the rise of multidrug-resistant bacteria and the fact that patients can develop complications associated with antibiotic use [17, 18].

Currently, there are no clear estimates on the incidence of bacterial co-infection in patients with COVID-19 and no clinical trials have been conducted on the use of empiric antibiotics in these patients [9]. Fluoroquinolones, such as ciprofloxacin and moxifloxacin, have been analyzed for their potential capacity to bind to the SARS-CoV-2 protease Mpro, blocking replication [19]. Furthermore, beta-lactam antibiotics are being evaluated in critically ill patients with SARS-CoV-2 infection, but more clinical trials are necessary in order to properly evaluate results [20].

Some researchers have concentrated on the use of macrolides in patients with COVID-19. Some macrolides, such as azithromycin and clarithromycin, are being studied not only for their anti-bacterial activity, but also their immunomodulatory and anti-inflammatory effects. They could be particularly useful in viral infections such as COVID-19, which are associated with an excessive inflammatory response, through the antibiotics’ attenuation of cytokine production [21,22,23]. Likewise, azithromycin has shown effects against virus replication and internalization processes in other viruses such as influenza A virus subtype H1N1 or Zika virus [24, 25].

With this background, this work aims to analyze the use of antibiotics in patients admitted to the hospital due to SARS-CoV-2 infection.

Methods

This work is a multicenter, nationwide, observational study based on patient data obtained from the SEMI-COVID-19 Registry.

Study design and population

The SEMI-COVID-19 Registry is an enterprise of the Spanish Society of Internal Medicine (SEMI, for its initials in Spanish) to advance knowledge on the epidemiology, clinical progress, risk factors, complications of patients infected with SARS-CoV-2 with the aim of improving SARS-CoV-2 treatment. The list of SEMI-COVID-19 Registry members can be found in Additional file 1.

Informed consent was obtained from all participants for using of their medical data for all research derived from the SEMI-COVID-19 registry. The registry is an anonymized online database of retrospective data on consecutive adult patients with COVID-19 hospitalized in internal medicine departments throughout Spain from March 1 to May 23, 2020. The diagnosis was confirmed microbiologically by real time transcription polymerase chain reaction (Rt-PCR) testing of a nasopharyngeal sample. Exclusion criteria were subsequent admissions of the same patient and denial or withdrawal of informed consent. Patients were cared for at their attending physician’s discretion, according to local protocols and their clinical judgment. Patient inclusion flow chart is shown in Fig. 1.

Fig. 1
figure 1

Patient inclusion flow chart

Full size image

The registry includes data on more than 300 variables in categories such as:

  • Sociodemographic and epidemiological data

  • Personal medical and medication history

  • Symptoms and physical examination findings upon admission

  • Laboratory test results

  • Radiological findings and their progress

  • Pharmacological treatment and ventilatory support

  • In-hospital complications and causes of death

More in-depth information on the registry and preliminary results are available in a previously published work [4].

The SEMI-COVID-19 Registry was approved by the Provincial Research Ethics Committee of Málaga (Spain).

Study conclusion

The primary endpoint was all-cause in-hospital mortality according to use of antibiotic therapy. The secondary endpoint was the specific effect of macrolides on the all-cause mortality rate. The follow-up period was from admission to discharge or death, including early readmissions.

We have analyzed the criteria for the use of antibiotics, any relationship to epidemiological or microbiological factors, and the evolution of analytical and radiological parameters.

Literature search

A literature search was conducting using the MEDLINE database with the following search terms: “antibiotics and COVID-19,” “bacterial co-infections and SARS-CoV-2,” and “azithromycin and COVID-19.” The most up-to-date evidence and all information regarding antibiotics, macrolides, and bacterial co-infections in COVID-19 reported in English or Spanish were selected.

Data analysis

The patients were initially divided into two groups according to use of antibiotic therapy. The first group, which included 12,238 patients, received antibiotics and the second, with 1498 patients, did not receive antibiotics.

Continuous quantitative variables were tested for normal distribution using rates of skewness and kurtosis, Levene’s test, or the Kolmogorov–Smirnov test, as appropriate. These variables are expressed as medians and interquartile range (IQR). Comparisons between groups were made using the Student’s T-test, Mann–Whitney U test, Wilcoxon test, analysis of variance (ANOVA), or the Kruskal–Wallis test. Categorical variables are expressed absolute values and percentages. Differences in proportions were analyzed using the Chi-square test, McNemar’s test, or Fisher’s exact test, as appropriate.

We also used a bivariate logistic regression to evaluate the relationship between groups of antibiotics and mortality. A multivariate analysis was carried out to correct for confounding variables using clinically relevant, statistically significant variables (p < 0.001) identified in the univariate analysis.

Measures of association are expressed as odds ratio (OR) with 95% confidence intervals (95% CI). Statistical analysis was carried out using STATA software (v14.2). Statistical significance was established as p < 0.05.

Results

Demographics, mortality, and clinical features

Patients were initially divided into two groups according to whether they received antibiotic therapy or not. Of a total of 13,932 patients included in this study, antibiotics were used in 12,238 (87.8%) and not used in 1498 (10.8%). A higher mortality rate was observed with the use of all antibiotics except macrolides, which showed a higher survival rate (OR 0.70, 95% CI 0.64–0.76; p < 0.001). Tables 1 and 2 show the type of antibiotic used and the number of patients who died or survived. Microbiological findings are shown on Table 3.

Table 1 Use of antibiotic therapy in COVID-19 patients admitted to internal medicine departments
Full size table
Table 2 Antibiotic used and relationship to mortality
Full size table
Table 3 Microbiological findings—SARS-CoV-2 infection
Full size table

Differences in fatality have been noted according to where the virus was acquired: mortality was higher among those who acquired the infection nosocomially (OR 1.98, 95% CI 1.71–2.30; p < 0.001) or in a nursing home (OR 2.80, 95% CI 2.46–3.18; p < 0.001) compared to those who were infected in the community (Table 4). Differences regarding the use of antibiotics and macrolides in particular according to where the infection was contracted are shown in Tables 5 and 6. Multivariate analyses of mortality based on the use of antibiotics and specifically on the use of macrolides were carried out with the possible confounding variables of age, degree of dependence, and place of disease acquisition. The results are shown in Tables 7 and 8.

Table 4 Mcrobiological findings and relationship to mortality
Full size table
Table 5 Microbiological findings according to use of antibiotics
Full size table
Table 6 Microbiological findings according to use of macrolides
Full size table
Table 7 Antibiotic therapy used and relationship to mortality (Multivariate analysis adjusted according to patient age and frailty)
Full size table
Table 8 Use of macrolides and relationship to mortality  (Multivariate analysis adjusted according to patient age and frailty)
Full size table

Older age was a factor that differed between those who received antibiotics versus those who did not in a significant manner (69 years [IQR 56–79] vs. 67 years [IQR 52–80]; p < 0.001). There was a lower rate of antibiotic use among patients with dementia (9.9% vs. 11.7%; p < 0.05), neurodegenerative disease (8.9% vs. 11.4%; p < 0.05), and moderate and severe dependence. This may be because we tend to be more cautious in the treatments applied to these groups of patients. Macrolides were more commonly used in men and in those between 40 and 80 years of age. They were less commonly used in patients with previous heart disease such as atrial fibrillation, myocardial infarction, or congestive heart failure. The demographic differences between groups that did and did not receive antibiotics and according to macrolide use are shown in Tables 9 and 10.

Table 9 Demographic data and comorbidities according to use of antibiotic therapy
Full size table
Table 10 Demographic data and comorbidities according to use of  macrolides
Full size table

Regarding patients’ previous treatment, a higher percentage of patients who were taking hydroxychloroquine received antibiotics (0.6% vs. 0.1%; p < 0.05). In the macrolide group, a lower percentage of patients were being treated with systemic corticosteroids (4% vs. 4.7%; p = 0.033) and biological therapies (1.1% vs. 1.6%; p = 0.016) (Tables 11 and 12).

Table 11 Use of antibiotic therapy according to habitual treatment
Full size table
Table 12 Use of macrolides according to habitual treatment
Full size table

In terms of patients’ clinical condition upon admission, the presence of fever (> 38 °C), cough, shortness of breath, arthralgia, fatigue, anorexia, and gastrointestinal symptoms were associated with an increased use of antibiotic therapy. Signs of general illness such as oxygen saturation < 90%, tachypnea, or tachycardia were also associated with increased rates of antibiotic use. Notably relevant is the presence of crackles on lung auscultation in up to 52.6% of patients. Like rhonchi (10.8% of patients), crackles were also associated with antibiotic use. All data on symptoms are shown in Table 13. Regarding the progression of respiratory parameters shown in Tables 14, 15, and 16, significant trends towards improvement were observed between the respiratory parameters on admission and those observed at 1 week in all patients.

Table 13 Use of antibiotic therapy according to initial clinical condition
Full size table
Table 14 Clinical outcomes in total population
Full size table
Table 15 Clinical outcomes among those who received antibiotics
Full size table
Table 16 Clinical outcomes among those who received macrolides
Full size table

Laboratory findings

Laboratory findings showed an improvement in inflammatory parameters after one week of hospitalization with the exception of procalcitonin and ferritin, which showed no statistically significant changes in either group (general or those receiving antibiotics). Full data are shown in Tables 17 and 18. In the case of interleukin-6, there was a substantial decrease in the total study population after one week (median 30 pg/mL [IQR 11.4–65] vs. 16 pg/mL [IQR 4.8–53.6]; p < 0.05), but not in those who received antibiotics (median 31.6 pg/mL [IQR 11.9–66] vs. 16 pg/mL [IQR 4.9–56]; p = 0.068). Tables 19 and 20 show the changes at one week after admission in inflammatory parameters in patients who received antibiotics or macrolides.

Table 17 Laboratory findings in total population
Full size table
Table 18 Laboratory findings among those who received antibiotics
Full size table
Table 19 Laboratory outcomes after using antibiotics
Full size table
Table 20 Laboratory outcomes after using macrolides
Full size table

The decision to start antibiotics was determined by the presence of increased classical inflammatory markers such as C-reactive protein (OR 2.14, 95% CI 1.91–2.41; p < 0.05), procalcitonin (OR 1.73, 95% CI 1.28–2.35; p < 0.05), or leukocytosis (OR 1.18, 95% CI 1.01–1.38; p < 0.05). It was also determined by the presence of inflammatory markers associated with COVID-19, such as elevated lactate dehydrogenase (OR 1.30, 95% CI 1.16–1.47; p < 0.05), interleukin-6 (OR 1.73, 95% CI 1.16–2.59; p < 0.05), or ferritin levels (OR 1.93, 95% CI 1.59–2.35; p < 0.05) (Table 21). Table 22 shows the use of different antibiotics according to the previously described laboratory findings, with beta-lactams being the most used antibiotics among all groups.

Table 21 Decision to start antibiotic therapy based on initial inflammatory parameters
Full size table
Table 22 Decision to start antibiotic therapy (and which one) based on initial inflammatory parameters
Full size table

Radiological findings

Pulmonary consolidation was present in 48.7% of patients and interstitial infiltrates in 62.6%. Involvement was mainly bilateral in both groups, particularly in those with interstitial infiltrates (bilateral involvement in 83.5% of patients with infiltrates). The presence of any kind of infiltrate was linked to antibiotic use (p < 0.05; see Table 23). Pleural effusion was present in less than 5% of patients and was not related to antibiotic use. A thoracic CT scan was performed in 774 patients (5.7%) and findings compatible with COVID-19 were observed in 88.7% of them; those with compatible findings had increased antibiotic use with (OR 3.53, 95% CI 1.85–6.73).

Table 23 Radiological outcomes after using antibiotics
Full size table

Antibiotic use was also related to radiological worsening at one week after admission (OR 1.89; 95% CI 1.63–2.20; p < 0.001). Statistically significant differences were observed in the presence of pulmonary condensation and interstitial infiltrates at one week after admission in the group which received antibiotics. Changes were also noted in the presence of pleural effusion in the antibiotic group, but the difference was not significant. In the group which received macrolides, the percentage of patients with interstitial infiltrates remained the same, unlike other groups, as can be seen in Tables 24 and 25.

Table 24 Radiological evolution among those who used antibiotic therapy
Full size table
Table 25 Radiological evolution among those who used macrolides
Full size table

Treatment and complications

Most patients received hydroxychloroquine (85.4%) and/or lopinavir/ritonavir (62.1%). In the antibiotic treatment group, more patients received hydroxychloroquine (87.3% vs. 70.1%; p < 0.001), lopinavir/ritonavir (62.1% vs. 55%; p < 0.001), and immunomodulators such as beta interferon, tocilizumab, anakinra, and systemic corticosteroids. The only therapy in which there were no differences between groups was immunoglobulins. All these data are shown in Table 26.

Table 26 Immunomodulatory therapies used among those who used antibiotic therapy
Full size table

Among the complications developed during hospitalization, higher mortality rates were observed in relation to several factors, including acute respiratory distress syndrome, acute heart failure, arrhythmias, acute kidney failure, shock, and sepsis. Bacterial pneumonia was found in 1481 patients (10.8%) and was more frequent among those who received antibiotics (OR 4.85, 95% CI 3.52–6.67; p < 0.001). Regarding respiratory support, oxygen via high-flow nasal cannula (OR 2.11, 95% CI 1.63–2.75; p < 0.001), non-invasive mechanical ventilation (OR 3.13, 95% CI 2.11–4.66; p < 0.001), and invasive mechanical ventilation (OR 4.21, 95% CI 2.84–6.25; p < 0.001) were used more often in the antibiotic group, as was prone positioning (OR 3.89, 95% CI 2.87–5.26; p < 0.001). A higher percentage of patients in the antibiotic group was transferred to intensive care units (ICU) compared to those who did not receive antibiotics (Table 27).

Table 27 Complications and clinical progress according to the  use of antibiotic therapy
Full size table

The median length of hospital stay was eight days (IQR 5–13). The death rate in the group that received antibiotics was 21.2% and the death rate in the group that did not receive antibiotics was 16.2% (OR 1.40, 95% CI 1.21–1.62; p < 0.001). Ninety-four percent of the deaths were directly caused by COVID-19, with the remaining 6% occurring due to other reasons. Just 3.8% of patients were readmitted at a median time of 9 days after discharge (IQR 3–17); in 58.7% of these cases, readmission was unrelated to COVID-19. All these data are shown in Table 28.

Table 28 Resolution of covid-19 according to use of antibiotic therapy
Full size table

Tables 29 and 30 show the multivariate statistical analysis of the relationship between the use of antibiotic therapy and macrolides and mortality, adjusted for relevant clinical and analytical variables. We have chosen the procalcitonin level cut-off of 0.15 ng/mL as it has the best sensitivity and specificity profile after analysis using ROC curves. After statistical adjustment in the multivariate analysis, the use of antibiotic therapy is not statistically significantly related to a reduction in mortality (OR 1.20, 95% CI 0.94–1.53, p = 0.14). On the other hand, the use of azithromycin is associated with a lower odds of death (OR 0.64, 95% CI 0.56–0.73, p < 0.001).

Table 29 Use of antibiotic therapy and relationship to mortality (Multivariate analysis adjusted according to clinical variables)
Full size table
Table 30 Use of macrolides and relationship to mortality (Multivariate analysis adjusted according to clinical variables)
Full size table

Discussion

Since the start of the COVID-19 pandemic, efforts have been made to show the role that antibiotics associated with antivirals, anti-inflammatories, and other immunomodulatory drugs may play in order to define an effective therapy against COVID-19.

Some authors think that the difficulty in finding antiviral treatments with proven efficacy along with the anxiety and uncertainty that this generates in physicians has likely led to the uncontrolled prescription of antibiotic therapy in patients worldwide [26]. Indeed, emerging data show that more than 90% of COVID-19 patients receive antibacterial drugs [27, 28].

In the Chinese city of Wuhan, where the pandemic started, most patients with COVID-19 seem to have received empiric antibiotic therapy, mostly respiratory fluoroquinolones [29]. The use of antifungal drugs and corticosteroids was more limited. Similar data are described in other studies in China, revealing use of antibiotic therapy in more than half of hospitalized patients [30,31,32,33].

In the United States of America, the strategy for empiric antibiotic therapy has been along these same lines. More prevalent antibiotic use was revealed in ICU patients, where 94.9% (224/236) were on antibiotics [34]. In another series in Detroit, antibiotic use in 69.2% (148 of 214 patients) of patients admitted to the conventional ward was documented; their study population had baseline characteristics that were similar to ours [35].

Langford et al. have conducted a rapid systematic review that determined that the majority of patients with COVID-19 received antibiotics (71.8%, 95% CI 56.1–87.7). The most common were broad-spectrum antibiotics, with fluoroquinolones and third-generation cephalosporins representing 74% of the antibiotics prescribed [36].

The work by Beovic et al. consisted of a survey aimed at doctors in Europe. As was the case in Asia and America, the study revealed indiscriminate use of broad-spectrum antibiotic therapy. In particular, the study highlights that Spain is one of the countries with the highest rates of antibiotic use—only 22.7% of patients with COVID-19 in the conventional ward were not routinely prescribed antibiotics—behind only Italy (18.2%) and Turkey (19.6%) [37].

What causes the indiscriminate use of empiric antibiotic therapy in COVID-19 patients?

Antibiotics are usually prescribed in light of the possibility that these patients may have a bacterial infection associated with the ailment that is either concomitant with the initial viral infection or in relation to an extended hospital stay [38, 39].

It is known that bacteria (especially Streptococcus pneumoniae and Staphylococcus aureus) as well as other viral or fungal co-infections are frequent complications that occur in seasonal influenza outbreaks which contribute to increased morbidity and mortality in these patients [40,41,The role of macrolides

Macrolides have been proposed as a possible treatment for severe acute respiratory distress syndrome caused by COVID-19 since the first months of the pandemic [21, 23]. These bactericidal antibiotics are widely used in habitual clinical practice against gram positive and atypical bacteria species that are usually associated with respiratory tract infections. The antiviral effects of macrolides have attracted considerable attention. Their ability to modulate the immune response and decrease the production of inflammatory cytokines makes them a very interesting tool for battling respiratory viral infections. The efficacy of macrolides in the treatment of other respiratory viruses such as rhinovirus, respiratory syncytial virus, and influenza has long been established [22, 25]. In addition to the aforementioned respiratory viruses, azithromycin has also been reported to inhibit Zika virus [24].

In terms of COVID-19, azithromycin was one of the drugs included in the large adaptive RECOVERY trial [67]. Based on preclinical and clinical evidence and some preliminary results in COVID-19 patients, azithromycin could have potential in the fight against this new disease [68].

In a clinical trial led by Gautret et al. in France, a combination of hydroxychloroquine and azithromycin was shown to be effective against COVID-19 [69]. Treatment efficacy was compared in 36 patients divided into three groups: six patients were treated with hydroxychloroquine combined with azithromycin, 14 with hydroxychloroquine in monotherapy, and 16 with a placebo. The results showed that by the sixth day of treatment, all patients in the HCQ + AZM group had no detectable virus in nasopharyngeal exudate samples compared to 57.1% of the HCQ group and 12.5% of the control group (p < 0.001).

In our study, we found a favorable outcome with the use of macrolides compared to other antibiotics. As we have highlighted, the mortality rate was lower in the macrolides group (unlike with other antibiotics) and indeed, the survival ratio was higher among patients who received them, a finding that was statistically significant (OR 0.70, 95% CI 0.64–0.76). Patients in whom macrolides were used were younger than those who received other antibiotics (68 years vs. 71 years). In order to control for possible confounding variables, a multivariate analysis was conducted that showed that the use of macrolides in our population continued to be linked to a lower mortality rate (OR 0.80, 95% CI 0.73–0.88).

Huttner et al. consider that macrolides and quinolones should be avoided due to the risk of cardiotoxicity [37]. Along these lines, a lower rate of use of azithromycin was observed among patients with previous heart disease in our study.

The risk of a rise in multidrug-resistant germs due to indiscriminate antibiotic use has been described in the literature [70,71,72]. The exact incidence of bacterial superinfections in COVID-19 patients is still not entirely clear and the incidence seems to be much lower than in severe influenza [8]. We agree with many other authors that establishing clear criteria for initiating antibiotic therapy in COVID-19 patients is essential in order to prevent the consequences of inappropriate prescribing [26, 37, 64]. We must be aware that a potential consequence of the COVID-19 pandemic is the long-term propagation of antimicrobial resistance resulting from increased patient exposure to antimicrobials that are often suboptimally or inappropriately used [72, 73]. This rapid growth in antibiotic prescribing can exercise a strong selective pressure on bacterial pathogens to develop resistance, leading to increased incidence of drug-resistant bacterial infections in the years following the COVID-19 pandemic. It has been calculated that ten million people could die from antibiotic-resistant bacterial infections each year by 2050 [39].

Recently, a group of members of ESCMID’s Study Group for Antimicrobial Stewardship (ESGAP) published a paper warning against non-critical use of antibiotics in COVID-19 patients along with some practical recommendations. Huttner et al. indicate that we should periodically reevaluate the suitability of our prescription and discontinue it as soon as possible when there is low suspicion of bacterial infection. In the event its continued use is warranted, switch to oral therapy early and give short cycles of five days [26]. It is important to educate healthcare providers in antimicrobial stewardship to prevent the consequences of excessive antimicrobial use such as toxicities, selection for opportunistic pathogens such as Clostridioides difficile (coinfection with SARS-CoV-2 results in a worsening of outcomes) and antimicrobial resistance [74, 75].

Conclusion

In this multicenter, retrospective study, the overall percentage of bacterial co-infection among patients with COVID-19 was low, but the use of antibiotics was high. There is insufficient evidence to support widespread use of empiric antibiotics in patients hospitalized for COVID-19. The majority of these patients may not require empiric antibacterial treatment and, if it is needed, there is promising evidence regarding the use of azithromycin as a potential treatment for COVID-19. However, more structured studies must be carried out in this regard.

Our outcomes provide evidence against the use of antibiotic therapy in most patients hospitalized for COVID-19 since it has not been proven to reduce the mortality rate of these patients. We recommend against routinely prescribing antibiotics to all hospitalized patients with COVID-19.

Future lines of research

There is a lack of data on bacterial co-infections in COVID-19 patients. This information is essential for determining the role of empiric antimicrobial therapy and antibiotic stewardship strategies. Biomarkers (CRP, procalcitonin) may play a role in deciding which patients should not receive antibiotics, but further investigation is required.

Prospective clinical studies on antibiotic prescription and systematic analyses of COVID-19 patients diagnosed with bacterial co-infection must conducted in order to evaluate the influence of current and future viral pandemics on antimicrobial resistance and the development of superinfections. This line of research is critical for avoiding unintended consequences resulting in broad antimicrobial resistance in the near future.

Lastly, standard guidelines for the administration of the antibiotics must be established.