key: cord-1005200-dhhoewo3 authors: Chedid, Marie; Waked, Rami; Haddad, Elie; Chetata, Nabil; Saliba, Gebrael; Choucair, Jacques title: Antibiotic usage in 2019 coronavirus disease (Covid-19) treatment: a rapid review on frequency, indications, and efficacy date: 2021-02-09 journal: J Infect Public Health DOI: 10.1016/j.jiph.2021.02.001 sha: 1f15d42e319b3c190f498c52d73dc1709514b12d doc_id: 1005200 cord_uid: dhhoewo3 OBJECTIVES: To report available information in the literature regarding frequency, indications, types of antibiotic usage, duration, and their efficacy in Covid-19 patients. METHODS: The search was conducted on April 30 and May 7, 2020, using Ovid database and Google search. Patients’ characteristics, clinical outcomes, as well as selected characteristics regarding antibiotic use (indication, class used, rates and types of bacterial secondary and co-infection, and duration of treatment) were analyzed. RESULTS: Nineteen clinical studies reporting data from 2834 patients were included. Mean rate of antibiotic use was 74.0 % of cases. Half the studies reported occurrence of a bacterial co-infection or complication (10 studies). Amongst the latter, at least 17.6 % of patients who received antibiotics had secondary infections. Pooled data of 4 studies show that half of patients receiving antibiotics were not severe nor critical. Detailed data on antibiotic use lack in most articles. CONCLUSIONS: The present review found a major use of antibiotics amongst Covid-19 hospitalized patients, mainly in an empirical setting. There is no proven efficacy of this practice. Further research to determine relevant indications for antibiotic use in Covid-19 patients is critical in view of the significant mortality associated with secondary infections in these patients, and the rising antimicrobial resistance. However, the latter should not overshadow the issue of antimicrobial resistance but rather emphasize it, and this for two reasons. First, it appears that secondary bacterial infections are often responsible for fatalities among influenza pandemics, as was the case in the 1918 influenza outbreak and the 2009 H1N1 influenza pandemic (2) . Similarly, in a Wuhan-based study reporting outcomes and treatment for 191 patients hospitalized for Covid-19 (3), 50% of deaths were imputable to secondary bacterial infections. Thus, antibiotics appear to be a crucial defense against mortality in Covid-19 patients. Second, resistance to antimicrobials is already currently estimated to cause 700, 000 deaths worldwide yearly (1) and would therefore also be expected to play a significant role in Covid-19-related mortality. Regarding influenza, Infectious Diseases Society of America's updated guidelines in 2018 (4) stated that ''there are no data to support the safety or efficacy of antibiotic chemoprophylaxis to prevent bacterial complications.'' Similarly, the Covid-19 guidelines of the China National Health Commission (CNHC) (5) stated that ''blind or inappropriate use of antibiotic drugs should be avoided, especially broad-spectrum antibiotics.'' However, detailed data on relevant indications for antibiotic use in these patients needs to be investigated. We present here a rapid review of studies reporting use of antibiotics in hospitalized Covid-19 patients. We reported the information regarding frequency, indications, types of antibiotic usage, duration, and their efficacy in Covid-19 patients. Inclusion criteria were journal articles reporting clinical studies on treatment of Covid-19 patients with antibiotics. Case reports, non-clinical studies, reports on coronavirus other than the severe acute respiratory syndrome coronavirus 2, and articles not mentioning the use of antibiotic in these patients were excluded for the review. Studies for which data about antibiotic treatment were too J o u r n a l P r e -p r o o f scarce were excluded. Research was limited to English-language articles relative to adults. Two sources of information were used in this review. First, we searched on Google using the terms ''Covid-19'' and ''antibiotic use'' and selected the first result: an article questioning the impact of antibiotic use in Covid-19 patients on antibiotic resistance (6) . The author notes the creation of a website by Adam Roberts and Issra Bulgasim to report ''secondary infections, antibiotic chemotherapy and antibiotic resistance in the context of Covid-19'' (7) . As of April 30 th , there were 27 reported articles on the website from peer-reviewed published literature. We included fourteen studies as per our including criteria. Secondly, we searched Ovid on May 7 th , 2020 using ''Ovid Medline (R) and Epub ahead of print, In-Process, and other non-indexed citations, daily and versions (R)'' database. Four keywords were used with their associated MeSH terms: ''Covid*'' with its relevant associated MeSH terms (''coronavirus infections'', ''betacoronavirus'', ''pneumonia'', ''viral'', and ''severe acute respiratory syndrome''), "therapy*" with its associated MeSH terms (''drug therapy'' and ''drug therapy, combination''), ''treatment*'' and its associated MeSH terms (''treatment failure'' and ''treatment outcome''), and "antibiotics". This research retrieved 101 records. After eliminating case reports and non-journal articles from both research results (49 in total), 79 article titles and/or abstracts were assessed for eligibility. A full text read was performed later, to ensure the compliance of the chosen articles with inclusion criteria. Only 5 articles were ultimately selected through Ovid search. Most retrieved studies were retrospective, with 3 being multicenter studies (3, 8, 9) . One was a clinical trial (10), and 1 was a randomized clinical trial (11) . Twelve duplicates found in both searches were excluded. Searching through the bibliography of the studies did not provide additional studies. A flow chart is shown in figure 1 . The following characteristics were extracted from each study: country where the study was conducted, number of patients, percentage of chronic diseases (such as hypertension, diabetes, cardio-vascular disease, pulmonary disease, etc.) as reported in each study, percentage of severe cases, death rate, rate of antibiotic use, rate and type of secondary and co-infection, , types of antibiotics used, duration of antibiotic treatment, as well as rate of use of glucocorticoids and antivirals. Four articles used the guidelines from the CNHC to classify patients' severity (3, 8, (12) (13) . "Mild" was defined as mild clinical symptoms or asymptomatic with no signs of pneumonia on imaging, "Moderate" was defined as having fever or respiratory tract symptoms and signs of pneumonia on imaging; "Severe" was classified if one of the following was present: a) dyspnea with a respiratory rate of ≥ 30 per minute, b) saturation ≤ 93%, and c) PaO2 / FiO2 ≤ 300mmHg; "Critical" was classified if one of the following was present: a) respiratory failure requiring mechanical ventilation, b) shock, and c) co-existing multiple organ failure requiring close monitoring in the Intensive Care Unit (ICU). One article reported severity according to American Thoracic Society guidelines for community-acquired pneumonia (14) . Other articles (10, (16) (17) (18) (19) (20) reported severity in terms of presence of hypoxemia, acute respiratory distress syndrome, acute renal injury, septic shock or admission to the intensive care unit, without mentioning the overall prevalence of severe patients. For the latter studies, we only reported the most prevalent severity criterion to avoid overestimating the level of severity of the given cohort. infection. Nineteen studies were included, comprising 2834 patients in total. Most articles (sixteen) came from China, one from the United States (20) , one from Brazil (11), and one from Denmark (21) . Some studies reported age of the patients as a mean, others as a median and it ranged between 28 (22) and 69.5 (20) years old for median age and 52.9 (8) Only 4 studies comprising 375 patients reported frequency of use of different types of antibiotics (11, 15, 22, 23) . Fluoroquinolones were the most used, with 56.8% of patients (213 out of 375), followed by ceftriaxone in 39.5% of patients (148 out of 375), then azithromycin in 29,1% of patients (109 out of 375). Carbapenems were only used in 2 patients. Seven articles (12, 13, 17, 19, 20, 24, 25) reported the types of antibiotics used but with scarce data regarding their frequency of use. Only 3 studies reported duration of treatment: Chen et al. (24) reported that it ranged between 3 and 17 days, with a median of 5 days. Borba et al. (11) reported a duration of 7 days (for Ceftriaxone) and 5 days (for Azithromycin). Pedersen et al. (21) reported that clarithromycin was discontinued if cultures for atypical bacteria were negative, whereas duration of treatment for meropenem and piperacillin-tazobactam was at least eight days. Eight studies (10, 12, 13, 19, 21, 24, 25, 27) reported that 50% of deaths in their cohort were imputable to secondary infections. Three studies reported a higher antibiotic use rate in more severe patients. Guan Xu et al. (26) noted that antibiotic use rate was higher (48% vs 41%) when duration of symptoms exceeded 10 days. They also reported that antibiotics were administered if fever lasted for more than seven days. Xu et al. (26) noted that antibiotics were administered when C-reactive protein levels were 30 mg/L or more (normal range 0-8 mg/L). Pedersen et al. (21) selected Procalcitonin's trend to aid in antibiotic monitoring. This review exposes several critical findings related to antibiotic use in hospitalized Covid-19 patients. Four studies (3, 14, 17, 27) comparing survivors and non-survivors found no significant difference regarding antibiotic use. However, there was no study on survival rate according to presence or absence of empiric antibiotic treatment. Antibiotic efficacy should be further investigated prospectively in Covid-19 patients to minimize their useless use and minimize antimicrobial resistance. Conversely, impact of empiric antibiotherapy on secondary infections should also be further investigated, given that one study (24) reported an association between use of combination of antibiotics and occurrence of secondary infection. The most frequently used antibiotics were fluoroquinolones, macrolides and cephalosporins. Possible explanation for such use is lung coverage for pneumococcal, gram negative and atypical bacterial infections. Ventilator associated infections were reported in many studies, without mention of any specific involved organism. Two studies reported isolation of Staphylococcus J o u r n a l P r e -p r o o f species (17, 24) , but there was no mention of methicillin resistant Staph aureus isolates in any article. It is unclear why and how antibiotics were used in most of these studies. Specific patients' comorbidities should be addressed when deciding on the type of antibiotic and route of administration to use. Quinolones were frequently used in reported studies. However, these are associated with many adverse events including QT interval prolongation, tendon rupture and aortic dissection. (28) No adverse event was reported in these studies. Intravenous route of administration of antibiotics was the most used as many patients were defined as having severe The impact of Covid-19 on antimicrobial resistance is currently difficult to predict, however most studies report heavy empirical use contrasting with relatively low frequency of bacterial coinfection and secondary infections (30) . Antimicrobial exposure has been demonstrated to be a risk factor for increase microbial resistance. (31) In addition to that, long duration of hospitalization with intensive care unit stay increases the risk of infections with multidrug-resistant organisms. (32) Antimicrobial stewardship program is among other important strategies to reduce such risk. (33) Recent studies suggest that patients with altered gut microbiota might experience more severe As to the designs of the studies, most of them reported that a significant portion of patients were still in hospital by the end of the study (for example, 34.1% in Wang et al. (16) ). This may have led to an overestimation of the total rate of antibiotic use and secondary infections. Furthermore, classifications regarding patients' severity were heterogenous, rendering comparison between articles difficult. Only a limited number of published articles was included, mostly from Republic of China and this could have impacted the results. Nonetheless, we provided the rate of severe patients in each study, as this variable is critical to determine relevance of antibiotic use. Regarding types of secondary bacterial and co-infections, we decided to report the available results, although little information was presented. This review presented data from nineteen studies regarding antibiotic usage in 2834 patients with Co-infections: potentially lethal and unexplored in COVID-19 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 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