Use of antimicrobials in patients with COVID-19 without prior evaluation of an associated bacterial infection

This paper aims to clarify and present discussions about the COVID-19 disease, its variants and prevention measures, as well as clarifying the excessive use of antimicrobials in the protocols of patients infected with it, as this practice can intensify an already existing public health problem, which is antimicrobial resistance. The methodology used in this research was a literature review on bacterial resistance due to the indiscriminate use of antimicrobials and the possible impacts caused in the COVID-19 pandemic, as well as the variants of worldwide concern, based on the Scientific Electronic Library Online databases - SCIELO, National Library of Medicine - PubMed, CAPES Journal Portal, Academic Google and National Health Surveillance Agency (ANVISA). Based on the literature presented here, it is concluded that COVID-19 is a disease caused by the acute respiratory syndrome (SARS-CoV-2) presenting a clinical spectrum ranging from asymptomatic infections to severe conditions. Several variants have emerged in several countries modifying the dynamics of transmissibility and potential immune flight from the disease, the Delta variant (B.1.617.2) being a greater threat to public health due to its high transmissibility. The misuse and excessive use of antimicrobials prescribed for the treatment of this disease can favor the emergence of superbugs and such resistance is a global problem. Therefore, the help of laboratory and clinical tests is essential to carry out a therapeutic intervention, observing the best options for each clinical case, since COVID-19 is a new disease and still under study.


Introduction
In recent years, due to technological advances, access to the most diverse information on search sites, as well as discussions in virtual communities, has become fast and independent. This advance also promoted the growth of the indiscriminate and improper use of medicines without a medical prescription. According to Souza et al., 2008, self-medication can result in undesirable effects, ranging from the masking of evolving diseases to the emergence of iatrogenic diseases, that is, a disease state, adverse effects or complications caused or resulting from medical treatment (Ferraz et al., 1982;Souza et al., 2008).
According to Teixeira (2019), in Brazil, the sale of antimicrobials exceeds that of analgesics and antipyretics. The inappropriate use of these drugs can accelerate the bacteria's defense mechanisms, causing a certain type of antimicrobial to progressively lose its effectiveness (Teixeira, 2019). In addition, there is still the ingestion of antimicrobials from animal foods, which are treated with these drugs, with large amounts of them (Luiz et al., 2018;Miranda et al., 2018;Pereira et al., 2020).
Antimicrobial agents have different behaviors, acting as a bactericide, causing the death of microorganisms responsible for the infectious process. This group includes several drugs, such as: beta-lactams, aminoglycosides, rifampicin, vancomycin, quinolone, among others. While those with bacteriostatic actions, which inhibit bacterial growth, even though the microorganism remains viable, are: tetracyclines, chloramphenicol, macrolides, sulfamides, among others (Luiz, 2019;Oliveira Junior, 2016).
It should be remembered that the same antimicrobial can show a different activity against different microorganisms, including the antimicrobial activity can be different in a microorganism located in different geographic areas. Thus, the concept of antimicrobial activity requires standardization or quantification that is achieved through in vitro assays (antibiogram, dilution techniques and molecular biology) to prove the microorganism's susceptibility to the antimicrobial (Oliveira Junior, 2016).
According to the Ministry of Health (MS), COVID-19 is a disease caused by the coronavirus, called SARS-CoV-2, which has a clinical spectrum ranging from asymptomatic infections to severe conditions. According to the World Health Organization (WHO), about 80% of patients with COVID-19 may be asymptomatic or oligosymptomatic, while the remaining 20% of detected cases require hospital care. It is observed that in some patients with COVID-19 there are cases of secondary infection by some bacteria concomitantly, for this reason, the use of antimicrobials, mainly macrolides, was included as prophylaxis in the protocol of some cities .
Among the main variants of SARS-CoV-2, one has presented an imminent risk in Brazil and in other countries, the Delta variant (B.1.617.2), due to its greater transmissibility, leading to a worsening of the pandemic picture. The emergence of variants is a matter of global concern, as they are considered serious threats to public health, as currently available vaccines may have limits in terms of effectively blocking virus transmission (Planas et al., 2021;Yadav et al., 2021).
The present study is a literature review based on journal articles with the aim of clarifying and presenting discussions about the COVID-19 disease, its variants and prevention measures, as well as conducting a narrative about a possible health crisis, arising from the excessive use of antimicrobials, causing an increase in the profile of bacterial resistance, which already occurs and can be aggravated by the pandemic.

Methodology
The present study is characterized as a quantitative explanatory literature review. This type of research is considered to be that which seeks to identify explanations and their relations with the phenomenon studied (Gil, 2017).
To this end, a literature review was conducted on bacterial resistance due to the indiscriminate use of antimicrobials and the possible impacts caused by the pandemic of COVID-19, as well as the variants of worldwide concern. Such research was conducted between the months of august and september 2021, as the purpose of mapping the scientific production on the referred theme in the period comprising the years 2019 to 2021.
Data collection was based on the Scientific Electronic Library Online -SCIELO, National Library of Medicine -PubMed, CAPES Journal Portal, Google Scholar, National Agency for Sanitary Surveillance (ANVISA) and the Centers for Disease Control and Prevention (CDC). Books that are reference in the subject discussed were also used.
In this initial consultation a total of 189 articles were found, and then two stages of refinement were performed. In the first, we chose to remove the duplicate articles, and in the second, we chose to exclude those that were not within the scope of the intended study, leaving a total of 25 articles. For the refinement of article selection, the procedure indicated in Flowchart 1 was adopted. Research, Society and Development, v. 10, n. 12, e264101220410, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i12.20410

The Coronavirus
Coronavirus is characterized by a zoonotic virus, an RNA virus of the order Nidovirales, of the Coronaviridae family. This is a family of viruses that cause respiratory infections, which were first isolated in  variant (B.1.617.2) The B.1.617 lineage, originating in India, has spread to many countries such as the United Kingdom and Brazil,

SARS-CoV-2 Delta
Second refinement -Articles outside the scope of the study- 9 Total articles included (25) mechanism. Such a Protein S mutation increases adherence to host cell receptors and promotes a reduction in the action of antibodies (Abdool Karim & de Oliveira, 2021;OPAS, 2021 A recent study in the United Kingdom estimated that the effectiveness of vaccines is reduced against the newer variants, when compared to the original strain of coronavirus, especially with just one dose of it. Therefore, this finding reinforces efforts to expand vaccine coverage in two doses (Abdool Karim & de Oliveira, 2021;Frampton et al., 2021;PAHO, 2021).

Antimicrobial Drugs used to treat COVID-19
COVID-19 is a disease caused by acute respiratory syndrome 2 (SARS-CoV-2), and since December 2019, it has affected the world (Chen & Li, 2020). It has a clinical spectrum ranging from asymptomatic to severe infections. Although this is considered a virus in clinical medicine, it is observed that it has had some cases of secondary infection by some bacteria in concurrency, for this reason, the use of antimicrobials, especially macrolides, as prophylaxis (Vellano & Paiva, 2020).
However, with this conduct of use of antimicrobials as prophylaxis for all patients, that is, even for those without a diagnosis of clinical confirmation tests for COVID-19 infection, a scenario that was already threatened, that of bacterial resistance, can start.
Bacterial resistance can be classified as intrinsic and acquired, thus, the intrinsic form is understood as the naturally inherited resistance genetically, while the acquired one comes from external factors, such as the irrational use of antimicrobials (M. . Thus, bacterial resistance results in the bacterium's capacity to adapt, and when this is related to antimicrobials, it occurs when the bacterium expresses genes that encode the biochemical mechanism by inhibiting the production of enzymes that end up inactivating drugs, the alteration of action targets and alteration of the permeability of the outer membrane or efflux thereof (AR Teixeira et al., 2019).
The misuse and excessive use of antimicrobials favors the emergence of superbacteria, which are subdivided into extensively resistant, when the bacteria occurs in one or two classes; multidrug-resistant, when resistance occurs in an antimicrobial of three or more classes; or even in pan-resistant, when resistance occurs in all classes of antimicrobials (M. . Azithromycin (macrolide) is one of the drugs widely used in the early treatment of patients with COVID-19, with the aim of preventing or treating a possible secondary infection (pneumonia), as well as clarithromycin, among others. However, the etiology of the disease must be considered, if it is not of bacterial origin, there is no apparent reason for prescribing this drug (Paumgartten & Oliveira, 2020). According to Oliveira, Pereira and Zamberlam (2020), and according to the WHO, there is growing concern about the indiscriminate use of antimicrobials in the COVID-19 pandemic scenario. The Pan American Health Organization (PAHO) considers that antimicrobial resistance is equally dangerous when compared to the pandemic and that centuries of studies and medical progress could be destroyed if significant measures are not adopted regarding its rational use (PAHO, 2020).
Monitoring the use of antimicrobials in the region of the Americas, both in human and animal health, still requires special attention, although some countries in this region, such as Brazil, have contributed relevant information on antimicrobial sales to the WHO Report on Use Surveillance of Antimicrobials, however, such monitoring still needs to be expanded. PAHO supports in different sectors the fight against antimicrobial resistance, as well as its early detection and coordinated response against pathogens. It also supports the research, development and dissemination of scientific results, and alerts countries to act cooperatively, thus increasing public awareness on this issue (J.B. da Silva et al., 2020).
It is important to emphasize that this issue can have devastating consequences, ranging from sanitary crises to diseases that are already under control or emerging, as is the case with COVID-19. In addition to representing a public economic problem, another factor to be considered is that the pharmaceutical industries have not invested in research and development for the production of new antimicrobials, as they demand high expenses over a long period of time (MO da Silva & Aquino, 2018).

The problem of using antimicrobials in patients positive or not for COVID-19
It is believed that a possible way to try to minimize the problem of the use of antimicrobials in patients with COVID-19 would be to test the patient, who has already been positive for this disease, to verify if he actually has a secondary bacterial infection, requesting a test blood culture and/or antibiogram, in order to prescribe the antimicrobial and enable the appropriate therapy (Oliveira Junior, 2016). Such sensitivity tests are exams analyzed by microbiology laboratory professionals, easy to perform, low cost and high reliability, being commonly used in the development of therapeutic guides, with indication for any microorganism that causes an infectious process that requires the use of these drugs (ANVISA, 2017).
Thus, it would minimize the problem of putting the use of antimicrobials as a protocol for all patients. Otherwise there may be a critical situation related to its resistance, and also some undesirable adverse effects in patients due to the use of these drugs. Interactions between macrolides and other widely used medications are observed, such as: oral contraceptives, methylprednizone, digoxin, and some benzodiazepines, midazolam, warfarin. In addition, azithromycin should be avoided, or used with caution, in patients with severe renal or liver failure (Oliveira Junior, 2016;Paumgartten & Oliveira, 2020).

Final Considerations
Through these considerations, it can be concluded that COVID-19 is a disease caused by the acute respiratory syndrome (SARS-CoV-2) and has affected the whole world. It has a clinical spectrum ranging from asymptomatic to severe infections. Several variants have emerged in several countries, thus modifying the dynamics of transmissibility and potential immune flight from the disease. Currently, the Delta variant proves to be a greater threat to public health because of its increased transmissibility and that preventive measures must be taken to prevent its spread.
The misuse and excessive use of antimicrobials favors the emergence of superbugs and such resistance is a global problem and can be even more aggravated in our parents, due to their irrational use. Its rational use thus avoids major sanitary crises, until the achievement of better advances in the development of new drugs in this class of medications, which are already so outdated and without new therapeutic options. With the help of laboratory and clinical tests, a therapeutic intervention must be carried out, observing the best options for each clinical case, since COVID-19 is a new disease and still under study.
It is expected that, with the development of new therapies and current vaccines, clinical protocols for this disease will be better developed, until reaching its total eradication.
Finally, based on the literature presented, it is suggested that future work should include further clinical studies on the subject in question, since it is believed that such a procedure would bring a broad contribution to health promotion, public health, and scientific research.