Suboptimal antimicrobial stewardship in the COVID-19 era: is humanity staring at a postantibiotic future?

In the absence of potent antimicrobial agents, it is estimated that bacterial infections could cause millions of deaths. The emergence of COVID-19, its complex pathophysiology and the high propensity of patients to coinfections has resulted in therapeutic regimes that use a cocktail of antibiotics for disease management. Suboptimal antimicrobial stewardship in this era and the slow pace of drug discovery could result in large-scale drug resistance, narrowing future antimicrobial therapeutics. Thus, judicious use of current antimicrobials is imperative to keep up with existing and emerging infectious pathogens. Here, we provide insights into the potential implications of suboptimal antimicrobial stewardship, resulting from the emergence of COVID-19, on the spread of antimicrobial resistance.

Antimicrobial resistance (AMR) refers to the adaptation of microbial pathogens (bacteria, viruses, fungi and parasites) to antimicrobial drugs thereby resulting in drug inefficiency, persistent infections and increased risk of severe disease and transmission. AMR is one of the three greatest threats to global health [1], and could hamper prevention and treatment of common infections [2]. The burden of resistant infections is comparable to that of influenza, tuberculosis and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) combined [3]. In the absence of potent antimicrobial drugs, it is estimated that bacterial infections alone could cause hundreds of millions of deaths [4]. Hence, antimicrobial stewardship, a systematic approach aimed at optimizing antimicrobial use, is paramount. The increasing demand for antibiotic use, inappropriate prescription of antibiotics in high-income countries and over-the-counter sales of antibiotics in developing countries are some of the factors driving AMR globally [5]. Antimicrobial stewardship, if correctly implemented, has the potential to curb the increasing challenge of AMR. Indeed, some successes have been achieved in curtailing inappropriate use of antibiotics through antimicrobial stewardship. However, owing to the emergence of COVID-19, a novel disease yet to be fully understood in terms of pathophysiology and treatment, antimicrobial stewardship appears neglected [6-8], which may put humanity at a risk of widespread AMR and dearth of potent antimicrobial drugs.

In December 2019, COVID-19, caused by SARS-CoV-2, was reported in Wuhan city, China and had been associated with several deaths globally [9]. SARS-CoV-2 is a new member of coronaviruses, which are a group of highly diverse enveloped, positive-sense, single-stranded RNA viruses [10]. The control measures adopted to curb the spread of the virus include mandatory wearing of face masks, personal distancing, hand washing and sanitization [11] and recently, vaccination. The complex pathophysiology of COVID-19 and possible bacterial and/or fungal coinfections and superinfections have prompted the use of various antimicrobial drugs for its management [12].

The degree of antibiotic-resistant infections is strongly related to the level of antibiotic consumption [13]. Therefore, the repurposing, overuse and misuse of antimicrobials for COVID-19, as has been observed [14,15], may negatively impact human health. The development of AMR may be attributed to many factors, fundamental among them is the overutilization of prescribed antimicrobials. Once a microbe develops resistance to a single or multiple classes of antibiotics [16], it may spread the AMR gene(s) within and across species or genera [17]. Additionally, the current antibiotic pipeline is fragile, having narrow-spectrum or pathogen-specific potential drugs [18]. Thus, nonjudicious use of antimicrobials in the COVID-19 era could result in large-scale drug resistance.

The potential impacts of suboptimal antimicrobial stewardship in the COVID-19 era should be considered in the management of the ongoing pandemic. Therefore, this article focuses on how the emergence of COVID-19 era has compounded suboptimal antimicrobial stewardship and the potential implications for AMR development and spread within and across microbial species and genera. In addition, the need to remain committed to antimicrobial stewardship is emphasized and strategies to maintaining antimicrobial stewardship in the context of the pandemic are highlighted.

Antimicrobial stewardship: is it a challenge in the context of COVID-19?

The COVID-19 has resulted in increased usage of antimicrobials [8,11,19]. This could be attributed to the limited knowledge about the virus, its complex pathophysiology, possible syndemic with bacterial, fungal or protozoal infections, and a remarkable clinical similarity with sepsis [20]. Even though ruling out SARS-CoV-2 coinfection with bacterial or fungal infection could improve antimicrobial stewardship, secondary infections in COVID-19 patients is faced with diagnostic challenges. Notably, the high infectivity of the virus limits the use of invasive diagnostic procedures, such as bronchoscopy and radiologic imaging, which could generate aerosols thereby exposing health workers to the virus. This is further compounded by the poor sensitivity of conventional diagnostic tests in identifying the etiologic organisms responsible for respiratory infections; hence the use of a broad array of antibiotics may be inevitable.

Heightened hand sanitization: implications for the spread of antibiotic resistance

Many public health agencies and governments around the world have been promoting hand hygiene, which includes hand washing and hand sanitization, to limit the spread of SARS-CoV-2 [11]. Indeed, the sale of hand sanitizers surged by 3–5-times in 2020 compared with same period in 2019 in some countries [21]. Some antibacterial soaps and other disinfectants used to prevent the spread of SARS-CoV-2 contain hydrogen peroxide, sodium hypochlorite, benzalkonium chloride or many other antimicrobial agents. Further, hand sanitizers containing suboptimal concentrations of alcohol are on the market. The widespread use of these hand sanitizers and other disinfectants during the COVID-19 era could potentiate the development and spread of AMR traits. There is a likelihood of the emergence of alcohol-tolerant bacteria, a phenomenon already reported across several bacterial genera [22]. Other antibacterial compounds in soap, particularly triclosan and triclocarban could enhance AMR development. Although banned by the US FDA in 2016 [23], the high demand for antibacterial hand washing products has prompted the use of triclosan and triclocarban [24] in some countries. Triclosan is broad-spectrum antibacterial compound, with some antifungal and antiviral activity [25]. Resistance to triclosan develops via multiple mechanisms, including efflux pumps, which confers resistance to multiple antibiotics [26]. Thus, the use of triclosan-containing hand washing soaps in the COVID-19 era could result in cross-resistance to several antibiotics. Disinfectants, such as hydroperoxide, which could alter bacterial DNA may as well cause resistance development in bacteria.

Overuse of antibacterial drugs among COVID-19 patients

Rational antibacterial use in clinically stable patients requires culture and sensitivity test result [27]. Where culture and sensitivity test could not be performed, therapy is empiric but guided by epidemiological evidence [27]. Are these rational considerations made in the management of bacterial infections in the COVID-19 context? Antibacterial use in COVID-19 management is hinged on a SARS-CoV-2-associated superinfection with endogenous or hospital-acquired bacteria [28]. However, the rate of antibacterial drug usage is disproportionately higher than the rate of bacterial coinfection in the patients [29]. Some antibacterial drugs commonly prescribed for COVID 19 patients include fluoroquinolones, cephalosporins, carbapenem and linezolid, which are all broad-spectrum antibiotics, and macrolides [30]. It has been suggested that amidst the pandemic, the continuing threat posed by AMR may no longer be at the forefront of many peoples' minds [31], and as mentioned earlier, the over prescription of these drugs among others could result in a widespread antibiotic resistance. Therefore, to tackle this peril, an integrated prepared strategy is paramount [32].

Repurposing of antiparasitic drugs for the management of COVID-19

Repurposing of existing anti-parasitic drugs gained traction for the management of COVID-19, especially in the early phase of the pandemic [33]. For example, ivermectin, a broad-spectrum antiparasitic agent, has been suggested as an immunomodulator inhibiting the nuclear import of viral proteins [34]. Consequently, ivermectin has been tried both in vitro and in vivo for COVID-19 therapy [35,36]. Considering its broad anti-parasitic activity, a widespread use of ivermectin for COVID-19 treatment could lead to rapid development and spread of ivermectin resistance. Other antiparasitic drugs such as diethylcarbamazine, niclosamide and nitazoxanide, and hydroxychloroquine and chloroquine have been explored for COVID-19 treatment [37-39]. If successful, the widespread use of these drug to fight the pandemic may as well result in resistance.

Use of antiviral drugs against SARS-CoV-2 & other viral coinfections in COVID-19 patients

Severe COVID-19 is associated with immune dysregulation which may result in secondary viral infections [40]. Several antiviral drugs have been incorporated into the management of COVID-19, with some meant for diseases such as HIV and influenza are being diverted to COVID-19 treatment [41]. Administration of antivirals shortly after the onset of COVID-19 symptoms can reduce viral shedding. Furthermore, prophylactic treatment of contacts reduces their risk of being infected [42].

Remdesivir is one of the commonly used drugs in the COVID-19 context [43]. Remdesivir has a broad-spectrum antiviral activity incorporating both RNA and DNA viruses [44]. The drug inhibits viral RNA synthesis and viral mRNA capping in a wide range of viruses, including influenza virus and HIV [45]. A combination of HIV drugs, lopinavir/ritonavir, which are protease inhibitors, are being used to inhibit SARS-CoV-2 replication. Unfortunately, antiviral resistance against lopinavir/ritonavir has been reported previously [46]. Other antivirals such as umifenovir, a broad-spectrum drug that inhibits membrane fusion of the viral envelope by targeting the S protein–ACE2 interaction [41], and favipiravir, an RNA polymerase inhibitor initially used for Ebola and influenza [47], are also used. Notably, drug resistance has been reported for favipiravir [48].

The high demand of these antiviral drugs for treatment and prophylaxis of COVID-19 requires adequate stock of drugs. This may create two major problems. First, it may quicken the development of drug resistance. With already existing cases of antiviral resistance [49] for some of the drugs proposed for COVID-19 management, and the fact that most viruses develop mutations rapidly [50], overuse will escalate resistance to many viruses rendering the drugs ineffective. Second, the increased usage may lead to shortage of drugs not only for COVID-19 patients, but also HIV/AIDS patients. The influenza outbreaks in future might become pandemic if the influenza drugs are rendered ineffective due to resistance.

Treating fungal superinfections in COVID-19 patients with antifungal drugs

There are reports of deadly fungal superinfections caused by Aspergillus species and Candida albicans among severe COVID-19 patients across many regions [12,51]. This is worrying since there are few effective antifungal drugs; moreover, the few available antifungal drugs have serious side effects [52]. In an attempt to manage secondary fungal infections, antifungal drugs have been incorporated into the management of COVID-19 [53]. For instance, voriconazole and savuconazole, which both inhibit the cell membrane synthesis and caspofungin, which blocks cell wall synthesis [54] have been used to treat fungal superinfections associated with COVID-19 [51].

Cases of resistance against the above antifungal drugs have been reported [55,56]. Most of the antifungals drugs have broad-spectrum of activity as they target ergosterol, which is common in fungi [57], hence, development of resistance to one drug could affect many antifungals. With the slow discovery and development of antifungals, the widespread and indiscriminate use of the few available antifungals could render the antifungal armamentarium impotent and jeopardize the treatment of opportunistic fungal infections, especially among immune-compromised patients.

Strategies to maintain antimicrobial stewardship in the context of a pandemic: COVID-19

Antimicrobial stewardship is needed to curb the suboptimal use of antimicrobials in the ongoing and future pandemics. Strict policies should be set on the use of antimicrobials, with more sensitization to educate health workers and the public on AMR. The use of biocides for environmental and personal disinfection should be done cautiously and biocidal agents without or with a low selection pressure for antibiotic resistance should be prioritized. Rigorous infection prevention and control measures should be implemented to prevent hospital-acquired infections among COVID 19 patients. Additionally, efforts should be made toward reducing the turnaround time of COVID-19 tests through improved testing methods and facilities, as this will decrease the urge to initiate antibiotics empirically. Furthermore, studies toward improving antimicrobial stewardship should be an integral part of the pandemic response and beyond. Lastly, rapid and inexpensive diagnostic tests to distinguish between bacterial and viral respiratory tract infections, where available, should be deployed for coinfection testing in COVID 19 patients. Nonetheless, antimicrobial stewardship strategies for COVID-19 have previously been reviewed [58].

Future perspective

As previously highlighted, lack of timely and accurate differential diagnostic method for bacterial– and fungal–viral coinfections is a major driver for antibiotics overuse in COVID-19 treatment. Hence, advances in point-of-care (POC) diagnostics designed for timely identification of pathogenic bacteria or fungi in various clinical samples will potentially shape antibiotics therapy in the clinics in the years to come. Notably, POC biosensors and isothermal-based nucleic acid amplification tools, especially if they are miniaturized and optimized for both pathogen and resistance gene(s) detection, will pave the way for timely diagnosis of coinfections and obviate empiric treatment. Investigation of host or pathogen-derived biomarkers of bacterial, fungal and viral coinfections, as well as the translation of the discovered biomarkers into diagnostic tools, therefore, remains an interesting area of research that should be well explored in the coming years.

The high infectivity of SARS-CoV-2 has led to increased use of disinfectants and hand sanitizers to curb its transmission.

The desperate desire to avert COVID-19-related mortalities has occasioned suboptimal antimicrobial stewardship which could enhance the emergence of resistance.

While pharmaceutical companies and researchers work harder to avail new antibiotics, proposed stewardship interventions for COVID-19 should be put in practice to prevent resistance.