key: cord-0711855-26zzuphc authors: Lobie, Tekle Airgecho; Roba, Akililu Abraham; Booth, James Alexander; Kristiansen, Knut Ivan; Aseffa, Abraham; Skarstad, Kirsten; Bjørås, Magnar title: Antimicrobial resistance: A challenge awaiting the post COVID-19 era date: 2021-09-08 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.09.003 sha: 20c5f71376fdfb19cdf10a2942fc64ebda4323ed doc_id: 711855 cord_uid: 26zzuphc Microbe exposure to pharmaceutical and non-pharmaceutical agents plays a role in the development of antibiotic resistance. The risks and consequences associated with extensive disinfectant use during the COVID-19 pandemic remain unclear. Some disinfectants, like sanitizers, contain genotoxic chemicals that damage microbial DNA, like phenol and hydrogen peroxide. This damage activates error-prone DNA repair enzymes, which can lead to mutations that induce antimicrobial resistance. Public health priority programs that have faced drug-resistance challenges associated with diseases, such as tuberculosis, HIV, and malaria, have given less attention to risks attributable to the COVID-19 pandemic. Pathogen-specific programs, like the directly observed treatment strategy, which were designed to fight resistance against anti-tuberculosis drugs, have currently become impractical, because COVID-19 restrictions have limited in-person visits to health institutions. Here, we summarized the key findings of studies on the current state of antimicrobial resistance development, from the perspective of current disinfectant use. Additionally, we provided a brief overview of the consequences of restricted access to health services, due to COVID-19 precautions, and their implications on drug resistance development. Antimicrobial resistance (AMR) is a global public health concern (Prestinaci, Pezzotti, & Pantosti, 2015) . The main drivers of AMR include excess microbial exposure to antibiotic agents, mainly due to their overuse in agriculture and health facilities (Capozzi et al., 2013; Levy, 1998) . On the other hand, progress in developing new antibiotics has remained stagnant, due to scientific challenges, clinical hurdles, and low economic returns (Payne, Miller, Findlay, Anderson, & Marks, 2015) . In addition to well established factors that influence AMR, the overuse and misuse of existing antimicrobial agents have contributed to accelerating the spread of AMR, during and beyond the COVID-19 pandemic ( Fig. 1) Recent findings have identified mechanisms that linked antibiotic-resistance dissemination to the use of non-antibiotic pharmaceuticals (Wang et al., 2020) . Those findings are essential for understanding AMR in the context of the SARS-COV-2 pandemic, which has led to extensive use of non-pharmaceuticals (e.g., alcohol-based sanitizers) as a measure to prevent infection (Hui et al., 2020) . The marked increase in the use of hand sanitizers and environmental cleaners, without proof of their short-and long-term side effects, is a potential concern for human, animal, and environmental health (Campos et al., 2017; Mantlo et al., 2020) . Developing countries and regions with limited resources, a flawed pharmaceutical supply chain, and poor health service management systems might contribute most to AMR spread, because the quality of pharmaceutical products remains questionable (CDC., 2020) (Chokshi, Sifri, Cennimo, & Horng, 2019). Here, we briefly provide insight into how COVID-19 preventive measures, such as the use of disinfectants and disruptions in treatment modalities of AMR-targeted diseases, could potentially lead to an increase in AMR, beyond the pandemic. In 2017, the World Health Organization (WHO) released a report on drug-resistant bacterial pathogens that merit priority in research and development(WHO., 2017). Most pathogens in the list included bacteria that carry the enzyme, New Delhi metallo-beta lactamase 1 (NDM1), which confers resistance to the broader spectrum of mainstay antibiotics used for treating antibiotic- One WHO strategy for mitigating SARS-COV-2 infections was for everyone to use hand sanitizers and disinfectants as frequently as possible on a daily basis (CDC., 2020; Kratzel et al., 2020). As a result, the unseen world of microbial populations has been continuously exposed to pharmaceutical and non-pharmaceutical agents, at varying frequencies, concentrations, and doses (Haiderali, 2020) . Regardless of composition, the long and short-term effects of these products on microbial genetics and human health have apparently been overlooked; however, we believe that current practices do not lack potential impact. Therefore, based on the lessons learned about physiological and microbial molecular responses to different stresses, we might infer that the use of pharmaceutical and non-pharmaceutical agents will inevitably contribute to the emergence and spread of AMR, via mutagenic mechanisms that introduce microbial genome instability Upon exposure to antibiotic-based disinfectants, bacteria respond by forming a subpopulation that persists and can become highly tolerant to antibiotics. This "selected" subpopulation plays an essential role in the recalcitrance of biofilm infections (Fig. 2 )(Dorr et al., 2010) . Therefore, microbes can undergo both phenotypic and genotypic changes that modify the molecules targeted by the antibiotic (Lewis, 2007) . Moreover, the use of antibiotics has increased in current efforts to ameliorate COVID-19. Indeed, antibiotics were administered in nearly 70% of COVID-19 related hospital admissions and 80-100% of COVID-19 related intensive care unit admissions (Langford et al., 2020) . For instance, individuals received antibiotics, when they presented with either mild COVID-19, without pneumonia, or moderate COVID-19 with pneumonia(WHO., 2020a). The pandemic has posed a challenge to the preventive and control programs for public health priority diseases, such as tuberculosis (TB), HIV, and malaria. For instance, fighting the notoriously drug-resistant bacterial infection, TB, with a directly observed treatment strategy (DOTs) has become practically impossible, because COVID-19 related restrictions have prevented patients with TB from visiting health service centers(WHO., 2020b). In developing countries, where infectious diseases and other chronic illnesses are prevalent, the WHO global strategy and the recommendation for digital health interventions have remained elusive, due to low and limited internet coverage, where available (Labrique, Agarwal, Tamrat, & Mehl, 2020). These countries are burdened with far worse illnesses than COVID-19; thus, perhaps in that context, the COVID-19 measures are too strict, compared to methods for managing other illnesses. Consequently, the number of empirical treatments has increased, due to the lack of medical, physical, and laboratory examinations. Several global strategies have been established for combating AMR, through the tremendous collaborative efforts of international agencies, including the US Center for Disease Control and Prevention, the European Center for Disease Prevention and Control, the WHO, the United Nations interagency coordination group on AMR, and the Global antibiotic resistance partnership (Chaudhary, 2016) . If these achievements are undermined due to COVID-19 management strategies, we could experience even worse health, economic, social, and political crises. Exposure of microbes to disinfectants and non-pharmaceutical agents contribute to the microbial ability to evolve mechanisms that lead an increase in AMR. Furthermore, the COVID-19 related restrictions to health services limited access for proper diagnosis, treatment and management of patients with infectious diseases that need antibiotic based interventions. Cognizance and actions are desperately needed to confront the existing and emerging public health threats from drugresistant, multidrug-resistant, and total drug-resistant microbes. Therefore, because the course of the COVID-19 pandemic remains enigmatic, we would argue that the strategies for combating the emergence and spread of AMR should be incorporated into the pandemic response through different approaches. A robust expert recommendation and research on the formulations of disinfectants in current use, specifically, for the selection, introduction, and regulation of microbicides that have shown no or low selective pressure for inducing AMR is critical. For example, investigations should focus on disinfectant constituents, mechanisms of action, genetic targets, and short and long-term effects on the environment, humans, and the microbial population. Furthermore, strategies should be designed and implemented to reach patients with chronic infections like TB that require antibiotic management. In this regard, it is indispensable to strengthen the capacity of community health care providers to follow and assist patients without compromising safety and infection prevention measures. Importantly, alternatives to digital health (e-health) should be sought for areas with no or limited internet access. Here, we argue that internet expansion into the remotes is feasible provided there is investment and political commitment. The time is at hand to launch coordinated, collaborative measures to stem the further emergence and spread of untreatable infections and diseases, which could eventually lead to another public health emergency. Not applicable Increase in resistance of methicillin-resistant Staphylococcus aureus to beta-lactams caused by mutations conferring resistance to benzalkonium chloride, a disinfectant widely used in hospitals Antibioticinduced DNA damage results in a controlled loss of pH homeostasis and genome instability Toxic Exposures in Children Involving Legally and Illegally Commercialized Household Sanitizers Healthcareassociated infections and antibiotic resistance: a global challenge for the 21st century The impact of triclosan on the spread of antibiotic resistance in the environment Sanitizer Use Out and About. Handwashing in Community Settings A review of global initiatives to fight antibiotic resistance and recent antibiotics' discovery Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents Global Contributors to Antibiotic Resistance Emergence and dissemination of antibiotic resistance: a global problem Microbial Persistence and the Road to Drug Resistance DNA damage induced by occupational and environmental exposure to miscellaneous chemicals Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli Antimicrobial resistance: A global emerging threat to public health systems Translesion DNA Synthesis and Mutagenesis in Prokaryotes DNA damage tolerance: a double-edged sword guarding the genome Selection of Resistant Bacteria at Very Low Antibiotic Concentrations Coming clean about sanitisers The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health -The latest 2019 novel coronavirus outbreak in Wuhan, China Pfaender, S. Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 by WHO-Recommended Hand Rub Formulations and Alcohols Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study WHO Digital Health Guidelines: a milestone for global health Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis The challenge of antibiotic resistance Persister cells, dormancy and infectious disease In vitro efficacy of a copper iodine complex PPE disinfectant for SARS-CoV-2 inactivation Cleaning, disinfection and sterilization of surface prion contamination Emergence of Global Antibiotic Resistance A step closer to extreme drug resistance (XDR) in gramnegative bacilli Optimising Antibiotic Usage to Treat Bacterial Infections Time for a change: addressing R&D and commercialization challenges for antibacterials Benzalkonium Chlorides: Uses, Regulatory Status, and Microbial Resistance Increasing tolerance of hospital Enterococcus faecium to handwash alcohols Antimicrobial resistance: a global multifaceted phenomenon Nonantibiotic pharmaceuticals enhance the transmission of exogenous antibiotic resistance genes through bacterial transformation WHO. Guide to Local Production: WHO-recommended Handrub Formulations 39. WHO. Information note on Tuberculosis and COVID-19 We are indebted to the authors of articles used in this perspective. This perspective was unfunded. The authors declare that there is no conflict of interests.