key: cord-0818577-xwc8ylqk
authors: Seethalakshmi, P. S.; Charity, Oliver J.; Giakoumis, Theodoros; Kiran, George Seghal; Sriskandan, Shiranee; Voulvoulis, Nikolaos; Selvin, Joseph
title: Delineating the impact of COVID-19 on antimicrobial resistance: An Indian perspective
date: 2021-11-16
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2021.151702
sha: aa134eb1445df98319f00bd21010cf72ff3156ce
doc_id: 818577
cord_uid: xwc8ylqk

The COVID-19 pandemic has shattered millions of lives globally and continues to be a challenge to public health due to the emergence of variants of concern. Fear of secondary infections following COVID-19 has led to an escalation in antimicrobial use during the pandemic, while some antimicrobials have been repurposed as treatments for SARS-CoV-2, further driving antimicrobial resistance. India is one of the largest producers and consumers of antimicrobials globally, hence the task of curbing antimicrobial resistance is a huge challenge. Practices like empirical antimicrobial prescription and repurposing of drugs in clinical settings, self-medication and excessive use of antimicrobial hygiene products may have deteriorated the prevalence of antimicrobial resistance in India. However, the expanded production of antimicrobials and disinfectants during the pandemic in response to increased demand may have had an even greater impact on the threat of antimicrobial resistance through major impacts on the environment. The review provides an outline of the impact COVID-19 can have on antimicrobial resistance in clinical settings and the possible outcomes of the same on environment. This review calls for the up gradation of existing antimicrobial policies and emphasizes the need for research studies to understand the impact of the pandemic on antimicrobial resistance in India.

COVID-19 will raise AMR and impede the efforts taken to curb its spread, however, there are several determinants of the ongoing pandemic which could possibly fuel the prevailing AMR threat in India. With attention focused on tackling COVID-19, efforts to curb antimicrobial resistance have largely been put on hold in community and healthcare settings. The current pandemic will amplify the threat of antimicrobial resistance in India: practices that were already prevalent such as over-the-counter use of antimicrobial drugs and empirical prescription of broad-spectrum antibiotics will have increased with any increase in febrile respiratory illness, while COVID-19 has more specifically led to increased use of antimicrobials through repurposing and management of secondary infections. While the negative impact of the pandemic on antimicrobial stewardship and excessive consumption has been highlighted around the globe (Rawson et al. 2020; Ghosh et al. 2021 ), India as a world leader in production faces a greater threat; environmental contamination with antimicrobial waste resulting from a pandemic-altered manufacturing landscape. Excessive use of hygienic products, practice of self-medication, and expanded production of antimicrobials associated with COVID-19, could amplify the concentration of these compounds in the environment. This is further challenged by weak waste management infrastructure and poor sanitation observed in developing communities like India. Antimicrobial residues accumulating in the environment can induce the development of resistance in bacteria to antibiotics.

pandemic Viral respiratory infections have been closely linked to increased chances of bacterial coinfections (Rawlinson et al. 2003; Beadling and Slifka 2004) . Although secondary infections caused by bacteria and fungal pathogens were reported frequently in severe cases of COVID-19 (Chen et al. 2020 ), this finding is not universal (Hughes et al. 2020; Rawson et al. 2020; Garcia-Vidal et al. 2021) . Preliminary reports from China suggested 50% patients who died of COVID-19 were affected by secondary bacterial infections (Zhou et al. 2020 ). Concern about bacterial co-infections in COVID-19 will have been augmented by reports of coinfections in MERS-CoV intensive care patients (Memish et al. 2020) . It is apparent that coinfection may be more related to hospital-acquired and intensive care-associated secondary infection than COVID-19 alone and may not be the leading cause of death in contrast to coinfection in influenza (Morens et al. 2008) .

Several mechanisms could underlie a co-infection risk in COVID-19 patients: During viral infections, viruses can obstruct the configuration required for mucociliary clearance which could enhance the adherence of bacteria to mucins. In addition to this the dense mucus will prevent the entry of immune cells and antimicrobial substances (Wilson et al. 1996) . The inflammation stimulated by viral infection activates epithelial cells to alter the expression pattern of surface receptors which can also favor attachment of bacteria (Morris et al. 2007) . 6 There are several healthcare practises that have augmented the risk of secondary infection.

Mechanical ventilation, consumption of steroidal drugs and other comorbidities can act as a predisposing factor for secondary infections in critically ill COVID-19 patients (Chowdhary et al. 2020) . Susceptibility to unusual infections in the intensive care unit has been linked in part to the practise of "proning" patients (placing patients prone, face down, to improve ventilations), leading to greater risk of skin maceration and contact with fomites. Excessive use of personal protective equipment coupled with reduced attention to contact precautions when caring for patients has also been highlighted as a risk for nosocomial infection.

Increasing use of steroids in COVID-19 and biological therapies that impair cytokine responses may further augment the risk of fungal and bacterial co-infections. This may underlie the reasons why COVID-19 patients are reportedly vulnerable to opportunistic fungal infections such as pulmonary aspergillosis, mucormycosis, cryptococcosis, and pneumocystis pneumonia which have a high mortality rate (Song et al. 2020; Salehi et al. 2020 ).

In India, a high rate of secondary infections was observed in hospitalized COVID-19 patients of both intensive care unit (ICU) and non-ICU wards during the first wave of the pandemic (Vijay et al. 2021; Khurana et al. 2021) . A study by Vijay et al. (2021) found that 3.6% of COVID-19 patients developed secondary infections following hospitalization and the mortality rate amongst these patients was estimated to be 56.7%. The B.1.617 variant resulted in a massive surge of COVID-19 cases in India during the second wave (Vaidyanathan 2021 (Vaidyanathan ). al. 2021 . Among the 101 cases of COVID-19-associated mucormycosis reported globally, 82 cases are from India . Cases of fatal mucormycosis were reported amongst COVID-19 patients of India where the condition of patient deteriorated even after administration of amphotericin B (Nehara et al. 2021) . With a lack of population-based studies, the exact incidence of mucormycosis in India is not yet clear (Prakash et al. 2021 ).

The evidence base regarding secondary and co-infection in COVID-19 is hampered in two ways. Firstly, there is little contextual epidemiological information that allows COVID-19 to be compared with other, similar respiratory viral infections, except in large intensive care databases. As such, although secondary infections are documented in patients diagnosed with COVID-19, whether these are any more frequently observed than in other patients ventilated for pneumonia is unclear. Apart from highly virulent infections such as from species of Mucorales, it is also difficult to comment whether hospital acquired infections are connected to increased COVID-19 severity and mortality. Secondly, invasive diagnostic methods are not routinely undertaken in COVID-19 patients, in part related to infection control considerations, leading to an increase in empiric prescribing.

COVID-19 patients in ICU are subject to antimicrobial therapy more often and the decision to treat is based on laboratory markers of inflammation and severity of the disease (Mustafa et al. 2021) . Indeed, COVID-19 patients have been subject to antibiotic therapy even in the which un-targeted and empiric use of antimicrobials has increased in the wake of the pandemic.

The intersection between AMR and COVID-19 was highlighted by many researchers at the beginning of pandemic (Bengoechea and Bamford 2020; Cantón et al. 2020; Murray 2020) .

AMR in hospitalized COVID-19 patients have been reported from many countries. A study by Kampmeier et al. (2020) reported vanB clones of Enterococcus faecium in COVID-19 subjects from intensive care wards in Germany. New Delhi metallo-beta-lactamase (NDM)

producing Enterobacter cloacae were isolated from critically-ill COVID-19 patients in New York City, which resulted in the death of four out of five patients admitted at the medical center (Nori et al. 2020 Rutsaert et al. 2020; Blaize et al. 2020; Arastehfar et al. 2020) . Evidence comparing prevalence of AMR in specific bacterial and fungal species during the pandemic and prepandemic will no doubt emerge in countries where AMR is subject to routine mandatory surveillance.

trimethoprim/sulfamethoxazole with an overall resistance of 64% to 69% to third-generation cephalosporins and carbapenems (Khuranna et al. 2021) . Another study carried out by Vijay et al. (2021) reported nosocomial pathogens exhibiting resistance to cephalosporins, fluoroquinolones and β-lactam/β-lactamase inhibitor combinations, piperacillin/tazobactam and cefoperazone-sulbactam in COVID-19 patients. A greater occurrence of Candida auris blood stream infection was reported in India in COVID-19 patients; most of the C. auris clinical isolates were found to be resistant to antifungal agents such as amphotericin B and fluconazole (Chowdhary et al. 2020) . Candida infections resistant to these fungal agents is a matter of concern for low-resource countries where there is limited accessibility to echinocandins and is likely to eventually result in treatment failure (Chowdhary et al. 2020) .

Certain isolates of Syncephalastrum monosporum which caused mucormycosis in COVID-19 patients were found to exhibit elevated minimum inhibitory concentration of itraconazole and posaconazole . Incorporating AMR surveillance and stewardship alongside the COVID-19 response will be greatly advantageous (Getahun et al. 2020).

Several different guidelines have operated worldwide since the onset of the pandemic.

Combination therapy with azithromycin and hydroxychloroquine (HCQ) has been recommended in COVID-19 patients due to its antiviral potential despite its risk of prolonging the QT interval (Gautret et al. 2020) . In China, empirical use of antibiotics like azithromycin, amoxicillin or fluroquinolones has been recommended in mild cases of COVID-19 while broad-spectrum antibiotics were advocated in severe cases to eliminate all possible bacterial co-pathogens (Jin et al. 2020) . Initially in the UK, empirical oral administration of doxycycline was suggested in patients who were at increased risk of COVID-19-associated complications or when it was difficult to determine if the causative agent was bacterial or viral, perhaps because patients were asked to remain at home and not present to healthcare (NICE 2020). Later, antibiotic treatment was limited to confirmed bacterial co-infections (NICE 2021). Treatment guidelines for COVID-19 management in African countries recommend antibiotics, with Liberia suggesting use of antibiotics for COVID-19 associated symptoms such as cough, diarrhea and sore throat (Adebisi et al. Although repurposing antimicrobials such as HCQ, azithromycin and doxycycline might appear to be a reasonable approach to COVID-19 management, it is by no means clear that such drugs have any activity against COVID-19 apart from their already known antibacterial or anti-malarial activity; their injudicious use can have setbacks. The use of HCQ is a big concern for India as malaria is endemic in the country (WHO 2018; Principi and Esposito 2020), and its indiscriminatory use may contribute to resistance in Plasmodium sp. (Sutherland et al. 2007) . Typhoid fever is an important health concern for India specifically because of the emergence of azithromycin resistance in Salmonella enterica serovar Typhi 

The consumption of antimicrobials by humans and animals and their subsequent excretion is considered a major source of antimicrobial residues in the environment. Even though the concentration of antimicrobials is in low ranges of μg/kg to mg/kg (soil) and ng/L J o u r n a l P r e -p r o o f Journal Pre-proof to μg/L (water), their presence in such levels have been found to promote antimicrobial resistance (Gilbertson et al. 1990; Boxall et al. 2003; Göbel et al. 2004; Roberts and Thomas 2006; Watkinson et al. 2009 ). In addition to consumption of antimicrobials, the pharmaceutical industry acts as another important source for antimicrobial residues in the environment. The pharmaceutical industry comprises of active pharmaceutical ingredient (API) units that manufacture the raw materials of antimicrobials and units that formulate antimicrobials to finished pharmaceutical product (FPP) (Nahar 2020) . Residues emerging from these sources lays grounds for the development of AMR in bacteria. Times 2020). It can therefore be expected that the overall production of antimicrobials, especially those that have been recommended for treating COVID-19 is likely to have escalated. Increased production of antimicrobials coupled with poor waste management strategies is predicted to intensify the prevalence of AMR in environmental settings. , 2006) . Conventional WWTP processes either partially mineralise antimicrobials or transform them into metabolites with biological activity, resulting in the generation of residues, thereby allowing the entry of these compounds into the environment through effluent discharges or applications of sewage sludge (Miranda and Castillo 1998; Marcinek et al. 1998; Reinthaler et al. 2003; Lindberg et al. 2005; Silva et al. 2006) . Some antimicrobials get transformed into molecules that may have higher or similar antimicrobial effect than that of parent molecule. For example, transformed products of the antibiotic sulfamethoxazole modified at the para-amino group exhibits antibacterial effects like that of parent molecule whereas its 4-NO 2 and 4-OH derivates have higher inhibitory activity than Municipal solid waste landfills are also sentinels of antimicrobials and AMR residues which can disperse into surrounding environments (Li et al. 2017 ). It has been predicted that the risk of AMR is even serious in economies when a population of 20 million reside within ˂ 2 kilometers away from landfills (Wilson et al. 2016) . Antimicrobial residues in landfills could even result in depletion of microbes essential in biogeochemical cycles. This has been demonstrated in a study by Wu et al. (2017) where oxytetracycline present in landfill refuse reduced N 2 production capacity by >50% linked to depletion of Rhodothermus sp. and inhibits denitrification in the long term. Practices like long-term landfilling enriches the abundance of antimicrobial resistant genes (Wu et al. 2017) and abandoning these landfills are not an effective solution as they can still diffuse out for years (Velpandian et al. 2018) .

Alarming levels of pharmaceuticals have been recorded in aquifers adjoined to the Ghazipur landfill of the year 1984 and the leachate from the landfill was found to be continuously drained into the river Yamuna (Velpandian et al. 2018) . The overuse and misuse of antimicrobials linked to the continuing global pandemic can concentrate such landfills with antimicrobials and may present vital damage to the natural ecosystems. AMR is a huge burden for highly populated areas where clean water, sanitation and hygiene (WaSH) are not stringently followed and unrestricted use of antimicrobials prevails.

Since COVID-19 has brought an unprecedented change in antimicrobial consumption and production, it can be presumed that the composition of wastewater generated has changed, introducing new challenges to wastewater management. This inevitably leaves water resources at stake and the biota dependent on it. One study in India has confirmed an 

With numerous studies confirming the presence of antimicrobial resistant bacteria in the gut microbiota of wildlife species such as birds, reptiles, mammals and fish (Gilliver et al. 1999; Sjölund et al. 2008; Wheeler et al. 2012; Bonnedahl et al. 2014) , it is apparent that the 

Journal Pre-proof public health. There are no defined borders for microorganisms which can spread easily from one source to another. Infectious diseases with no reliable therapeutic options can further decimate public health infrastructure. AMR is however a silent pandemic that has worsened in the face of COVID-19 (Mahoney et al. 2021) . Ironically, lack of access to antimicrobials and healthcare currently costs more lives than AMR, particularly in resource limited countries (Frost et al. 2019b) . However, if the bacteria impacting resource-limited countries develop AMR, then a more catastrophic situation will arise where even those who reach healthcare cannot be treated. The solution will be to address AMR without delay and ensure rational use without affecting accessibility to antimicrobials for those who need them most (Ginsburg and Klugman 2020). Research studies assessing the prevalence of AMR in humans, animals and environment is required urgently to assess the overall impact of COVID-19 and plan mitigation strategies for the future. Accelerating the COVID-19 vaccination drive in India can also help reduce the incidence of AMR to an extent, as vaccines can reduce the need for hospitalization in patients infected with the virus (Sheikh et al. 2021 ) and dependency on antimicrobials.

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