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Year : 2021  |  Volume : 53  |  Issue : 3  |  Page : 187--191

Antimicrobial resistance: An unseen threat prowling behind the COVID-19 outbreak

Vidya Mahalmani1, J Kumaravel2, Manav Jain2, Ajay Prakash2, Bikash Medhi2,  
1 Department of Pharmacology, Jawaharlal Nehru Medical College, KAHER, Belgaum, Karnataka, India
2 Department of Pharmacology, PGIMER, Chandigarh, India

Correspondence Address:
Prof. Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh - 160 012

How to cite this article:
Mahalmani V, Kumaravel J, Jain M, Prakash A, Medhi B. Antimicrobial resistance: An unseen threat prowling behind the COVID-19 outbreak.Indian J Pharmacol 2021;53:187-191

How to cite this URL:
Mahalmani V, Kumaravel J, Jain M, Prakash A, Medhi B. Antimicrobial resistance: An unseen threat prowling behind the COVID-19 outbreak. Indian J Pharmacol [serial online] 2021 [cited 2021 Jul 31 ];53:187-191
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,Coronavirus disease-2019 (COVID-19) has played a havoc that has had an enormous impact on social life, health, and economy worldwide. The World Health Organization, on June 1, 2020, addressed the danger of antimicrobial resistance (AMR) “one of the most urgent challenges of our time,” that is further made worse by this pandemic.[1]

,COVID-19 outbreak has masked longer-term and major public health problems like the steady upsurge in AMR in the dark. However, one should not lose sight of existing problems that might possibly be aggravated by this pandemic. The pandemic lays emphasis on the need to take into consideration bacterial coinfections and other secondary infections during as well as subsequent to the viral outbreaks that have proven to be the most important cause of morbidity and mortality.


 Antibiotic Use in the Coronavirus Disease-2019 Pandemic

,Different countries have experienced multiple waves of COVID-19 pandemic. This has increased huge pressure on researchers and doctors to make and implement various strategies to fight this pandemic. Evidence suggests that with a rapid surge in the number of COVID-19 cases, there has been an upsurge even in the antimicrobial use (AMU). Rampant use of antimicrobials might worsen the problem of AMR. The priority during the pandemic is to treat and save lives of patients. All the personnel and resources in the health-care systems have been redirected in COVID-19 diagnosis and management.

,Therefore, AMR surveillance has been compromised due to shortage of health personnel as well as resources. Recommendations with respect to antibiotic use vary across countries.

,AMR is a global issue that has had an impact on humans, animals, and environment. A well-coordinated multidisciplinary approach is required to address this issue.[2]

,An independent review on AMR conducted in May, 2016 revealed that globally, antimicrobial-resistant infections were anticipated to give rise to at least 7 lakh deaths/year and the number is expected to rise up to 10 million deaths/year by 2050.[3]

,Evidence suggests that majority of hospitalized COVID-19 patients were put on antimicrobials, to treat to prevent superadded bacterial and fungal infections, regardless of a small percentage of these coinfections.[4],[5],[6] On April 2020, an international survey was conducted that involved 166 study participants from 23 nations and 82 hospitals, revealed the usage of broad-spectrum antimicrobials in COVID-19 patients.[7] A review conducted by Rawson et al. revealed the widespread use of broad-spectrum antimicrobials where 72% of COVID-19 cases received antimicrobials, while only 8% of them were reported to have coinfections.[8]

,These data suggest an increase in AMU greater than the prevalence of superadded bacterial/fungal infections. This could greatly cause an upsurge in the emergence of multidrug-resistant microorganisms. Moreover, substantial amount of these antimicrobials also reach the environment affecting the ecosystem as well. Globally, the widespread use of disinfectants and sanitizers for prolonged duration could lead to emergence of resistant bacteria to both antimicrobials and biocides as well. Injudicious use of antimicrobial prophylaxis or therapy should be stopped in mild COVID-19 infection. Thus, implementation of the antimicrobial stewardship program is of utmost importance during this pandemic.


 Bacterial Infections and Coronavirus Disease-2019

,Bacterial infections can complicate the already associated viral respiratory illness and can significantly increase the morbidity and mortality.[9] These can be present both as coinfections at the time of admission or as superinfection (secondary) from the hospital source. In a review analysis by Westblade et al., the risk of coinfections was found to be <4%.[10] About 57% of the admitted patients received empirical antimicrobial therapy while only 15% had received targeted or laboratory-based therapy highlighting the inappropriate use of antimicrobial agents in patients with COVID-19 infection.[11]

,Advancing age and comorbid conditions, although, were important risk factors but were not found to be associated with coinfections, as reported, in all the studies.[11],[12],[13] The bacterial coinfections were more common in patients who are admitted in intensive care unit (ICU) for COVID-19.[11],[14],[15],[16],[17],[18],[19]

,The laboratory parameters typically which are reflective of bacterial coinfections include lymphocytosis, neutrophilia, and increased procalcitonin levels but they lacked the sensitivity, specificity, and positive predictive value to independently predict coinfections in COVID-19 patients.[11],[12] The positivity rate of blood culture was found to be lower than respiratory culture in these patients.[11],[12],[17],[20],[21],[22],[23],[24]

,The most common organisms from these patients were Staphylococcus aureus, Staphylococcus pneumoniae, and Haemophilus influenzae.[10] These coinfections resulted in prolonging the hospital stay and increased in-hospital mortality as compared to patients who were without coinfection.[11] The risk of hospital-acquired infections (HAI) in COVID-19 patients was found to be very high, with frequency up to 22% in COVID-19 patients who are admitted, with even higher risk up to 48% in patients who are admitted to ICU. The mean duration of acquiring infections was found to be 1–2 weeks.[10],[13],[14]

,Various studies had identified independent risk factors for HAIs which include the presence of hypoxia at the time of admission, requirement of mechanical ventilation, and need for ICU within 48 h of admission. Some laboratory-based parameters including lymphopenia, leukocytosis, elevated procalcitonin and C-reactive protein (CRP), and need for dialysis for acute kidney injury were also considered as independent risk factors.[25],[26],[27],[28],[29]

,The most commonly isolated organism from the bloodstreams was CoNS, Enterococcus spp., Klebsiella spp., Pseudomonas aeruginosa, and S. aureus, while P. aeruginosa, Klebsiella species, and S. aureus were most commonly isolated from the respiratory source.[10] The incidence of VAP was found to be higher in COVID-19 patients, but the isolated organism was found similar to the non-COVID patients.[30] Similar to the coinfections, the COVID-19 patients with HAI had higher incidence of prolonged hospital stay, morbidity, and mortality.[13],[27],[28]

,A case–control study by Nasir et al. also highlighted that severity of illness at the time of admission and use of steroids are increasing the risk of bacterial infections in COVID-19 patients.[31] Reports of cases of multidrug-resistant bacteria had been reported in US and Europe in COVID-19 patients. Most of such cases were attributed to a lack of adherence to standard contact hygiene maintaining practices due to overburdening of hospitals due to rising COVID-19 cases, and such hospitals are at risk to have multidrug-resistant infections not only in COVID patients but also in other patients.[32]


 Superadded Bacterial Infections in Coronavirus Disease-2019: Risk Factors

,Risk factors include severity of COVID-19 per se, steroid usage, patient on ventilator, catheterization, central line and peripheral intra-arterial and intravenous line, and comorbid conditions such as diabetes. Hospital acquired infections are the most common form of superadded infections in COVID-19 mainly targeting respiratory tract, gram negative bacteria being the main causative agent.[31]


 Challenges in Identification of the Pathogen

,As mentioned earlier, in majority of the cases, antimicrobials are prescribed empirically in patients with COVID-19. According to a study conducted in COVID-19 patients by Huang et al., chest X-ray showed that 98% of them had bilateral lung involvement, but only 28% had ample sputum to do a Gram stain or culture.[33] Furthermore, fears about aerosol-producing techniques (such as deep airway suctioning or bronchoalveolar lavage) constitute a major setback to procure sputum samples for bacterial identification.[34]

,One can wear personal protective equipment while performing such procedures. However, developing countries have limited resources and infrastructure which pose major challenges to medical fraternity.


 Antimicrobial Resistance and Coronavirus Disease-2019

,It is difficult to differentiate bacterial pneumonia from that of viral pneumonia. The general public has access to information about the use of antimicrobials in COVID-19 instances through a variety of media. Lack of awareness regarding antibiotic use along with fear due to COVID-19 infection has led to overuse of over-the-counter antibiotics, especially in underdeveloped countries with lack of antibiotic control mechanisms and limited access to health-care facilities. Doxycycline and azithromycin have been prescribed for almost all patients who develop symptoms.

,A study by Sultana et al. recommended the use of azithromycin to community-acquired pneumonia only. According to authors, apart from antibacterial efficacy in bacterial superinfection, there is no conclusive data that azithromycin may be advantageous in COVID-19.”[35]

,According to a study by Sieswerda et al., when hospitalized COVID-19 patients improve clinically, empirical antimicrobials for probable bacterial coinfections must be stopped after 5 days.[36] A review by Clancy and Nguyen revealed that the proportion of coinfections in COVID-19 cases varied largely from 0% to 100% coinfections in deceased patients and wide discrepancy in antibiotic usage taking into consideration the severity of disease, oscillating between 20% to 100% antibiotics.[37]


 Justification for Empirical Use of Antibiotics in Coronavirus Disease-2019

,Criteria for empirical use of antibiotics need to be considered in COVID-19 cases. Criteria include severity of the condition per se, presence of risk factors for the occurrence of bacterial infection, laboratory findings, and radiological findings.[10] Algorithm for diagnostic evaluation and decision-making in the use of antimicrobial agents in COVID-19 cases is given in [Figure 1]. According to IDSA guidelines, the initial antibiotic to be considered for CAP includes combination of beta-lactam antibiotic and a respiratory fluoroquinolone or a macrolide preferable azithromycin. These combination therapies usually cover S. aureus, Haemophilus influenza, and Streptococcus pneumonia with exception of MRSA. The prevalence of MRSA organisms varies according to local geographic regions, and anti-MRSA treatment needs to be considered based on the prevalence of MRSA.[38]{Figure 1}


 Mitigation Strategies

,Strict regulations should be enforced for OTC drugs that will definitely reduce excessive and unnecessary use of antimicrobials. Infection prevention and control measures should also be implemented in all health-care settings. The general public should be made aware of the importance of hand hygiene practices as well. Rapid testing can help in early detection of COVID-19 patients, and initiation of symptomatic therapy at early stage of the disease might prevent progression of the disease and probability of secondary infections might be less. Antibiotics can be reserved for severe COVID-19 patients.

,COVID-19 symptomatology often overlaps with other respiratory tract infections. As a result, certain typical symptoms/signs such as anosmia and loss of taste sensation can be helpful in diagnosing COVID-19 disease. Biomarkers such as procalcitonin and C-reactive protein though used as predictors of disease severity are not that useful in differentiating between COVID-19 disease and other bacterial coinfections.[39] [Table 1] summarizes various challenges faced during COVID-19 pandemic and strategies to overcome these challenges.{Table 1}


 Antimicrobial Stewardship in Coronavirus Disease-2019

,Antimicrobial stewardship refers to coordinated approach to improve the prescribing pattern of antimicrobials as well as their rational use. It monitors and guides the rational use of antimicrobials including duration of treatment, route of administration, dosing interval. It can monitor and improve adherence with treatment guidelines during respiratory virus pandemics associated with superadded bacterial infections.

,The most challenging part during this COVID-19 pandemic is distinguishing COVID-19 pneumonia from bacterial pneumonia. Antibiotics should be considered as a part empirical therapy due to the uncertainty about secondary bacterial infections, lack of approved antiviral drug for the present pandemic, and the high mortality rates.[40] During this pandemic, antibiotics should be used cautiously and wisely to avoid unwanted AMR. Antimicrobial stewardship team should monitor and give suggestions to the treating physician to consider de-escalation and escalation of antibiotics on daily day-to-day basis.


 Antibiotic Overuse in Paediatric Population

,It is well documented that children are less commonly affected and most of them are asymptomatic or present with mild symptoms.

,A small proportion (<10%–20%) of symptomatic children might require hospitalization and 1% to 3% might also require intensive care admission. As per the guidelines by Indian Academy of Paediatrics, antibiotics are indicated only in children with moderate disease if bacterial coinfection is suspected. Antibiotics such as amoxicillin/amoxiclavulinic acid/ceftriaxone are used. Antimicrobials are also used in case of severe disease and multisystem inflammatory syndrome in children (MIS-C).[41]

,However, due to gap in knowledge and lack of enough scientific evidence, there is a significant variation in the prescription pattern of antibiotics. A study by Yock-Corrales et al. revealed somewhat increased antibiotic prescriptions in COVID-19 children and especially in those presenting with severe symptoms or MIS-C. Therefore, prospective studies are required to impart sufficient evidence to identify and manage bacterial infections in children with COVID-19.[42]



,AMR was already a global issue before the outbreak COVID-19. With the emergence of COVID-19, an addition to the existing global crisis has devastated social, health, and economic sectors across the globe. Lack of better understanding of pathophysiology and potential therapy has put medical fraternity under pressure. Secondary bacterial coinfections associated with COVID-19 have led to widespread use of empirical antibiotics. Therefore, antimicrobial stewardship program has to be strictly implemented to curtail the rampant use of antimicrobials and prevent the worsening of AMR, a global threat.


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