Antimicrobial Resistance – A Silent Pandemic

Written by Dr Shreyjit Kaur

Judging by the media coverage in the ‘recent’ years, it is easy to conclude that antimicrobial resistance is a ‘recent’ issue. However, antimicrobial resistance existed even long before antimicrobials were discovered, synthesized, or commercialized. In fact, bacteria isolated from glacial waters over 2000 years old have been demonstrated to have ampicillin resistance, whereas others isolated from permafrost over 30,000 years old showed vancomycin resistance. In fact, many antibiotics used in clinical practice today are produced naturally by the environmental organisms. Penicillin, for example, is produced naturally by Penicillium moulds (principally P. chrysogenum and P. rubens) as a defensive strategy against bacteria. Since the introduction of penicillin into clinical use, Staphylococcus aureus has been known to be resistant to penicillin antibiotics. In the early 1940s, penicillin was a very effective antimicrobial agent against bacteria. As a result, it was widely used by people to combat a variety of infectious diseases. However, due to the overuse of penicillin, its efficacy has reduced as bacteria began to develop various resistance mechanisms. Thus, antibiotic resistance emerged soon after the first antibiotic was discovered.

Antimicrobial resistance (AMR) occurs when bacteria, viruses, fungi, and parasites evolve and no longer respond to antibiotics, making infections more challenging to treat and raising the likelihood of spread of disease, severe illness, and death. AMR is a natural phenomenon that occurs when microorganisms such as bacteria are exposed to the selective pressure of antibiotics; resultant of which susceptible bacteria are either killed or inhibited, while bacteria that are either naturally/intrinsically resistant or that have acquired antibiotic-resistant traits have a greater chance to survive and multiply. The inappropriate and excessive use of antibiotic drugs such as inappropriate choices, inadequate dosing, poor adherence to the treatment guidelines; contribute to the rise of antibiotic resistance. The main sectors involved in the development of antibiotic resistance are: human medicine in community and in hospital, animal production and agriculture, and the environmental compartment.

Antimicrobial agents use various mechanisms to block bacterial pathogenesis and are classified as either bactericidal or bacteriostatic; and are crucial in the prevention and treatment of infectious diseases. Several areas of modern medicine heavily rely on the availability of effective antibiotic drugs such as chemotherapy for cancer treatment, organ transplantation, hip replacement surgery, intensive care for pre-term neonates etc.  In fact, infections caused by multidrug-resistant bacterial strains are one of the major factors influencing morbidity and mortality in the patients who are undergoing these procedures.

The increasing prevalence of drug-resistant pathogens, with new and emerging resistance mechanisms, resulting in AMR, continues to jeopardize our ability to treat even common infections. The rapid global spread of multi- and pan-resistant bacteria (also known as “superbugs”), that cause infectious diseases which are very hard to treat with the existing antibiotics, is particularly concerning. 

Given below are some of the examples of AMR pathogens which are giving rise to a huge burden on the global public health:

• Strains of Staphylococcus aureus resistant to anti-staphylococcal penicillins are termed MRSA (Methicillin-resistant Staphylococcus aureus) which can be either hospital-acquired (HA-MRSA) or community-acquired (CA-MRSA). MRSA can cause various severe infections such as bloodstream infections, sepsis, pneumonia, infections of skin, soft tissue and surgical site. MRSA infections require second-line antibiotics, such as vancomycin, which are less effective, more expensive, and require careful monitoring to avoid adverse side effects; or newer antibiotics such as linezolid and daptomycin, that are also quite expensive and lead to various side effects. 
• The emergence and propagation of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is one of the most dreading challenging to the disease control worldwide. The main causes for the development of resistant tuberculosis include incorrect treatment, prescription errors, poor patient compliance, poor drug quality etc. MDR-TB is defined as tuberculosis caused by a multidrug-resistant strain, which is resistant to both rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is defined as TB caused by an MDR strain that is also resistant to any fluoroquinolone and to any of the second-line injectable drugs (capreomycin, kanamycin, or amikacin).
• Multidrug-resistant Klebsiella pneumoniae mediated by extended-spectrum beta-lactamases (ESBLs) includes resistance against all penicillins, cephalosporins (including third-generation cephalosporins) and aztreonam, are another cause of concern. There are very few treatment options for infections due to carbapenemase-resistant Klebsiella pneumoniae, one being an old and rather toxic antibiotic, colistin.
• Non-typhoidal Salmonella (NTS) refers to all serotypes of Salmonella enterica (except for serovars Typhi and Paratyphi), including 1500 serotypes; the most common being S. Enteritidis, S. Typhimurium and S. Heidelberg, that can be found worldwide in domestic and wild animals. They are more invasive and are associated with enteric fever. Being a zoonotic pathogen, the widespread and extensive use of antimicrobial agents in food animal production for growth promotion, prophylaxis or treatment purposes has contributed to the spread of antibiotic resistance in NTS. Multidrug resistance to different and commonly used antimicrobial agents such as ampicillin, chloramphenicol, sulphonamides and tetracycline is frequent in NTS. Fluoroquinolone-resistance is also a cause of greater concern.
• Multidrug resistance in Escherichia coli has become a major concern in both human and veterinary medicine around the world. Although E. coli is innately susceptible to almost all clinically significant antimicrobial agents, this bacterial species has a higher potential for resistance gene accumulation, predominantly through horizontal gene transfer. Resistance to various antibiotics such as broad-spectrum cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, polymyxins is understood to be conferred by genes encoding extended-spectrum β-lactamases, carbapenemases, 16S rRNA methylases, plasmid-mediated quinolone resistance (PMQR) genes, mcr genes respectively. Colistin resistance in E. coli appears to be linked to the worldwide utilisation of colistin in veterinary medicine.
• Drug-resistant Candida auris is among the most common invasive fungal infections, with increasing resistance to fluconazole, amphotericin B, and voriconazole, as well as evolving caspofungin resistance.
• Antiviral drug resistance is a growing issue in immunocompromised patients. Due to the emergence of drug-resistant HIV (HIVDR), all antiretroviral (ARV) drugs, including newer classes, are at risk of becoming partially or completely inactive.
• Among the most serious threats to malaria control is the advent of drug-resistant parasites, which leads to increased malaria morbidity and mortality. Resistance to artemisinin has been confirmed in certain parts of the world, as has resistance to a number of artemisinin-based combination therapy (ACT) partner drugs. In some countries, Plasmodium falciparum resistance to sulfadoxine-pyrimethamine has resulted in the failure of artesunate-sulfadoxine-pyrimethamine therapy.

Much has already been written and proposed for combatting antimicrobial resistance throughout these years, but the questions still remain – do we fully understand the gravity of the current situation? Or simply, are we just doing enough? Well, the answers may not be very encouraging as the urgency of combatting this is spelled out by the rising resistance to carbapenems, a group of ‘last-resort antibiotics.’ In fact, there were an estimated 4·95 million (3·62-6·57) deaths associated with bacterial AMR in 2019, including 1·27 million deaths attributable to bacterial AMR. Thus, it is established that AMR is a leading cause of death around the world, with the highest burdens in low-resource settings.

There is a need of adequate and appropriate surveillance in many parts of the world where large information gaps exist on microbes of major public health importance, to ensure an accurate analysis of the real situation and trends over the time. Different and coordinated strategies against AMR should be implemented, giving due consideration to the type of pathogen involved – human or zoonotic, the setting of its spread – hospital or community and other specific factors contributing to the emergence of resistance. In the hospital setting, multiple infection control measures and antimicrobial stewardship programmes – administered by multidisciplinary teams of experts such as physicians, pharmacists, microbiologists, epidemiologists etc. – are very essential to prevent emergence, transmission and propagation of antimicrobial-resistant microorganisms and to ensure the efficacy and potency of the various available antimicrobial agents. There is also a great need to reduce the misuse and overuse of antibiotics and inappropriate antibiotic prescriptions through suitable actions e.g., information campaigns for the consumers and patients, information and training for the healthcare professionals and workers, improved and upgraded diagnostics for treatment decisions, treatment guidelines, and prescription audits. In veterinary medicine, there is an urgent need to step up and take appropriate action for monitoring and regulating the use of antimicrobials in food animals, strengthening surveillance and monitoring, and reducing the need for antimicrobials through better animal husbandry.

It is not an understatement to say that – throughout history, humans have fought a long and tedious battle with the microorganisms especially bacteria and continue to do so, which are a cause of major mortality and morbidity all over the world. There is an urgent need for innovative approaches for the development of new antibiotics and other products to limit the menace of antimicrobial resistance. There is a shortage of new antibiotics in the pipeline, as only two novel antibiotic classes have been approved in the last 30 years (oxazolidinones and cyclic lipopeptides), but both of these molecular compounds target Gram-positive microbes. There are very few effective drugs available for treating multidrug-resistant infections caused by Gram-negative bacteria, which are the predominant threat at this time. Also, the development of new vaccines may reduce the prevalence of infectious diseases, reducing the need for antibiotics. For example, the introduction of pneumococcal conjugate vaccines has resulted in a decrease in resistant Streptococcus pneumoniae.

Further, the development of rapid point-of-care diagnostic modalities may be beneficial in minimizing clinical uncertainty, avoiding unnecessary antibiotic treatments, and selecting effective antibiotics when first-line treatments have been rendered ineffective due to AMR. The recent discovery of a newer antibiotic teixobactin, with an excellent activity against Gram-positive pathogenic microbes, including drug-resistant strains, ‘paves the stone’ for a new class of antibiotics and promises hope for the future and serves as a model for upcoming pathbreaking clinical researches and resolutions.

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