A Global Crisis and Alternative Strategies to Overcome Such Crisis
Nabanita Baruah, Pinki Mallik, Meghali Nag, Fatima Siddiqua, Dr Kandarpa Kumar Saikia
Department Of Bioengineering and Technology, Gauhati University, Jalukbari, Guwahati
Corresponding Author: Nabanita Baruah, Department of bioengineering and Technology, Gauhati University, Guwahati – 781014, India Email: [email protected]
Abstract: Antibiotic has been a boon for the mankind since its discovery. But with the passage of time, target microorganisms have become resistant to antibiotic. Antibiotic resistance is multifactorial. This has now become a global threat to human health undermining the power of antibiotic against deadly bacterial infections leading to increase in global mortality rate caused by bacterial infection. Hence, it is of utmost importance to find out alternate strategies to culminate health hazards caused by antibiotic resistance through studying about the severity of such global crisis multidimensionally as well as a profound study of advantages and disadvantages of usage of antibiotics, types of antibiotic resistance, mechanism of such resistance and combination approaches that target different pathways.
Keywords: Antibiotics, Resistance, Mechanism, Pathways
1.0
Introduction: The expedition of antibiotic has come a long way in this era of modern medicine. From being discovered in 1928 by Alexender Fleming (Penicillin) to numerous both broad spectrum and narrow spectrum antibiotic [1], antibiotic treatment has shown tremendous benefits against microbial infections over time by lowering mortality and morbidity caused by the same. The benefits of application of antibiotics also includes cessation of infection incidence in transplant patients, reduction of surgical infection by antibiotic prophylaxis etc. Despite so many advantages, antibiotics possess a number of disadvantages such as hypersensitivity, drug toxicity and antibacterial resistance [3]. Beside these, oral doses of penicillin, carbapenem, clindamycin, metronidazole and tetracycline may show side effects such a Nausea, vomiting, diarrhoea, and gastrointestinal problems [4]. Among such disadvantages, antibiotic resistance is the most common and now it has become a kindling global issue.
Bacterial antibiotic resistance can be primary/natural/non genetic origin of resistance and acquired/genetic origin of drug resistance. Natural resistance can be intrinsic or induced. Intrinsic resistance occurs within a bacterial species as a result of reduced permeability of bacterial outer membrane and action of efflux pump (not as a result of horizontal gene transfer) without prior exposure to antibiotics while multi-drug efflux pump causes induced resistance in a bacterium [5]. Acquired/ genetic origin of drug resistance is again two types - Chromosome mediated resistance and Transferable drug resistance. In chromosome mediated resistance, Chromosomal mutations results in antibiotic resistance through modifications in outer-membrane porins of gram-negative bacteria [6], while in transferable drug resistance, acquisition of genetic materials (permanent or temporary) occurs via Horizontal Gene Transfer (HGT) [5]. Bacterial antibiotic resistance can also be a result of improper practice of broad-spectrum antibiotics [16]. Today, a number of bacteria possess resistance against a number of broad-spectrum antibiotics. Such bacterial strains have caused thousands of deaths per year [21]. Among these bacteria, Staphylococcus aureus, Clostridium difficile, Enterococcus faecium [21][22][23] etc., are predominant. It has also contributed to economic and clinical burden in higher income countries [33].
The mechanism of antibiotic resistance can be studied in different categories on the basis of the type of resistance. Some of these are alteration or inactivation of drug, modification of target drug binding sites, reduced intracellular drug accumulation, antibiotic sequestration, efflux pumps etc [5]. A better understanding of the underlying mechanism of antibiotic resistance can give an insight to the multitarget or combination approaches for the mitigation of such problem.
2.0
History, merit and demerit of using antibiotics:
2.1 History: The practice of using antibiotic producing microbes began almost 2000 years ago in some countries where traditional dressings of mouldy breads were used for the treatment of open wounds. MRSA (methicillin-resistant Staphylococcus aureus) was recently reported to be killed by an Anglo-Saxon recipe used to exist 1000 years ago. About 100 years back, Paul Ehrlich developed the synthetic arsenic-based pro drug salvarsan (no longer in clinical use) and neo-salvarsan circa to treat Treponema pallidam. Later, sulfonamide prodrug Prontosil discovered by Gerhard Domagk took place of salvarsan. Despite sulfonamide being first broad-spectrum antimicrobials in clinical use, its use was outmoded by Penicillin discovered by Alexender Fleming in 1928. Antibiotic discovery reached its peak during the period of 1940 to 1960, when antibiotics such as neomycin and streptomycin were discovered by Selman Waksman [1]. First antibiotics of the second generation of broad-spectrum penicillin were Ampicillin and amoxicillin discovered in 1961 and 1972 respectively. Carbenicillin (1957), tircacillin (1971) and piperacillin (1977) were the next generation of penicillin. After penicillin, the second class of beta-lactam antibiotics called cephalosporins (1949) was discovered. Though more progress of advanced-generation cephalosporins for clinical use is still going on, Ceftobiprole (2002), and ceftaroline (2005) may be less susceptible to development of resistance, thereby offering treatment options for MRSA [2].
2.2 Merit of using Antibiotics: Antibiotics have shown tremendous benefits by lowering mortality rates in acute bacterial and surgical infections. Chances of death is lowered by application of proper antibiotic at the onset of surgical sepsis. Antibiotic prophylaxis reduces chance of surgical site infection significantly in high-risk group of patients. the occurrence of infection in transplant recipients is significantly diminished by prophylactic peri-operative antibiotic therapy. Long-term antibiotic prophylaxis is highly beneficial in patients on immunosuppressive therapy.[3]
2.3 Demerit of using Antibiotics: Major disadvantages of using antibiotics includes austere side effects such as hypersensitivity, drug toxicity and antibacterial resistance.[3] Side effect of amoxicillin (5-8% of cases)and cephalosporin (5-10% of cases) prescribed in periodontal treatments causes hypersensitivity as a result of cross reaction, penicillin anaphylactic shock occurs at the rate of 0.05% of cases and other side effects allied with oral lesions are nephritis, eosinophilia, and hemolytic anemia. Nausea, vomiting, diarrhea, and gastrointestinal problems are the common side effects of oral doses of penicillin, carbapenem, clindamycin, metronidazole and tetracycline. The application of ampicillin, amoxicillin and tetracycline sometimes results in vaginal candidiasis. Moreover, broad spectrum antibiotics do not show proper result in case of women who use oral contraceptives and those who are epileptic. Tetracycline may cause local tissue toxicity, sensitivity towards light.[4]
3.0
Types of antibiotic resistance:
Bacterial antibiotic resistance can be natural or acquired. Natural bacterial antibiotic resistance is non genetic in nature i.e., no mutation or other genetic changes involved. This type of resistance can be both intrinsic and induced. Intrinsic resistance occurs within a bacterial species. It arises due to reduced permeability of bacterial outer membrane as well as action of efflux pump and it does not need any prior exposure to antibiotics. It is noteworthy that horizontal gene transfer does not play any role in the evolvement of intrinsic bacterial resistance. On the other hand, induced resistance is caused by multi-drug efflux pump [5]. Acquired drug resistance is of genetic origin and it has two types - Chromosome mediated resistance and Transferable drug resistance. In chromosome mediated resistance, chromosomal mutations bring about alterations in outer-membrane porins of gram-negative bacteria, as a result of which antibiotic resistance occurs [6]. In case of transferable drug resistance, acquisition of genetic materials occurs via Horizontal Gene Transfer (HGT), and this phenomenon can be either permanent or temporary. [5].
4.0 Causes of antibiotic resistance:
There are many causes of antibiotic resistance among them most prominent are like, in the developing world, almost all the antibiotics are available in market and can be bought without any medical prescription which is one of the most important factors in causing the resistance.; the increased demand for less expensive and off-label uses of drugs which contributed significantly to the advent of the resistant strains. Resistance emerges as a stepwise attainment of chromosomal mutations; the food chain can be considered as the main route of transmission of antibiotic-resistant bacteria between animal and human populations. Antibiotic resistance can also occur as a natural selection process where nature empowers all bacteria with some degree of low-level resistance which make bacteria resistance against previously available antibiotics. In some developed countries, animals receive antibiotics in their food or water which is responsible for carrying microbe resistance to that specific antibiotic into human body [7]. Antimicrobial resistance in bacterial pathogenesis is a worldwide challenge associated with high mortality and morbidity. Multidrug resistant patterns in gram positive and negative bacteria had resulted in difficult-to-treat and even untreatable infections with conventional antimicrobials. Because the early identification of causative microorganisms and their antimicrobial susceptibility patterns in patients with bacteraemia and other serious infections is lacking in many healthcare settings and in most of the cases broad spectrum antibiotics are used liberally and mostly unnecessarily [8]. Colistin which is a last-resort antibiotic, used to treat complicated infections caused by multidrug-resistant (MDR) gram-negative bacteria. But the excessive use of this antibiotic has caused the emergence of plasmid-borne mcr genes encoding resistance bacteria against colistin [9]. The emergence of vancomycin resistance in Enterococcus faecium which is both a common inhabitant of the human intestinal tract and an opportunistic pathogen have become a global concern in hospital infection control. Vancomycin-resistant E. faecium belonging to clonal complex 17 have been disseminating in hospital equipments and have become endemic in many countries whereas sequence type 80 (ST80) is one of the most predominant clones among CC17 in many European countries [10]. Malaria is also one of the most prevalent public-health problems in many tropical countries. The cause of the anti-malarial drug resistance is associated with certain genotypes which are known as drug resistance markers. Mutations in the Plasmodium falciparum, chloroquine resistance transporter (Pfcrt) was reported by following the widespread implementation of chloroquine [11]. Pseudomonas aeruginosa is an opportunistic pathogen which causes infections with high rates of mortality and morbidity in hospitals. Resistance to carbapenems in P. aeruginosa is mainly associated with decreased porin expression or the acquisition of carbapenemases belonging to Ambler classes A or B [12]. The ESKAPE bacteria consisting of Enterococcus spp, S. aureus, K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp has gained global attention recently as WHO listed them as priority antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. These bacteria have the ability to develop high level resistance to multiple drugs which causes limiting therapeutic options and increasing morbidity and mortality. Studies have also confirmed that ESKAPE bacteria and their resistant clones are actively transmitted in hospitals and communities in both developed and developing countries. The threat posed by these resistant bacteria is more in developing countries due to poor infection, prevention and control measures, sub-optimal hygiene conditions, lack of surveillance and the dearth antimicrobial stewardship programs. MDR-ESKAPE bacteria have been reported in intensive care units where immune-compromised patients suffering from some non-communicable diseases like diabetes, cancers, chronic lung, cardiovascular and kidney diseases were highly affected [13]. Report shows that poorer countries are experiencing much higher levels of resistance because of several factors like greater availability of second and third-line treatments in developed countries compared to the third world countries. Regional instances of higher resistance levels are causing a global effect due to rapid intercontinental travel allowing the dissemination of resistant bacterial strains globally [14]. Poor sanitation conditions are causing spread and small healthcare budgets prevented access to new effective but more expensive antibiotics [15]. In recent times COVID-19 might cause a rise in the inappropriate use of broad-spectrum antibiotics, which is one of the main causes for the development of MDR bacteria [16].
Mechanism of antibiotic resistance:
Antimicrobial resistance mechanisms fall into many categories on the basis of their Intrinsic or acquired resistance. For example, intrinsic resistance uses mechanism of limiting uptake, drug inactivation and drug efflux again, acquired resistance mechanisms uses drug target modification, drug inactivation, drug efflux etc [5]. Some of the mechanisms are described below-
4.1 Intrinsic resistance: This kind of resistance is result of the natural resistance or the microorganisms not including the structure of the target antibiotic. Gram-negative bacteria are naturally resistant to vancomycin because it does not pass in the outer membrane. Similarly, other wall-less bacteria like L-form shape of bacteria, Mycoplasma and Ureaplasma are naturally resistant to beta-lactam antibiotics that inhibit the cell wall synthesis [17].
4.2 Alteration or inactivation of drug: Antibiotic modification is a commonly used strategy for rendering an antibiotic ineffective, especially in the case of aminoglycoside antibiotics like kanamycin, gentamycin, chloramphenicol and b-lactams [18]. Many bacteria produce enzymes that irreversibly modify and inactivate the antibiotics, such as