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LETTER TO THE EDITOR
Year : 2017  |  Volume : 49  |  Issue : 2  |  Page : 208-210
 

Antibiotic resistance: Alternative approaches


Department of Biotechnology, Ministry of Science and Technology, New Delhi, India

Date of Web Publication16-Jun-2017

Correspondence Address:
Rajneesh Kumar Gaur
Department of Biotechnology, Ministry of Science and Technology, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_574_16

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How to cite this article:
Gaur RK. Antibiotic resistance: Alternative approaches. Indian J Pharmacol 2017;49:208-10

How to cite this URL:
Gaur RK. Antibiotic resistance: Alternative approaches. Indian J Pharmacol [serial online] 2017 [cited 2019 Sep 15];49:208-10. Available from: http://www.ijp-online.com/text.asp?2017/49/2/208/208141


Sir,

The first antibiotic “Penicillin” was discovered in 1928 by Alexander Flaming, but sulfonamides are introduced in 1937 as first effective antimicrobials. Currently, the fifth generation of antibiotics is now in the market. The use of antimicrobials also parallels the development of microbial resistance against them, for example, the development of resistance to sulfonamides reported in the late 1930s. The microbes acquired resistance against every generation of antimicrobials as a result of evolutionary pressure.

A recent report of Wellcome Trust, UK, estimated that the death occurred due to antimicrobial resistance (AMR) is around 0.7 million. A recent research predicted that continuous rise in AMR will lead to the death of 10 million people per year and a reduction of 2%–3.5% in gross domestic product by 2050. As a result, this will cost up to USD 210 trillion to the entire world.[1] Trauma Center of All Indian Institute of Medical Sciences (AIIMS), New Delhi, an Indian institution reported that more than 50% Gram-negative bacteria possess resistance to different class of antibiotics.[2] These figures are alarming, and the situation is further compounded with a substantial drop in the rate of antibiotic discovery.[3]

The factors leading to AMR are well identified and include over and indiscriminate usage of antibiotics, easy availability of substandard and illegitimate antimicrobials, poor sanitation, excessive use of newer and potent antibiotics, to be used only for severely infected patients, in hospitals, resistance development through food and poultry products, and scientific factors such as genetic jugglery, intrinsic resistance, the existence of resistome and subsistome, and natural “r” genes, anthropogenic activities. Considering the severity of the situation, several steps have been taken in past few years after the WHO's intervention and initiatives in this direction. In 2011, a “National Policy for Containment of Antimicrobial Resistance” was formulated by Government of India. A “National Programme for Containment of AMR” was initiated to establish a laboratory-based surveillance system through strengthening of laboratories for AMR in the country and to generate quality data on AMR for pathogens especially of public health importance, to create awareness among healthcare providers and in the community regarding rational use of antibiotics, to strengthen infection control guidelines, practices, and promote rational use of antibiotics. Indian Council of Medical Research (ICMR) established a “National Anti-microbial Resistance Research and Surveillance Network” for compiling the national data on AMR at different levels of health care and to strengthen AMR surveillance in the country. Inspite of taking measures at the administrative level, the progress to stop the development of AMR is almost negligible at the clinical level.

In last few decades, the AMR leads to the generation of “superbugs, i.e. microbes with enhanced morbidity and mortality” and super-resistant strains with increased virulence and enhanced transmissibility. Although Netherlands and Scandinavia are excellent models for successfully reducing AMR through series of highly coordinated and regulated approach(es), most of the countries are struggling to reduce the spectrum of resistant microbes. Scientifically and technically, several solutions are proposed and tried either to prevent or delay the AMR. These steps include strict control of antibiotic use by humans, introduction of new semisynthetic/synthetic antibiotics, antibiotic cycling, i.e., replacement of antibiotics showing no AMR with alternative structural classes in hospitals periodically, combinations of antibiotics having different inhibitory mechanisms, for example, a fluoroquinolone plus a macrolide, using enzyme inhibitors along with antibiotic such as clavulanic acid with β-lactam antibiotics, and immunological approaches such as vaccine development and strengthening innate immune system.[4] Recently, new scientific approaches are proposed to invert the selective advantage of resistant bacteria through exploiting the existing facts such as the mutations that induce synergy between a drug and another compound [5] and profitable use of synergistic and antagonistic interactions among drugs.[6]

The decades of experience show that resistance to antibiotics cannot be avoided, but AMR can be sufficiently delayed or its onset can be manipulated. Since the AMR first observed, efforts have been focused on the development of novel antibiotics or modifications of the existing antibiotics and restricting their usage. However, the rational of solving the AMR challenge from clinicians' point of view, i.e., rationality and dosing of fixed-dose combinations, plasma drug concentration over time, interindividual variability, etc., is not very well considered. The existing phenomenon of pharmacokinetics or pharmacodynamics can be exploited as an alternative strategy to significantly delay the AMR development.

Currently, the understanding of the rationality and dosing of fixed-dose combinations is poor among clinicians.[7] The fixed doses of an antibiotic are administered after a defined interval to maintain a sustained plasma drug concentration, and therefore, the microbe is exposed to a particular drug concentration for a longer period, which allows them to develop mechanism(s) against antibiotic lethality. Therefore, the first alternative strategy would be to flush the microbe with gradually increasing concentration of a single or a combination of antibiotics. A clinician can start therapy with the lowest possible dose of a single or a combination of antibiotic(s) and gradually increasing the concentration of the drug and dose duration with each dose. The hypothesis is to gradually putting the microbes under increasing drug concentration might lead to a very less time for AMR development as a result of the failure of microbes to cope up with gradually increasing selective pressure. The basis of the hypothesis is that below minimum inhibitory concentration nonresistant pathogens reproduce faster than resistant one and within the therapeutic window, nonresistant pathogens get killed, and resistant pathogens breeds. While the drug dosage above the therapeutic window will be useful in killing of resistant mutants.[8] In both cases, whether the drug is to be administered for a shorter or longer duration, studies may be carried out to optimize the duration between the two doses for maintaining the gradual increase in plasma drug concentration on the one side and to avoid the drug toxicity on the other side.

Second, another alternative strategy could be randomly modulating the drug plasma concentration within the therapeutic window, i.e., between the threshold concentration and below the concentration leads to toxicity. The hypothesis behind the strategy is to reduce the sustained exposure of an infectious agent to a fixed drug or drug combinations concentration and avoiding infectious agent to keep under variable selective pressure. The strategy is basically to constantly fluctuating the drug plasma concentration of an anti-infective agent within the therapeutic window. It is like making the infectious agent to struggle through exposing it with constantly variable plasma drug concentration and then flushing them out through creating the constantly changing environment around microbes within the therapeutic window. It is predictable that usage of an alternate low and high drug plasma concentration cannot be more useful and will soon lead to the development of AMR. Therefore, studies are required with a number of antimicrobial agents to find out which combination of randomly selected drug plasma concentration combinations will be more successful. This strategy might be especially successful where the combination of anti-infective agents is used to treat a disease.

Third, the advent of new biotechnology techniques and tools is relevant to resolve the AMR at the molecular level through studying the pathogens genetic makeup, their interaction with vectors, and the host at the molecular level. Some of the major initiatives in this direction have been taken in parts of the world such as Genome's Canada – a Genome-based initiative to beat superbugs.[9] Indeed, the studies at genomic, proteomic, and metabolic level require the development of consortium and a huge investment to tackle the AMR. The question remains, is there any affordable solution especially for developing countries. There is a strong possibility of developing the immunological therapy against broad spectrum of microbes including parasites, i.e. creating the time-tested vaccines, which can effectively stimulate the immune system. The outer membrane or cell wall of the microbes holds the key for the development of passive or active immune therapy, i.e., through finding the antigen(s) which may either generate antibodies or preferentially the active immunity. It is possible that these antigens might have common architecture in different microbes infecting different types of organisms, such finding will add a new chapter in the development of vaccines. Possibly, such vaccines may be useful simultaneously in humans and animals. Therefore, developing countries must focus on the membrane biology of major microbes, vectors, factors, and the host cells facilitating the invasion and survival of microbes. This strategy might produce results of commercial importance in a shorter duration and may lead to the eradication of many infectious agents like polio. Furthermore, it will also reveal new targets for the development of new therapeutics including new antimicrobials. This approach will be more useful as the chances of a microbe architecture modification as a result of immune system attack is very low. In addition, this will automatically reduce dependency on antimicrobials and resultant reduction of AMR.

AMR is not restricted to human beings rather also constantly extending to economically important livestock. Worldwide, the major pharmaceutical companies are looking forward for increasing their returns based on the existing tools with minimal investment in the anti-infective sector. Development of a new antimicrobial is always a first priority; however, alternate strategies can be effectively used to reduce the dependence on antimicrobials and to delay the onset of AMR, which will be helpful especially when the pipeline for new antimicrobials is almost barren since last few years.

The views expressed in the article are personal and have no relation with the authors official position in Department of Biotechnology, Ministry of Science and Technology, New Delhi.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
O'Neill J. The Review on Antimicrobial Resistance. Wellcome Trust, London, UK; 2014.  Back to cited text no. 1
    
2.
Behera B, Mathur P. High levels of antimicrobial resistance at a tertiary trauma care centre of India. Indian J Med Res 2011;133:343-5.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Laxminarayan R. Antibiotic effectiveness: Balancing conservation against innovation. Science 2014;345:1299-301.  Back to cited text no. 3
    
4.
Davis J, Davis D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010;74:417-33.  Back to cited text no. 4
    
5.
Baym M, Stone LK, Kishony R. Multidrug evolutionary strategies to reverse antibiotic resistance. Science 2016;351:aad3292.  Back to cited text no. 5
    
6.
Tekin E, Beppler C, White C, Mao Z, Savage VM, Yeh PJ. Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs. J R Soc Interface 2016;13. pii: 20160332.  Back to cited text no. 6
    
7.
Goswami N, Gandhi A, Patel P, Dikshit R. An evaluation of knowledge, attitude and practices about prescribing fixed dose combinations among resident doctors. Perspect Clin Res 2013;4:130-5.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Abdul-Aziz MH, Lipman J, Mouton JW, Hope WW, Roberts JA. Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: Optimizing efficacy and reducing resistance development. Semin Respir Crit Care Med 2015;36:136-53.  Back to cited text no. 8
    
9.
Engelhardt R. Genomic Canada formerly Public Health Agency of Canada Gerard Wright, McMaster University. Beating Superbugs: Innovative Genomics and Policies to Tackle AMR, Policy Brief No. 11; 2016.  Back to cited text no. 9
    




 

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