1. INTRODUCTION:

Antimicrobial resistance (AMR) is the ability of a microbe to resist the effects of medication previously used to treat them. This broader term also covers antibiotic resistance, which applies to bacteria and antibiotics.¹The WHO defines antimicrobial resistance as a microorganism's resistance to an antimicrobial drug that was once able to treat an infection by that microorganism. Antimicrobial resistance happens when microorganisms (such as bacteria, fungi, viruses, and parasites) change when they are exposed to antimicrobial drugs (such as antibiotics, antifungals, antivirals, antimalarials, and anthelmintics). Microorganisms that develop antimicrobial resistance are sometimes referred to as superbugs.²

Resistance can appear spontaneously because of random mutations; or more commonly following gradual buildup over time, and because of misuse of antibiotics or antimicrobials.³

Antibiotics should only be used when needed as prescribed by health professionals. The prescriber should closely adhere to the five rights of drug administration: the right patient, the right drug, the right dose, the right route, and the right time. Narrow-spectrum antibiotics are preferred over broad-spectrum antibiotics when possible, as effectively and accurately targeting specific organisms is less likely to cause resistance.⁴

A World Health Organization (WHO) report released April 2014 stated, this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country.

2. Why Antimicrobial resistance is a global threat?:

A major area of concern is multi-drug resistant tuberculosis (MDR-TB) that is resistant to the two most powerful anti-TB drugs. The World Health Organization (WHO) estimated that in 2014, there were about 480,000 new cases of MDR-TB.⁵ Antimicrobial resistance (AMR) is an accepted threat to global health, but it is not a new problem. When Alexander Fleming discovered penicillin, he warned of the risk of development of resistance during his Nobel Prize speech in 1945.⁶

2.1 Effects of AMR on individual health:

Treatment failure caused by AMR contributes to additional side effects, longer hospital stays, psychological disorders due to reduced quality of life, burden on families and a greater likelihood of death as a result of inadequate or delayed treatment's'. An example is the treatment of patients with multidrug-resistant Tuberculosis, who have to undergo a two-year treatment programme.⁶

2.2 Effects of AMR on economy:

The latest report from the World Health Organization (WHO), "AMR Global report on surveillance 2014", shows estimates of economic burden. In the EU alone costs of treatment of resistant pathogens are estimated at about EUR 1.5bn annually.⁶ Antibiotic resistance when bacteria change so antibiotics no longer work in people who need them to treat infections is now a major threat to public health.

‘Without urgent, coordinated action by many stakeholders, the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill,’ says Dr. Keiji Fukuda, WHO’s Assistant Director-General for Health Security.^{7, 8}

3. What causes the drug resistance?:

Drug resistance emerges only when the two components come together in an environment or host, which can lead to a clinical problem. Selected resistance genes and their hosts spread and propagate under continued antimicrobial selection to amplify and extend the problem to other hosts and other geographic locations. There are more than 15 classes of antibiotics whose targets are involved in essential physiological or metabolic functions of the bacterial Cell. None has escaped a resistance mechanism.

Drug resistance is mobile the genes for resistance traits can be transferred among bacteria of different taxonomic and ecological groups by means of mobile genetic elements such as bacteriophages, plasmids, naked DNA or transposons. These genes are generally directed against a single family or type of antibiotic, although multiple genes, each bearing a single drug resistance trait, can accumulate in the same organism. In the absence of plasmids and transposons (which generally mediate high-level resistance), a step-wise progression from low-level to high-level resistance occurs in bacteria through sequential mutations in chromosomes.⁹

4. Mechanisms of Antimicrobial Resistance:

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are,

4. 1 Drug inactivation or modification:

An example of this mechanism is enzymatic deactivation of penicillin G in some penicillin-resistant bacteria through the production of β-lactamases. The emergence of carbapenem-resistant Gram-negative pathogens poses a serious threat to public health worldwide. Klebsiella pneumoniae carbapenemases (KPCs) and carbapenemases of the oxacillinase-48 (OXA-48) type have been reported worldwide. New Delhi metallo-β-lactamase (NDM) carbapenemases were originally identified in Sweden in 2008 and have spread worldwide rapidly.¹⁰ Most commonly, the protective enzymes produced by the bacterial cell will add an acetyl or phosphate group to a specific site on the antibiotic, which will reduce its ability to bind to the bacterial ribosomes and disrupt protein synthesis.¹¹

4.2 Alteration of target- or binding site:

An example of this mechanism is alteration of PBP—the binding target site of penicillins in penicillin-resistant bacteria. Another protective mechanism found among bacterial species is ribosomal protection proteins. These proteins protect the bacterial cell from antibiotics that target the cell’s ribosomes to inhibit protein synthesis. The mechanism involves the binding of the ribosomal protection proteins to the ribosomes of the bacterial cell, which in turn changes its conformational shape. This allows the ribosomes to continue synthesizing proteins essential to the cell while preventing antibiotics from binding to the ribosome to inhibit protein synthesis.

4.3 Alteration of metabolic pathway:

An example of this mechanism is some sulfonamide-resistant bacteria do not require paraaminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides, instead, like mammalian cells; they turn to using preformed folic acid.

4.4 Reduced drug accumulation:

By decreasing drug permeability or increasing active efflux (pumping out) of the drugs across the cell surface.¹² These pumps within the cellular membrane of certain bacterial species are used to pump antibiotics out of the cell before they are able to do any damage. They are often activated by a specific substrate associated with an antibiotic.¹³Examples of some major antibiotics are shown in Table 1.

Table 1: Major antibiotic families and their mechanisms of action

Mechanism of action	Antibiotic families
Inhibition of cell wall synthesis	Penicillins- Cephalosporins, Carbapenems, Daptomycin, Monobactams, Glycopeptides
Inhibition of protein synthesis	Tetracyclines- Aminoglycosides, Oxazolidonones, Streptogramins, Ketolides, Macrolides, Lincosamides.
Inhibition of DNA synthesis	Fluoroquinolones
Competitive inhibition of folic acid synthesis	Sulfonamides- Trimethoprim
Inhibition of RNA synthesis	Rifampin
Other	Metronidazole

5. How to reduce antibiotic resistance?:

Antibiotic stewardship programmes appear useful in reducing rates of antibiotic resistance.

In 2014, the WHO stated:

5.1 People can help tackle resistance by:

· Using antibiotics only when prescribed by a doctor;

· Completing the full prescription, even if they feel better;

· Never sharing antibiotics with others or using leftover prescriptions.

5.2 Health workers and Pharmacists can help tackle resistance by:

· Enhancing infection prevention and control;

· Only prescribing and dispensing antibiotics when they are truly needed;

· Prescribing and dispensing the right antibiotic(s) to treat the illness.

5.3 Policymakers can help tackle resistance by:

· Strengthening resistance tracking and laboratory capacity;

· Regulating and promoting appropriate use of medicines.

5.4 Policymakers and industry can help tackle resistance by:

· Fostering innovation and research and development of new tools;

· Promoting cooperation and information sharing among all stakeholders.

6. Role of Pharmacist in Tackling Antimicrobial Resistance:

AMR has clear links to not just human health but also animal health, farming and the environment. The governments, health care professionals, pharmaceutical companies, Pharmacists and the public has important role in Tackling AMR.

6.1 Screening the use of Antimicrobials:

In everyday practice Pharmacists have a role to play as they clinically screen drugs as part of their practice. Pharmacists also should be aware of the potential of antibiotic-related drug-drug interactions. For example interactions concerning the fluoroquinolone and macrolide classes of antibiotic are particularly important in this regard. When checking medicines prescribed, it is important to check that antibiotics are prescribed appropriately.

Following care must be taken while screening antibiotic prescriptions.

· To check whether the prescribed antibiotic is the most appropriate for the infection according to guidelines?

· To check whether the dose, route, frequency and duration is appropriate for the patient?

6.2 Counseling the people by educating them about how to prevent infections:

Preventing the infections will definitely help in reducing the Antimicrobial Resistance in our society because it reduces the need for using these antibiotics. Personal hygiene is most important in preventing transmission of various infections. The WHO recommends that washing your hands is most important in preventing transmission of infections.

6.3 Awareness regarding importance of Vaccines:

Pharmacist can create awareness in the society about the importance of Vaccines because Vaccines can decrease the use of antibiotics directly by preventing primary infection and indirectly by preventing bacterial super-infection.

6.4 Promote rational use of Antibiotics:

Pharmacist is the important link between the physician and the patient. Thus by the way of counseling the patients about rational use of medicines such as importance of taking antibiotics for the prescribed duration without fail. In this way the community Pharmacist can contribute a lot in reducing the rise of AMR that occurs as a result of inappropriate/over-use of these medicines.

6.5 Reduce excess use of antibiotics but enable access when antibiotics are truly needed:

For the Pharmacist it is important to prevent the emergence of antimicrobial resistance by limiting use to only when it is necessary. But it is equally important for the Pharmacists to be aware of life threatening conditions such as sepsis which is a common and potentially life-threatening condition triggered by an infection. Sepsis is a life threatening condition and must be treated quickly with antibiotics usually in a hospital setting. It is important that we ensure the effectiveness of antibiotics to be able to treat serious infections such as this. Community pharmacists in particular need to be aware of the sepsis warning symptoms that require urgent medical attention.

7. CONCLUSION:

Antimicrobial Resistance has become a global health threat in all parts of the world as we are already seeing the impact of resistant infections in everyday life for example; many urinary tract infections are becoming resistant these days. Resistant infections claim hundreds of thousands of deaths each year in all parts of the world. The increasing rate of resistance among common pathogens, broader-spectrum agents are now required for the empirical therapy of many common infections. These agents are usually more expensive, have more deleterious effects on protective micro flora, and can be more toxic or less effective.

Now there is a need for a better management for responsible use of Antimicrobial for our better health and also for the health of generations to come. As an important part of healthcare system, the Pharmacist along with healthcare professionals can help in reducing the rise of Antimicrobial Resistance.

8. LIST OF ABBREVIATIONS:

AMR: Antimicrobial Resistance

MDR: Multi-drug Resistance

MDR: TB- Multi-drug Resistance Tuberculosis

TB -Tuberculosis

WHO: World Health Organization

KPCs: Klebsiella pneumonia carbapenemases

OXA-48: Carbapenemases of the oxacillinase-48

NDM: New Delhi metallo-β-lactamase

9. REFERENCES:

1. Review on Antimicrobial Resistance, amr-review.org., retrieved on 15 September 2017.

2. Antimicrobial resistance, http://www.who.int/mediacentre/factsheets/fs194/en/, retrieved on 15 September 2017.

3. About Antimicrobial Resistance (https://www.cdc.gov/drugresistance/about.html). www.cdc.gov. retrieved on 16 September 2017.

4. https://en.wikipedia.org/wiki/Antimicrobial_resistance, retrieved on 16 September 2017.

5. Victoria Rutter, Diane Ashiru, Roger Odd, Antimicrobial Resistance and Stewardship-a Focus on the Commonwealth, Pharma Times, 49 (08), August 2017.

6. Antimicrobial Resistance: Global Health Threat, Pharma Times, 49 (08), August 2017.

7. http://www.who.int/mediacentre/news/releases/2014/amr-report/en/, retrieved on 20 September 2017.

8. WHO’s first global report on antibiotic resistance reveals serious, worldwide threat to public health, How to tackle resistance, http://www.who.int/mediacentre/news/releases/2014/amr-report/en/, retrieved on 20 September 2017.

9. Stuart B Levy and Bonnie Marshall, Antibacterial resistance worldwide: causes, challenges and responses, Nature Medicine Supplement 10(12) 2004.

10. Lee, C. R., Lee J. H., Park K. S. Kim, Y. B. Jeong, Global Dissemination of Carbapenemase-Producing Klebsiella pneumoniae: Epidemiology, Genetic Context, Treatment Options, and Detection Methods. Frontiers in Microbiology, 7(7), June 2016.

11. Criswell, Daniel. "The “Evolution” of Antibiotic Resistance." Institute for Creation Research. N.P., 2004. http://www.icr.org/article/evolution-antibiotic-resistance/ retrieved 22 September 2017.

12. Xian-Zhi Li,Hiroshi Nikaido, Efflux-Mediated Drug Resistance in Bacteria: an Update. Drugs. 69 (12), 2009.

13. Rustam I. Aminov, Roderick I. Mackie, Evolution and ecology of antibiotic resistance genes, Microbiology Letters, 271(2), 2007.

Received on 07.10.2017 Modified on 01.11.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(4): 143-146.

DOI: 10.5958/0975-4377.2017.00023.4