Antimicrobial Resistance (AMR): Introduction, Types of Drug Resistance, Mechanism and National Surveillance

achaurasiya

6 years ago

Antimicrobial resistance (AMR) Introduction

Antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses, and fungi.
AMR is an increasingly serious threat to global public health that requires action across all government sectors and society.
Without effective antibiotics, the success of major surgery and cancer chemotherapy would be compromised.
The cost of health care for patients with resistant infections is higher than care for patients with non-resistant infections due to the longer duration of illness, additional tests, and use of more expensive drugs.
In 2016, 490 000 people developed multi-drug resistant( MDR) Tuberculosis ( TB) globally, and drug resistance is starting to complicate the fight against HIV and malaria, as well.

What is antimicrobial resistance (AMR)?

AMR 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”.
As a result, the medicines become ineffective and infections persist in the body, increasing the risk of spread to others.

Why is AMR a global concern?

New resistance mechanisms are emerging and spreading globally, threatening our ability to treat common infectious diseases, resulting in prolonged illness, disability, and death.
Without effective antimicrobials for prevention and treatment of infections, medical procedures such as organ transplantation, cancer chemotherapy, diabetes management and major surgery (for example, cesarean sections or hip replacements) become very high risk.
Antimicrobial resistance increases the cost of health care with lengthier stays in hospitals and more intensive care required.
Antimicrobial resistance is putting the gains of the Millennium Development Goals at risk and endangers the achievement of the Sustainable Development Goals.

What accelerates the emergence and spread of AMR?

AMR occurs naturally over time, usually through genetic changes. However, the misuse and overuse of antimicrobials are accelerating this process. In many places, antibiotics are overused and misused in people and animals, and often given without professional oversight. Examples of misuse include when they are taken by people with viral infections like colds and flu, and when they are given as growth promoters in animals or used to prevent diseases in healthy animals. Antimicrobial resistant-microbes are found in people, animals, food, and the environment (in water, soil, and air). They can spread between people and animals, including from food of animal origin, and from person to person. Poor infection control, inadequate sanitary conditions, and inappropriate food handling encourage the spread of antimicrobial resistance.

The present situation of AMR

Resistance in bacteria

AMR is present in every country.
Patients with infections caused by drug-resistant bacteria are at increased risk of worse clinical outcomes and death and consume more healthcare resources than patients infected with non-resistant strains of the same bacteria.
Resistance in Klebsiella pneumoniae – common intestinal bacteria that can cause life-threatening infections – to a last-resort treatment (carbapenem antibiotics) has spread to all regions of the world. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections, and infections in newborns and intensive-care unit patients. In some countries, because of resistance, carbapenem antibiotics do not work in more than half of people treated for K. pneumoniae infections.
Resistance in E. coli to one of the most widely used medicines for the treatment of urinary tract infections (fluoroquinolone antibiotics) is very widespread. There are countries in many parts of the world where this treatment is now ineffective in more than half of patients.
Treatment failure to the last resort of medicine for gonorrhea (third-generation cephalosporin antibiotics) has been confirmed in at least 10 countries (Australia, Austria, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden, and the United Kingdom of Great Britain and Northern Ireland).
WHO recently updated the treatment guidelines for gonorrhea to address emerging resistance. The new WHO guidelines do not recommend quinolones (a class of antibiotic) for the treatment of gonorrhea due to widespread high levels of resistance. In addition, treatment guidelines for chlamydial infections and syphilis were also updated.
Resistance to first-line drugs to treat infections caused by Staphlylococcus aureus—a common cause of severe infections in health facilities and the community—is widespread. People with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection.
Colistin is the last resort treatment for life-threatening infections caused by Enterobacteriaceae which are resistant to carbapenems. Resistance to colistin has recently been detected in several countries and regions, making infections caused by such bacteria untreatable.

Resistance in tuberculosis (TB)

WHO estimates that, in 2014, there were about 480 000 new cases of multidrug-resistant tuberculosis (MDR-TB), a form of tuberculosis that is resistant to the 2 most powerful anti-TB drugs. Only about a quarter of these (123 000 cases) were detected and reported. MDR-TB requires treatment courses that are much longer and less effective than those for non-resistant TB. Globally, only half of the MDR-TB patients were successfully treated in 2014.
Among new TB cases in 2014, an estimated 3.3% were multidrug-resistant. The proportion is higher among people previously treated for TB, at 20%.
Extensively drug-resistant tuberculosis (XDR-TB), a form of tuberculosis that is resistant to at least 4 of the core anti-TB drugs, has been identified in 105 countries. An estimated 9.7% of people with MDR-TB have XDR-TB.

Resistance in malaria

As of July 2016, resistance to the first-line treatment for P. falciparum malaria (artemisinin-based combination therapies, also known as ACTs) has been confirmed in 5 countries of the Greater Mekong subregion (Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand, and Viet Nam). In most places, patients with artemisinin-resistant infections recover fully after treatment, provided that they are treated with an ACT containing an effective partner drug. However, along the Cambodia-Thailand border, P. falciparum has become resistant to almost all available antimalarial medicines, making treatment more challenging and requiring close monitoring. There is a real risk that multidrug resistance will soon emerge in other parts of the subregion as well. The spread of resistant strains to other parts of the world could pose a major public health challenge and jeopardize important recent gains in malaria control.
A “WHO Strategy for Malaria Elimination in the Greater Mekong subregion (2015-2030)” was endorsed by all 5 countries, as well as China.

Resistance in HIV

In 2010, an estimated 7% of people starting antiretroviral therapy (ART) in developing countries had drug-resistant HIV. In developed countries, the same figure was 10–20%. Some countries have recently reported levels at or above 15% amongst those starting HIV treatment, and up to 40% among people re-starting treatment. This requires urgent attention.
Increasing levels of resistance have important economic implications as second and third-line regimens are 3 times and 18 times more expensive, respectively, than first-line drugs.
Since September 2015, WHO has recommended that everyone living with HIV start on antiretroviral treatment. Greater use of ART is expected to further increase ART resistance in all regions of the world. To maximize the long-term effectiveness of first-line ART regimens, and to ensure that people are taking the most effective regimen, it is essential to continue monitoring resistance and to minimize its further emergence and spread. In consultation with countries, partners, and stakeholders, WHO is currently developing a new “Global Action Plan for HIV Drug Resistance (2017-2021)”.

Resistance in influenza

Antiviral drugs are important for the treatment of epidemic and pandemic influenza. So far, virtually all influenza A viruses circulating in humans were resistant to one category of antiviral drugs – M2 Inhibitors (amantadine and rimantadine). However, the frequency of resistance to the neuraminidase inhibitor oseltamivir remains low (1-2%). Antiviral susceptibility is constantly monitored through the WHO Global Influenza Surveillance and Response System.
Need for coordinated action
Antimicrobial resistance is a complex problem that affects all of society and is driven by many interconnected factors. Single, isolated interventions have limited impact. Coordinated action is required to minimize the emergence and spread of antimicrobial resistance.
All countries need national action plans on AMR.
Greater innovation and investment are required in the research and development of new antimicrobial medicines, vaccines, and diagnostic tools.

WHO response towards AMR

WHO is providing technical assistance to help countries develop their national action plans, and strengthen their health and surveillance systems so that they can prevent and manage antimicrobial resistance. It is collaborating with partners to strengthen the evidence base and develop new responses to this global threat.
WHO is working closely with the Food and Agriculture Organization of the United Nations (FAO) and the World Organisation for Animal Health (OIE) in a ‘One Health’ approach to promote best practices to avoid the emergence and spread of antibiotic resistance, including optimal use of antibiotics in both humans and animals.
A political declaration endorsed by Heads of State at the United Nations General Assembly in New York in September 2016 signaled the world’s commitment to taking a broad, coordinated approach to address the root causes of antimicrobial resistance across multiple sectors, especially human health, animal health, and agriculture. WHO is supporting the Member States to develop national action plans on antimicrobial resistance, based on the global action plan.
WHO has been leading multiple initiatives to address antimicrobial resistance:

World Antibiotic Awareness Week

Held every November since 2015 with the theme “Antibiotics: Handle with care”, the global, multi-year campaign has an increasing volume of activities during the week of the campaign.
The Global Antimicrobial Resistance Surveillance System (GLASS)
The WHO-supported system supports a standardized approach to the collection, analysis, and sharing of data related to antimicrobial resistance at a global level to inform decision-making, drive local, national and regional action.

Global Antibiotic Research and Development Partnership (GARDP)

A joint initiative of WHO and Drugs for Neglected Diseases initiative (DNDi), GARDP encourages research and development through public-private partnerships. By 2023, the partnership aims to develop and deliver up to four new treatments, through the improvement of existing antibiotics and acceleration of the entry of new antibiotic drugs.

Interagency Coordination Group on Antimicrobial Resistance (IACG)

The United Nations Secretary-General has established IACG to improve coordination between international organizations and to ensure effective global action against this threat to health security. The IACG is co-chaired by the UN Deputy Secretary-General and the Director-General of WHO and comprises high-level representatives of relevant UN agencies, other international organizations, and individual experts across different sectors.

Antimicrobial resistance- An emerging problem

Antibiotics are valuable and most utilized therapeutic agents.
The emergence of multi-drug resistance has limited therapeutic options.
Need for the development of newer drugs.
Hence, resistance monitoring is of paramount importance.
In vitro susceptibility testing, the mainstay for monitoring therapy and detecting resistance.

The emerging problem of antimicrobial resistance in bacteria

Multidrug-resistant strains of Gram-negative bacteria (Pseudomonas, Klebsiella, Enterobacter, Acinetobacter, Salmonella species)
Gram-positive organisms (Staphylococcus, Enterococcus, Streptococcus species)
Methicillin-resistant Staphylococcus aureus vancomycin-resistant enterococci
The spread of penicillin-resistant pneumococci (PRP)
MDR Tuberculosis

Outcomes of Antimicrobial resistance (AMR)

Longer treatment
Longer duration of illness
Higher mortality
Treatment with expensive drugs
Increased burden on health system
The patient acts as a reservoir of resistant organisms to the community

Control of Antimicrobial Resistance (AMR)

Not possible with the single effort of a country/organization/person

Instead, it is the mutual responsibility of

Laboratories
Clinicians
Hospital Infection Control Committees
Other health concerned authorities

AMR Surveillance in Nepal

Started in the year 1999 -technical assistance from ICDDR, B (Dhaka)
Financial support from USAID
1999-2003: ICDDR, B provided the technical support
National Public Health Laboratory then acting as the focal point laboratory for coordination of AMR activities in Nepal
2004/2005: NPHL continued the AMR surveillance program on its own with support from USAID
2006- TILL DATE: supported by WHO

Currently Monitoring Pathogens in AMR Surveillance by National Public Health Laboratory (NPHL) of Nepal

Vibrio cholerae
Shigella species
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria gonorrhoeae
Salmonella species (included since 2002)
ESBL E. coli (included since 2009)
Methicillin Resistant S. aureus (included since 2013)
Multidrug resistant Klebsiella species
Multidrug resistant Acinetobacter species

Participating Laboratories of Nepal for AMR program

Eastern Development Region

Mechi Zonal Hospital (since 2012)
B. P. Koirala Institute of Health Sciences (BPKIHS) , Dharan
Koshi Zonal Hospital, Biratnagar

Central Development Region

Patan Hospital ,Lalitpur
Kanti Children’s Hospital, Kathmandu
Tribhuvan University Teaching Hospital, Kathmandu
Kathmandu Model Hospital, Kathmandu (since 2012)
KIST Medical College, Lalitpur (since 2012)
Dhulikhel Hospital, Kavre
Central Veterinary Lab, Kathmandu (since 2012)
Paropakar Maternity & Women’s Hospital, Kathmandu (since 2016)
Sukraraj Tropical & Infectious Disease Hospital, Kathmandu (since 2016)

Western Development Region

United Mission Hospital, Palpa
Lumbini Zonal Hospital, Butwal
Western Region Hospital, Pokhara
Manipal Teaching Hospital, Pokhara

Mid-Western Development Region

Mid-Western Regional Hospital, Surkhet (since 2012)
Bheri Zonal Hospital, Nepalgunj ( Since 2012)

Far Western Development Region

Mahakali Zonal Hospital, Kanchanpur (since 2012)
Seti Zonal Hospital, Dhangadi ( since 2012)
Bayalpata Hospital, Achham

Mechanism of Antibiotics Resistance

It is of two types and they are-

Intrinsic ( natural) method and
Acquired ( genetic method): It is further of two types- A) Chromosomal method ( mutation) and B) Extrachromosomal methods ( plasmids)

Intrinsic Resistance

It occurs naturally.

Lack target

No cell wall; innately resistant to penicillin

Innate efflux pumps

The drug blocked from entering cell or ↑ export of drug (does not achieve adequate internal concentration). e.g. E. coli, P. aeruginosa

Drug inactivation

Cephalosporinase in Klebsiella

Acquired resistance

Mutations

It refers to the change in the DNA structure of the gene.
Occurs at a frequency of one per ten million cells.

e.g. Mycobacterium tuberculosis, Mycobacterium leprae , MRSA.

Often mutants have reduced susceptibility.

Plasmids

Extrachromosomal genetic elements can replicate independently and freely in the cytoplasm.
Plasmids that carry genes resistant ( r-genes) are called R plasmids.
These r-genes can be readily transferred from one R-plasmid to another plasmid or to a chromosome.
Much of the drug resistance encountered in clinical practice is plasmid-mediated.

Mechanisms of Antimicrobial Resistance (AMR) Gene Transfer

Transfer of r-genes from one bacterium to another

Conjugation
Transduction
transformation

Transfer of r-genes between plasmids within the bacterium

By transposons
By Integrons

Biochemical Mechanisms of Antibiotic Resistance

Prevention of drug accumulation in the bacterium
Modification/protection of the target site
Use of alternative pathways for metabolic / growth requirements
By producing an enzyme that inactivates the antibiotic
Quorum sensing

Decreased permeability: Porin Loss

Antibiotics normally enter bacterial cells via porin channels in the cell wall
New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells.

Efflux pumps

Cytoplasmic membrane transport proteins.
A major mechanism for resistance in Tetracyclines.
Some gram -ve bacteria inhibit the plasmid-mediated synthesis of porin channels, which obstructs the influx of hydrophilic Penicillins e.g. ampicillin.

Structurally modified antibiotic target site

Antibiotics normally bind to specific binding proteins on the bacterial cell
surface.
Antibiotics are no longer able to bind to modified binding proteins on the bacterial cell surface.

Modification/Protection of the Target site

Resistance resulting from altered target sites:

Target sites Resistant antibiotics

Ribosomal point mutation Tetracyclin, macrolides
clindamycin
Altered DNA gyrase Fluoroquinolones
Modified penicillin bind Penicillin
proteins ( S. pneumonaie)
Mutation in DNA dependent
RNA polymerase (M. tuberculosis) Rifampicin

Antibiotics inactivation

Inactivating enzymes target antibiotics
Enzymes bind to antibiotic molecules.
Enzymes destroy antibiotics or prevent binding to target sites.

By producing enzymes that inactivate antibiotic

a) Inactivation of β-lactam antibiotics

S. aureus, N. gonorrheae, H. influenzae, Produce ß-lactamase which cleaves -lactam ring.

b)Inactivation of Chloramphenicol

Inactivated by chloramphenicol acetyltransferase.
Gram-ve (enzyme present constitutively hence higher resistance) gram +ve bacteria (enzyme is inducible )

c) Inactivation of Aminoglycosides

Inactivated by acetyl, phospho and adenylyl transferases present in gram +ve and gram –ve.

Use of alternative pathways for metabolic / growth requirements

Resistance can also occur by an alternate pathway that bypasses the reaction inhibited by the antibiotic Sulfonamide resistance can occur from an overproduction of PABA.

Quorum sensing

Microbes communicate with each other and exchange signaling chemicals (Autoinducers)
These autoinducers allow the bacterial population to coordinate gene expression for virulence, conjugation, apoptosis, mobility, and resistance.

Types of drug resistance

Multidrug-resistant (MDR),
Extensively drug-resistant (XDR) and
Pandrug-resistant (PDR) bacteria

MDR is defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR is defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories), and PDR is defined as non-susceptibility to all agents in all antimicrobial categories.

Drug Mechanism of Resistance

Penicillin and cephalosporin- β- lactamase cleavage of the lactam ring
Aminoglycosides- Modification by phosphorylating, adenylating, and acetylating enzymes
Chloramphenicol – Modification by acetylation
Erythromycin -Change in receptor by methylation of r RNA
Tetracycline -Reduce uptake/Increased export