Antbiotic resistance

Antimicrobial
Resistance
Dr Karuna Sree P
Asst. Professor
Dept. Of Pharmacology
KIMS

Contents
 History
 Antimicrobial resistance
 Mechanisms of antibiotic resistance
 Strategies to contain resistance
 Develop new antibiotics
 Judicious use of antibiotics
 Indian scenario
 Antibiotic policy at KIMS
 Summary
3/23/20152 Dr Karuna Sree p, Dept. Of Pharmacology

Evolution of Chemotherapy
 A pre- Ehrlich era before 1891
 The period of Paul Ehrlich
 Magic bullets
 The period after 1935 – highlighted by
the discovery of sulfonamides &
antibiotics

In his 1945 Nobel Prize lecture, Fleming himself
warned of the danger of resistance –
“It is not difficult to make microbes resistant to
penicillin in the laboratory by exposing them to
concentrations not sufficient to kill them, and the
same thing has occasionally happened in the
body… …and by exposing his microbes to non-
lethal quantities of the drug make them
resistant.”
History
Nobel Lecture, December 11, 1945
Sir Alexander
Fleming
The Nobel Prize in
Physiology or Medicine 1945

…EVOLUTION OF RESISTANCE TO
ANTIBIOTIC

Timeline of Antibiotic Resistance

???  antimicrobial resistance
 Infections with resistant organisms are associated
with increased morbidity and mortality
 Extended stays in hospitals
 Reduced treatment options - Untreatable infections
 Increased healthcare costs
 Compromises health security, damage trade &
Economy
Patients with an antimicrobial-resistant
infection may suffer more and pay more
for treatment.http://www.cdc.gov/drugresistance/about.html

Where antimicrobial resistance is present
 It is a serious global challenge.
 Every continent and country faces the menace of
antibiotic resistant “super bugs.”
 Very high rates of resistance observed in
common bacteria (for eg., E. coli, K.pneumoniae
& Staph.aureus, gonorrhoea) that cause
common health-care associated & community-
acquired infections

Bacterial evolution Vs mankind’s ingenuity
11
• Adult humans contains 1014 cells,
only 10% are human – the rest are
bacteria
• Antibiotic use promotes Darwinian
selection of resistant bacterial
species
• Bacteria have efficient mechanisms
of genetic transfer – this spreads
resistance
• Bacteria double every 20 minutes,
humans every 30 years
• Development of new antibiotics has3/23/2015Dr Karuna Sree p, Dept. Of Pharmacology

Selection Pressure
Bacteria Sensitive to antibiotic
Bacteria Resistant to antibiotic
After
Antibiotic
Use

Antimicrobial resistance
Antimicrobial resistance is a broader
term, encompassing resistance to
drugs to treat infections caused by
bacteria as well as parasites (e.g.
malaria), viruses (e.g. HIV) and fungi
(e.g. Candida)
http://www.who.int/mediacentre/factsheets/fs194/en/

Other similar terms
 Antibiotic tolerance : when the antibiotic no
longer kills the microorganisms but merely
inhibits its growth / multiplication.
 Tolerant microorganisms grow after
antibiotic is stopped whereas resistant
microorganisms multiply even in the
presence of antibiotic.

Factors contributing to Antibiotic
Resistance
Environmental
Factors
Drug
Related
Factors
Patient
Related
Factors
Prescriber
Related
Factors
Antibiotic
Resistance

1. Environmental Factors
 Huge populations and overcrowding
 Rapid spread – increased travelling
 Poor sanitation
 Increases community acquired resistance
 Ineffective infection control program
 Widespread use of antibiotics in animal husbandry
and agriculture and as medicated cleansing products

Widespread Use of Antimicrobials in Animal
Husbandry and Agriculture
 The extensive worldwide exploitation of
antibiotics in animal care (medicated animal
feed) and agriculture (growth promoters)
constantly selects for strains of bacteria that are
resistant to the drugs.

2. Drug Related
 Over the counter availability of
antimicrobials
 Counterfeit and substandard drug causing
sub-optimal blood concentration
 Irrational fixed dose combination of
antimicrobials
 Soaring use of antibiotics
Policy
Decision
at Higher
level

Soaring Antibiotic Use
Antibiotic use (and misuse) has soared since the
first commercial versions were introduced and
now includes many nonmedicinal applications.
2 >50Million
Ton
Million
Ton
1954 2014

3. Patient Related
 Poor adherence of dosage Regimens
 Poverty
 Lack of sanitation concept
 Lack of education
 Self-medication
 Misconception
Patient
Counseling,
Awareness
Program 3/23/201521 Dr Karuna Sree p, Dept. Of Pharmacology

Physician / Prescriber Related
 Inappropriate use of available drugs
 Increased empiric poly-antimicrobial use
 Overuse of antimicrobials
 Inadequate dosing
 Lack of current knowledge and training

DEVELOPMENT OF RESISTANCE:
Emerging and Re-emerging Diseases
 Emerging and re-emerging diseases are another source
for resistance.
 Emerging diseases have not been seen before.
 Re-emerging are caused by organisms
resistant to treatment.
 For eg., In India NMEP changed to NVBDCP due to
remerging of disease

DEVELOPMENT OF RESISTANCE:
Emerging and Re-emerging Diseases
• 2008 – outbreak of H1N1 virus
• 2014 - outbreak of Ebola virus

How the bacteria develops
resistance ?

Antibiotic Resistance
Natural
Lack of
metabolic
process /
target site
Acquired
Genetic
methods
Chromosomal
methods -
Mutation
Extra
chromosomal
methods –
Plasmids
Within /between
bacteria
Biochemical
mechanisms
By producing
enzymes
Preventing drug
accumulation
Modifying target
site
Use alternative
pathways
Quorum sensing

Some microorganisms may ‘born’ resistant,
some ‘achieve’ resistance by mutation or
some have resistance ‘thrust upon them’ by
plasmidsSome are born great, some achieve
greatness or some have greatness thrust
upon them

Natural / Intrinsic Resistance
It occurs naturally.
1. Lack target :
• No cell wall; innately resistant to penicillin
2. Innate efflux pumps:
• Drug blocked from entering cell or ↑
export of drug (does not achieve
adequate internal concentration). Eg. E.
coli, P. aeruginosa
3. Drug inactivation:
• Cephalosporinase in Klebsiella

Acquired resistance
MUTATIONS
• It refers to the change in DNA structure of the gene.
• Occurs at a frequency of one per million cells.
• Even though Mutation rate is low → during course of
therapy – sensitive strains die – resistant strains
continue to grow & multiply – selection of
mutants
• Single step / Multistep
• Eg.Mycobacterium.tuberculosis,Mycobacterium
lepra , MRSA.
• Often mutants have reduced susceptibility

Plasmids – carriers of DNA
• Replicate independently and freely in cytoplasm.
• R-plasmids : Those which carry genes resistant
(r-genes) to antimicrobials
• r-Genes readily transferred from one R-plasmid
to another plasmid or to chromosome.
• Much of the drug resistance
encountered in clinical practice
is plasmid mediated

Methods of plasmid mediated transfer of
antibiotic resistance
• 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

Transfer of Plasmid : Conjugation
 Main mechanism for spread of resistance(single
/ multidrug)
 The conjugative plasmids make a connecting
tube (sex pili) between the two bacteria through
which plasmid itself can pass.
 Commonly observed in bacteria present at high
density – as in gut.

Bacterial Conjugation

Transduction
 Less common method
 The plasmid DNA enclosed in a bacteriophage
(bacterial virus) is transferred to another
bacterium of same species.
 Seen in Staphylococci , Streptococci

Bacterial Transduction

Transformation
 It poses least clinical problem.
 Free DNA is picked up from the environment by
the bacteria (from a cell belonging to closely
related or same strain).
 New DNA is incorporated into the genome &
becomes resistant.

Bacterial Transformation

by Transposons
 Transposons are DNA segments that cannot self
replicate but can self transfer between palsmids /
plasmid to chromosome.
 The donor plasmid containing the Transposons,
co-integrate with acceptor plasmid & replicate
during cointegration.
 Both plasmids then separate and each contains
the r-gene carrying the transposon.
 Eg., Staphylococci, Enterococci

Resistance mediated By transposons

by Integrons
 Integron is a large mobile DNA
unit, can spread Multidrug
resistance
 Packed with multiple gene
casettes, consisting of a
resistance gene attached to a
small recognition site.
 They encode several bacterial
functions. Eg. resistance &
virulence.
 They cannot promote self 3/23/201540 Dr Karuna Sree p, Dept. Of Pharmacology

Biochemical mechanisms of antibiotic
resistance
 Prevention of drug accumulation in the bacterium –
altering porin channels / efflux pumps
 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 through Porin
channels
Example : pencillins

Efflux pumps
• Cytoplasmic membrane transport proteins.
• Major mechanism for resistance in Tetracyclines.
• Eg.,
 ATP Binding Cassette
 Major Facilitator Superfamily (MFS)
 Multidrug And Toxic Compound Exporter (MATE)
 Staphylococcal Multidrug Resistance
Transporters(SMR)
 Resistance Nodulation Division Family (RND)

Efflux transporters :
Drug resistance

Modification/Protection of the Target site
Target sites Resistant Antibiotics
Ribosomal point mutation Tetracyclines,
Macrolides,
Clindamycin
Altered DNA gyrase Fluoroquinolones
Modified penicillin binding
proteins (S. pneumoniae)
Penicillins
Mutation in DNA dependant
RNA polymerase
(M.tuberculosis)
Rifampicin

Use of alternative pathways for metabolic /
growth requirements
• Resistance can also occur by alternate pathway
that bypasses the reaction inhibited by the
antibiotic.
• Sulfonamide resistance can occur from
overproduction of PABA

By producing enzymes that inactivates
antibiotic
 Inactivation of β-lactam antibiotics
• S. aureus, N. gonorrohoea, H.influenza, Produce
β-lactamase which cleaves -lactam ring
 Inactivation of Chloramphenicol
• Inactivated by chloramphenicol acetyltransferase .
• Gram-ve (enzyme present constitutively hence
higher resistance) gram +ve bacteria (enzyme is
inducible )
 Inactivation of Aminoglycosides
• Inactivated by acetyl, phospho & adenylyl
transferases Present in gram +ve and gram –ve .

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

Why named quorum sensing
 Single autoinducer from single microbe is
incapable of inducing any such change
 But when its colony reaches a critical
density(quorum), threshold of autoinduction is
reached and gene expression starts
 QS signal molecules AHL, AIP, AI-2 & AI-3 have
been identified in Gm-ve bacteria
 AI-2 QS –system is shared by GM+ve bacteria
also

WHY INHIBIT QUORUM SENSING
 Proved to be very potent method for bacterial
virulence inhibition.
 Several QS inhibitors molecules has been
synthesized which include AHL, AIP, and AI-2
analogues
 QS inhibitors have been synthesized and have
been isolated from several natural extracts such as
garlic extract.
 QS inhibitors have shown to be potent virulence
inhibitor both in in-vitro and in-vivo, using infection
animal models.

Strategies to control / prevent
Resistance
Develop new antibiotics
Bypass the drug resistance
Judicious use of the existing antibiotics:
Containment of drug resistance

New Antibiotic Development
 Only one group of antibiotics in last 35 years
 Only 15 antibiotics of 167 under development
had a new mechanism of action with the
potential to combat of multidrug resistance.
 Lack of incentive for
companies to develop
antibiotics.

Hope is not exhausted….yet
 Phage therapy
 Use of the lytic enzymes found in mucus and
saliva
 Agents that target type IIA topoisomerases
 Antimicrobial peptides (AMPs), lipopeptides
(AMLPs)  target bacterial membranes, making it
nearly impossible to develop resistance (bacteria
would have to totally change their membrane
composition).

Alternate Approaches
Phage therapy
• Phage Therapy is the therapeutic use of lytic
bacteriophages to treat pathogenic bacteria infections an
important alternative to antibiotics
• Invade bacterial cells and disrupt bacterial metabolism
and cause lysis of bacteria.
• The success rate was 80–95% with few gastrointestinal
or allergic side effects. British studies also demonstrated
significant efficacy of phages against Escherichia coli,
Acinetobacter spp., Pseudomonas spp and
Staphylococcus aureus.
Efflux Pump Inhibitors: verapamil

Some newer antibiotics
 Ceftobiprole/ceftaroline: V generation
cephalosporins
 Iclaprim: inhibits Dihydrofolate reductase
 Telavancin: inhibition of cell wall synthesis and
disruption of membrane barrier function
 Dalbavancin: inhibits cell wall synthesis
 Tedizolid
 Oritavancin
 Bedaquiline – multi drug resistant TB - approved
 Delamanid – multi drug resistant TB – in trials
New approved
antibiotics -2014

Judicious Use of Antibiotics
 Capable of containing antibiotic
resistance
 Cannot eliminate the possibility of
antibiotic development as resistance
is an evolutionary process

Containment of Resistance
 Containment of antibiotic resistance is
a multi-pronged program
 Involves all stake holders
 Physicians
 Patients
 Pharmaceuticals

Patient role in containment
 Finish the full course of treatment.
 Do not stockpile the leftover doses
 Do not medicate yourselves
 Do not treat your family and friends

Strategy of Containment
Antibiotic
Resistance
Evolutionary
Process
Faulty Use of
Antibiotics
Hospital Environmental
Empirical
Use
Definitive Use
Community
Acquired Antibiotic
Resistance
Hospital Acquired
Use of antimicrobials before
pathogen responsible for a
particular illness or the
susceptibility to a particular
antimicrobial is known

Faulty Antibiotic Use
 Antimicrobials are over prescribed
 Available without prescription - i.e., over the
counter drugs

Over Prescribed Antibiotics
 Clinician should first determine whether
antimicrobial therapy is warranted for a given
patient

Empirical Microbial Selection
 Indicated on the basis of clinical findings?
 Is it prudent to wait until such clinical findings
become apparent?
 Can some simple bed side test done to confirm
your suspicion?
 Microscopy
 Gram staining
 Have appropriate clinical specimens been obtained
to establish a microbial diagnosis?
 What are the likely etiological agents

 What measures should be taken to protect
individuals exposed to the index case to prevent
secondary cases (1), and what measures should
be implemented to prevent further exposure (2)?
12 3/23/201564 Dr Karuna Sree p, Dept. Of Pharmacology

Infection control
 Simple measure of hand wash
prevents many infections.
 Alcohol hand rub to be used
between patient contact

 Is there clinical evidence (e.g. from clinical
trials) that antimicrobial therapy will confer
clinical benefit for the patient?
(Evidence-based medicine)

Definitive Treatment
• Can a narrower spectrum agent be
substituted for initial empiric drug?
• Is one agent or combination of agents
necessary?

Examples
 -lactam + Aminoglycosides
 Extended spectum Penicillins + -lactamase
Inhibitors
 Anti-tubercular regimen
 Anti-leprotic regimen
 Co-trimoxazole
 Artemisinin based Combination Therapy (ACT) in
Malaria

What is the
 Right dose
 Right route of administration
 Right duration of therapy?

Definitive treatment
What specific test to identify patients
who will not respond to treatment?

What adjunctive measures can be
undertaken to eradicate infection?
 Vaccination
 Steroid
 Drainage of pus
 Amputation
 Removal of catheter

Who’s Work?
Microbiologist
Physician
Pharmacologist
Advise the
proper and
adequate
antibiotics with
balancing the
economy of 3/23/201572 Dr Karuna Sree p, Dept. Of Pharmacology

Indian scenario
 Currently no functioning national antibiotic policy
or a national policy
 No restriction on Over The Counter (OTC)
dispensing of antibiotics
 Indian hospitals have varying standards of
infection control.
 Some hospitals reported very high Gram-negative
resistance rates, with very high prevalence of
ESBL(Extended Spectrum Beta Lactamases)
producers – resistant to imipenems & only sensitive to
colistin

Indian scenario
 A Roadmap to Tackle the Challenge of
Antimicrobial Resistance - A Joint meeting of
Medical Societies in India – organised in 2012 :
lead to evolution of CHENNAI DECLARATION
 Stake Holders : Ministry of health, DCGI, state, MCI,
NABH, Infection control team(ICT) in all hospitals, ICMR,
to standardize the laboratories, National task force for
vigilance, to interact with global organizations - WHO and
the involvement of medical professionals, societies,
NGOs, journals, media, public as well as veterinary
practice.

Ghafur A, Mathai D, Muruganathan A, Jayalal JA, Kant R, Chaudhary D, et al. "The Chennai Declaration“ Recommendations of "A
roadmap- to tackle the challenge of antimicrobial resistance" - A joint meeting of medical societies of India. Indian J Cancer
2012;49:84-94

Hospital Acquired Drug Resistance
 Hospital infection control committee &
Antibiotic policy
 Hospital Antibiogram
Hospital specific antibacterial Resistance Pattern
 Identification of potential pathogen most likely to
cause infection
 Previous antibacterial therapy
 Prescription auditing

Hospital infection control committee
 Leadership of infection control specialist
 Team members
 Medical superintendent
 General manager
 Housekeeping supervisor
 Operation theater in-charge
 Chief executive officer
 Medical director
 Representatives of major departments.
 Antibiotic steward - for giving second opinion
 The committee should meet at least once in three months
and discuss important infection control issues
 The level of compliance to antibiotic policy
 Antibiotic resistance pattern (antibiogram)
 The compliance to infection control guidelines

Hierarchy of
infection control
committee

Veterinary antibiotic usage
Clinical & epidemiological
evidence s/o passage of
resistant strains from animals
to humans
 Some countries reported 50% of
antimicrobials being used in agriculture
/ animal husbandry.
 In India magnitude is not well studied

Methods to curb the spread of resistance from
animals to human
 Need to evaluate the extent & indications of use.
 Need to ascertain and monitor the prevalence of resistant
bacteria, like zoonotic food borne bacteria in animals
 Need to quantify the rate of transfer of medically-relevant
resistance genes & bacteria from animals to humans.
 Regular monitoring antibiotic residues in food of animal origin
 Formulation/implementation of proper regulations for
observance of withholding or withdrawal periods between the
use of antibiotics and animal slaughter or milking to avoid
residues of antibiotics in milk and meat.

Hospital Antibiotic Policy - KIMS
 To curb the common misuse and overuse of
antibiotics
 Restricts the occurrence of antibacterial
resistance among the hospital strains
 Controls the spread of such infections to
susceptible and critically ill patients in the
hospital and the subsequent infection into the
community.
 Saves money for the patient and increases
patient satisfaction with decreased side effect

Hospital Antibiogram
 A periodic summary of antimicrobial
susceptibilities of local bacterial isolates
submitted to the hospital's clinical
microbiology laboratory.
 Used by clinicians to assess local
susceptibility rates, as an aid in selecting
empiric antibiotic therapy, and in monitoring
resistance trends over time within an
institution

Antibiogram of KIMS Hospital
Am
ox+
CA
Gent
a
Ami
ka
Nitrof
urant
oin
Norfl
ox
Cotri
moxa
zole
Cefta
zidim
e
Cefta
zidim
e+
CA
Piper
icilin
+
Tazo
Imipe
nem
E.coli 14.8 52.3 89.6 76.4 15.62 19.3 8.82 60 20 100
Klebsiell
a
0 66.66 100 45.4 50 60 9.09 100 0 100
Pseudo
monas
0 50 50 Tobra
100
50 0 Netil
100
0 50 100
Acineto
bacter
25 50 50 0 25 50 0 0 50 100
Proteus 100 100 100 --- 50 0 0 --- 100 ---
Susceptibility pattern of gram negative isolates
from urine (% senstivity)

Antibiogram of KIMS Hospital
 Susceptability pattern of Gram positive isolates
(% sensitivity)
Organis
m
Ampi
cillin
Amo
x +
CA
G Amik
a
Cipr
o
Cefo
xitin
Cotri
m
Eryth
ro
Piper
cilin+
TZ
Vanc
omyc
in
Staph.a
ureus
40 40 80 100 40 40 100 40 --- 100
Enteroc
occus
0 66.66 66.66 66.66 0 --- --- ---- 66.66 100
Pneumo 66.66 66.66 100 0 33.3
3
--- 0 66.66 ---- 100
Enteroc
occus
(urine)
-- 50 12.5 28.57 15.3
8
--- --- --- 12.5 100

Summary
 Target definitive therapy to known pathogen
 Treat infection, not contamination
 Treat infection, not colonization
 Know when to say “no” to higher antibiotics
 Isolate Pathogen
 Break the chain of contagion – Keep your hands
clean.
 Start simple bed side test: Gram stain,
microscopy 3/23/201585 Dr Karuna Sree p, Dept. Of Pharmacology

Thank Q

Antbiotic resistance

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