Mechanisms of antibiotic

resistance in bacteria

Misuse of Antibiotics: The

Worldwide Crisis of
Resistant Bacterial
Infections
James A. Wilde MD
Medical Director, GUARD
Associate Professor of Emergency Medicine and Pediatrics
Medical College of Georgia

What Causes Infections?

Infections are caused by one of four life
forms:

Virus
Bacteria
Parasites
Fungus

75% or more of all infections

less than 25%
less than 1% in the US
less than 1% in the US

Virus:

Can live in the environment for years

Attack humans by invading cells of certain organs

Hepatitis virus: attacks the liver cells

Encephalitis virus: attacks the brain cells
Cold virus: attacks the throat and breathing passages
Diarrhea virus: attacks the small intestine

Cannot reproduce or grow unless inside a cell

Sucks the energy from the cell, eventually kills it
Too small to be seen with most microscopes

Bacteria

Easily visible with a microscope

Can live and grow wherever they find food

Mountain streams
Ocean water
Rotting animal or plant
Sewer
Topsoil
Blood/skin/throat/lungs/urinary bladder/intestine

Some divide and grow every 20 minutes

Many produce poisons

Diseases Caused by
Viruses and Bacteria
Virus
Common cold
Diarrhea (99%)
Acute Bronchitis
Influenza (flu)
Measles
Chicken Pox
AIDS
Rabies
Hepatitis

Bacteria
Urine infections
Strep Throat
Boils/abscesses
Gangrene
Some pneumonia
Ear infections (half)
Sinus infections (< half)
Bubonic Plague
Tuberculosis

How Do We Cure These Infections?

Bacterial infections
Immune system (white blood cells, etc)
Antibiotics (Penicillin, etc.)
Viruses
Immune system
Anti-viral medications: not much help
Antibiotics do NOTHING to harm a virus

Fact
Bacteria are the cause of the
vast majority of deaths due to
infection in the United States:
sepsis, meningitis, pneumonia

Fact
Most viral infections get better
all by themselves in 1-3 weeks;
no medications are required:
colds, flu, stomach virus

% Patients

Resolution of Acute
Bronchitis
100
No Antibiotic

80

(+) Antibiotic

60
40
20
0
0

10

12

14

16

Days with cough

Stott, BMJ 1976

18

Gonzales et al., JAMA, 1997

Examined rate of antibiotic use for common

cold, bronchitis in private physicians offices

Colds: 51% given antibiotics

Upper respiratory infection: 52%
Bronchitis: 66%

These antibiotics are unnecessary!!!

HISTORICAL PERSPECTIVE
Antibiotics introduced 60 years ago
Bacteria from pre-antibiotic era had

virtually no resistance genes

Staph aureus was uniformly sensitive
to Penicillin at the time of its release

What are antibiotics?

Have been used by fungi to kill

bacteria for many millions of years

First discovered in 1929 by A.
Fleming
Brought into widespread use in
the 1940s
Antibiotics are chemicals that kill
bacteria
Their introduction was arguably
the biggest medical breakthrough
since sanitation

Penicillin

A discovery by accident

A fungal spore that the wind might

have blown into his lab while Fleming
was on vacation in 1928, forever
changed the course of medicine...
A. Fleming named the substance
Penicillin, after the mould Penicillium
notatum but was unable to isolate
the substance
In the late 1930s and early 1940s, E.
Chain & H. Florey managed to
produce larger amounts of penicillin,
and ran successful trials on mice
Nobel prize in 1945
http://nobelprize.org/medicine/educational/pe
nicillin/readmore.html

How antibiotics work

Inhibition of nucleic acid synthesis

Inhibition of protein synthesis

Polyenes; Polymyxin

Interference with enzyme system

Tetracyclines; Chloramphenicol

Action on cell membrane

Rifampicin; Chloroquine

Sulphamethoxazole

Action on cell wall

Penicillin; Vancomycin
penicillin works by blocking the formation of peptide bonds in
the bacterial cell wall and thereby weakens it, leaving the
bacterium susceptible to osmotic lysis

Antibiotic use and misuse

During the 1940s and 1950s antibiotics were

extremely effective
They were (and still are) widely prescribed,
often for medical conditions that did not require
them
Antibiotics started to be used in agriculture:
dosing cattle with antibiotics increases yield,
and battery farming relies on antibiotics to
control infection
By the 1970s the World was awash with
antibiotics.

Resistance

As early as 1946, scientists (including A.

Fleming) were warning of the possible

dangers of antibiotic-resistant bacteria
A few bacteria in populations that have
never been exposed to artificial antibiotics
probably carry alleles that give resistance to
antibiotics
Resistance alleles can also arise by
mutation
Resistant bacteria can use a number of
mechanisms to overcome antibiotics

Mechanisms of resistance

Imipenem resistan
Pseudomonas
aeruginosae
Streptococcu
s
pneumoniae
resistance to
penicillins

Tetracycline

MRSA
penicillin
binding
protein
PBP2A

Penicillins,
Cephalosporin
s
Hawkey, P. M BMJ 1998;317:657-660

How Antibiotic Resistance

Happens

Emergence of Antimicrobial
Resistance

Susceptible Bacteria

Resistant Bacteria
Mutations

XX

Resistance Gene Transfer

New Resistant Bacteria

Bacterial Resistance
Mechanisms

Resistance Mechanisms
Inside the Bacterial Cell

Mechanisms of antibiotic resistance

Efflux Pumps
Hydrolysis
Reduced Uptake
Sequestering
Enzymatic Modification

The Science Creative Quarterly 2: Jan-March 2007.

 To date, more than 100 resistance

genes have been identified

These genes allow the bacteria to
shield themselves from the antibiotic
Resistance genes can be transferred
from one bacterial species to another:
spread of resistance is RAPID

Mechanisms of Antibiotic Resistance

Antibiotic

Method of resistance

Chloramphenicol

reduced uptake into cell

Tetracycline

active efflux from the cell

-lactams, Erythromycin, Lincomycin

eliminates or reduces binding of

antibiotic to target

-lactams, Erythromycin

hydrolysis

Aminoglycosides, Chloramphenicol,
Fosfomycin, Lincomycin

inactivation of antibiotic by
enzymatic modification

-lactams, Fusidic Acid

sequestering of the antibiotic by

protein binding

Sulfonamides, Trimethoprim

metabolic bypass of inhibited

reaction

Sulfonamides, Trimethoprim

overproduction of antibiotic target

(titration)

Bleomycin

binding of specific immunity

protein to antibiotic

Chronology of Development of
Antibiotic Resistance
Antibiotic
Penicillin
Streptomycin
Tetracycline
Erythromycin
Gentamicin
Vancomycin

Year introduced Resistance identified

1942
1947
1952
1955
1967
1956

1946
1947
1956
1956
1970
1987

Resistance:
The World 2000

In much of South-East Asia, resistance to penicillin has

been reported in up to 98% of gonorrhoea strains.
In Estonia, Latvia, and parts of Russia and China, over
10% of tuberculosis (TB) patients have strains resistant to
the two most effective anti-TB drugs.
Thailand has completely lost the use three of the most
common anti-malaria drugs because of resistance.
A small but growing number of patients are already
showing primary resistance to AZT and other new
therapies for HIV-infected persons.

The consequences of antibiotic

resistance
Increased morbidity & mortality

best-guess therapy may fail with the patients

condition deteriorating before susceptibility results
are available
no antibiotics left to treat certain infections

Greater health care costs

more investigations
more expensive, toxic antimicrobials required
expensive barrier nursing, isolation, procedures, etc.

Therapy priced out of the reach of

third-world countries

some

Clinical Significance of Antibiotic

Resistance
Therapeutic failures and relapse
Facilitates spread in the hospital under

antibiotic pressure
Need to use more costly and toxic agents
The emergence of untreatable pathogens

Evolution of Drug Resistance in

S. aureus
Penicillin
Methicillin
S. aureus

Penicillin-resistant
[1950s]

S. aureus

Methicillinresistant
[1970s]
S. aureus (MRSA)

[1997]

Vancomycin

[1990s]
Vancomycin-

resistant
S. aureus

[ 2002 ]

Vancomycin
intermediateresistant
S. aureus
(VISA)

Vancomycin-resistant
enterococci (VRE)

Proportion of S. aureus Nosocomial

Infections Resistant to Oxacillin (MRSA)
Among Intensive Care Unit Patients,
1989-2003*

*Source: NNIS System, data for 2003 are incomplete

Emergence of Vancomycin
Resistant Enterococci
Non-Intensive Care Unit Patients
Intensive Care Unit Patients

Source: NNIS Data

Antibiotics in Animal Feed

rationale
Promotes growth
Decreases amount of feed

needed
Prevents infectious diseases
Facilitates confinement housing
Lowers costs

ANTIMICROBIAL RESISTANCE:
The role of animal feed antibiotic additives

48% of all antibiotics by weight is added to animal feeds to

promote growth. Results in low, subtherapeutic levels which are
thought to promote resistance.
Farm families who own chickens feed tetracycline have an
increased incidence of tetracycline resistant fecal flora
Chickens at Spanish supermarkets have >90% of cultured
campylobacter resistant to quinolones
39% of enterococci in the fecal flora of pigs from the
Netherlands is resistant to vancomycin vs 0% in Sweden.
(Sweden bans antibiotic additives in animal feed)

Cross-resistance Between Growth

Promoters and Antibiotics for Human
Use
Vancomycin
Avilamycin
Everninomicin
Virginiamycin Synercid
Tylosin
Erythromycin
Avoparcin

Decrease in VRE After Removing

Avoparcin From Animal Feed

EID 1999; Vol 5

US New Antibacterial Agents

Year

No. Approved

Agents

1991

20

1992

Temafloxacin, lomefloxacin, cefpodoxime

1993

Piperacillin/Tazobactam

1994

Lowest number of new agents (22) since 1988

1995

Dirithromycin, ceftibutin

1996

Meropenem, levofloxacin, sparfloxacin, Cefepime

1997

Grepafloxacin, Trovafloxacin

1998

Rivaled 1994

1999

Dalfopristin/quinupristin, gatifloxacin, moxifloxacin

2000

Linezolid

2001

Ertapenem, ceftidoren

2002

89 drugs approved, no antibacterial agents

2003

Daptomycin, gemifloxacin

Multiple agents

INDONESIA
AMRIN Study (The Antimicrobials

Resistance in Indonesia Prevalence and

Prevention) : 2000 2005

The antimicrobial resistance has become a

public health threat in Indonesia

IARW (Indonesia Antimicrobials

Resistance Watch)
Antibiotic Policy in hospitals

Waiting Room
Poster