Rationalism of

Antibiotic Therapy
Consequences of Misuse
Dr.T.V.Rao MD

Dr.T.V.Rao MD
 ANTIMICROBIAL AGENT

• Any chemical or drug used to

treat an infectious disease,
either by inhibiting or killing
the pathogens in vivo

Dr.T.V.Rao MD
 Beginning of Antibiotics with Discovery of
Pencillin
• The
discovery of penicillin
has been attributed to
Scottish scientist
Alexander Fleming in
1928 and the
development of
penicillin for use as a
medicine is attributed
to the Australian Nobel
Laureate
Howard Walter Florey. Dr.T.V.Rao MD
Discovery of Pencillin
Awarded Nobel Prize

Dr.T.V.Rao MD
Selman Waksman
 The term "antibiotic"
was coined by
Selman Waksman in
1942 to describe any
substance produced by
a microorganism that is
antagonistic to the
growth of other
microorganisms in high
dilution
Dr.T.V.Rao MD
Chemotherapeutic Agents
• Antimicrobial agents –
that are produced
synthetically but have
action similar to that of
antibiotics and are
defined as
chemotherapeutic
agents
• Eg Sulphonamides,
Quinolones.
Dr.T.V.Rao MD
 Definition
• Bacteriostatic - Antimicrobial agents that
reversibly inhibit growth of bacteria are called
as bacteriostic ( Tetracyclnes, Chloramphenicol )
• Bactericidal – Those with an irreversible lethal
action on bacteria are known as bactericidal
( Pencillin, Isoniazid )

Dr.T.V.Rao MD
 Development of anti-infectives ertapenem tigecyclin
daptomicin
linezolid
telithromicin
The development quinup./dalfop.
cefepime
of anti-infectives … ciprofloxacin
aztreonam
norfloxacin
imipenem
cefotaxime
clavulanic ac.
cefuroxime
gentamicin
cefalotina
nalidíxico ac.
ampicillin
methicilin
vancomicin
rifampin
chlortetracyclin
streptomycin
pencillin G
prontosil

1920 1930 1940 1950 1960 1970 1980 1990 2000

Dr.T.V.Rao MD
 Uses of Antimicrobial Agents
• Antimicrobial agents are widely employed to
cure bacterial diseases
• Definition of Antibiotic – Antibiotics are
substances that are derived from a various
species of microorganisms and are capable of
inhibiting the growth of other microorganism
even in small concentrations.

Dr.T.V.Rao MD
 ANTIBIOTICS

• Substances derived
from a
microorganism or
produced
synthetically, that
destroys or limits
the growth of a
living organism

Dr.T.V.Rao MD
 ANTIBIOTICS – Sources

1. Natural
a.Fungi – penicillin, griseofulvin
b.Bacteria – Bacillus sp.
(polymixin, bacitracin) ;
Actinomycetes (tetracycline,
chloramphenicol,
streptomycin)
2. Synthetic Dr.T.V.Rao MD
 ANTIMICROBIAL AGENT

Ideal Qualities:
1. kill or inhibit the growth of pathogens
2. cause no damage to the host
3. cause no allergic reaction to the host
4. stable when stored in solid or liquid form
5. remain in specific tissues in the body long enough
to be effective
6. kill the pathogens before they mutate and become
resistant to it

Dr.T.V.Rao MD
 Basic Classes of Antibiotics
•Although a large number of antibiotics exist, they fall into only a few classes with
an even more limited number of targets.

–β-lactams (penicillins) –cell wall biosynthesis

–Glycopeptides (vancomycin) –cell wall biosynthesis

–Aminoglycosides (gentamycin) –protein synthesis

–Macrolides (erythromycin) –protein synthesis

–Quinolones (ciprofloxacin) –nucleic acid synthesis

–Sulfonamides (sulfamethoxazole) –folic acidMDmetabolism

Dr.T.V.Rao
 Prescribing an antibiotic
 Is an antibiotic necessary ?
 What is the most appropriate
antibiotic ?
 What dose, frequency, route and
duration ?
 Is the treatment effective ?

Dr.T.V.Rao MD
 Is an antibiotic necessary ?
 Useful only for the treatment of bacterial
infections
 Not all fevers are due to infection
 Not all infections are due to bacteria
 There is no evidence that antibiotics
will prevent secondary bacterial
infection in patients with viral
infection
Dr.T.V.Rao MD
 Choice of regimen
 Oral vs parenteral
 Traditional view
 “serious = parenteral”
 previous lack of broad spectrum oral antibiotics
with reliable bioavailability
 Improved oral agents
 higher and more persistent serum and tissue
levels
 for certain infections as good as parenteral

Dr.T.V.Rao MD
 Advantages of oral treatment
 Eliminates risks of complications associated
with intravascular lines
 Shorter duration of hospital stay
 Savings in nursing time
 Savings in overall costs

Dr.T.V.Rao MD
 Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Antimicrobial Resistance:
Key Prevention Strategies
Susceptible Pathogen
Antimicrobial-Resistant
Pathogen Pathogen
Prevent Prevent
Transmission Infection

Infection
Antimicrobial
Resistance
Effective
Optimize Use Diagnosis
& Treatment

Antimicrobial Use
Dr.T.V.Rao MD
 Emerging Resistance
• Antibiotic resistance is a
consequence of evolution
via natural selection. The
antibiotic action is an
environmental pressure;
those bacteria which have a
mutation allowing them to
survive will live on to
reproduce. They will then
pass this trait to their
offspring, which will be a
fully resistant generation.

Dr.T.V.Rao MD
Irrational Use of Third Generation
Cephalosporins
• Several studies have
demonstrated that
patterns of antibiotic usage
greatly affect the number
of resistant organisms
which develop. Overuse of
broad-spectrum
antibiotics, such as second-
and third-generation
Cephalosporins, generate
resistant strains.

Dr.T.V.Rao MD
Origin of Drug Resistant Strains

• The resistant strains arise either by mutation

and selection or by genetic exchange in which
sensitive organisms receive the genetic
material ( part of DNA) from the resistant
organisms and the part of DNA carries with it
the information of mode of inducing
resistance against one or multiple
antimicrobial agents.

Dr.T.V.Rao MD
RESISTANCE

ACQUISITION OF BACTERIAL RESISTANCE

ACQUIRED RESISTANCE

 Species develop ability to resist an

antimicrobial drug to which it is as a
whole naturally susceptible
 Two mechanisms:
1. Mutational – chromosomal
2. Genetic exchange –
transformation, transduction,
conjugationDr.T.V.Rao MD
 Self Medication
• The greatest possibility of evil in self-medication is
the use of too small doses so that instead of
clearing up infection, the microbes are educated to
resist penicillin and a host of penicillin-fast
organisms is bread out which can be passed to
other individuals and from them to other until they
reach someone who gets a septicemia or a
pneumonia which penicillin cannot save.
• . Sir AlexanderFlemming

Dr.T.V.Rao MD
 Historical aspects

• 1980s –ESBL producing GN bacteria

• 1990 Vancomycin resistant Enterococci
emerged
2000 VISA (intermediate level resistance)
2002-VRSA (high level resistance)
2002- Linezolid resistant enterococci and
Staphylococci reported

Dr.T.V.Rao MD
 Evolution of b-Lactamase
Plasmid-Mediated TEM and SHV Enzymes

Third-Generation
Ampicillin Cephalosporins

1965 1970s 1980s 1987 2000

1983

1963
TEM-1
TEM-1 ESBL >120 ESBLs
Reported in ESBL in
E coli in Worldwide
28 Gram- Europe
S paratyphi United
Negative
States
Species

Dr.T.V.Rao MD
Resistance to Antibiotics

•Bacteria (and viruses) are very resourceful creatures and they have developed resistanc
mechanisms to essentially every antibiotic that has been developed.

•Moreover, increased use of antibiotics results in increased resistance (the paradox of

antibiotics).

•The basic resistance mechanisms are quite simple:

1.Modify the antibiotic

2.Modify the target of the antibiotic

3.Destroy the antibiotic

4.Make it more difficult for the antibiotic to get into the cell

5.Actively remove the antibiotic from the cell

Dr.T.V.Rao MD
 Plasmids
• Plasmid seem to be ubiquitous in bacteria, May encode
genetic information for properties
1 Resistance to Antibiotics
2 Bacteriocins production
3 Enterotoxin production
4 Enhanced pathogen city
5 Reduced Sensitivity to
mutagens
6 Degrade complex organic molecules
T.V.Rao MD

Dr.T.V.Rao MD
 Resistance Transfer Factor
RTF
• Plasmids – helps to spread multiple drug resistance
• Discovered in 1959 Japan
• Infections caused due to Shigella spread resistance to
following Antibiotics
Sulphonamides
Streptomycin
Choramphenicol,
Tetracycline

Dr.T.V.Rao MD
 RTF
• Shigella + E.coli
excreted in the stool
resistant to several
drugs in vivo and vitro
• Plasmid mediated –
transmitted by
Conjugation
• Episomes spread the
resistance

Dr.T.V.Rao MD
 Transposons and R factor

• R forms may have evolved as a collection of

Transposons
• Each carrying Genes that confers resistance to one or
several Antibiotics
• Seen in Plasmids,
Microorganisms
Animals
Laboratory Manipulations are called as Genetic
Engineering

Dr.T.V.Rao MD
 Plasmid Mediated Drug
resistance
Sulphonamides --- Reduce permeability
Erythromycin ---- Modification of ribosome's
Tetracyclnes ----- Reduced permeability
Chloramphenicol ---- Acetylation of drug
Streptomycin ----- Adenylation of drug
Pencillin ----- Hydrolysis of lactum ring

Dr.T.V.Rao MD
RESISTANCE

ACQUIRED RESISTANCE – EXAMPLES:

1. Resistance (R) plasmids

 Transmitted by conjugation
2. mecA gene
 Codes for a PBP with low affinity
for -lactam antibiotics
 Methicillin-resistant S. aureus

Dr.T.V.Rao MD
RESISTANCE

ORIGIN OF DRUG RESISTANCE

NON-GENETIC

1. Metabolically inactive organisms may

be phenotypically resistant to drugs
– M. tuberculosis
2. Loss of specific target structure for a
drug for several generations
3. Organism infects host at sites where
antimicrobials are excluded or are
not active – aminoglycosides (e.g.
Gentamicin) vs. Salmonella enteric
fevers (intracellular)
Dr.T.V.Rao MD
RESISTANCE

GENETIC

1. Chromosomal
 Occurs at a frequency of 10-12 to 10-7
 20 to spontaneous mutation in a locus
that controls susceptibility to a given
drug  due to mutation in gene that
codes for either:
a. drug target
b. transport system in the membrane
that controls drug uptake

Dr.T.V.Rao MD
RESISTANCE

GENETIC
2. Extrachromosomal
a. Plasmid-mediated
 Occurs in many different species, esp. gram
(-) rods
 Mediate resistance to multiple drugs
 Can replicate independently of bacterial
chromosome  many copies
 Can be transferred not only to cells of the
same species but also to other species and
genera

Dr.T.V.Rao MD
 Practices Contributing to
Misuse of Antibiotics

< Inappropriate specimen selection and collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD
RESISTANCE

LIMITATION OF DRUG RESISTANCE

1. Maintain sufficiently high levels of the

drug in the tissues  inhibit original
population and first-step mutants.
2. Simultaneous administration of two
drugs that do not give cross-resistance
 delay emergence of mutants resistant
to the drug (e.g. INH + Rifampicin)
3. Limit the use of a valuable drug  avoid
exposure of the organism to the drug
Dr.T.V.Rao MD
 What Is Antimicrobial Stewardship?

• A comination of infection control and antimicrobial

management
• Mandatory infection control compliance
• Selection of antimicrobials from each class of drugs that does
the least collateral damage
• Collateral damage issues include
– MRSA
– ESBLs
– C difficile
– Stable derepression
– MBLs and other carbapenemases
– VRE
• Appropriate de-escalation when culture results are available
Dellit TH, et al. Clin Infect Dis. 2007;44:159-177.
Dr.T.V.Rao MD
 IDSA Guidelines – Definition of
Antimicrobial Stewardship

• Antimicrobial stewardship is an activity that

promotes

– The appropriate selection of antimicrobials

– The appropriate dosing of antimicrobials

– The appropriate route and duration of

antimicrobial therapy

Dr.T.V.Rao MD
 The Primary Goal of
Antimicrobial Stewardship
• The primary goal of antimicrobial stewardship is to

– Optimize clinical outcomes while minimizing unintended

consequences of antimicrobial use

• Unintended consequences include the following

– Toxicity

– The selection of pathogenic organisms, such as C difficile

– The emergence of resistant pathogens

Dr.T.V.Rao MD
 The Primary Goal of
Antimicrobial Stewardship
• The primary goal of antimicrobial stewardship is to

– Optimize clinical outcomes while minimizing unintended

consequences of antimicrobial use

• Unintended consequences include the following

– Toxicity

– The selection of pathogenic organisms, such as C difficile

– The emergence of resistant pathogens

Dr.T.V.Rao MD
 Practices Contributing to
Misuse of Antibiotics

< Inappropriate specimen selection and collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD
Inappropriate Antibiotic Use

< Use of antibiotics with no clinical

indication (eg, for viral
infections)
< Use of broad spectrum
antibiotics when not indicated
< Inappropriate choice of empiric
antibiotics
Dr.T.V.Rao MD
Inappropriate Drug Regimen

< Inappropriate dose - ineffective

concentration of antibiotics at site of
infection

< Inappropriate route - ineffective

concentration of antibiotics at site of
infection

< Inappropriate duration

Dr.T.V.Rao MD
 Multi Drug resistant pathogens
• If a bacterium carries several
resistance genes, it is called
multiresistant or, informally, a
superbug. The term antimicrobial
resistance is sometimes use to
explicitly encompass organisms other
than bacteria
Dr.T.V.Rao MD
 Antibiotic Resistance
Threat to Humans and Animals
• Antibiotic resistance has become a serious
problem in both developed and
underdeveloped nations. By 1984 half of those
with active tuberculosis in the United States
had a strain that resisted at least one
antibiotic.In certain settings, such as hospitals
and some childcare location

Dr.T.V.Rao MD
Dr.T.V.Rao MD
Between 1962 and 2000, no major classes of
antibiotics were introduced

Fischbach MA and Walsh CT Science 2009

Dr.T.V.Rao MD
 Physicians Can Impact
Patients

Optimize patient evaluation Optimize consultations with

Adopt judicious antibiotic other clinicians
prescribing practices Use infection control measures
Immunize patients Educate others about judicious
use of antibiotics
Dr.T.V.Rao MD
Antibiotic Pressure and Resistance in Bacteria:
Conclusions
• Bacteria evolve resistance to antibiotics in
response to environmental pressure exerted
by the use of antibiotics.
• Many of these bacteria are significant
pathogens.
• Our responsibility to our community is to use
antibiotics prudently, for appropriate
indications.

Dr.T.V.Rao MD
 Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

12 Steps to Prevent Antimicrobial

Resistance
Prevent Transmission
12 Break the chain
11 Isolate the pathogen Use Antimicrobials Wisely
10 Stop treatment when cured
9 Know when to say “no” to vanco
8 Treat infection, not colonization
7 Treat infection, not contamination
6 Use local data Diagnose & Treat Effectively
5 Practice antimicrobial control
4 Access the experts
3 Target the pathogen Prevent Infections
2 Get the catheters out
1 Vaccinate

Dr.T.V.Rao MD
 Conclusions
 Antibiotic resistance is a major problem
world-wide
 Resistance is inevitable with use
 No new class of antibiotic introduced over
the last two decades
 Appropriate use is the only way of
prolonging the useful life of an antibiotic

Dr.T.V.Rao MD
Are we overusing Antibiotics

Dr.T.V.Rao MD
Choose the Appropriate Antibiotic

Think before
prescribing Are
we using Right
drug for the
Right bug ?

Dr.T.V.Rao MD
The e-programme created by Dr.T.V.Rao MD
for teaching the Medical Graduates in the
Developing world.
Email
doctortvrao@gmail.com

Dr.T.V.Rao MD