ANTIBIOTICS

USE, MISUSE, CONSEQUENCES

Dr.T.V.Rao MD

DR.T.V.RAO MD

WHAT IS A ANTIBIOTIC

Antibiotic (from the Ancient Greek: anti, "against", and bios, "life") is a substance or compound that kills bacteria or inhibits its growth. Antibiotics belong to the broader group of antimicrobial compounds, used to treat infections caused by microorganisms, including fungi and protozoa.
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EARLY DEFINITION OF ANTIBIOTIC

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life
DR.T.V.RAO MD

BEGINNING OF ANTIBIOTICS WITH DISCOVERY OF PENICILLIN

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
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FLEMING AND PENICILLIN

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ANTIBIOTIC/ANTIMICROBIAL AGENT
Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms
DR.T.V.RAO MD

EARLY DEFINITION OF ANTIBIOTIC

The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life
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
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DISCOVERY OF PENICILLIN AWARDED NOBEL PRIZE

DR.T.V.RAO MD

Brief History of Antibiotics

1928- Penicillin discovered by Fleming 1932- Sulfonamide antimicrobial activity discovered {Erlich}

1943- Drug companies begin mass production of penicillin

1948- Cephalosporins precursor sent to Oxford for synthesis 1952- Erythromycin derived from Streptomyces erythreus 1956- Vancomycin introduced for penicillin resistant staphylococcus 1962- Quinolone antibiotics first discovered

1970s- Linezolid discovered but not pursued

1980s- Fluorinated Quinolones introduced, making then clinically useful 2000- Linezolid introduced into clinical practice
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Antibiotic sulfanilamide (prontosil penicillin

natural source

Penicillium notatum

first description as discoverer anti-infective drug G.Domagk 1932 A.Fleming, Flor 1941 Chain

streptomycin
cephalosporin bacitracin chloramphenicol polymyxin

Streptomyces griseus
Cephalosporium acremonium Bacillus subtilis Streptomyces venezuellae Bacillus polymyxa Streptomyces aureofaciens Streptomyces fradiae

1944
1945 1945 1947 1947 1948 1949

S.A.Waksman G.Brotzu B.A.Johnson

I.Ehrlich
C.G.Ainsworth B.M.Duggar

chlortetracyclin
neomycin

S.A.Waksman

oxytetracyclin MD DR.T.V.RAO

Streptomyces rimosus

1950

A.C.Finlay
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Development of anti-microbials
The development
ertapenem tigecyclin daptomicin linezolid telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G

of anti-infectives

prontosil

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DEFINITION
Bacteriostatic Antimicrobial agents that reversibly inhibit growth of bacteria are called as bacteriostatic (Tetracycline's, Chloramphenicol )
with an irreversible lethal action on bacteria are known as bactericidal ( Penicillin, Isoniazid )

Bactericidal Those

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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.

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IDEAL ANTIBIOTIC
Toxic to microbes, and not to humans Bactericidal rater than bacteriostatic Effective against broad range of bacteria Should not be allergic and hypersensitive reactions Should be active in plasma, and other body fluids Desired levels should be reached rapidly and maintained for adequate period of time. Should not give drug resistance, long shelf life, Cheaper

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HOW DRUGS ACT

Drugs differ on their capabilities to act at different sites on bacteria. Some drugs have more than one site of action
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RESISTANCE AND SUSCEPTIBILITY

Determined by in vitro activity, pharmacologic characteristics, and clinical evaluation. The minimal inhibitory concentration (MIC) can be comfortably exceeded by doses tolerated by the patient. Susceptible - implies their MIC is at a concentration attainable in the blood or other body fluid at the recommended dose. Resistant - MIC is not exceeded by normally attainable levels

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MAJOR MECHANISMS OF ANTIMICROBIAL DRUGS

1 Inhibition of cell wall synthesis 2 Inhibition of cell membrane function 3 Inhibition of protein synthesis ( inhibition of translation and transcription of genetic material) 4 Inhibition of nucleic acid synthesis.
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Inhibition of cell wall synthesis

Target: block peptidoglycan (murein) synthesis

Peptidoglycan
Polysaccharide (repeating disaccharides of Nacetyl glucosamine and N-acetylmuramic acid) + cross-linked pentapeptide Pentapeptide with terminal D-alanyl-D-alanine unit required for cross-linking

Peptide cross-link formed between the free amine of the amino acid in the 3rd position of the peptide & the D-alanine in the 4th position of another chain
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Inhibition of cell wall synthesis

A. -lactam antibiotics inhibit transpeptidation reaction (3rd stage) to block peptidoglycan synthesis involves loss of a D-alanine from the pentapeptide Steps:

a. binding of drug to PBPs

b. activation of autolytic enzymes (murein hydrolases) in the cell wall

c. degradation of peptidoglycan
d. lysis of bacterial cell
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Inhibition of cell wall synthesis

A.-lactam antibiotics
Penicillin binding proteins (PBPs) enzymes responsible for: a. cross-linking (transpeptidase) b. elongation (carboxypeptidase) c. autolysis
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Inhibition of cell wall synthesis

A. -lactam antibiotics

Lysis of bacterial cell

o Isotonic environment cell swelling rupture of bacterial cell o Hypertonic environment microbes change to protoplasts (gram +) or spheroplasts (gram -) covered by cell membrane swell and rupture if placed in isotonic environment
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PENICILLINS AND CEPHALOSPORINS

Pencillin and cephalosporins act inhibiting Trans peptidases, the enzyme catalyses the final linking step in synthesis of peptidoglycan. Due to this reason Pencillin in bactericidal for grwoing bacteria since new peptidoglycan is synthesized at that stage only. In nongrwoing cells pencillin is inactive An intact beta lactum is essential for antibacterial activity of pencillins
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CLASSIFICATION OF PENCILLINS
Natural Benzyl penicillin Phenoxymethyl penicillin Penicillin v Semi synthetic and pencillase resistant

1 Methicillin 2 Nafcillin 3 Cloxacillin 4 Oxacillin 5 Floxacillin

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PENICILLINASE (B LACTAMASE)

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Figure 20.8

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SEMI SYNTHETIC PENICILLINS

Penicilinase-resistant penicillins Carbapenem: very broad spectrum

Monobactams: Gram negative

Extended-spectrum penicillins Penicillins + -lactamase inhibitors
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OTHER INHIBITORS OF CELL WALL SYNTHESIS

Cephalosporins
2nd, 3rd, and 4th generations more effective against gramnegatives
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Figure 20.9

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EXTENDED SPECTRUM PENCILLINS

Aminopencillins - Ampicillin, Amoxycillin
Carboxypencillins Carbencillin, Ticarcillin Ureidopencillin - Piperacillin Resistance to penicillin is due to pencillinase commonly called as lactamase The enzyme opens Betalactum ring hydrolytically and thus converts the antibiotic to inactive pencillonic acid.

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INHIBITORS TO BETALACTAMASE
Clavulinic acid which is a product of Strept.clavuligerus Acts against the Staphylococcal beta lactamase. And plasmid mediated Betalactamase of Gram negative bacteria. Salbactum this is a semisyntetic sulfone derivative with weak antibacterial activity

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CEPHALOSPORINS
Like penicillin acts similar Products of the molds of genus Cephalosporium except cefoxilin Divided into 4 generation of Cephalosporins depending on the spectrum of activity.
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DIFFERENT GENERATIONS OF CEPHALOSPORINS

Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first Cephalosporins were designated first generation while later, more extended spectrum Cephalosporins were classified as second generation Cephalosporins.

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MAJOR GENERATIONS OF CEPHALOSPORINS

Cephalosporins are divided into 3 generations: 1st generation: Cephelexin, cefadroxil, cephradine 2nd generation: Cefuroxime, cefaclor 3rd generation: cefotaxime, Ceftazidime, cefixime - these give the best CNS penetration

4th and 5th generation

Cephalosporins are already available

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BASIS OF GENERATIONS IN CEPHALOSPORINS

Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first cephalosporins were designated first generation while later, more extended spectrum cephalosporins were classified as second generation cephalosporins.

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ADVANTAGES WITH NEWER GENERATIONS

Each newer generation of cephalosporins has significantly greater gramnegative antimicrobial properties than the preceding generation, in most cases with decreased activity against grampositive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity
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OTHER DRUGS
Imipenem: a carbapenem with a broader spectrum of activity against Gram positive and negative aerobes and anaerobes. Needs to be given with cilastatin to prevent inactivation by the kidney.
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QUINOLONES
Quinolones are the first wholly synthetic antimicrobials. The commonly used Quinolones.

Act on the DNA gyrase which prevents DNA polymerase from proceeding at the replication fork and consequently stopping synthesis.
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AMINOGLYCOSIDES
Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds Eg Streptomycin, Act at the level of Ribosome's and inhibits protein synthesis Other Aminoglycosides Gentamycin, neomycins,paromomycins,tobra mycins Kanamycins and spectinomycins

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TETRACYCLINE'S
Broad spectrum antibiotic produced by Streptomyces species 1. Oxytetracycle, chlortetracycle and tetracycline Tetracyclnes are bacteriostatic drugs inhibits rapidly multiplying organisms

Resistance develops slowly and attributed to alterations in cell membrane permeability to enzymatic inactivation of the drug
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CHORAMPHENICOL
Chloramphenicol is bacteriostatic drug Can produce bone marrow depression Chloramphenicol interferes with protein synthesis.

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MACROLIDES,AZALIDES,KETOLIDES
Contain macro cyclic lactone ring Erythromycin. Is popularly used drug Other drugs Roxithromycin,Azithromycin Inhibits the protein synthesis. Used as alternative to pencillin allergy patients.

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OTHER ANTIMICROBIAL AGENTS

Lincomycins Clindamycin resembles Macrolides in biting site and antimicrobial activity. Streptogramins Quinpristin / dalfopristin useful in gram positive bacteria

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ANTIBIOTICS IN ANAEROBES
Major anaerobes Anaerobic cocci, clostridia and Bactericides are susceptible to Benzyl pencillin

Bact.fragilis as well as many other anaerobes are treatable with Erythromycin,Lincomycin, tetracycline and Chloramphenicol
Clindamycin is effective against many strains of Bacteroides DR.T.V.RAO MD

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METRONIDAZOLE IN ANAEROBIC INFECTIONS

Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.

But also useful in treating parasitic infections

Trichomonas, Amoebiasis and other protozoan infections.

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METRONIDAZOLE IN ANAEROBIC INFECTIONS

Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.

But also useful in treating parasitic infections

Trichomonas, Amoebiasis and other protozoan infections.

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OTHER BETA-LACTAMS INCLUDE

Other beta-lactams include:

Aztreonam: a monocytic beta-lactam, with an antibacterial spectrum which is active only against Gram negative aerobes, including Pseudomonas aeruginosa, Neisseria meningitidis and N. gonorrhoea.

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Emergence of Antibiotic-Resistant Bacteria

S aureus Gram-negative rods N. gonorrhoeae
P e n i c i l l i n A m p i c i l l i n

H. influenzae M. catarrhalis S. pneumoniae Enterococcus sp.

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3rd gen Cephalosporins

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Quinolones

Cohen; Science 1992;257:1050

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ANTIBIOTIC RESISTANCE
Antibiotic resistance is the ability of a micro organism to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves naturally via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmid exchange.

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ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIA

WHAT IS IT ?

Selection pressure of antibiotics has led to the emergence of antibiotic-resistant bacteria.

Antibiotics can effect bacteria unrelated to the targeted infectious agent; these may be normal flora, leading to the emergence of resistant mutants inhabiting the same environment.

DR.T.V.RAO MD

Baquero et al., International Report 1996;23:819 51

ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIA

HOW DOES IT OCCUR?

All antibiotics do NOT kill bacteria in the same way.

Various classes of antibiotics work on different aspects of bacterial replication.

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RESISTANCE AND SUSCEPTIBILITY

Determined by in vitro activity, pharmacologic characteristics, and clinical evaluation. The minimal inhibitory concentration (MIC) can be comfortably exceeded by doses tolerated by the patient. Susceptible - implies their MIC is at a concentration attainable in the blood or other body fluid at the recommended dose. Resistant - MIC is not exceeded by normally attainable levels

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DRUG RESISTANCE
In spite discovery of several antibiotics several microorganisms attained resistance. The major factor contributing to persistence of infectious disease has been the tremendous capacity of microorganisms for circumventing the action of inhibitory drugs.

The drug resistance continues to be a threat for usefulness of the chemotherapeutic agents.
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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)
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DNA gyrase

Cell wall synthesis

-lactams &

Quinolones

DNA-directed RNA polymerase

Rifampin

Glycopeptide (Vancomycin) Trimethoprim

DNA
THFA mRNA Ribosomes
50 30 50 30 50 30

Folic acid synthesis

Sulfonamides

DHFA

Protein synthesis inhibition

Macrolides & Lincomycins

PABA
Protein synthesis mistranslation
Aminoglycosides
Cohen. Science 1992; 257:1064 DR.T.V.RAO MD
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Protein synthesis inhibition

Tetracycline's

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.
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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

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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

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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
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ANTIBIOTIC RESISTANCE
Antibiotic resistance is a specific type of drug resistance when a microorganism has the ability of withstanding the effects of antibiotics. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by conjugation, transduction, or transformation.

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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

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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

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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
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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

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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
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BIOCHEMICAL MECHANISMS OF DRUG RESISTANCE

Resistance arises due to Biochemical changes Increased synthesis of drug antagonist Decreased permeability to drug Increased destruction of inhibitor

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DIFFERENTIATION OF MUTATION AND TRANSFERABLE DRUG RESISTANCE

Mutation Transferable

Usually one drug

Low degree of resistance Increasing dose can benefit Prevented by combination of drugs

Multiple drugs
High degree of resistance Increasing dose do not benefit Can not be prevented by combination of drugs

Low virulence of bacteria

High virulence of bacteria

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PLASMID MEDIATED DRUG RESISTANCE

Sulphonamides --- Reduce permeability Erythromycin Tetracyclnes Streptomycin Pencillin ---- Modification of ribosome's ----- Reduced permeability ----- Adenylation of drug ----- Hydrolysis of lactum ring

Chloramphenicol ---- Acetylation of drug

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ANTIBIOTICS RESISTANCE AND PLASMIDS

Many antibiotic resistance genes reside on plasmids facilitating their transfer. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes used to explicitly encompass organisms other than bacteria
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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
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BETWEEN 1962 AND 2000, NO MAJOR CLASSES OF ANTIBIOTICS WERE INTRODUCED

Fischbach MA and Walsh CT Science 2009

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EXTENDED-SPECTRUM -LACTAMASES
-lactamases capable of conferring bacterial resistance to

the penicillins
first-, second-, and third-generation cephalosporins aztreonam (but not the cephamycins or carbapenems)
These enzymes are derived from group 2b -lactamases (TEM-1, TEM-2, and SHV-1)

differ from their progenitors by as few as one AA

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CARBAPENEMASES
Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems Resilient against inhibition by all commercially viable lactamase inhibitors
Subgroup 2df: OXA (23 and 48) carbapenemases Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems
IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae
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K. PNEUMONIA CARBAPENEMASES )
KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumonia Substrate hydrolysis spectrum includes cephalosporins and carbapenems
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K.PNEUMONIAE CARBAPENEMASE-PRODUCING BACTERIA

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Nordmann P et al. LID 2009

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Antibiotic resistance
Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious diseases
Keith. Poole. J Antimicrob Chemother 2005; 56: 20-51

Evolution of bacteria towards resistance is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable
Patrice Courvalin. Emerg Infect Dis 2005; 11: 1507-6

Antibiotic resistance has resulted in a continuous need for new therapeutic alternatives
Carl Erik Nord. Clin Microbiol Infect 2004;10 (Supp 4)

There is a need to re-invigorate antimicrobial development, which has been downgraded by major pharmaceutical houses DR.T.V.RAO MD 78

David Livermore. Lancet Infect Dis 2005; 5:450-59

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

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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

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PHYSICIANS CAN IMPACT PATIENTS

Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients
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PHYSICIANS CAN IMPACT OTHER CLINICIANS

Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics
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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.

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ARE WE OVERUSING ANTIBIOTICS

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DEDICATED HANDWASHING HAS MANY SOLUTIONS TO PREVENT SPREAD OF DRUG RESISTANT STRAINS

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 Programme created by Dr.T.V.Rao MD for Medical Professionals in the Developing World

Email doctortvrao@gmail.com

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