Rationalism of Antibiotic Therapy -

7/29/2019 Rationalism of Antibiotic Therapy -

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Dr.T.V.Rao MD 1


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Fleming and Penicillin

Dr.T.V.Rao MD 2


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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 reachsomeone who gets a septicemia or a

pneumonia which penicillin cannot save.

Sir AlexanderFlemming

Self Medication

Dr.T.V.Rao MD 3


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50 penicillin's

71 cephalosporins

12 tetracycline's

8 aminoglycosides

1 monobactam 5 Carbapenems

9 macrolides

2 streptogramins

3 dihydrofolate

reductase

inhibitors

1 oxazolidinone

5.5 quinolones

Antibiotic brands

Dr.T.V.Rao MD 4


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Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-Generation

Cephalosporins

1963

1965

TEM-1

E coli

S paratyphi

1970s

TEM-1

Reported in

28 Gram-

Negative

Species

1980s1983

ESBL

in

United

States

1987

ESBL in

Europe

2000

>120 ESBLs

Worldwide

Dr.T.V.Rao MD 5


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1920 1930 1940 1950 1960 1970 1980 1990 2000

ertapenem

tigecyclindaptomicinlinezolid

telithromicinquinup./dalfop.

cefepimeciprofloxacin

aztreonam

norfloxacinimipenemcefotaxime

clavulanic ac.cefuroxime

gentamicincefalotina

nalidxico ac.

ampicillinmethicilin

vancomicinrifampin

chlortetracyclinstreptomycin

pencillin Gprontosil

The developmentof anti-infectives

Development of anti-microbials

Dr.T.V.Rao MD 6


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1962 and 2000, no major classes of

antibiotics were introduced

Fischbach MA and Walsh CT Science 2009Dr.T.V.Rao MD 7


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A Changing Landscape for

Numbers of Approved Antibacterial Agents

Bars represent number of new antimicrobial agents approved by the FDA during the period listed.

0

0

2

4

6

8

10

12

14

16

18

Numberofagentsapproved

1983-87 1988-92 1993-97 1998-02 2003-05 2008

Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912

Resistance


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Dr.T.V.Rao MD 9


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Antibiotics Biology and Society

About 50% of the antibiotics producedtoday are used in the livestock industry.

What impact does this have on the

treatment of human diseases?

Dr.T.V.Rao MD 10


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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, sub therapeutic levels which arethought to promote resistance.

Farm families who own chickens feed

tetracycline have an increased incidence oftetracycline resistant fecal flora

Dr.T.V.Rao MD 11


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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 12


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How are antibiotics overused or

Misused?

Seven out of ten Americans receive

antibiotics when they seek

treatment for a common cold!Only one-third of patients use

antibiotics the way doctors tell them.

This allows bacteria to become

resistant by not killing them

completely. Dr.T.V.Rao MD 13


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Antibiotic Prescribing

Children are real Concern

Antibiotics were

prescribed in 68% of

acute respiratory tract

visits and of those,80% were unnecessary

according to CDC

guidelines

Children are ofparticular concern

because they have the

highest rates of

antibiotic use.Dr.T.V.Rao MD 14


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We too Contribute for Creating

Drug Resistance Every time a person

takes antibiotics,

sensitive bacteria are

killed, but resistantmicrobes may be left to

grow and multiply.

Repeated and improper

uses of antibiotics areprimary causes of the

increase in drug-

resistant bacteria.Dr.T.V.Rao MD 15


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The consequences of antibiotic

resistance Increased morbidity & mortality

best-guess therapy may fail with the patientscondition deteriorating before susceptibility resultsare 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 somethird-world countries

Dr.T.V.Rao MD


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Costs Associated with

Increased Bacterial

Resistance

Treatment failures

Morbidity and mortality

Risk of hospitalization

Length of hospital stays

Need for expensive and broad

spectrum antibiotics

Dr.T.V.Rao MD 17


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Social factors fuelling resistance

Poverty encourages the development ofresistance through under use of drugs

Patients unable to afford the full course ofthe medicines

Sub-standard & counterfeit drugs lackpotency

Globalization, increased travel andtrade ensure that resistant strainsquickly travel elsewhere. So does excessive

promotion. Dr.T.V.Rao MD


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Developed countries Overuse

In wealthy countries, resistance is emergingfor the opposite reason the overuse ofdrugs.

Unnecessary demands for drugs by patientsare often eagerly met by health services andstimulated by pharmaceutical promotion

Overuse of antimicrobials in food productionis also contributing to increased drugresistance.

Dr.T.V.Rao MD 19


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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 Oxacillin5 Floxacillin

Dr.T.V.Rao MD 20


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Contain macro cyclic

lactone ring

Erythromycin. Is

popularly used drug

Other drugs

Roxithromycin,Azithromy

cin

Inhibits the protein

synthesis.

Used as alternative to

pencillin allergy patients.

Macrolides,Azalides,Ketolides

Dr.T.V.Rao MD 21


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Dr.T.V.Rao MD 22


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Like penicillin acts

similar

Products of the molds

of genusCephalosporium

except cefoxilin

Divided into 4

generation of

Cephalosporins

depending on the

spectrum of activity.

Cephalosporins

Dr.T.V.Rao MD 23


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Major generations ofCephalosporins

Cephalosporins are divided into 3 generations:

1st generation: Cephalexin, cefadroxil,

cephradine

2nd generation: Cefuroxime, cofactor

3rd generation: cefotaxime, Ceftazidime,

cefepime - these give the best CNS penetration

4th generation Cephalosporins are alreadyavailable

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Cephalosporins are

grouped into

"generations" based on

their spectrum of

antimicrobial activity. Thefirst Cephalosporins were

designated first

generation while later,

more extended spectrumCephalosporins were

classified as second

generation

Cephalosporins.

Different Generations ofCephalosporins

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5th Generation Cephalosporins

Ceftaroline is a new intravenous (IV)

cephalosporin that was FDA-approved

October 2010. It is labelled for the

treatment of adults with infections

caused by susceptible bacteria,

specifically skin and skin structureinfections (SSSIs) caused by methicillin-

sensitive

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5th Generation Cephalosporins

Staphylococcus aureus (MSSA), methicillin-

resistant S aureus (MRSA), Streptococcus

pyogenes, Streptococcus agalactiae,

Escherichia coli, Klebsiella pneumoniae, orKlebsiella oxytoca; and community acquired

pneumonia (CAP) caused by Streptococcus

pneumoniae (with or without concurrentbacteraemia), MSSA, E coli, Haemophilus

influenza, K.pneumoniae, or K oxytoca

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Ceftaroline is effective

Ceftaroline is a fifth generation

cephalosporin with excellent

activity against GPCs includingMRSA & DRSP Affinity for all PBPs

including PBP 2 and PBP 2X NotESBL stable, Not active against

Non fermentersDr.T.V.Rao MD 28


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Several studies have

demonstrated that patterns

of antibiotic usage greatly

affect the number of

resistant organisms whichdevelop. Overuse of broad-

spectrum antibiotics, such

as second- and third-

generation Cephalosporins,generate resistant strains.

Irrational Use of Third Generation

Cephalosporins

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Advantages with Newer generations

Each newer generation of cephalosporins

has significantly greater gram-negative

antimicrobial properties than the

preceding generation, in most cases with

decreased activity against gram-positive

organisms. Fourth generationcephalosporins, however, have true

broad spectrum activity

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Other Beta-lactams include

Other beta-lactams include:

Aztreonam: a monocytic beta-

lactam, with an antibacterialspectrum which is active only against

Gram negative aerobes, including

Pseudomonas aeruginosa, Neisseria

meningitides and N. gonorrhoea.

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How are Carbapenems Used?

Uses by Clinical Syndrome

Bacterial meningitis

Hospital-associatedsinusitis

Sepsis of unknown origin

Hospital-associatedpneumonia

Use by Clinical Isolate

Acinetobacterspp.

Pseudomonas aeruginosa

Alcaligenes spp.

Enterobacteriaceae

Mogenella spp.

Serratia spp.

Enterobacter spp.

Citrobacterspp. ESBL or AmpC + E. coli

and Klebsiella spp.

Reference: Sanford GuideDr.T.V.Rao MD 32


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Spectrum of Activity

DrugStrep spp. &

MSSA

Entero-

bacteriaeae

Non-

fermentorsAnaerobes

Imipenem + + + +

Meropenem + + + +

Ertapenem + +Limited

activity+

Doripenem + + + +


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Emerging Carbapenem Resistance in

Gram-Negative Bacilli

Significantly limits treatment options forlife-threatening infections

No new drugs for gram-negative bacilli

Emerging resistance mechanisms,carbapenemases are mobile,

Detection of carbapenemases andimplementation of infection control practicesare necessary to limit spread

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Daptomycin (Cubicin)

New drug class (lipopeptide)

Rapidly bactericidal

New mechanism of action: acts bybinding to cell membrane and disrupting

the cell membrane potential

No cross resistance

Dose: 4-6 mg/kg once daily


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Imipenem: a

carbapenem with a

broader spectrum of

activity against Grampositive and negative

aerobes and

anaerobes. Needs to

be given withcilastatin to prevent

inactivation by the

kidney.

Other drugs

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Quinolones are the first

wholly synthetic

antimicrobials. The

commonly used

Quinolones. Act on the DNA gyrase

which prevents DNA

polymerase from

proceeding at thereplication fork and

consequently stopping

synthesis.

Quinolones

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Aminoglycosides are group ofantibiotics in which aminosugars liked by glycoside bonds

Eg Streptomycin,

Act at the level of Ribosome's

and inhibits protein synthesis Other Aminoglycosides

Gentamycin,neomycins,paromomycins,tobramycins Kanamycins and

spectinomycins

Aminoglycosides

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Dr.T.V.Rao MD 39


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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

Tetracycline's

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Lincomycins

Clindamycin

resembles Macrolides

in biting site andantimicrobial activity.

Streptogramins

Quinpristin /

dalfopristin

useful in gram

positive bacteria

Other Antimicrobial agents

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Major anaerobesAnaerobic cocci,clostridia andBactericides aresusceptible to Benzylpencillin

Bact.fragilis as well asmany other anaerobesare treatable with

Erythromycin,Lincomycin,tetracycline andChloramphenicol

Clindamycin is effectiveagainst many strains of

Bacteroides

Antibiotics in Anaerobes

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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 otherprotozoan infections.

Metronidazole in Anaerobic

Infections

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Treatment ofN. gonorrhoea

Only current CDC-recommended options for treating

N. gonorrhoea infections are from a single class of

antibiotics, the cephalosporins.

Ceftriaxone, available only as an injection, is therecommended treatment for all types of gonorrhea

infections (i.e., urogenital, rectal, and pharyngeal).

Cefixime is the only oral agent recommended for

treatment of uncomplicated urogenital or rectal gonorrhea

Reduced susceptibility to cefixime being described in

Japan and other countries


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In spite discovery of several

antibiotics several

microorganisms attained

resistance.

The major factor contributing

to persistence of infectiousdisease 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.

Drug Resistance

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Use of antibioticswith no clinical

indication (eg, for

viral infections)

Use of broadspectrum antibiotics

when not indicated

Inappropriate choiceof empiric antibiotics

Inappropriate Antibiotic Use

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If a bacterium carries

several resistance

genes, it is called

multiresistant or,informally, a

superbug. The term

antimicrobial

resistance issometimes use to

explicitly encompass

organisms other than

bacteria

Multi Drug resistant pathogens

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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 AADr.T.V.Rao MD 48


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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 atleast one antibiotic. In

certain settings, such as

hospitals and some

childcare location

Antibiotic Resistance

Threat to Humans and Animals

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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 inEnterobacteriaceae

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KPCs are the most

prevalent of this

group of enzymes,

found mostly ontransferable plasmids

in K.pneumonia

Substrate hydrolysis

spectrum includescephalosporins and

carbapenems

K. pneumonia carbapenemases)

Dr.T.V.Rao MD 51

C f A tibi ti d


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Consequences of Antibiotic drug

Resistance

People infected with drug-resistant organisms

are more likely to have longer and more

expensive hospital stays, and may be more

likely to die as a result of the infection. Theyrequire treatment with second- or third-

choice drugs that may be less effective, more

toxic, and more expensive. This means thatpatients with an antimicrobial-resistant

infection may suffer more and pay more for

treatment. (Issues with Insurance)Dr.T.V.Rao MD 52

Emerging Trends in Antibiotic


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Emerging Trends in Antibiotic

Resistance Reports of methicillin-resistant

Staphylococcus aureus (MRSA)apotentially dangerous type of staph bacteria

that is resistant to certain antibiotics andmay cause skin and other infectionsinpersons with no links to healthcare systemshave been observed with increasing

frequency in the United States andelsewhere around the globe.

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Gram negative bacteria a great threat

Multi-drug resistantKlebsiella speciesand Escherichia coli

have been isolatedin hospitalsthroughout theUnited States.

It is a Universalphenomenon

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WHAT NEXT

Indian hospitals have reported very high

Gram-negative resistance rates, with very high

prevalence of ESBL (Extended Spectrum Beta

Lactamases) producers and also highcarbapenem resistance rates. Increasing

carbapenem resistance will invariably result in

increased usage of colistin, currently the lastline of defence, with a potential for colistin-

resistant and Pan Drug Resistant bacterial

infections.Dr.T.V.Rao MD 55


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Fungi too becoming resistant

Antimicrobial

resistance is

emerging among

some fungi,particularly those

fungi that cause

infections intransplant patients

with weakened

immune systems.Dr.T.V.Rao MD 56


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Resistance in Virus

Antimicrobial

resistance has also

been noted with

some of the drugsused to treat human

immunodeficiency

virus (HIV) infectionsand influenza.

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Parasites too are Problematic

The development of

antimicrobial resistance to

the drugs used to treat

malaria infections has been

a continuing problem inmany parts of the world for

decades. Antimicrobial

resistance has developed to

a variety of other parasites

that cause infection.

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Identification of The Etiological

Agent Laboratory diagnosis

Interpretation of the report

What is isolated is not necessarily thepathogen

Was the specimen properly collected ?

Is it a contaminant or colonizer ?

Sensitivity reports are at best a guide

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The role of combinationantimicrobial therapy forthe prevention of resistanceis limited to those situationsin which there is

A high organism load A high frequency of

mutational resistanceduring therapy.

Classic examples are

tuberculosis or HIVinfection.

Limitations of combination of antibiotics

Dr.T.V.Rao MD 60

Problems With Improper Use of


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Problems With Improper Use of

Antibiotics

They dont help the patient at all

Expense: 75% of outpatient antibiotics are used for

respiratory infections Patient expectations: why no better?

Side effects: diarrhea, rash, allergy

Development ofresistance: the antibioticwont work when you really DO need it for a

bacterial infection

Dr.T.V.Rao MD 61

WHO


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WHOglobal strategy on reducing theantibiotic resistance

The WHO Global Strategy forContainment of Antimicrobial

Resistance identifies theestablishment and support of

microbiology laboratories as a

fundamental priority in guiding

and assessing intervention

efforts.Dr.T.V.Rao MD 62

Importance of local antibiotic


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Importance of local antibiotic

Resistance data

Resistance patterns vary From country to country

From hospital to hospital in the same

country From unit to unit in the same hospital

Regional/Country data useful only

for looking at trends NOT guideempirical therapy

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Streamlining or De-Escalation

of TherapyOn the basis of culture and sensitivity

reports we can more effectively target

the causative pathogens, by eliminationof redundant combination therapy

Resulting in decreased Ab exposure and

substantial cost savings

Dr.T.V.Rao MD

Continuous Medical Education


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Training and educating

health care professionals on

the appropriate use of

antibiotics must include

appropriate selection,

dosing, route, and durationof antibiotic therapy. To

ensure that training and

education is working, there

should be extensivecollaboration between the

antibiotic stewardship and

hospital infection prevention

and control teams.

Continuous Medical Education

a Must ..

Dr.T.V.Rao MD 65

Antibiotic Pressure and Resistance in Bacteria


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Antibiotic Pressure and Resistance in Bacteria

What factors promote their development and spread ?

Alteration of normal flora

Practices contributing to misuse of antibiotic

Settings that foster drug resistance

Failure to follow infection control principlesDr.T.V.Rao MD 66

P ti C t ib ti t


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Inappropriate specimen selection and

collection

Inappropriate clinical tests

Failure to use stains/smears

Failure to use cultures and susceptibility tests

Practices Contributing to

Misuse of Antibiotics

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Hospital Intensive care units

Oncology units

Dialysis units

Rehab units

Transplant units

Burn units

Settings that Foster Drug Resistance

Dr.T.V.Rao MD 68

What Is Antimicrobial Stewardship?


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What Is Antimicrobial Stewardship?

A combination 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 69

IDSA G id li D fi i i f


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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 ofantimicrobial therapy

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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 71



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Inappropriate specimen selection and collection

Inappropriate clinical tests

Failure to use stains/smears

Failure to use cultures and susceptibility tests


Misuse of Antibiotics

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Identification of The Etiological

Agent Laboratory diagnosis

Interpretation of the report

What is isolated is not necessarily thepathogen

Was the specimen properly collected ?

Is it a contaminant or colonizer ?

Sensitivity reports are at best a guide

Implementation of WHONET CAN HELP TO MONITOR


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Dr.T.V.Rao MD 74

Implementation ofWHONET CAN HELP TO MONITORRESISTANCE

Legacy computersystems, quality

improvement teams, and

strategies for optimizing

antibiotic use have thepotential to stabilize

resistance and reduce

costs by encouraging

heterogeneous

prescribing patterns and

use of local susceptibility

patterns to inform

empiric treatment.

Growing importance of


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G o g po ta ce o

WHONET World over antimicrobial

resistance is a majorpublic health problem.The WHONET software

program puts eachlaboratory data into acommon code and fileformat, which can bemerged for national or

global collaboration ofantimicrobial resistancesurveillance

Dr.T.V.Rao MD 75

h h l i


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Whonet helps us in

The understanding of thelocal epidemiology ofmicrobial populations;

the selection ofantimicrobial agents; theidentification of hospitaland communityoutbreaks; and the

recognition of qualityassurance problems inlaboratory testing.

Dr.T.V.Rao MD 76

Drugs Under Development


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Drugs Under DevelopmentPRSP, MRSA,VISA,VRE

Lipopetides (Daptomycin: narrow

therapeutic index)

Glycyclines

Glycopeptides (Vancomycin analogues)

Fluoroquinolones

Macrolides/Ketolides

Evernimicin (trials on hold)

Dr.T.V.Rao MD 77

Ph i i C I t


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Physicians Can Impact

Other clinicians

Patients

Optimize patient evaluationAdopt judicious antibiotic

prescribing practicesImmunize patients

Optimize consultations withother cliniciansUse infection control measuresEducate others about judicioususe of antibiotics

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Treatment should belimited to bacterial

infections, using

antibiotics directed

against the causative

agent, given in optimal

dosage, interval and

length of treatment, with

steps taken to ensure

maximum patientcompliance with the

treatment regimen and

only when the benefit of

treatment outweighs the

A good clinical practice saves antibiotics

Dr.T.V.Rao MD 79

Continuous Medical Education a Must


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Training and educating healthcare professionals on the

appropriate use of antibiotics

must include appropriate

selection, dosing, route, and

duration of antibiotic therapy.To ensure that training and

education is working, there

should be extensive

collaboration between the

antibiotic stewardship andhospital infection prevention

and control teams

Continuous Medical Education a Must

..

Dr.T.V.Rao MD 80

Ch i D l ti


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Chennai Declaration

The Chennai Declaration wants India to takeurgent initiatives to formulate an effectivenational policy to control the rising trend ofantimicrobial resistance and to ban on over-the-

counter sale of antibiotics. Chennai: The Chennai Declaration: A roadmap to

tackle the challenge of antimicrobial resistancepublished in the latest edition of Indian Journal of

Cancer has recommended to make it mandatoryto set up an Infection Control Team (ICT) in allhospitals.

Dr.T.V.Rao MD 81

Ed i h Ed d


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Educating the Educated

The recommendations include offering Post-MD/DNB (internal medicine) sub-specialisation inInfectious Diseases at all post-graduate centresthat offer sub-speciality training, compulsory

training in infection control and infectiousdiseases training in under-graduate and postgraduate curriculum in all specialities. TheMedical Council of India should introduce one-week antibiotic stewardship and infection controltraining in the third, fourth and final year ofMBBS and two-week training at the PG level.

Dr.T.V.Rao MD 82

C ti T k f


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Creating a Task force

Recommending the setting up of a NationalTask Force to guide and supervise the regional

and State infection control committees, the

paper suggests that the National AccreditationBoard for Hospitals & Healthcare Providers

(NABH) insist on strict implementation of

hospital antibiotic and infection control policy,during hospital accreditation and re-

accreditation processes.

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Are we overusing Antibiotics

Dr.T.V.Rao MD 84

Good hand washing practices still reduces


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Good hand washing practices still reduces

antibiotic resistance and spread

Dr.T.V.Rao MD 85

Concl sions


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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 ofprolonging the useful life of an

antibioticDr.T.V.Rao MD 86

Antibioticssave Lives


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SaveAntibioticsfrom Misuse

Dr.T.V.Rao MD 87


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Rationalism of Antibiotic Therapy -