RATIONAL USE OF RATIONAL USE OF ANTIBIOTICSANTIBIOTICS

R. Anita IndriyantiR. Anita IndriyantiPharmacological DepartmentPharmacological DepartmentBandung Islamic UniversityBandung Islamic University

References :References :

1. Lippincott’s Illustrated Reviews :1. Lippincott’s Illustrated Reviews :

Pharmacology, 2Pharmacology, 2ndnd ed ed

(Chapter 28)(Chapter 28)

2. Buku Pedoman Kuliah Farmakoklinik2. Buku Pedoman Kuliah Farmakoklinik

Farmakologi IIIFarmakologi III

Jilid 1 edisi 2Jilid 1 edisi 2

Prof. DR. Herri S. Sastramihardja, dr., Prof. DR. Herri S. Sastramihardja, dr., SpFKSpFK

A medical doctor has to know the A medical doctor has to know the definite clinical pharmacology of definite clinical pharmacology of antibiotics, how to select and use antibiotics, how to select and use them rationally.them rationally.

30% of inpatient individuals has 30% of inpatient individuals has been given antibioticsbeen given antibiotics

Side effectSide effect Resistance

Definition Ideal antibiotics

Classification SpectraIn vitro

Chemical structures

Mechanism of action

AB

DEFINITIONDEFINITION

AB are chemical substances obtained from AB are chemical substances obtained from microbes/microorganisms (bacteria, fungi, microbes/microorganisms (bacteria, fungi, actinomycetes) that able to inhibit or actinomycetes) that able to inhibit or eradicate the growth of the other eradicate the growth of the other microorganisms.microorganisms.

AntimicrobialAntimicrobial all antiinfections all antiinfections

semisyntheticsemisynthetic

syntheticsynthetic

nature nature antibiotics antibiotics

IDEAL ANTIBIOTICS CRITERIAIDEAL ANTIBIOTICS CRITERIA

1.1. Most selective, most effective to infectied Most selective, most effective to infectied microorganismsmicroorganisms

2.2. More bactericidal effect in the site of More bactericidal effect in the site of actionaction

3.3. Antibacterial effect is not interfered by Antibacterial effect is not interfered by body fluid, exudate, plasma protein or body fluid, exudate, plasma protein or enzymes and persist for a long duration enzymes and persist for a long duration in the bloodin the blood

4.4. Minimal toxicityMinimal toxicity5.5. Resistance develops slowlyResistance develops slowly6.6. Given by any routeGiven by any route7.7. Reachable costReachable cost

In vitroIn vitro1. Primary bacteriostatic effect 1. Primary bacteriostatic effect inhibit the inhibit the growth of m.ogrowth of m.o

Sulfonamide, tetrac, chloramph, Sulfonamide, tetrac, chloramph, erythromycin (low concentration), erythromycin (low concentration), lincomycin, clindamycin and fusidic acidlincomycin, clindamycin and fusidic acid

2. Primary Bactericidal Effects 2. Primary Bactericidal Effects Eradicate/killEradicate/killPen, cef, aminoglic, erythromycin (high Pen, cef, aminoglic, erythromycin (high concentration), cotrimazol. Rifampisin concentration), cotrimazol. Rifampisin and vankomycin.and vankomycin.

Those classification is not absolute but Those classification is not absolute but relativerelative

SPECTRUM OF AB EFFECTSSPECTRUM OF AB EFFECTS1. Narrow spectrum antibiotics (NSAB)1. Narrow spectrum antibiotics (NSAB)

Main effect : sensitive for gram positive Main effect : sensitive for gram positive bacteria and bacilbacteria and bacile.g. : Pen. G, Pen. Resistent penicillinase e.g. : Pen. G, Pen. Resistent penicillinase semisynthetics, bacitracin, macrolides, semisynthetics, bacitracin, macrolides, lincomycin, vancomycinlincomycin, vancomycin

2. Broad Spectrum Antibiotics (BSAB)2. Broad Spectrum Antibiotics (BSAB)Main effect : sensitive for gram positive Main effect : sensitive for gram positive and gram negative bacteriaeand gram negative bacteriaee.g. : Pen. (ampicillin and amoxycillin), e.g. : Pen. (ampicillin and amoxycillin), cefalosporins, tetracyclins, cefalosporins, tetracyclins, chloramphenicol, trimetroprim and chloramphenicol, trimetroprim and sulfonamides sulfonamides

Widely used of BSAB Widely used of BSAB an umbrella in an umbrella in treating the unidentified bacterial treating the unidentified bacterial infectioninfection

resistance resistance

RESISTANCE andRESISTANCE and

MECHANISM OF ACTION recall in MECHANISM OF ACTION recall in

microbiologymicrobiology

SIDE EFFECTSSIDE EFFECTS

1.1. ALLERGIC REACTIONALLERGIC REACTION2.2. TOXIC REACTIONTOXIC REACTION

Direct effects in unproper dose e.g. : Direct effects in unproper dose e.g. : aminoglycosidesaminoglycosides

3.3. SUPERINFECTION : new infection caused by SUPERINFECTION : new infection caused by pathogen microbes or fungi during AB pathogen microbes or fungi during AB therapy to primary infection.therapy to primary infection.SUPERINFECTION : frequentSUPERINFECTION : frequent

potentially harmed potentially harmed riskriskCausa : Enterobacter, Pseudomonas, Causa : Enterobacter, Pseudomonas, Candida and other fungi. Those agents are Candida and other fungi. Those agents are difficult to be eradicated by today available difficult to be eradicated by today available antibiotics.antibiotics.

AVOIDING SUPERINFECTIONAVOIDING SUPERINFECTION1.1. Stop the giving antibioticsStop the giving antibiotics2.2. Treatment according to bacterial Treatment according to bacterial

identification and sensitivity testidentification and sensitivity test

The specimen was taken from feces The specimen was taken from feces and secretion of upper respiratory and secretion of upper respiratory tract, to be analyzed tract, to be analyzed

RATIONAL THERAPY OF ANTIBIOTICSRATIONAL THERAPY OF ANTIBIOTICS

PHARMACOKINETICSPHARMACOKINETICSPHARMACODINAMICSPHARMACODINAMICS

ANTIBIOTICS HOST

CHARACTERISTICCHARACTERISTICOF ANTIBIOTICSOF ANTIBIOTICS

HOST ASPECTS

BIOCHEMICAL & PHYSIOLOGICAL & PATHOLOGICAL CONDITIONS

DEFINITION OF RATIONAL USE OF DEFINITION OF RATIONAL USE OF ANTIBIOTICS (WHO)ANTIBIOTICS (WHO)

PROPER INDICATIONPROPER INDICATION

PROPER DRUGPROPER DRUG

PROPER DOSAGEPROPER DOSAGE

SE MONITORINGSE MONITORING

RATIONAL USE OF ABRATIONAL USE OF AB

PROCEDURESPROCEDURES

STEPS TO PROCEDURESSTEPS TO PROCEDURES

Define the patient problems specify the therapeutic objectives

Verify the suitable of your personal treatment

Start the treatment

Give information, instruction and warning

Monitoring and stop treatment

Clinical diagnosis

Identification, sensitivity test of bacteria

Pharmacodynamics

Pharmacokinetics

Host factors

RATIONAL USE OF ANTIBIOTICSRATIONAL USE OF ANTIBIOTICS

THERAPYTHERAPY ERADICATING ERADICATING M.OM.O

DEFINITIVE THERAPYDEFINITIVE THERAPY

EMPIRIC THERAPYEMPIRIC THERAPY

PROPHYLAXISPROPHYLAXIS

IN NON SURGICALNON SURGICAL CONDITIONS

IN SURGICALSURGICAL CONDITIONS

PREVENTION IN HIGH PREVENTION IN HIGH SUSCEPTIBILITY TO SUSCEPTIBILITY TO GET INFECTIONGET INFECTION

DEFINITIVE THERAPYDEFINITIVE THERAPY

It is the most effective, least toxicity It is the most effective, least toxicity and the narrowest selectionand the narrowest selection

Based on :Based on :* identification of bacteria* identification of bacteria* sensitivity test* sensitivity test* interpretation in the content of the * interpretation in the content of the

overall clinical pictureoverall clinical picture* the AB of choice directed to M.O* the AB of choice directed to M.O

EMPIRIC AB THERAPYEMPIRIC AB THERAPYGiving AB directly without identification Giving AB directly without identification and sensitivity test of bacteria, but…… and sensitivity test of bacteria, but…… obtaining specimen for lab. analysis obtaining specimen for lab. analysis before giving AB.before giving AB.

Empiric AB therapy based on local Empiric AB therapy based on local epidemiological data : epidemiological data :

- What is the pathogen M.O potentially What is the pathogen M.O potentially infectedinfected

- AB given based on susceptibility patternAB given based on susceptibility pattern- Initiated after obtaining specimenInitiated after obtaining specimen- Started with AM combination or single Started with AM combination or single

BSABBSAB

SELECTING AB IN EMPIRIC THERAPYSELECTING AB IN EMPIRIC THERAPY

The site of infectionThe site of infection

There are barriers inside the body :There are barriers inside the body :

brain, prostate, bonebrain, prostate, bone

Other : foreign bodiesOther : foreign bodies

local factorslocal factors

Patient’s history :Patient’s history :

PATIENT HISTORYPATIENT HISTORYAge Age baby, child, adult, old age ! baby, child, adult, old age !

Immune system Immune system immunocompromised! immunocompromised! Who?Who?

Renal dysfunction Renal dysfunction accumulation! How ? accumulation! How ?

Hepatic dysfunction Hepatic dysfunction metabolism! How ?metabolism! How ?

Genetic factors Genetic factors G6-PD. Attention, G6-PD. Attention, contraindication !contraindication !

Pregnancy Pregnancy teratogenic, embryogenic teratogenic, embryogenic

Lactation Lactation vulnerable AB for new born vulnerable AB for new born

INDICATION IN EMPIRIC THERAPYINDICATION IN EMPIRIC THERAPY

Infection of unknown originInfection of unknown originNeutropenic patientsNeutropenic patientsCharacteristic symptoms of meningitisCharacteristic symptoms of meningitis

MISUSE of AB :MISUSE of AB :Treatment of untreatable infectionTreatment of untreatable infectionTherapy of fever of unknown originTherapy of fever of unknown originImproper dosageImproper dosageInappropiate reliance on AB aloneInappropiate reliance on AB aloneLack of adequate bacterial informationLack of adequate bacterial information

STRATEGIC FOR EMPIRIC THERAPYSTRATEGIC FOR EMPIRIC THERAPY

Empiric therapy :Empiric therapy :Coverage by a combination of antibiotics such asCoverage by a combination of antibiotics such as

Clindamycin plus gentamycinClindamycin plus gentamycin Effective against gram positive, gram negatives and anaerobesEffective against gram positive, gram negatives and anaerobes

OrOr A single broad spectrum ABA single broad spectrum AB Such as imipenem/cilastatinSuch as imipenem/cilastatin

Receive culture reportReceive culture report With sensitivitiesWith sensitivities

If gram positive onlyIf gram positive only if mixedif mixed↓ ↓ ↓ ↓

Continue gram pos.Continue gram pos. continue therapycontinue therapyCoverage, discontinueCoverage, discontinue as initiated as initiatedGram neg. and anaerobicGram neg. and anaerobicCoverageCoverage

If gram negative onlyIf gram negative only If anaerobic onlyIf anaerobic only ↓ ↓ ↓ ↓

Continue gram neg.Continue gram neg. continue anaerobic coverage,continue anaerobic coverage,coverage, discontinuecoverage, discontinue discontinue gram discontinue gram

positive positive Gram pos. and anaerobicGram pos. and anaerobic and gram negative coverageand gram negative coverageCoverageCoverage

Chapter 28, Fig.28.1 Lippincott’s ed.2nd

PROPHYLAXISPROPHYLAXIS

SURGICAL SURGICAL

1.1. Contaminated op.Contaminated op.

2.2. Clean – Clean – contaminated opcontaminated op

3.3. Selected op Selected op may may suffer suffer

post-op.infectionpost-op.infection

NON SURGICAL

PREVENT :

1. Streptococcal infection in patient with a history of RHD

2. In pre-dental extraction who have implanted prosthetic devices

3. TB/meningitis in close contact individual

4. Protect fetus from infection in HIV-infected pregnant woman

Common Error in AB prophylaxisCommon Error in AB prophylaxis1.1. Selection of wrong ABSelection of wrong AB2.2. The initial therapy too early or too The initial therapy too early or too

latelate3.3. Excessive durationExcessive duration4.4. Inappropriate use of BSABInappropriate use of BSAB

DISADVANTAGES TO PROPHYLACTIC ABDISADVANTAGES TO PROPHYLACTIC AB

1.1. Toxic/allergic reactionToxic/allergic reaction

2.2. Superinfection with more resistant Superinfection with more resistant floraflora

3.3. The infection may be temporarily The infection may be temporarily maskedmasked

4.4. Ecology of the hospital flora may be Ecology of the hospital flora may be alteredaltered

COMMON CAUSES OF FAILURE OF AB COMMON CAUSES OF FAILURE OF AB THERAPY THERAPY

DRUGS : DRUGS : өө inappropriate drug inappropriate drugөө inadequate dose inadequate doseөө improper route of improper route of

administrationadministrationөө accelerated inactivation accelerated inactivationөө poor penetration poor penetration

HOST : HOST : өө poor host defence poor host defence өө undrained pus undrained pus өө retained infected foreign retained infected foreign bodiesbodies

өө crusta/necrotic tissues crusta/necrotic tissues

Cont.Cont.- Pathogen - Pathogen

өө drug resistence drug resistenceөө superinfection superinfectionөө dual infection initially dual infection initially

- Laboratory : - Laboratory : өө erroneous report of susceptible erroneous report of susceptible

pathogenpathogen

AB – COMBINATIONAB – COMBINATION

Synergisme (3) :Synergisme (3) :

1) Blockade of sequential steps in1) Blockade of sequential steps in

a metabolit sequencea metabolit sequence

- Trimethoprim - sulfamethoxazol- Trimethoprim - sulfamethoxazol

2) Inhibition of enzymatic inactivation2) Inhibition of enzymatic inactivation

- Amoxycillin - clavulanat- Amoxycillin - clavulanat

3) Enhancement - Aminoglycosides3) Enhancement - Aminoglycosides

- Penicillins - Aminoglycosides- Penicillins - Aminoglycosides

Antagonism (2) :Antagonism (2) :

1. Inhibition of cidal activity by static 1. Inhibition of cidal activity by static agentagent

- Tetracyclines – Betalactam AB- Tetracyclines – Betalactam AB

2. Induction of enzymatic inactivation2. Induction of enzymatic inactivation

- Ampicillin - Piperacillin- Ampicillin - Piperacillin

CLINICAL INDICATION OF AB CLINICAL INDICATION OF AB COMBINATION :COMBINATION :

► ► Mixed infectionMixed infection► ► Synergism effectSynergism effect► ► Risk of developing resistant Risk of developing resistant organism <organism <► ► Increase AB coverage orIncrease AB coverage or► ► Infection of unknown originInfection of unknown origin

DISADVANTAGES OF AB COMBINATIONDISADVANTAGES OF AB COMBINATION

- Increase risk of toxicity- Increase risk of toxicity

- Increase MDR-pathogens- Increase MDR-pathogens

- Increase cost- Increase cost

- Increase antagonism (bacteriostatic - Increase antagonism (bacteriostatic

+ bactericide)+ bactericide)