PENGANTAR PENGANTAR ANTIMIKROBAANTIMIKROBA

Ika FikriahIka Fikriah

AntibioticsAntibiotics

Substances produced by Substances produced by various species of various species of microorganisms : bacteria, microorganisms : bacteria, fungi, actinomycetes fungi, actinomycetes

that suppress the growth of that suppress the growth of other microorganisms and to other microorganisms and to destroy them.destroy them.

Classification and mechanism of action

ANTIMICROBA ACTIVITYANTIMICROBA ACTIVITY

Minimal inhibitory concentration Minimal inhibitory concentration (MIC)(MIC)

Minimal lethal concentration (MLC)Minimal lethal concentration (MLC)

Dilution Susceptibility Dilution Susceptibility TestsTests

determination of MIC and MLCdetermination of MIC and MLC Mueller-Hinton brothMueller-Hinton broth read at 16-20 hoursread at 16-20 hours

Susceptibility Testing Antibiotic Susceptibility Testing Antibiotic

Determination of MICDetermination of MIC

8 4 02 1 Tetracycline (μg/ml)

MIC = 2 μg/ml

Determination of MIC

Chl Amp

Ery

Str

Tet

Disk Diffusion Test

Selective toxicitySelective toxicity

therapeutic dose: drug level required therapeutic dose: drug level required for clinical treatmentfor clinical treatment

toxic dose: agent too toxic for hosttoxic dose: agent too toxic for host therapeutic index: ratio of therapeutic therapeutic index: ratio of therapeutic

dose to toxic dosedose to toxic dose

Selection of the ATBSelection of the ATB Requires clinical judgment, detailed knowledge Requires clinical judgment, detailed knowledge

of pharmacological and microbiological factors.of pharmacological and microbiological factors.

Empirical therapy – initial – infecting organism Empirical therapy – initial – infecting organism not identified – single broad spectrum agent/ not identified – single broad spectrum agent/ combination combination

Definitive therapy- microorganism identified – Definitive therapy- microorganism identified –

a narrow –spectrum low toxicity regiment to a narrow –spectrum low toxicity regiment to complete the course of treatment complete the course of treatment

Susceptibility vs. ResistanceSusceptibility vs. Resistance Dose of drug has to be sufficient to produce Dose of drug has to be sufficient to produce

effect inhibit or kill the microorganism:effect inhibit or kill the microorganism: However concentration of the drug must However concentration of the drug must

remain below those that are toxic to human remain below those that are toxic to human cells cells

If can be achieved – microorganism If can be achieved – microorganism susceptible to the ATBsusceptible to the ATB

If effective concentration is higher than If effective concentration is higher than toxic- microorganism is resistanttoxic- microorganism is resistant

ResistanceResistance

Failure to reach the target ( absence/ Failure to reach the target ( absence/ mutation of porin, anaerobic condition)mutation of porin, anaerobic condition)

The drug is inactivated (aminoglycoside-The drug is inactivated (aminoglycoside-modyfing enzyme, beta lactamase)modyfing enzyme, beta lactamase)

The target is altered (reduced binding/ The target is altered (reduced binding/ substitution of a new target)substitution of a new target)

Factors Influencing The Factors Influencing The

EffectivenessEffectiveness

Pharmacokinetic factorsPharmacokinetic factors Location of infectionLocation of infection Penetration of drugPenetration of drug The dose and dosis frequencyThe dose and dosis frequency Knowledge of the status of the patientKnowledge of the status of the patient Route of administration Route of administration

Host factorHost factor Host defence mechanismHost defence mechanism Local factorLocal factor Age (biotransformation,distribution, Age (biotransformation,distribution,

elimination)elimination) Genetic factors (genetic & Genetic factors (genetic &

metabolic abnormalities) metabolic abnormalities) PregnancyPregnancy Drug allergyDrug allergy

Host Defence MechanismHost Defence Mechanism

Immunocompetent host Immunocompetent host bacteriostaticbacteriostatic

Impaired host Impaired host bacteriocidic bacteriocidic

bacterial endocarditis~phagocitic cell bacterial endocarditis~phagocitic cell absent absent

bacterial meningitis~phagocitic bacterial meningitis~phagocitic ineffective, neutropenic patients~totol ineffective, neutropenic patients~totol mass phagocitic cell reducedmass phagocitic cell reduced

Local factorLocal factor pus, hemoglobin in infected pus, hemoglobin in infected

hematoma, pH, anaerobic, hematoma, pH, anaerobic, vascular supplyvascular supply

the presence of foreign bodythe presence of foreign body

Disanvantages of Disanvantages of combinations of combinations of

antimicrobial agentsantimicrobial agents

Risk of toxicityRisk of toxicity The selection of multiple-The selection of multiple-drug resistantdrug resistant

Increased costIncreased cost Antagonism effectAntagonism effect

The prophylaxis of The prophylaxis of infection with infection with

antimicrobial agentsantimicrobial agents Protection of healthy patients who are Protection of healthy patients who are

in close contact with a casein close contact with a case Patients with structural lesions of the Patients with structural lesions of the

heart predisposising to endocarditisheart predisposising to endocarditis Patients undergoing organ Patients undergoing organ

transplantation or cancer chemotherapytransplantation or cancer chemotherapy Prevention of wound infections Prevention of wound infections In dirty and contaminated surgical In dirty and contaminated surgical

proceduresprocedures

SuperinfectionsSuperinfections The appearance of bacteriological The appearance of bacteriological

and clinical evidence of a new and clinical evidence of a new infection during the chemotherapy infection during the chemotherapy of a primary oneof a primary one

Very dangerous Very dangerous Very difficult to eradicateVery difficult to eradicate Broad spectrum, prolonged Broad spectrum, prolonged

administration administration

Beta-Lactam AntibioticsBeta-Lactam Antibiotics PenicillinPenicillin

bactericide, broad spectrumbactericide, broad spectrumpenicillin G, nafcillin, procain penicillin, ampicillin, penicillin G, nafcillin, procain penicillin, ampicillin, amoxicillinamoxicillinresistance by beta-laktamaseresistance by beta-laktamase

CephalosporinCephalosporinbactericide, broad spectrum, stable beta-laktamasebactericide, broad spectrum, stable beta-laktamaseFirst gen (cefadroxil, cefazolin, cefalexin)First gen (cefadroxil, cefazolin, cefalexin)Second gen (cefaclor, cefuroxime, cefoxitin)Second gen (cefaclor, cefuroxime, cefoxitin)TTthth gen (cefotaxime, cefixime, ceftriaxone) gen (cefotaxime, cefixime, ceftriaxone)FFthth gen (cefepime gen (cefepimeOral, parenteralOral, parenteral

Protein Synthesis InhibitorsProtein Synthesis Inhibitors Aminoglycosides Aminoglycosides

Streptomycin, GentamycinStreptomycin, Gentamycin Resistance by modification or target mutationResistance by modification or target mutation

TetracyclinesTetracyclines resistance by exportresistance by export

MacrolidesMacrolides erythromycin, clindamycin, azithromycinerythromycin, clindamycin, azithromycin used for patients allergic to penicillinused for patients allergic to penicillin resistance by target mutationresistance by target mutation

streptomycin, kanamycin, neomycin, streptomycin, kanamycin, neomycin, tobramycintobramycin

inhibit protein synthesisinhibit protein synthesis cause misreading of mRNAcause misreading of mRNA

bactericidal: Gram -bactericidal: Gram - streptomycin: tuberculosis, plaguestreptomycin: tuberculosis, plague side effects include damage to 8th cranial side effects include damage to 8th cranial

nervenerve

Aminoglycosides: Aminoglycosides: StreptomycesStreptomyces

Aminoglycosides: Aminoglycosides: StreptomycesStreptomyces Mode of actionMode of action - The tetracyclines reversibly bind to - The tetracyclines reversibly bind to

the 30S ribosome and inhibit binding of aminoacyl-t-the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.RNA to the acceptor site on the 70S ribosome.

Spectrum of activitySpectrum of activity - Broad spectrum; Useful - Broad spectrum; Useful against intracellular bacteriaagainst intracellular bacteria

ResistanceResistance - Common - Common Adverse effectsAdverse effects - Destruction of normal intestinal - Destruction of normal intestinal

flora resulting in increased secondary infections; flora resulting in increased secondary infections; staining and impairment of the structure of bone and staining and impairment of the structure of bone and teeth.teeth.

MacrolidesMacrolides ( (bacteriostaticbacteriostatic))

erythromycin, clarithromycin, azithromycin, erythromycin, clarithromycin, azithromycin, spiramycinspiramycin

Mode of actionMode of action - The macrolides inhibit - The macrolides inhibit translocationtranslocation by binding to 50 S ribosomal by binding to 50 S ribosomal subunitsubunit

Spectrum of activitySpectrum of activity - Gram-positive - Gram-positive bacteria, bacteria, Mycoplasma, LegionellaMycoplasma, Legionella (intracellular bacterias)(intracellular bacterias)

Resistance - CommonResistance - Common

Erythromycin (macrolide): Erythromycin (macrolide): Streptomyces erythraeusStreptomyces erythraeus

bacteriostaticbacteriostatic binds to 23s rRNA of 50 S subunit: inhibits binds to 23s rRNA of 50 S subunit: inhibits

chain elongationchain elongation narrow to medium spectrum: gram + bacteria, narrow to medium spectrum: gram + bacteria,

penicillin allergic patients, diphtheria, penicillin allergic patients, diphtheria, mycoplasmas, mycoplasmas, LegionellaLegionella

ChloramphenicolChloramphenicol, Lincomycin, , Lincomycin, Clindamycin (bacteriostatic)Clindamycin (bacteriostatic)

Mode of actionMode of action - These antimicrobials bind to the - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase 50S ribosome and inhibit peptidyl transferase activity.activity.

Spectrum of activitySpectrum of activity - Chloramphenicol - Broad range- Chloramphenicol - Broad range- Lincomycin and clindamycin - Restricted range- Lincomycin and clindamycin - Restricted range

ResistanceResistance - Common - Common Adverse effectsAdverse effects - Chloramphenicol is toxic (bone - Chloramphenicol is toxic (bone

marrow suppression) but is used in the treatment of marrow suppression) but is used in the treatment of bacterial meningitis.bacterial meningitis.

ChloramphenicolChloramphenicol

This inhibits bacterial protein synthesis. This inhibits bacterial protein synthesis. It is well absorbed and widely distributed , It is well absorbed and widely distributed ,

including to the CNS.including to the CNS. It is metabolized by glucoronidation in the It is metabolized by glucoronidation in the

liver.liver. Although an effective broad-spectrum Although an effective broad-spectrum

antibiotics, its uses are limitid by its serious antibiotics, its uses are limitid by its serious toxicity.toxicity.

PENGGUNAAN ANTIBIOTIKA YANG TIDAK RASIONAL

MENGOBATI INFEKSI VIRUS DENGAN ANTIBIOTIKA

MENGOBATI SETIAP PANAS DENGAN ANTIBIOTIKA TANPA DATA KLINIS /MIKROBIOLOGIS

MENGGUNAKAN ANTIBIOTIKA TIDAK EFEKTIF INVIVO / TIDAK SAMPAI PADA TARGET

MENGGUNAKAN ANTIBIOTIKA EFEKTIF INVITRO TETAPI TIDAK INVIVO

MENGGUNAKAN ANTIBIOTIKA YANG TOKSIK

MENGGUNAKAN ANTIBIOTIKA BROAD SPEKTRUM DAN POTENT WALAUPUN ADA YANG SPESIFIK DAN TIDAK BROAD SPEKTRUM

MENGGUNAKAN ANTIBIOTIKKA YANG MAHAL WALAUPUN YANG MURAH MASIH EFEKTIF

MONITORING HASIL PENGOBATAN DENGAN ANTI MIKROBA

MENEGAKKAN KEMBALI PENYEBAB INFEKSI APAKAH OLEH INFEKSI BARU (SUPERINFEKSI)

MENENTUKAN KEMBALI TEST KEPEKAAN INVITRO

MENGUKUR KADAR OBAT DALAM URINE, DARAH ATAU JARINGAN APAKAH KADAR OBAT MASIH CUKUP

MEMASTIKAN BAHWA KEGAGALAN TERAPI BUKAN OLEH TINDAKAN NON OBAT SEPERTI DRAINASE, INSISI ABSES, BENDA ASING DALAM TEMPAT INFEKSI

MENGHILANGKAN KEMUNGKINAN BAHWA INFEKSI DISEBABKAN OLEH FAKTOR LAIN SEPERTI PLEBITIS/HIPERSENSITIF