antibiotik juni 2008

7/28/2019 Antibiotik Juni 2008

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Antibiotic Therapy

Identify infecting organism

Evaluate drug sensitivity

Target site of infection

Drug safety/side effect profile

Patient factors

Cost


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Classification of Antibiotics

Bacteriostatic Bactericidal


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Classification of Antibiotics

Chemical Structure

Spectrum of ActivityMechanism of Action


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Mechanism of Action


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Inhibitors of Cell Wall Synthesis


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Beta Lactam Antibiotics

Penicillins

Cephalosporins

Carbapenems

Monobactams


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Penicllins

Derived from the fungus Penicillium

Therapeutic concentration in most tissuesPoor CSF penetration

Renal excretion

Side effects: hypersensitivity, nephritis,neruotoxicity, platelet dysfunction


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Natural Penicillins

Penicillin G, Penicillin V


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Antistaphylococcal Penicillins

Methicillin

Nafcillin

Oxacillin

Dicloxacillin


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Aminopenicillins

Amoxicillin +/- clavulanate

Ampicillin +/- sulbactam


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Antipseudomonal Penicillins

Carbenicillin

Ticarcillin +/- clavulanate

Piperacillin +/- tazobactam


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Cephalosporins

Structurally similar topenicillins

Therapeutic

concentration in manytissues, 3rd and 4thgeneration into CSF

Renal Excretion

Side Effects allergy

disulfiram-like effect

anti-Vitamin K


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Generations of Cephalosporins


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Monobactams

Aztreonam

single beta lactam ring

narrow spectrum:gram-negative aerobes

Enterobacteriacea

Pseudomonas

given IV/IM

renal excretion

little cross-reactivitywith other beta lactams

side effects: phlebitis,rash, elevated LFTs


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Carbapenems

Meropenem/Imipenem

broad spectrum

active against MRSA

given IV

penetrates CSF

renal metabolism and

excretionaddition of cilastin

side effects: GI upset,eosinophilia, neutropenia,

lowering of seizure threshold


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Vancomycin

Tricyclic glycopeptide

Inhibits synthesis of phospholipids and

cross-linking of peptidoglycansActivity against gram-positive organisms

Useful for beta lactam resistant infections

Widely distributed, penetrates CSFRenal elimination, follows creatinine cl.

Side effects: phlebitis, red man syndrome,

ototoxicity, nephrotoxicity


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Protein Synthesis Inhibitors

Human Ribosome

80S 40S

60S

Bacterial Ribosome

70S 30S

50S


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Tetracyclines

Isolated from Streptomyces aureofaciens

Reversibly bind 30S ribosomal subunit

Penetrate sinus mucosa, saliva and tears

Metabolized in liver-->excreted in bile-->reabsorbed-->eliminated in urine

Side effects: GI upset, hepatotoxicity,photosensitivity, bony deposition

Contraindicated in pregnant or breast

feeding women, children under 8 y/o


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Tetracyclines


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Aminoglycosides

Derived from Streptomyces and Micormonospora

Irreversible binding to 30S subunit

Actively transported into bacterial cellsVariable tissue penetration, unreliable CSF levels

Concentrate within perilymph

Renal eliminationNephrotoxicity, ototoxicity, neurotoxicity


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Aminoglycosides


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Macrolides

Macrocyclic lactone structure


Therapeutic concentrations inoropharyngeal and respiratory secretions

No CSF penetration

Metabolized in liver, excreted in feces andurine

Side effects: GI upset, ototoxicity,

hepatotoxicity


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Erythromycin


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Alternate Macrolides

Clarithromycin Azithromycin


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Chloramphenicol

Isolated from Streptomyces

Reversible binding to 50S subunit

Broad spectrum of activityIndicated for severe anaerobic infections or

unresponsive life-threatening infections

Widely distributed, enters CSF

Metabolized in liver (inhibits P-450), eliminatedin urine

Toxicities: reversible anemia, hemolytic anemia,

aplastic anemia, gray baby syndrome


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Clindamycin

Semisynthetic derivative of Lincomycin


Covers anaerobes and gram + aerobes

Widely useful for head and neck infections

Penetrates saliva, sputum, pleural fluid, and bone,but not CSF

Metabolized in liver-->reabsorbed-->eliminated inurine

Side effects: rash, neutropenia/thrombocytopenia,

pseudomembranous colitis


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Inhibitors of Metabolism

Sulfonamides

Trimethoprim

Interfere with theproduction of folicacid coenzymes that

are required forpurine and pyrimidinesynthesis


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Sulfonamides

Derived from prontosil

Competitve antagonist ofPABA

Wide distribution, penetrateCSF, cross placenta

Metabolized in liver,eliminated in urine

Side effects: rash,angioedema, Stevens-Johnson syndrome,kernicterus

Avoid in pregnancy andinfants


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Sulfonamides


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Trimethoprim

Inhibits dihydrofolate reductase

1000x higher affinity for bacterial enzyme

than human enzymeSimilar spectrum and pharmacokinetic

profile as sulfas

Side effects: folate deficiency anemia,leukopenia, granulocytopenia


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Co-Trimoxazole (TMP/SMX)

Combination gives synergistic antibacterialaction


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Co-Trimoxazole (TMP/SMX)

I hibit f N l i A id


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Inhibitors of Nucleic Acid

Function/Synthesis

Fluoroquinolones

Bind bacteria DNA gyrase (topoisomerase II)

Concentrate in sinus and middle ear mucosa,penetrate cartilage and bone

Partially metabolized in liver-->GI or renal excretion

Side effects: nausea, dizziness, phototoxicity,nephrotoxicity

Avoid in pregnant or nursing women

? Use in children--possible effect on articularcartilage


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Fluoroquinolones


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Antimycobacterial Therapy

Must address two distinct populations oftubercle bacilli

First-line treatment: regimens of 3-4drugs for 6 months to 2 years

Second-line therapy: reserved for multi-

drug resistant organisms or unresponsiveinfection


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First-Line Agents

Isoniazide

Rifampin

PyrazinamideEthambutol

Streptomycin

Isoniazide

most potent drug

inhibits formation of

outer mycolic acidwidely distributes and

penetrates CSF

metabolized in liver,

excreted in urine,saliva, and sputum

side effects:hypersensitivity,neuropathy,hepatotoxicity


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Rifampinfrom Streptomyces

antibacterial and anti-tubercule

interferes with RNAtranscription

wide distribution, penetratesCSF

metabolized in livergives orange-red color to

stool, urine and tears

side effects: rash, GI upset,hepatotoxicity


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Pyrazinamide

hydrolyzed topyrazinoic acid

unclear mechanism

widely distributed,including CSF

side effects: GIupset, hepatotoxicity,hyperuricemia


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Ethambutol

inhibits cell wallsynthesis and

maintenance

widely distributed,penetrates CSF

partially metabolized,

excreted in urine

potential for opticneuritis


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Streptomycin

aminoglycoside

binds 30S subunit

penetrates synovial,pleural, pericardial, andascitic fluids but not CSF

renal excretion

side effects:hypersensitivity,paraesthesias, auditoryor vestibular dysfunction,nephrotoxicity


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Antimycobacterials for Leprosy

Dapsonestructurally related to

sulfonamides

PABA antagonist

activity against M. leprae

also effective forpneumocystis and brownrecluse spider bites

wide distribution

acetylated in liver, eliminatedin urine

side effects: erythemanodosum leprosum,

peripheral neuropathy,methemoglobinemia

Clofaziminesynthetic phenazine dye

binds DNA and inhibitsreplication and transcription

activity against M. leprai andMAI

wide distribution, does notpenetrate CSF

partially metabolized,excreted in bile

side effects: GI upset,red/purple discoloration ofskin and body fluids


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Antibiotic Prophylaxis

Post-op wound infection is the second mostcommon nosocomial infection.

Cost of this complication approaches $5billion annually.

Prolongs hospital length of stay by 15 days.

Costs nearly $22,000 more for one post-opwound infection that to use prophylacticclindamycin on 100 patients.

antibiotik juni 2008

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