Introduction to antimicrobIntroduction to antimicrobial agentsial agents

Definition: Use of drugs to combat infectious diseases and cancer.

Antimicrobial drug ( 抗微生物药 )

Antiparasitic drug( 抗寄生虫药 )

Anticancer drug ( 抗癌药 )

1. Chemotherapy,化学治疗

Antimicrobial drugAntimicrobial drug

Antimicrobial drugs either kill microbes (microAntimicrobial drugs either kill microbes (microbicidal) or prevent the growth of microbes (micbicidal) or prevent the growth of microbes (microbistatic).robistatic).

AntibacterialAntibacterial

AntiviralAntiviral

AntifungalAntifungal

AntiparasiticAntiparasitic

Antimicrobial ChemotherapyAntimicrobial Chemotherapy

Differential toxicity: based on the concept that the Differential toxicity: based on the concept that the drug is more toxic to the infecting organism than to drug is more toxic to the infecting organism than to the hostthe host

Majority of antibiotics are based on naturally Majority of antibiotics are based on naturally occurring compoundsoccurring compounds

or may be semi-synthetic or syntheticor may be semi-synthetic or synthetic

What is the ideal antibioticWhat is the ideal antibiotic

Have the appropriate spectrum of activity for the clinical Have the appropriate spectrum of activity for the clinical

setting.setting.

Have no toxicity to the host, be well tolerated.Have no toxicity to the host, be well tolerated.

Low propensity for development of resistance.Low propensity for development of resistance.

Not induce hypersensitivies in the host.Not induce hypersensitivies in the host.

What is the ideal antibioticWhat is the ideal antibiotic

Have rapid and extensive tissue distributionHave rapid and extensive tissue distribution

Have a relatively long half-life.Have a relatively long half-life.

Be free of interactions with other drugs.Be free of interactions with other drugs.

Be convenient for administration.Be convenient for administration.

Be relatively inexpensiveBe relatively inexpensive

DefinitionsDefinitions

Spectrum of ActivitySpectrum of Activity: : Narrow spectrum - drug is effective against a limited Narrow spectrum - drug is effective against a limited number of speciesnumber of species

Broad spectrum - drug is effective against a wide Broad spectrum - drug is effective against a wide variety of speciesvariety of species

Gram negative agentGram negative agentGram positive agentGram positive agentAnti-anaerobic activityAnti-anaerobic activity

DefinitionsDefinitions

Minimum Inhibitory Concentration (MIC)Minimum Inhibitory Concentration (MIC)- minimum concentration of antibiotic required to inhibit the - minimum concentration of antibiotic required to inhibit the growth of the test organism.growth of the test organism.

Minimum Bactericidal Concentration (MBC)Minimum Bactericidal Concentration (MBC)- minimum concentration of antibiotic required to kill the test - minimum concentration of antibiotic required to kill the test organism.organism.

Bacteriostatic Bacteriostatic

BactericidalBactericidal

DefinitionsDefinitions

Chemotherapeutic Index ( CI ): LDChemotherapeutic Index ( CI ): LD5050/ED/ED50 50 or LDor LD55/ED/ED9595

PAE (Post antibiotic effect): PAE (Post antibiotic effect): the continued suppression the continued suppression of antibacterial growth after the administration of of antibacterial growth after the administration of antibiotic has ceased and serum concentrations have antibiotic has ceased and serum concentrations have fallen below the minimum inhibitory concentration .fallen below the minimum inhibitory concentration .

病原微生物病原微生物抗微生物药抗微生物药抗菌作用抗菌作用

耐药性耐药性

抗病能力

抗病能力

致病作用

致病作用 不良反应

不良反应

体内过程

体内过程

机 体机 体

Five modes of antimicrobial actionFive modes of antimicrobial action

(i)    Inhibition of cell wall synthesis(i)    Inhibition of cell wall synthesis(ii)     Disruption of cell membrane function(ii)     Disruption of cell membrane function(iii)    Inhibition of protein synthesis(iii)    Inhibition of protein synthesis(iv)    Inhibition of nucleic acid synthesis (iv)    Inhibition of nucleic acid synthesis (v)     Action as antimetabolites(v)     Action as antimetabolites

PeptidoglycanPeptidoglycan

The glycan backbone The glycan backbone

Peptidoglycan cross-bridgesPeptidoglycan cross-bridgesTetrapeptide

side chainTetrapeptide

side chain

Targets of antimicrobial drugsTargets of antimicrobial drugs

————Disruption of cell membrane functionDisruption of cell membrane function————

————Disruption of cell membrane functionDisruption of cell membrane function————

PolymyxinPolymyxin

CationicCationic and alters cytoplasmic membrane lters cytoplasmic membrane

permeability by binding to a negatively charpermeability by binding to a negatively char

ged site in the lipopolysaccharide layerged site in the lipopolysaccharide layer

Amphotericin BAmphotericin BAssociates with ergosterol, the main cAssociates with ergosterol, the main component of fungal cell membranesomponent of fungal cell membranes

Associates with ergosterol, the main cAssociates with ergosterol, the main component of fungal cell membranesomponent of fungal cell membranes

Drugs that disrupt cell membrane Drugs that disrupt cell membrane functionfunction

Inhibition of protein synthesisInhibition of protein synthesis

Generally work at different stages of prokaryotic mRNA tGenerally work at different stages of prokaryotic mRNA translation into proteins, like initiation, elongation ranslation into proteins, like initiation, elongation (includin(including g aminoacyl tRNA entry, proofreading, peptidyl transfer a entry, proofreading, peptidyl transfer a

nd ribosomal translocation) and terminationnd ribosomal translocation) and termination.).)

The antibiotic only affects 70S ribosomes in the bacteria The antibiotic only affects 70S ribosomes in the bacteria and does nothing for the 80S ribosomes in human.and does nothing for the 80S ribosomes in human.

Inhibition of protein synthesisInhibition of protein synthesis

MacrolidesMacrolides

LincomycinLincomycin

ChloromycetinChloromycetin

TetracyclinesTetracyclinesAminoglycosidesAminoglycosides

bind to 50sbind to 50s

bind to 30sbind to 30s

Inhibition the Synthesis of metabolitesInhibition the Synthesis of metabolites

Antibiotics that mimic the structure of the specific Antibiotics that mimic the structure of the specific substrate that the normal substrate is replaced and don’t substrate that the normal substrate is replaced and don’t have contact with the enzyme which acts on a substrate have contact with the enzyme which acts on a substrate to produce a certain metabolically important metabolite to produce a certain metabolically important metabolite inside the cell. inside the cell.

Action of sulfanilamide Action of sulfanilamide

QuinolonesQuinolones

Inhibit the DNA gyraseInhibit the DNA gyrase→ → Interfer with Interfer with DNA replication

RifampicinRifampicin

Inhibits DNA-dependent RNA polymeraseInhibits DNA-dependent RNA polymerase →mRNA↓→mRNA↓

—— Inhibitors of nucleic acid synthesis

———— Inhibitors of nucleic acid synthesis

——

Antimicrobial resistanceAntimicrobial resistance

ResistanceResistance: : the inability to kill or inhibit the organism the inability to kill or inhibit the organism with clinically achievable drug concentrations with clinically achievable drug concentrations

Resistance may be innate (naturally resistant)Resistance may be innate (naturally resistant)

Resistance may be acquiredResistance may be acquired - mutation - mutation - acquisition of foreign DNA - acquisition of foreign DNA

Antimicrobial resistanceAntimicrobial resistance

Factors which may accelerate the development of Factors which may accelerate the development of

resistanceresistance

- inadequate levels of antibiotics at the site of - inadequate levels of antibiotics at the site of

infectioninfection

- duration of treatment too short - duration of treatment too short

- overwhelming numbers of organisms - overwhelming numbers of organisms

- overuse / misuse of antibiotics - overuse / misuse of antibiotics

Antimicrobial resistanceAntimicrobial resistance

General mechanisms of resistance:General mechanisms of resistance:

Inactivation / destruction of antibioticInactivation / destruction of antibiotic Altered binding siteAltered binding site Altered permeabilityAltered permeability Efflux (pumps) mechanismsEfflux (pumps) mechanisms Bypass of metabolic pathwaysBypass of metabolic pathways

Resistance gene transmissionResistance gene transmission

Principles of use of antibacterial agentsPrinciples of use of antibacterial agents

Proper selection of an antibacterial agent is based on a nProper selection of an antibacterial agent is based on a number of factors.umber of factors.

The identity of the pathogenThe identity of the pathogen

The site of infectionThe site of infection

Pharmacokinetics (PK) Pharmacokinetics (PK)

Pharmacodynamics (PD) Pharmacodynamics (PD)

Potential toxicityPotential toxicity

Possible drug interactions, Possible drug interactions,

Cost, and convenience of administration.Cost, and convenience of administration.

Prophylaxis for infectionProphylaxis for infection

Prevention of Rheumatic Fever Prevention of Rheumatic Fever

Epidemic cerebrospinal meningitisEpidemic cerebrospinal meningitis Infective endocarditis Infective endocarditis

SurgerySurgery