tuberclosis
2016-12-28 20:44:29 0 举报AI智能生成
mycobacterium tuberclosis
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host defense
innate immunity
humoral
omplement
interferons
Interleukin-1 (IL-1)
lysozyme
lactoferrin and transferrin
cellular
phagocytosis
phagocytes
def
most white blood cells
classification
neutrophils/PMNs
increase number when inflammation
release cytokines/chemokines, activate immunity
produce ROS, superoxide, H2O2, reactive nitrogen species
intracellular killing
monocytes become macrophage and dendritic cells
largest of all white blood cells (leukocytes)
half stored in spleen
roles in immunity
replenish resident macrophages under normal states
response to inflammation, move to infection aera and divide into macrophage and DCs
monocytes to macrophage
bone marrow
blood (infammatory monocyte)
spread to tissues
natural killer cells
eosinophils
platelets
receptors / signaling pathways
latent in macrophages
granuloma formation (macrophage cannot get rid of pathogen)
bacteria can tolerate pH and radicals / ROS
also in cryptococcus
antibiotics
mechanisms
penicillin
inhibits formation of crossbonds in peptidoglycan
1. target: DD-transpeptidase (aka penicillin binding protein)
2. precursor buildup activate bacterial cellw all hydrolases
cell wall weaken, osmotic pressure, lysis
Ciprofloxacin
nucleic acid synthesis (DNA gyrase / topoisomerase) inhibitor
both G+ and G- bacteria
resistance due to gyrase subunit mutation
rifampicin
RNA polymerase, interfere with transcription initiatin but not polymerisation
QUICK resistance due to Pol mutation
used in mycobacterium infections
protein synthesis related
broad spctrum
toxic!
examples
Streptomycin
30s ribosome. cause misread
Tetracyclines
block attachment of tRNA
Erythromycin
block protein synthesis after initiation
resistance due to enzymatic methylation of 23s rRNA
history
1929 Fleming penicillin
antimicrobial therapy
administer drug to an infected person to destroy the infective agent without harming the host cells
sources
natural origin
synthetic agents
semi-synthetic
drug combination
erduce emergence of drug resistance
synergisms
concepts
selective toxicity
target microbial not host
spectrum
broad
narrow
stability
must live their routine
enough half-life, effective concentration at target
antibiotic action
bacteriostatic
block growth, no harm to viability
likely reversible
bacteriocidal
block growth, viability loss
no direct lysis, e.g. quinolones
bacteriolytic
lysis. e.g. penicillin
assays
disk diffusion
liquid medium assay
MIC: minimum inhibitory concentration
tube
MBC: minimum bactericidal concentration
plate
pathogen
cell envelop
mycolic acids
basics
actinobacteria
obligate parasites
Ziehl-neelsen staining
high lipid content in cell wall
acid-fast stain
carbol fuchsin stains all cells, after destained with alcohol,
only acid fast bacteria with thick waxy lipid layer retain stain.
counterstain: methyl blue as non-acid fast bacteria
disease
epidemiology
communicable
route: inhalation
RISK
immunocompromised
malnutrition, poverty
pulmonary
signs
bad cough
chest pain
fatigue and weak, weight loss
diagnosis
mantoux test
tuberculin reactivity
blood test
Interferon gamma release assay (IGRA)
ELISA: against IFNgamma
sputum smear microscopy
however often undetected
multi-drug resistance
first line
isoniazid (INH)
mycolic acid
MDR-TB
rifampicin
RNA pol
pyrazinamide (PZA)
ribosomal subunit S1
MDR-TB
ethambutol (EMB)
arabinogalactan synthesis
second line drugs
LIMITED OPTIONS
not avilable
chemotherapy requried, adverse reactions
develop extreme drug resistance (XDR-TB)
resistance
resistance
superbug
MRSA
examples
vancomycin
inhibit transglycosylation and transpeptidationn
bind to terminal dipeptide in side chain
resistance: use of fifferent dipeptide
last resort for MRSA
larger compared to penicillin
mechanisms
drug
destruction by enzyme
modification
availibility
impermeability
efflux pump
beta-lactamase
penicillin...etc
drug target
modification
addition of phosphate, acetyl group
overproduction
more targets with altered sensitivity
acquire
mutations
genes
suppress binding sites
enhance effluw pump recognition
promoters
enhance expression of drug target
enhance the drug destroying enzymes
gene duplications
increased expression
multiple drug targets
horizontal / lateral gene transfer
uptake genes from other (species)
combat
speed up new development
track resistance data
direct observed dosing (TB) - DOTS
use
narrow specturm antibiotics
antimicrobial cocktails
restrict antimicrobial use
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