Download antimicrobial drugs

chapter 15
microbial mechanisms of pathogenicity
pathogenesis
portals of entry & exit
inoculation vs. disease: preferred portal of entry
entry DOES NOT EQUAL disease
entry into preferred portal of entry DOES NOT EQUAL disease
ID50: infectious dose for 50% of population
– inhalation anthrax: <104 spores
– V. cholerae: 108 cells
LD50 : lethal dose for 50%
– botulinum toxin: 0.03 ng/kg
– E. coli shiga toxin: 250 ng/kg
pathogenesis: enzymes
hyaluronidase
& collagenase
coagulase &
kinase
leukocidins
toxicity: bacterial toxins
allow spread and cause damage to the host
• toxigenicity: ability to produce a toxin
• toxemia: toxin in blood
• toxoid: immunization
• antitoxin: Ab to toxin
exotoxin
source
endotoxin
Gram positive/enterics Gram negative
expressed gene
outer membrane component
chemical make-up
protein
lipid
neutralized by
antitoxin?
yes
no
fever?
no
yes
LD50 (relative)
small
large
cytotoxins: hemolysins
neurotoxins: Clostridium
enterotoxins: V. cholerae
endotoxins: fever
Salmonella virulence
mechanisms of pathogenicity
Inactivating host defenses
chapter 15 learning objectives
1.
Describe pathogenesis from exposure to disease. What factors contribute to disease?
2.
Relate preferred portal of entry and ID50 to the likelihood of infection.
3.
Know how to interpret ID50 and LD50 results.
4.
Describe what is meant by invasiveness and the mechanisms and factors that affect invasiveness (adherence,
penetration, avoidance of phagocytosis, ability to cause damage).
5.
Be able to list enzymes produced by microbes than enhance pathogenicity and virulence as well as describe the effects
of these enzymes on the host (i.e., hyaluronidase, collangenase, coagulase, kinase).
6.
Differentiate between an endotoxin and an exotoxin as far as source, chemistry and type of molecule (protein, or
polysaccharide/lipid). List and understand how examples from class work (e.g., cytotoxin, hemolysin, neurotoxin,
enterotoxin, endotoxin). It is not necessary to know the particular details of how each of the three types of exotoxins
work.
STUDY ANIMATION URLs
endotoxin production
virulence factors animation
exotoxin production
penetrating host tissues
inactivating/avoiding the host defenses (just for your information)
avoiding host defenses (just for your information)
chapter 20
antimicrobial compounds
chemotherapeutic agents
Paul Ehrlich- 1910’s
• salvarsan (synthetic arsenic)
to treat syphilis
Alexander Fleming- 1928
• Penicillium notatum
Howard Florey- 1940
• P. notatum effectivity
antimicrobials
inhibition of protein synthesis:
inhibition of cell wall synthesis:
chloramphenicol, erythryomycin, tetracyclines,
streptomycin
penicillins, cephalosporins, bacitracin, vancomycin
DNA
mRNA
Transcription
Protein
Translation
Replication
Enzyme
inhibition of metabolite synthesis:
sulfanimide, trimethoprim
inhibition of NA replication & Xscription:
quinolones, rifampin
injury to plasma membrane:
polymyxin B
protein synthesis inhibition
Chloramphenicol
Binds to 50S portion and
inhibits formation of
peptide bond
50S
portion
Protein
synthesis site
tRNA
Messenger
RNA
Streptomycin
Changes shape of 30S portion,
causing code on mRNA to be
read incorrectly
30S portion
Direction of ribosome
movement
Tetracyclines
70S prokaryotic
ribosome
Translation
Interfere with attachment of
tRNA to mRNA–ribosome
complex
GFA: metabolite inhibition & synergism
GFAs: nucleic acid inhibition
Phosphate
Cellular
thymidine
kinase
Guanine
nucleotide
DNA polymerase
Nucleoside
Phosphate
Viral
Thymidine
kinase
False nucleotide
(acyclovir triphosphate)
Acyclovir (resembles nucleoside)
DNA polymerase blocked
by false nucleotide.
Assembly of DNA stops.
Incorporated into DNA
penicillin & cell wall synthesis inhibition
CELL WALL FORMATION
autolysins cut wall

new “bricks” inserted

transpeptidase bonds bricks
PENICILLIN ACTION
transpeptidase binds pen.

forms PBP-antibiotic structure

no new bond formation

cell ruptures
Abx resistance
1.
outdated, weakened, inappropriate
Abx use
2.
use of Abx in animal feed
3.
long-term, low-dose Abx use
4.
aerosolized Abx in hospitals
5.
failure to follow prescribed treatment
the episilometer (E) test- the MIC
Abx resistance
1. loss of porins
- Abx/drug movement into cell
2. Abx modifying enzymes
-cleave β-lactam ring
-Anx non-functional
3. efflux pumps
- movement out of cell
4. target site mutations
-enzymes
-polymerases
-ribosomes
-LPS layer
Resistance mechanisms
the effect of -lactamase on -lactam Abx
VERY STABLE RESISTANCE
•
NDM-1 (metallo- -lactamase)
• K. pneumoniae & E. coli, plasmids &
chromosomal
• KPC (K. pneumoniae
carbapenemase,
class of -lactamase)
RESISTANCE RESISTED
•
clavulinic acid/sulbactam bind lactamase
• can be hydrolyzed by high copy #
plasmid -lactamase
-lactams
Narrow-spectrum
• β-lactamase sensitive
benzathine penicillin
benzylpenicillin (penicillin G)
phenoxymethylpenicillin (penicillin V)
procaine penicillin
• Penicillinase-resistant penicillins
methicillin, oxacillin
nafcillin, cloxacillin
dicloxacillin, flucloxacillin
• β-lactamase-resistant penicillins
temocillin
Moderate-spectrum
amoxicillin, ampicillin
Broad-spectrum
co-amoxiclav (amoxicillin+clavulanic
acid)
Extended-spectrum
azlocillin, carbenicillin
ticarcillin, mezlocillin, piperacillin
Cephalosporins
• 1st generation: moderate
cephalexin, cephalothin
cefazolin
• 2nd generation: moderate, anti-Haemophilus
cefaclor, cefuroxime, cefamandole
• 2nd generation cephamycins: moderate, antianaerobe
cefotetan, cefoxitin
• 3rd generation: broad spectrum
ceftriaxone, cefotaxime
cefpodoxime, cefixime
ceftazidime (anti-Pseudomonas activity)
• 4th generation: broad, anti-G+ & β-lactamase
stability
cefepime, cefpirome
• Carbapenems and Penems: broadest spectrum
imipenem (with cilastatin), meropenem
ertapenem, faropenem, doripenem
• Monobactams
aztreonam (Azactam), tigemonam
nocardicin A, tabtoxinine-β-lactam
bacterial resistance
2009 CASE STUDY, U. of Pittsburgh Medical Center
• 6/2008- post-surgical hospitalization, septicemia (E. coli & E. cloacae)
• 7/2008- UTI, E. coli & P. mirabilis
• 8/2008- UTI, E. coli (imipenem S) & K. pneumoniae (imipenem R & ertapenem R)
• 9/2008- abdominal tissue infection, E. coli & K. pneumoniae (both R to Abx)
• 11/2008- sputum P. aeruginosa & S. marcescens, K. pneumoniae
• 12/2008- MDR-pneumonia, A. baumanii & M. morganii
• 1/2009- sputum, S. marcescens (ertapenem & imipenem R)
chapter 20learning objectives
1.
What is the major difference between an antibiotic and a drug? What were the first drug and antibiotic?
2.
Antimicrobial agents target which areas of the bacterial cell? How specifically do antibiotics inhibit protein synthesis?
3.
Describe the mechanism of action of penicillin on the bacterial cell.
4.
List and explain the effects of antibiotic/drug action on the bacterial cell and the action of penicillin specifically.
5.
Discuss the mode of action of growth factor analogs in general and sulfa drugs and acyclovir specifically.
6.
How are antibiotic use and antibiotic resistance related? How are antibiotics abused?
7.
Define bacteriolytic, bacteriostatic, bactericidal, MIC, MBC. Describe how MIC is calculated and what it will tell you about a
given bacterium.
8.
Understand the four major ways that antibiotic resistance is achieved. Include -lactamases and clavulanate/clavulinic acid
specifically.
STUDY ANIMATION URLs
mechanisms of Abx resistance
the origins of Abx resistance
the emergence of Abx resistance
cell wall formation, ß-lactam ABx and resistance