Nosocomial infection and antibiotic resistance Flashcards
What is an antibiotic?
an antimicrobial agent produced by a micro-organism that kills or inhibits other micro-organisms
What are most antibiotics produced by?
soil-dwelling fungi or bacteria
What is minimal inhibitory concentration?
lowest concentration of antibiotic required to inhibit growth
What is resistance?
when an antibiotic concentration required to inhibit growth is above the breakpoint (clinically-achievable conc.)
How does antibioic use contribute to resistance strains?
provides selective pressure for the acquisition and maintenance of resistance genes
Why are gram negative bacteria generally harder to treat/
harder to find antibiotics as outer membrane provides very good barrier of protection
What are the main gram negative ressitant bacterial pathogens?
pseudomonas aeruginosa; E.coli- ESBL and NDM-1; salmonella; acinetobacter baumanii; neisseria gonorrhoeae
What are the main gram positive resistant bacterial pathogens?
s. aureus; strep pneumo; c.diff; enterococcus; M.tb
What infections is pseudomonas involved in?
CF; burn wound infections
What infections is E.coli involved in?
GI; neonatal meningitis; septicaemia; UTI
What infections is salmonella involved in?
GI; typhoid
What infections is acinetobacter baumanii invovled in?
opportunistic- wounds; UTI; pneumonia
What is selective toxicity?
toxicity that selects for pathogens using the large number of different pathways in microbes vs mammals
What is the MOA of beta-lactams?
interfere with the synthesis of peptidoglycan by binding to and inhibiting penicillin binding proteins which are involved in the synthesis of peptidoglycan
What is hte MOA of tetracycline?
inhibits protein synthesis by binding to the 30S ribosomal subunit preventing the interaction of charged aminoacyl-tRNAs with the mRNA/ribosome complex preventing elongation of the peptide (bacteriostatic)
What is the MOA of chloramphenicol?
inhibits protein synthesis by binding to 50S ribosomal subunit and blocking peptidyl transfer step- bacteriostatic
What is the MOA of quinolones?
targets DNA gyrase in gram negs and topoisomeras IV in gram pos preventing DNA replication- bactericidal
What is the MOA of sulphonamides?
bacteriostatic by blocking folic acid metabolism- mimic PABA and compete for an enzyme that synthesises folic acid
Give examples of aminoglycosides?
gentamicin and streptomycin
What is the MOA of aminoglycosides?
target protein synthesis, RNA proofreading and case damage to cell membrnae
What type of infection are macrolides used to treat?
gram positive
What is the MOA of macrolides?
targets 50S ribosomal subunit preventing amino-acyl transfer and truncation of polypeptides
What are the 4 mechanisms of antibiotic resistance?
altered target site; inactivation of antibiotic; altered metabolism; decreased drug accumulation
How can an altered target site arise in antibiotic resistance?
acquisition of alternative gene or a gene that encodes a target-modifying enzyme
How does MRSA use altered target site as a mechanism of resistance?
MRSA encodes an alternative PBP-PBP2a with low affinity for beta-lactams
How does strep. pneumo use altered target site as a mechanism of resistance?
resistance to erythromycin by acquisition of the erm gene which encodes an enzyme which methylates the AB target site on the ribosome
Give examples of inactivation of antibiotic as a method of resistance?
beta-lactamase production or chloramphenicol acetyl-transferase
What is an example of an antibiotic that is created to avoid beta lactamase?
co-amoxiclav: amoxicillin plus clavulonic acid a beta lactamase inhibitor
What is the function of beta-lactamase?
breaks a bond in the beta lactam ring of penicillin to disable tohe molecule
Give an example of altered metabolism as a mechanism for resistance?
increased production of enzyme substrate can out-compete antibiotic inhibitor- e.g increased PABA confers resistance to sulphonamides or using other metabolic pathways reducing need for PABA
What are the methods of decreased drug accumulation as a method of resistance?
reduced penetration of ABx into bacterial cell (permeability) and/or increased efflux so drug doesn’t reach required conc
What are the sources of antibiotic resistance genes?
plasmids; transposons; naked DNA
What is the problem with plasmids in antibiotic ressitance?
often carry multiple antibiotic resistance genes so selection for one maintains resistance to all
What are transposons?
allow transfer of genes from plasmid to chromosome and vice versa
What is naked DNA?
DNA from dead bacteria released into environment
How can genes responsible for conferring abx resistance be shared between bacteria?
transformation; transduction and conjugation
What is transformation?
uptake of extracellular DNA
What is transduction?
phage-mediated transfer
What is conjugation?
pilus-mediated DNA transfer
How did vancomycin resistant S.aureus arise?
conjugal transfer of plasmid and transposition of the vanA operon from enterococcus faecalis
How did vancomycin insensitive S.aureus arise?
spontaneous point mutations at multiple loci
What are the 2 types of MRSA?
hospital acquired and community acquired
What is the difference between hospital and community acquired MRSA?
HA- more resistance to oxacillin and CA- more virulent : evidence of selection pressures as people in hospital are sick so dont need high virulence but have high abx whereas CA-healthy so need high virulence
Why did MRSA emerge and spread in hospital?
high selection pressure for resistance with lots of sick people prone to infection; indwelling medical deivces gives access to deep tissues —fitness costs of resistance outweighed by advantage of resistance and pressnce of large susceptible population
Why does resistnace come at a price for bacteria?
more drug resistnace results in lower virulence
What gene encodes beta-lactamase?
blaZ
What represses the RNA transcription of blaZ?
Blal
What causes the inactivation of Blal?
binding of penicillin to to BlaR1 which causes BlaR1 autocatalytic activation which cleaves Blal into inactive fragments
What is often found on the same plasmid with the gene for beta-lactamase?
additional antimicrobial ressitance genes
Why is it assumed that mecA was acquired from one of the several coagulase-negative staph species?
there is no homologue of mecA in MSSA
How does resistance to quinolones arise?
stepqise acquisition of chromosomal mutations
Which enzymes do quinolones act upon?
DNA gyrase; topoisomerase IV
What are the new agents available with activity against drug-resistance staphylococci?
dalfopristin and linezolid; daptomycin
What is the general MOA of dalfopristin and linezolid?
protein synthesis inhibitors
What is the MOA of daptomycin?
damages the cytoplasmic mechanism
What is the mortality rate of S.aureus bacteraemia?
20-40%
