Anti-microbial Therapies 1- Prokaryotes And Eukaryotes (12) Flashcards
What are beta-lactams?
- group of antibiotics
- e.g. penicillin and methicillin
- interfere w/ synthesis of peptidoglycan component of bacterial cell wall
- bind to penicillin-binding proteins (PBPs)–> enzymes involved in peptidoglycan synthesis
What is an antibiotic?
an antimicrobial agent produced by a microorganism that kills or inhibits other microorganisms
What is an anti-microbial?
chemical that selectively kills or inhibits microbes (bacteria, fungi, viruses)
What is minimal inhibitory concentration (MIC)?
the lowest conc. of AB needed to inhibit bacterial growth
Why does routine use of antibiotics lead to resistance?
it provides a selective pressure for the acquisition and maintenance of resistance genes (N.B. natural selection–> resistant mutants outcompete others)
What are the downsides of antibiotic resistance?
- increased time to find effective therapy
- need additional approaches e.g. surgical drainage
- newer drugs= expensive
- need to use more toxic drugs e.g. vancomycin
- need to use less effective 2nd choice ABs
What are the major AB resistant bacterial pathogens?
Gram -ve - Pseudomonas aeruginosa - E.coli - Salmonella spp. - Acinetobacter abumannii - Neisseria gonorrhoeae Gram +ve Staphylococcus aureus Streprococcus pneumoniae - Clostridium difficile - Enterococcus spp - Mycobacterium tuberculosis
What is an aminoglycoside?
- e.g. gentamicin, streptomycin
- bactericidal
- target protein synthesis, RNA proofreading and cause damage to cell membrane
- v toxic, but inc. use due to resistance to other ABs
What is rifampicin?
- bactericidal
- targets RNA polymerase
- spontaneous resistance is frequent
- secretions turn red–> affects compliance
What is vancomycin?
- bactericidal
- targets bacterial cell wall: lipid 2 component of biosynthesis and D-ala residues in wall crosslinking
- v toxic, but inc. use due to resistance to other ABs
What is linezolid?
- bacteriostatic
- gram +ve spectrum
- inhibits protein synthesis
What is daptomycin?
- bactericidal
- targets bacterial cell membrane
- gram +ve
- toxicity limits dose
What allows safe targeting and selective toxicity?
the large number of differences between mammals and bacteria
e.g. peptidoglycan biosynthesis, different molecules for protein synthesis etc…
What are the 4 mechanisms of antibiotic resistance?
- altered target site structure e.g. MRSA encodes an alternative PBP (2a) w/ low affinity for beta-lactams
- inactivation of AB e.g. beta-lactamase
- altered metabolism e.g. inc. production of enzyme substrate can outcompete AB inhibitor
- decreased drug accumulation by pumping AB out of bacterial cell, so drug doesn’t reach effective conc.
What are macrolides?
- e.g. erythromycin, azithromycin
- gram +ve and -ve infections
- targets protein synthesis through 50S ribosomal subunit
What are quinolones?
- synthetic, broad spectrum, bactericidal
- target DNA gyrase in gram -ve and topoisomerase in gram +ve
What are sources of antibiotic resistance genes?
- plasmids–> circular DNA, often carry multiple AB resistance genes–> if one is needed, bacterium keeps all
- transposons–> integrate into chromosomal DNA–> allow transfer of genes from plasmid to chromosome and vice versa
- naked DNA released from dead bacteria
By what mechanisms can AB resistance genes be shared between bacteria?
- transformation: uptake of extracellular DNA
- conjugation: pilus-mediated DNA transfer
- transduction: phage-mediated DNA transfer
What are some non-genetic mechanisms of resistance?
- biofilm
- hiding intracellularly
- slow growth
- spores e.g. C.difficile
- persisters (don’t replicate)
What are other reasons for AB treatment failure?
- inappropriate choice for organism
- poor penetration of AB into target site
- inappropriate dose
- inappropriate administration
- presence of AB resistance within commensal flora (normal bacteria)
What are some hospital-acquired infections?
- MRSA
- VISA
- Clostridium difficile
- VRE
- ESBL/NDM-1
- P.aeruginosa
- Acineterbacter baumannii
- Stenotrophomonas maltophilia
What are risk factors for HAI?
- high number of ill people (immunosuppression)
- crowded wards
- presence of pathogens
- broken skin
- indwelling devices e.g. intubation
- AB therapy may suppress normal flora (so no competition)
- transmission by staff (contact w/ multiple patients)
How do we address AB resistance?
- prescribing strategies: tighter controls, temporary withdrawal of certain classes
- reduce use of broad-spectrum ABs
- quicker identification of infections caused by resistant strains
- combination therapy
- knowledge of local strains/resistance patterns
How do we overcome resistance?
- modification of existing medications
- combinations of AB and inhibitor e.g. e.g. beta-lactamase inhibitors
