ANTIBIOTIC RESISTANCE Flashcards
Antibiotic era
Term used to describe the time since the widespread availability of antibiotics to treat infection
Post-antibiotic era
Term used to describe the time after widespread antibiotic resistance has reduced the availability of antibiotics to treat infection. Bacteria have always had to deal with antibiotics and always will, so they constantly develop antibiotic resistance by spontaneous mutation and natural selection. The pharmaceutical industry has to play catch-up with the bacteria, but at the moment the rate of development of resistance is outstripping the rate of development of new antibiotics.
Sensitivity testing
Add organism, add antibiotics, incubate, read, and interpret results then clinical interpretation.
Can also do it on liquid media: microtitre plate susceptibility testing.
Culture micro-organism in the presence of antimicrobial agent Determine whether minimum inhibitory concentration (MIC = where visible growth is inhibited) is above a predetermined ‘breakpoint’ level High enough to kill the organism.
Sustained at the site of infection for long enough using practicable dosing regimens.
Uses and limitations of sensitivity testing
To inform antibiotic therapy:
- First-line antibiotic choice if infection does not require immediate treatment eg infectious endocarditis, osteomyelitis (unless patient is septic)
- Second-line choice after empiric therapy: ‘Smart smart then focus’
- Second line choice after failure of initial therapy: Uncomplicated UTI in general practice
To provide epidemiological data – ‘surveillance’
Sensitivity results are collated locally, nationally and internationally
• To inform local guidelines and antibiotic choices
• To provide epidemiological data
• To provide early warning of threats to public health
Causes of antibiotic resistance
- Absent target
Antibacterial agents/fungi and Antiviral agents/bacteria. Where you give a patient an antibacterial when they actually don’t have an infection so drug is ineffective.
Causes of antibiotic resistance
Decreased Permeability
- Vancomycin:Gram-negative bacilli: Gram-negatives have an outer membrane that is impermeable to vancomycin
- Gentamicin:anaerobic organisms. Uptake of aminoglycosides requires an O2 dependent active transport mechanism
Causes of antibiotic resistance
Target modification
- Flucloxacillin: MRSA: Altered penicillin-binding protein (PBP2’, encoded by MecA gene) does not bind β-lactams. (Methicillin-resistant Staphylococcus aureus)
- Vancomycin: VRE- Altered peptide sequence in Gram-positive peptideoglycan (D-ala D-ala → D-ala D-lac) Reduces binding of vancomycin 1000-fold.
- Trimethoprim: Gram-negative bacilli- Mutations in dhr (dihydrofolate reductase gene)
Causes of antibiotic resistance
Enzymatic degradation
- Penicillins and cephalosporins: β-lactamases; Staphylococcal penicillinase Inactivates penicillin/amoxicillin
- Extended-spectrum β-lactamases (ESBL): Inactivate penicillins and cephalosporins
- Carbapenemases
- Gentamicin: aminoglycoside modifying enzymes
- Chloramphenicol: chloramphenicol acetyltransferase (CAT)
- Enzyme causes the antibiotic to be hydrolysed and rendered ineffective.
Causes of antibiotic resistance
Drug efflux
Multiple antibiotics, especially in Gram-negative organisms
- Antifungal triazoles and Candida spp. Sends antibiotic back out of the organism so it can’t stay in and work.
Development and spread of resistance
- Many resistance mechanisms are encoded by single genes eg antibiotic-modifying enzymes, altered antibiotic targets
- Resistance genes encoded in plasmids: Circular DNA sequences transmitted within and between species, Mainly by conjugation
Horizontal transfer
Enabled by transposons and integrons, DNA sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosome. Often contain ‘cassettes’ with multiple resistance genes
- Vertical transfer
Chromosomal or plasmid-borne resistance genes transferred to daughter cells on bacterial cell-division
Causes of antibiotic resistance
- Mixture of sensitive and resistant bacterial strains exposed to antibiotics
- Sensitive strains will die out
- Resistant strains will become the dominant colonising strains
- Subsequent endogenous infection more likely to be caused by antibiotic-resistant strains
- Antibiotic-resistant strains may be transferred to other people
Bacterial infections become resistant to antibiotics traditionally used to treat them:
- Meticillin-resistant Staphylococcus aureus (MRSA)
- Vancomycin/glycopeptide-resistant enterococci (VRE/GRE)
- Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL)
- Carbapenemase-producing Enterobacteriaceae (CPE)
- Multi-drug resistant tuburculosis (MDR-TB)
- Extremely-drug resistant tuberculosis (XDR-TB)
- Others: Enterobacteriaceae resistant to amoxicillin, ciprofloxacin, gentamicin, carbapenems etc. And Pseudomonas resistant to ceftazidime, carbapenems etc.
Implications for antibiotic use
Empiric therapy: Risk of under-treatment if ‘traditional’ antibiotic is used or Risk of excessively broad-spectrum treatment if risk of resistance is taken into account
Targeted therapy: Requires use of alternatives which may be:
- Expensive eg linezolid, tigecycline, daptomycin vs. flucloxacillin for MRSA
- Toxic eg colistin vs. meropenem for CPE
- ‘Last line’ eg meropenem vs. ciprofloxacin for multi-resistant Enterobacteriaceae
