Antibiotic era
Time since widespread availability of antibiotics to treat infection
Post-Antibiotic era
Time after widespread antibiotic resistance has reduced the availability of antibiotics to treat infection
Organisms resistant to antibiotics
- Methicillin-resistant Staphylococcus aureus (MRSA)
- Vancomycin/glycopeptide-resistant enterococci (VRE/GRE)
- Extended-spectrum B-lactamase-producing Enterobacteriaceae (ESBL)
- NDM-1 producing Gram-negative bacilli
- Multi-drug resistant tuberculosis (MDR-TB)
- Extremely-drug resistant tuberculosis (XDR-TB)
- Enterobacteriaceae resistant to amoxicillin, ciprofloxacin, gentamicin, carbapenems
- Pseudomonas resistant to ceftazidime, carbapenems
Resistance effecting empiric therapy
- Risk of under-treatment
- Risk of excessively broad-spectrum treatment (can lead to resistance)
Resistance effecting targeted therapy
Requires use of alternatives
- Expensive
- Last line
- Toxic
Examples of expensive alternative antibiotics
- Linezolid
- Tigecycline
- Daptomycin vs flucloxacillin (MRSA)
Examples of last line alternative antibiotics
Meropenem vs ciprofloxacin (multi-resistant Enterobacteriaceae)
Examples of toxic alternative antibiotics
Colistin vs meropenem for NDM-1 producers
Reasons for sensitivity testing
- Enable transition from empiric > targeted therapy
- Explain treatment failures
- Provide alternative antibiotics (if treatment fails/adverse effects)
- Provide alternative oral antibiotics with IV no longer required
Limitations of sensitivity testing
- Organism tested may not be cause of infection
- Correlation between antimicrobial sensitivity and clinical response is not absolute
- Clinical resistance in vivo
Example of clinical resistance in vivo
AmpC B-lactamase genes in eneterobacteriaceae
Resistance mechanisms
- No target
- Reduced permability
- Altered target
- Over-expression of target
- Enzyme degradation
- Efflux pump
No target
No effect (trying to use antibacterial agent to treat fungi/viruses)
Reduced permeability
Drug cannot enter
Examples of reduced permeability
- Gram-negative bacilli have an outer membrane that is impermeable to vancomycin
- Uptake of aminoglycosides (gentamicin), requires O2 dependent active transport mechanism - only aerobic organisms
Target alteration examples
- MRSA altered penicillin-binding protein (PBP2’ MecA gene) doesn’t bind B-lactams (Flucloxacillin)
- VRE alterted peptide sequence in gram +ve peptideoglycan reduces beinding of vancomycin
- Mutations in dhr in gram -ve bacilli means trimethoprim cannot bind
Over-expression of target
Effect diluted
Enzymatic degradation
Drug destroyed
Enzymatic degradation examples
- B-lactamases (Penicillins and cephalosporins)
- Aminoglycoside modifying enzymes (gentamicin)
- Chloramphenical acetyltransferase (cholramphenicol)
Drug efflux
Drug expelled
Examples of drug efflux
Multiple antibiotics (gram -ve organisms, antifungal triazoles and candida)
Resistance mechanisms often encoded by a single gene
Antibiotic-modifying enzymes and altered antibiotic targets
Resistance genes encoded in plasmids
Transmitted between species by conjugation
Horizontal transfer of resistance
Enabled by transposons and integrons, transfered plasmid > plasmid/plasmid > chromosome, contain ‘cassettes’ mutiple resistance genes
Vertical transfer of resistance
Bacterial cell-division
Consequences of antibiotic exposure
- Sensitive strains exposed to antibiotics at sub-lethal concentrations
- Chance of survival enhance by development of resistance
- Resistant strain out-compete sensitive strains
- Resistance perpetuated by vertical transfer