Core Microbiology - Antibiotic Resistance (2)

Question 1

Antibiotic era

Answer 1

Time since widespread availability of antibiotics to treat infection

Question 2

Post-Antibiotic era

Answer 2

Time after widespread antibiotic resistance has reduced the availability of antibiotics to treat infection

Question 3

Organisms resistant to antibiotics

Answer 3

• 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

Question 4

Resistance effecting empiric therapy

Answer 4

• Risk of under-treatment

- Risk of excessively broad-spectrum treatment (can lead to resistance)

Question 5

Resistance effecting targeted therapy

Answer 5

Requires use of alternatives

• Expensive
• Last line
• Toxic

Question 6

Examples of expensive alternative antibiotics

Answer 6

• Linezolid
• Tigecycline
• Daptomycin vs flucloxacillin (MRSA)

Question 7

Examples of last line alternative antibiotics

Answer 7

Meropenem vs ciprofloxacin (multi-resistant Enterobacteriaceae)

Question 8

Examples of toxic alternative antibiotics

Answer 8

Colistin vs meropenem for NDM-1 producers

Question 9

Reasons for sensitivity testing

Answer 9

• 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

Question 10

Limitations of sensitivity testing

Answer 10

• Organism tested may not be cause of infection
• Correlation between antimicrobial sensitivity and clinical response is not absolute
• Clinical resistance in vivo

Question 11

Example of clinical resistance in vivo

Answer 11

AmpC B-lactamase genes in eneterobacteriaceae

Question 12

Resistance mechanisms

Answer 12

1. No target
2. Reduced permability
3. Altered target
4. Over-expression of target
5. Enzyme degradation
6. Efflux pump

Question 13

No target

Answer 13

No effect (trying to use antibacterial agent to treat fungi/viruses)

Question 14

Reduced permeability

Answer 14

Drug cannot enter

Question 15

Examples of reduced permeability

Answer 15

• 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

Question 16

Target alteration examples

Answer 16

• 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

Question 17

Over-expression of target

Answer 17

Effect diluted

Question 18

Enzymatic degradation

Answer 18

Drug destroyed

Question 19

Enzymatic degradation examples

Answer 19

• B-lactamases (Penicillins and cephalosporins)
• Aminoglycoside modifying enzymes (gentamicin)
• Chloramphenical acetyltransferase (cholramphenicol)

Question 20

Drug efflux

Answer 20

Drug expelled

Question 21

Examples of drug efflux

Answer 21

Multiple antibiotics (gram -ve organisms, antifungal triazoles and candida)

Question 22

Resistance mechanisms often encoded by a single gene

Answer 22

Antibiotic-modifying enzymes and altered antibiotic targets

Question 23

Resistance genes encoded in plasmids

Answer 23

Transmitted between species by conjugation

Question 24

Horizontal transfer of resistance

Answer 24

Enabled by transposons and integrons, transfered plasmid > plasmid/plasmid > chromosome, contain ‘cassettes’ mutiple resistance genes

Question 25

Vertical transfer of resistance

Answer 25

Bacterial cell-division

Question 26

Consequences of antibiotic exposure

Answer 26

• 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