Antimicrobials 2

Question 1

What does prophylaxis mean in clinical human use>

Answer 1

To prevent infection e.g. around some surgical procedures (perioperative)

Question 2

What is clinical resistance (treatment failure) dependent on?

Answer 2

• Concentration of antibiotic at site of infection (PK)
• Activity v infecting organism there (PD)
• Host defences

Question 3

What are the types of resistance?

Answer 3

• Acquired

- Intrinsic

Question 4

What resistant bacteria are in the community?

Answer 4

• Penicillin and multi-resistant pneumococci (PRP)
• Erythromycin resistant Group A strep
• Multi-resistant salmonellae (Cipro R)
• N. gonorrhoea (PPNG, cipro, cefixime R)
• Community acquired MRSA
• Drug resistant TB global issue

Question 5

What resistant bacteria are in hospitals?

Answer 5

• Methicillin resistant S. aureus (MRSA)- Glycopeptides resistant as well
• Glycopeptide resistant enterococci (VRE)
• Extended spectrum beta lactamase (ESBL) producing Klebsiella pneumoniae
• Klebsiella pneumoniae carbapenemases (KPC) and others, carbapenemases producing Enterobacteriaceae (CPE) usually multi resistant to other agents too
• Other multi-drug resistant Gram negatives (Enterobacter, Serratia, Acinetobacter spp)

Question 6

What resistance is there in other pathogens?

Answer 6

• Antivirals: HSV, HIV, CMV
• Antiprotozoals: P. falciparum
• Antifungals: azole and echinocandin resistant yeasts

Question 7

What are the factors that promote the success of Antibiotic Resistance?

Answer 7

1. Antibiotic usage- too much/ too little antibiotic
2. Effective Genetic Mobility- plasmid carriage, transposons, integrins
3. Efficient Resistance Mechanism- bacterial factors

Question 8

What antibiotic dose is needed to prevent emergence of resistance?

Answer 8

Between 32 to 64 mg/L

Around 48

Question 9

What is the evidence for association between use of antibiotics and resistance?

Answer 9

• Multi-R bacteria hospitals> community
• Pre-antibiotic era: hospital infections: Streptococcus pneumoniae and Streps A, antibiotic era: hospital infections more resistant: Pseudomonas, E coli, Klebsiella
• Patients with resistant bacteria more likely t have had prior antibiotic
• Restriction used to control outbreaks

Question 10

Hoe does chromosome mutation select a resistant variant?

Answer 10

Spontaneous mutation- 1:10^6- 10^12 per generation

Usually independent of antibiotic usage= selection of mutation, often by the killing of antibiotic sensitive bacteria

Question 11

What are the locations of resistance genes?

Answer 11

• Chromosome
• Plasmid
• Transposon
• Integron

Question 12

How do plasmids relate to antibiotic resistance?

Answer 12

• Agents of infectious resistance
• Extra chromosomal double stranded DNA
• Autonomous replication
• Transferred by conjugation (sex pili)
• Promiscuous

Question 13

Describe plasmid transfer of Antibiotic Resistance genes

Answer 13

Bacterial cell resistant to ampicillin
R-plasmid transferred to bacterial cell sensitive to ampicillin by sex pilus
No resistant

Question 14

How do plasmids acquire new genes?

Answer 14

Transposition (jumping genes)
Transposon go between plasmid and chromosome
Unable to replicate independently

Question 15

How do transposons acquire new genes?

Answer 15

Integrons- gene capture and expression systems- “natural” genetic engineering

Question 16

What is an integron?

Answer 16

• Genetic element
• Usually resides on transposon
• Able to ‘poach’ resistant genes (extracts DNA segments and inserts into other DNA segments)

Question 17

What are the main mechanisms of resistance?

Answer 17

1. Target site alteration
2. Reduced access (efflux or impermeability)
3. Drug inactivation
4. Metabolic bypass

Question 18

What is modification?

Answer 18

-Bacterium modifies configuration of site so affinity is reduced- antibiotic can no longer bind to site

Question 19

Examples of modification (binding sites)

Answer 19

• MRSA has altered penicillin binding protein (PBP) 2a instead of PBP 2
• Ribosome (gentamycin)
• DNA gyrase (quinolone) altered

Question 20

How is access to target sites reduced?

Answer 20

Efflux- tetracyclines, macrolides, quinolones (flow out via pump)
Impermeability- altered porins

Question 21

What enzymes result in drug inactivation/ destruction?

Answer 21

• Beta lactamases
• Aminoglycoside modifying enzymes
• Erythromycin esterase
• Chloramphenicol acetyltransferase

Question 22

Which antibiotics are involved in metabolic bypass?

Answer 22

Sulphonamides

Trimethoprim

Question 23

How are these antibiotics involved in metabolic bypass?

Answer 23

Effect compromised by hyperproduction or additional target site
Synthase- sulphonamides, extra target dihydropteroate synthetase
Reductase (hyperproduction)- trimethoprim

Question 24

What are the strategies for control of resistance?

Answer 24

1. Conservation= remove devices (urinary and central catheters), drain abscesses (antibiotics don’t penetrate), source control
2. Prudent use= antibiotic polices (VRE in RIE), good prescribing practice (discourage topicals) de-escalation and date to stop)
3. Surveillance= use, R organisms, infection syndromes
4. Infection control= hand decontamination and disinfectant policies