T1ii / 20A05: Outline the mechanisms of antimicrobial resistance

20A05: Exam Report

Outline the mechanisms of antimicrobial resistance (50% of marks). Briefly outline the pharmacology of ciprofloxacin (50% of marks).

71% of candidates passed this question.

Most candidates had a structured answer to mechanisms of resistance that covered the major categories (alter target protein, prevent entry, efflux, degrade drug) and provided an example of a bacteria and the affected antibiotic, as was required to answer the question in full. Ciprofloxacin, whilst perhaps not a first line drug in the ICU, was not well known by many candidates. Better
answers included a brief outline of class, mechanism of action (action on DNA gyrase to inhibit replication), spectrum (Gram negatives particularly mentioning Pseudomonas, lesser Gram-positive cover, not anaerobes, some atypical), PK (with correct dose, wide penetration into tissues including bone/prostate etc., predominantly renal excretion), side effects/toxicity (common or
specific to cipro e.g. QT, tendinitis, arthropathy) and an example of resistance.

T1ii / 20A05: Outline the mechanisms of antimicrobial resistance (50 marks). Briefly outline the pharmacology of ciprofloxacin (50 marks)

Resistance = when the maximal level of the agent tolerated is insufficient to inhibit growth

  1. Natural – bacteria do not possess molecular target for that drug
  2. Acquired:

1. Modification of Antimicrobial Molecule

a. Chemical Alteration of the Antibiotic

        • Production of enzymes capable of introducing chemical changes to the antimicrobial molecule
        • Example: Aminoglycoside Modifying Enzymes (AMEs) which modify the hydroxyl/amino groups of the aminoglycoside, enabling resistance E Faecium

b. Destruction of the Antibiotic Molecule

        • b-lactamases produced by bacteria hydrolyse the b-lactam ring
        • \negates penicillin
        • still sensitive to cephalosporins
        • ESBLs = even more widespread resistance
        • R to cephalosporins/penicillin/b-lactamase inhibitors (Clav Acid)
        • Only Mero is effective

2. Prevention of Antibiotic Reaching Target

a. Decreased permeability

        • Many a/b have targets inside bacteria or on their membrane
        • Example: Vancomycin is not active against Gm- bacteria as it cannot penetrate the outer membrane
        • Example: P aeruginosa is very good at altering porin fn/expression to limit permeability of a/b

b. Efflux pumps

        • P aeruginosa possess an efflux system to pump a/b out of the cell

3. Change/Bypass of Target Site

      • Changing of target site = ¯affinity of drug
      • Example: VRE
        • Glycopeptides bind to D-Ala-D-Ala
        • Bacterial remodelling of cell wall to provide new substrate D-Ala-D-Lactate prevents Vancomycin binding
        • Especially common in enterococci (E Faecium)

4. Resistance Due to Global Cell Adaptive Processes

      • Example: Daptomycin resistance
      • Altered cell wall metabolism resulting in changes in surface charge of the bacteria and produces an electrostatic ‘repulsion’ of Daptomycin from the cell wall of enterococci

Ciprofloxacin

Class

Quinolone

Dose

400mg (IV) q8h

 

500-750mg (po) bd (step-down)

Mechanism

Bacteristatic & Bactericidal

MoA

Inhibits DNA gyrase enzymes

Promotes breakage of DNA

Time v Concentration

Combination concentration and time dependent killing

Post dose effect

Spectrum​

Covers

Doesn't Cover

Most G -ve including Pseudomonas

Atypicals including Legionella

Anaerobes

Indications

Intra-abdominal (with Metronidazole)

 

Expansion of G -ve cover in setting of renal impairment/allergy where other drugs cannot be used (ie Aminoglycosides)

PK

A

70% OBA.  Delayed by food

D

20% PPB

M

4 metabolites, probably hepatic

E

Renal excretion of metabolites

A/E

CNS – headache, insomnia, dizziness, hallucinations

Renal – interstitial nephritis

CVS – QTC prolongation, TdP, arrhythmias

GI – C Diff

Skin – toxic epidermal necrolysis

Drug Interaction – with warfarin, increases PT

MSK – long term use assosciated with msk toxicity particularly to cartilage ie AAA, spontaneous tendon rupture 

Resistance

Can evolve on therapy

Monitoring

ECG (QT)