Drug Resistance Mechanisms & Superinfection

DRUG RESISTANCE MECHANISMS & SUPERINFECTION


DRUG RESISTANCE MECHANISMS & SUPERINFECTION

DRUG RESISTANCE IN BACTERIA:

  • Types: Natural or acquired.

Development of acquired resistance:

  • Types:
    • Single step mutation & multi-step mutation
  • Single step mutation – Seen with streptomycin & rifampicin.
  • Multi-step mutation – Seen with erythromycin, tetracycline & chloramphenicol.

Transfer of drug resistance:

  • Transferred from one microorganism to other by gene transfer called “infectious resistance”, via conjugation, transduction or transformation.

Description:

1. Conjugation:

  • Due to physical contact between bacteria.
  • Responsible for multidrug resistance.
  • Eg: Seen with chloramphenicol & streptomycin.

2. Transduction:

  • Transfer of resistance gene through bacteriophage.
  • Eg:  Seen with penicillin, erythromycin & chloramphenicol.

3. Transformation:

  • Transfer of resistance gene through environment.
  • Not significant clinically.
  • Eg:  Seen with penicillin G.

Remember easily:

Transfer of antimicrobial drug resistance:

  • Conjugation – Multiple drug resistance
  • Transduction – Staph. aureus
  • Transformation – Pneumococci & Neisseria

Significance:

  • Resistance pressurizes antimicrobial selection process.
  • Antimicrobials allow resistant organisms to grow preferentially.

Mechanism of resistance:

5 different mechanisms involved,

1. Decreased target affinity:

  • Eg:  Seen with pneumococci & staphylococci – By altering penicillin-binding proteins.

2. Alternative metabolic pathway development:

  • Eg: Seen with sulfonamide-resistant organisms.
  • Synthesized from folic acid instead of synthesizing from PABA.

3. Elaboration of enzymes inactivating drug:

  • ß-lactamases – For Penicillins & cephalosporins
  • Chloramphenicol acetyltransferase – For chloramphenicol.
  • Aminoglycoside inactivating enzymes – For Aminoglycosides.

Remember easily:

  • A – Aminoglycosides.
  • B – Beta-lactams.
  • C – Chloramphenicol.

4. Decreased drug permeability:

  • Due to loss of specific channels.
  • Eg: Aminoglycosides & tetracyclines.
  • Attain much lower drug concentration in resistant organisms than insensitive ones.

5. By efflux pumps development:

  • Tetracyclines, erythromycin & fluoroquinolones.
  • Results inactive drug extrusion from resistant microorganisms.

SUPERINFECTION

  • Refers to new infection development, due to inappropriate antimicrobial therapy.
    • Due to inappropriate destruction of normal microbial flora.
    • Normal flora produces bacteriocin for host defense.
  • Eg: Broad spectrum antibiotics (tetracyclines, chloramphenicol, clindamycin, aminoglycosides & ampicillin) destructs normal flora –> new infection development.
  • Seen in immunocompromised patients (Most common).
  • Common sites: 
    • Oropharynx, intestine, respiratory & genitourinary tracts.
  • Organisms involved: 
    • Candida albicans, Clostridium difficile, staphylococci, proteus & pseudomonas
    • Clostridium difficile superinfection – Results in pseudomembranous colitis.
      • Due to 3rd generation cephalosporins (most commonly).
  • Treatment:
    • DOC – Metronidazole.
    • Alternative drug – Vancomycin.

Effects of superinfection:

  • Enhancing drug effects: 
    • Eg: Enhanced warfarin anticoagulant effects –  
    • Due to commensal flora loss & decreased vitamin K formation.

Note on Concentration-Dependent Killing (CDK) & Time Dependent Killing (TDK):

CDK:

  • Killing effect of drug is high, depending on concentration.
  • Ratio of peak concentration to MIC is more.
  • Eg: Aminoglycosides & fluoroquinolones.
  • Dosage preference: Large single dose produce better action (compared to daily dose divided into 2-3 portions).

TDK:

  • Antimicrobial action depends on length of time.
  • Drug concentration is above MIC levels.
  • Eg: Seen with β-lactams & macrolides.
  • Dosage preference: Multiple daily doses preferred over single dose.

Post-antibiotic effect (PAE):

  • Antibiotic exposure stops microbial growth.
  • In an antibiotic-free medium, growth resumes yet after lag period.
  • Inhibitory effect of antibiotics presents even at concentration lowered than MIC.
  • This period is known as PAE.

Eg:

  • Against gram +ve bacteria – 
    • Long PAE (> 1.5 hours) seen with most antimicrobials
  • Against gram -ve bacteria:
    • Carbapenems
    • Drug affecting protein synthesis – Aminoglycosides, chloramphenicol & tetracycline.
    • Drugs affecting DNA synthesis – Quinolones & rifampicin.
  • Rifampicin prolongs PAE of isoniazid.
    • Hence,isoniazid given thrice weekly on rifampicin combination.
    • Short course tuberculosis chemotherapy – Administered daily, if used alone.

Exam Important

  • Development of acquired resistance is by either single step mutation & multi-step mutation.
  • Single step mutation is seen with streptomycin & rifampicin.
  • Multi-step mutation is seen with erythromycin, tetracycline & chloramphenicol.
  • Drug resistance is transferred from one microorganism to other by gene transfer called “infectious resistance”, via conjugation, transduction or transformation.
  • Conjugation is responsible for multidrug resistance & also with chloramphenicol & streptomycin.
  • Transduction is transfer of resistance gene through bacteriophage, as seen with penicillin, erythromycin & chloramphenicol.
  • Transformation transfers resistance gene through environment,  as seen with penicillin G.
  • Sulfonamide-resistant organisms choose an alternative metabolic pathway development, ie., synthesized from folic acid instead of synthesizing from PABA.
  • Penicillins & cephalosporins utilize ß-lactamases for inactivating drug.
  • Chloramphenicol utilize Chloramphenicol acetyltransferase for drug resistance development.
  • Aminoglycoside inactivating enzymes helps in developing resistance among aminoglycosides.
  • Tetracyclines, erythromycin & fluoroquinolones develop efflux pumps for drug resistance mechanisms.
  • Broad spectrum antibiotics (tetracyclines, chloramphenicol, clindamycin, aminoglycosides & ampicillin) destructs normal flora resulting in superinfection. 
  • Superinfection is most commonly seen with immunocompromised patients.
  • Oropharynx, intestine, respiratory & genitourinary tracts are the most common sites for superinfection.
  • Clostridium difficile superinfection results in pseudomembranous colitis, mostly due to 3rd generation cephalosporins.
  • Due to commensal flora loss & decreased vitamin K formation, there is enhanced warfarin anticoagulant effects.
  • Aminoglycosides & fluoroquinolones act by CDK (Concentration-Dependent Killing).
  • β-lactams & macrolides act by TDK (Time Dependent Killing).
  • Rifampicin prolongs PAE of isoniazid, hence, isoniazid is given thrice weekly on rifampicin combination.
Don’t Forget to Solve all the previous Year Question asked on DRUG RESISTANCE MECHANISMS & SUPERINFECTION

Module Below Start Quiz

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this:
Malcare WordPress Security