DRUG RESISTANCE MECHANISMS & SUPERINFECTION
DRUG RESISTANCE MECHANISMS & SUPERINFECTION
DRUG RESISTANCE IN BACTERIA:
- Types: Natural or acquired.
Development of acquired resistance:
- 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.
- Due to physical contact between bacteria.
- Responsible for multidrug resistance.
- Eg: Seen with chloramphenicol & streptomycin.
- Transfer of resistance gene through bacteriophage.
- Eg: Seen with penicillin, erythromycin & chloramphenicol.
- Transfer of resistance gene through environment.
- Not significant clinically.
- Eg: Seen with penicillin G.
Transfer of antimicrobial drug resistance:
- Conjugation – Multiple drug resistance
- Transduction – Staph. aureus
- Transformation – Pneumococci & Neisseria
- 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.
- 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.
- 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).
- 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):
- 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).
- 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.
- Against gram +ve bacteria –
- Long PAE (> 1.5 hours) seen with most antimicrobials
- Against gram -ve bacteria:
- 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.
- 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.