MicrobiologyTier 1Medical Sciences concept

Antibiotic resistance mechanisms (beta-lactamase hydrolysis, efflux, porin loss, target modification)

Core concept

Four mechanisms

1. Enzymatic inactivation - the dominant mechanism clinically
- Beta-lactamases hydrolyse the beta-lactam ring
- Aminoglycoside-modifying enzymes (acetyl-, adenylyl-, phosphotransferases)
- Chloramphenicol acetyltransferase; erm-independent esterases
2. Target modification
- Altered PBP - PBP2a from mecA -> MRSA; altered PBP2x/2b -> penicillin-resistant pneumococcus
- Altered peptidoglycan precursor - VRE (below)
- Ribosomal methylation - erm -> MLSb (macrolide-lincosamide-streptogramin B) resistance
- gyrA/parC mutation -> fluoroquinolone resistance
- rpoB -> rifampicin; katG/inhA -> isoniazid; 23S rRNA -> linezolid
3. Reduced uptake - porin loss (OmpK35/36 in Klebsiella, OprD in Pseudomonas -> carbapenem)
4. Active efflux - AcrAB-TolC, MexAB-OprM; broad and often multi-drug
Bypass - dihydropteroate/dihydrofolate reductase substitution (sulfonamides/trimethoprim); vanA operon
Intrinsic vs acquired: acquired resistance travels on plasmids, transposons and integrons - horizontal transfer by conjugation, transformation and transduction is why resistance spreads faster than any organism can evolve it

Beta-lactamase classification (Ambler)

Class	Type	Examples	Inhibited by clavulanate/tazobactam?	Inhibited by avibactam/vaborbactam?
A	Serine	TEM, SHV, CTX-M (ESBL), KPC	ESBL yes; KPC no	Yes
B	Metallo (Zn2+)	NDM, VIM, IMP	No	No
C	Serine	AmpC (chromosomal, inducible)	No	Yes
D	Serine (oxacillinase)	OXA-48, OXA-23 (Acinetobacter)	No	Avibactam yes; vaborbactam no

Carbapenem resistance in Gram-negatives is most often a carbapenemase, not porin loss or efflux alone - the single most examined fact here
- KPC (class A), NDM/VIM/IMP (class B metallo), OXA-48 (class D)
ESBL - CTX-M dominant worldwide; hydrolyses third-generation cephalosporins and aztreonam; treat serious infection with a carbapenem - MERINO showed piperacillin-tazobactam was inferior for bloodstream infection
AmpC "SPACE/SPICE" organisms (Serratia, Providencia, indole-positive Proteus, Citrobacter, Enterobacter, Morganella, Hafnia) - inducible chromosomal AmpC -> treatment-emergent resistance to third-generation cephalosporins; use cefepime, a carbapenem or a non-beta-lactam
Metallo-beta-lactamases hydrolyse everything except aztreonam (monobactams resist MBLs) -> aztreonam + avibactam (avibactam covers the accompanying serine enzymes) is the rational NDM regimen; cefiderocol (siderophore cephalosporin, Trojan-horse iron uptake) is the other option

Two named exam mechanisms

VRE - vanA/vanB operon replaces the peptidoglycan terminal D-Ala-D-Ala with D-Ala-D-Lac
- -> ~1,000-fold loss of vancomycin hydrogen bonding
- VanA: resistant to vancomycin AND teicoplanin (plasmid, Tn1546, inducible by both)
- VanB: resistant to vancomycin, SUSCEPTIBLE to teicoplanin (not induced by teicoplanin)
- VanC (E. gallinarum, E. casseliflavus) is intrinsic, low-level, D-Ala-D-Ser
MRSA - mecA on SCCmec encodes PBP2a, low affinity for all beta-lactams -> resistance to every beta-lactam except the anti-MRSA cephalosporins (ceftaroline, ceftobiprole)

Resistance mechanism dictates the drug, not the susceptibility report alone
- ESBL bacteraemia -> meropenem
- AmpC organism -> avoid ceftriaxone even if reported susceptible
- KPC -> ceftazidime-avibactam or meropenem-vaborbactam
- NDM/VIM/IMP -> aztreonam-avibactam or cefiderocol (ceftazidime-avibactam is inactive)
- OXA-48 -> ceftazidime-avibactam
- MRSA -> vancomycin, daptomycin (not for pneumonia - inactivated by surfactant), linezolid, ceftaroline
- VRE -> linezolid, daptomycin (high dose), teicoplanin if vanB
Inducible clindamycin resistance - erythromycin-resistant/clindamycin-susceptible S. aureus: do a D-test before using clindamycin
Antimicrobial stewardship principles: shortest effective course, source control, de-escalate on culture, avoid treating colonisation, IV-to-oral switch
Resistance also arises during therapy - rifampicin, fusidic acid and fluoroquinolones must never be used as monotherapy for staphylococcal deep infection

Pharmacodynamic indices of antibiotic efficacy - time- vs concentration-dependent killing
MRSA, VRE and multi-resistant Gram-negative infection
Antimicrobial stewardship; infection prevention and control
Molecular biology - ribosome as antibiotic target
Tuberculosis drug resistance (MDR/XDR)
Febrile neutropenia and empiric therapy

3 more sections, plus exam facts

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