STEPTRACKERMICROBIOLOGY + PHARMACOLOGY | CELL WALL INHIBITORS & RESISTANCE | HIGH-YIELD REVIEW

β-Lactams II, Vancomycin & Resistance

The broadest β-lactams, the non-β-lactam wall drugs used for resistant gram-positives, and the four ways bacteria defeat antibiotics.

FOCUS ON
Carbapenems (imipenem + cilastatin, meropenem, ertapenem): broadest β-lactams, gram ⁺/⁻/anaerobes; ertapenem misses Pseudomonas; imipenem → seizures. Aztreonam (monobactam): gram ⁻ aerobes only, incl. Pseudomonas; safe in penicillin allergy. Vancomycin: binds D-Ala-D-Ala → blocks glycan polymerization; gram ⁺ only (MRSA, C difficile orally, penicillin-resistant pneumococcus); toxicities: nephro-, ototoxicity, vancomycin infusion reaction (histamine; slow the infusion). Resistance: D-Ala-D-Lac (VRE). Daptomycin: membrane depolarization; inactivated by surfactant → not for pneumonia; ↑ CPK. Resistance mechanisms: enzymatic inactivation, altered target, ↓ entry, efflux.
DRUG · TOPIC
MECHANISM
USE
TOXICITY · NOTES
Imipenem-cilastatin · meropenem
Carbapenem; resists most β-lactamases (incl. ESBL)
Serious mixed infections, ESBL organisms, Pseudomonas
Cilastatin blocks renal dehydropeptidase · seizures (imipenem) · C difficile
Ertapenem
Carbapenem, once daily
Community intra-abdominal, ESBL outpatient therapy
No Pseudomonas, Acinetobacter
Aztreonam
Monobactam; binds PBP3
Gram ⁻ rods incl. Pseudomonas in patients with severe penicillin allergy
No gram ⁺ or anaerobe coverage
Vancomycin (IV)
Binds D-Ala-D-Ala terminal of peptidoglycan precursors → no polymerization
MRSA, S epidermidis, Enterococcus (ampicillin-resistant), resistant pneumococcus
Nephrotoxicity, ototoxicity, infusion reaction (flushing) · monitor troughs/AUC
Vancomycin (oral)
Not absorbed → stays in colon
C difficile colitis
IV vancomycin doesn't reach the gut lumen
Daptomycin
Inserts in gram ⁺ membrane → depolarization
MRSA/VRE bacteremia, right-sided endocarditis
Myopathy, ↑ CPK · inactivated by surfactant → no pneumonia
Bacitracin · fosfomycin · polymyxins
Blocks peptidoglycan carrier · MurA inhibitor · disrupts gram ⁻ membrane
Topical · cystitis · MDR gram ⁻ (colistin)
Polymyxins: nephro- and neurotoxicity
Enzymatic inactivation
β-lactamases (penicillinase, ESBL, AmpC, carbapenemases KPC/NDM); aminoglycoside-modifying enzymes; chloramphenicol acetyltransferase
Most common resistance in gram ⁻
Often plasmid-borne → spreads
Altered target
PBP2a (mecA → MRSA); altered PBPs (resistant pneumococcus); D-Ala-D-Lac (VRE); methylated rRNA (macrolides); mutated DNA gyrase (FQ); rpoB (rifampin)
Gram ⁺ resistance
β-lactamase inhibitors don't help
Decreased entry
Porin loss in gram ⁻ outer membrane
Carbapenem-resistant Pseudomonas (OprD)
—
Efflux pumps
Pump drug out
Tetracyclines, macrolides, fluoroquinolones
—
Stewardship
Narrowest effective drug, shortest duration
De-escalate after cultures
Reduces C difficile and resistance

Mechanism — how VRE escapes vancomycin

Normal precursor ends in D-Ala-D-Ala
→
Vancomycin binds tightlyBlocks wall synthesis
vanA operon (transposon)
→
Precursor ends in D-Ala-D-Lac
→
Binding 1000× weaker → resistantUse linezolid or daptomycin

Resistance mechanisms

MECHANISM
EXAMPLE
WORKAROUND
Enzyme
β-lactamase, ESBL, KPC
Inhibitor combos, carbapenem, avibactam
Altered target
PBP2a (MRSA), D-Ala-D-Lac (VRE)
Vancomycin, ceftaroline · linezolid, daptomycin
Less entry
Porin loss
Different class
Efflux
Tetracycline pumps
Different class

How it's tested

COMMON CONFUSIONMRSA resistance (altered PBP2a) isn't overcome by β-lactamase inhibitors — piperacillin-tazobactam doesn't treat MRSA.
THE TRAPFlushing and itching during a fast vancomycin infusion is a histamine release reaction, not an allergy — slow the rate and give antihistamines.
YOUR APPROACHResistant organism → which mechanism → which class escapes it → organ-specific limits (daptomycin lung, oral vs IV vancomycin).

If you see… think…

Seizure in a patient on a carbapenem with renal failure → imipenem
Why cilastatin is given with imipenem → blocks renal dehydropeptidase
Severe penicillin allergy with Pseudomonas → aztreonam
Red flushing of face and neck during vancomycin → infusion reaction (slow it)
Oral drug for C difficile → vancomycin or fidaxomicin
Enterococcus resistant via D-Ala-D-Lac → VRE
Drug that fails in pneumonia because surfactant binds it → daptomycin
MRSA gene → mecA (PBP2a)
Klebsiella resistant to meropenem → KPC carbapenemase
Last-line gram ⁻ drug with nephrotoxicity → colistin (polymyxin E)