Beta Lactam Resistance

Resistance to beta-lactams arises through four main routes: hydrolysis by beta-lactamases, alteration or replacement of PBPs, reduced permeability through porin loss, and efflux. Beta-lactamases are the dominant mechanism in Gram-negative bacilli; PBP changes dominate in Gram-positive cocci. Most clinical failures involve more than one mechanism.

Beta-lactamases.

• Class A serine enzymes: penicillinases (TEM-1, SHV-1), ESBLs (CTX-M, extended TEM and SHV) that hydrolyse third generation cephalosporins and aztreonam but not cephamycins or carbapenems, and KPC carbapenemases.
• Class B metallo-beta-lactamases (NDM, VIM, IMP): zinc-dependent, hydrolyse all beta-lactams except aztreonam; not inhibited by clavulanate, tazobactam, avibactam, vaborbactam or relebactam.
• Class C AmpC cephalosporinases: chromosomal and inducible in Enterobacter, Klebsiella aerogenes, Citrobacter freundii, Serratia, Morganella, Providencia and Pseudomonas; plasmid-mediated (CMY, DHA) in E. coli and Klebsiella; hydrolyse cephalosporins and cephamycins, and are not inhibited by clavulanate.
• Class D oxacillinases: OXA-48-like in Enterobacterales; OXA-23, OXA-24/40, OXA-58 in Acinetobacter baumannii.

Altered targets. PBP2a (mecA or mecC) in MRSA; PBP5 changes in ampicillin-resistant Enterococcus faecium; mosaic PBP2x, 2b and 1a in penicillin-resistant pneumococci; PBP3 changes in beta-lactamase-negative ampicillin-resistant H. influenzae.

Permeability and efflux. Loss of OmpK35 and OmpK36 with ESBL or AmpC in Klebsiella gives carbapenem resistance; loss of OprD and upregulation of MexAB-OprM in Pseudomonas.

Beta-lactam classes differ in which mechanisms defeat them:

• Penicillins: defeated by almost all beta-lactamases; inhibitors restore activity against class A enzymes.
• Cephalosporins: first and second generations are hydrolysed by ESBLs and AmpC; third generation agents are hydrolysed by ESBLs and AmpC; cefepime is stable to AmpC but not to ESBL; ceftaroline is stable to PBP2a but not to ESBLs.
• Carbapenems: stable to ESBL and AmpC; hydrolysed by KPC, MBLs and OXA carbapenemases.
• Aztreonam: stable to MBLs; hydrolysed by ESBL, AmpC and KPC.
• Newer inhibitor combinations: avibactam, relebactam, vaborbactam and durlobactam inhibit class A, C and (some) D enzymes but not MBLs.

Matching the drug to the mechanism.

• ESBL producers: carbapenem (meropenem 1 g every 8 hours or ertapenem 1 g daily) for bacteraemia and severe infection; piperacillin-tazobactam and cefepime are unreliable.
• Inducible AmpC organisms: cefepime 2 g every 8 hours (if the MIC is low) or a carbapenem; avoid ceftriaxone, ceftazidime and piperacillin-tazobactam for serious infection.
• KPC: ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam.
• OXA-48-like: ceftazidime-avibactam or cefiderocol.
• MBL producers: ceftazidime-avibactam with aztreonam, aztreonam-avibactam, or cefiderocol.
• Carbapenem-resistant A. baumannii: sulbactam-based regimens with a partner.
• MRSA: ceftaroline or ceftobiprole as the beta-lactam options.
• Penicillin-resistant pneumococcal meningitis: ceftriaxone 2 g every 12 hours with vancomycin until the MIC is known.

Testing. Request carbapenemase identification when a carbapenem is non-susceptible; check for D-test and cefoxitin screening in staphylococci; extended susceptibility reporting for pneumococci in meningitis.

Pitfalls. The inoculum effect makes beta-lactams less effective against high-burden infections with beta-lactamase producers; therapy with a third generation cephalosporin can select derepressed AmpC mutants in Enterobacter during treatment; reported “susceptible” results for ESBL producers do not guarantee clinical success.

Monitoring. Clinical response at 48 to 72 hours, repeat cultures for bacteraemia, review of susceptibility when the isolate changes, drug levels for the beta-lactam where available in critical illness.

Special groups. Renal impairment: carbapenems and cefepime need dose adjustment because of neurotoxicity. Pregnancy: carbapenems and cephalosporins are acceptable when indicated. Children: weight-based carbapenem dosing (meropenem 20 mg/kg every 8 hours, 40 mg/kg in meningitis). Region: CTX-M ESBLs are widespread in East Africa, so empirical carbapenem use is common in severe sepsis, which in turn raises carbapenem resistance and makes culture-directed de-escalation important.