Carbapenem core structure

• Derivatives of thienamycin (Streptomyces cattleya)
• Differ from penicillins: carbon replaces sulfur at position 1, double bond between C2 and C3
• Trans-1α-hydroxyethyl side chain at C6 → stability against ESBLs and AmpC β-lactamases
• The broad spectrum of carbapenems is directly linked to this structural stability

From thienamycin to clinical agents

• Thienamycin: too chemically unstable for clinical use
• Imipenem: N-formimidoyl derivative of thienamycin
  • Degraded by renal DHP-I → requires cilastatin
• Meropenem & ertapenem: 1β-methyl substituent at C2
  • Stable to DHP-I → no cilastatin needed
• Doripenem: available outside the US

PBP binding profile

• Carbapenems inhibit cell wall synthesis by binding to PBPs
• Preferential binding: PBPs 1a, 1b, 2, and 4
• Lesser binding to PBP3 (the main target of aminopenicillins and cephalosporins)
• Multi-PBP binding → broad spectrum of activity

Outer membrane penetration

• Carbapenems cross the gram-negative outer membrane through specific OMPs
• OprD (P. aeruginosa): imipenem’s primary entry portal
• OmpK35/OmpK36 (K. pneumoniae)
• OmpC/OmpF (Enterobacter spp.)
• Loss of these porins contributes to resistance

Time-dependent killing

• Carbapenems display time-dependent bactericidal activity
• Key PK/PD parameter: fT>MIC
• Target: 50%–100% of the dosing interval
• Clinical implication: extended or prolonged infusions optimize this target

β-Lactamase-mediated resistance

• Class A (KPC carbapenemases): Serine-based; K. pneumoniae carbapenemase is the most important globally

• Class B (Metallo-β-lactamases/MBLs): Zinc-dependent; hydrolyze ALL carbapenems; NO clinically available BLI inhibits them

• Class D (OXA-type): Found frequently in A. baumannii; emerging in Enterobacterales

Class A carbapenemases: KPC

Class B: Metallo-β-lactamases

• Zinc-dependent enzymes (NDM, VIM, IMP)
• Hydrolyze ALL β-lactams except aztreonam
• No clinically available BLI inhibits MBLs
• Treatment strategy: aztreonam + ceftazidime-avibactam
• Intrinsic MBLs in S. maltophilia, E. meningoseptica

Class D: OXA-type carbapenemases

• Found predominantly in Acinetobacter baumannii
• OXA-48-like enzymes emerging in Enterobacterales
• Generally not inhibited by vaborbactam or relebactam
• Limited treatment options

Porin-mediated resistance in P. aeruginosa

• OprD loss: Major contributor to carbapenem resistance
• Imipenem: OprD is the primary entry portal → most affected by OprD loss
• Meropenem: less dependent on OprD → less affected
• OprD loss often occurs during therapy

Efflux-mediated resistance

• MexA-MexB-OprM system in P. aeruginosa
• Meropenem is a substrate; imipenem is NOT
• Upregulation → increased meropenem resistance
• Combined with OprD loss → high-level resistance to both agents

Porin-mediated resistance in enterobacterales

• OmpK35/OmpK36 loss in K. pneumoniae
• OmpC/OmpF loss in Enterobacter spp.
• Often combined with β-lactamase production
• Contributes to resistance even without carbapenemase production

PBP-mediated resistance in Gram-positives

• Low-affinity PBP targets → class-wide β-lactam resistance
• PBP2a in MRSA → carbapenem resistance
• PBP5 in E. faecium → carbapenem resistance
• 40%–50% of S. aureus strains are MRSA
• 60%–80% of E. faecium strains are ampicillin-resistant

PBP binding resistance

PBP-mediated resistance in MDR strains

• PBP3 four-amino-acid insertions (typically YRIN or YRIK between residues 333–334 in the β2b–β2c loop, adjacent to the transpeptidase active site) reduce susceptibility to PBP3-targeting β-lactams (aztreonam, cefepime, ceftazidime).

• First described in 2015 with reduced aztreonam–avibactam susceptibility, these insertions are now common in globally disseminated high-risk E. coli lineages (ST167, ST405, ST410, ST648), which frequently co-carry NDM metallo-β-lactamases plus CMY cephalosporinases or CTX-M ESBLs.

• Many β-lactams rely predominantly on PBP3 inhibition and are therefore vulnerable to these target alterations; carbapenems, with broader PBP binding, are less affected — though carbapenem–β-lactamase inhibitor combinations differ in their behavior.

• Whole-genome sequencing is needed to rapidly detect uncommon resistance genotypes such as PBP3 insertions and guide rational combination therapy.

CRE: A growing threat

Why breakpoints changed

• Higher 2010 breakpoints missed resistance mechanisms
• Revised breakpoints negate need for routine carbapenemase detection (mCIM, Carba NP)
• But: confirming carbapenemase genes may still guide treatment
  • KPC → meropenem-vaborbactam preferred
  • MBL → aztreonam + ceftazidime-avibactam
  • OXA-48 → ceftazidime-avibactam

Two new combinations

Meropenem-vaborbactam

• Dose: 4 g IV q8h via 3-hour infusion (2 g meropenem + 2 g vaborbactam)
• Vaborbactam designed specifically to bind KPC
• Preferred agent for KPC-producing CRE (IDSA 2023 guidance)?
• Vaborbactam does NOT enhance activity vs P. aeruginosa (unless carbapenemase present)
• Dose adjustment based on MDRD formula

Imipenem-relebactam

• Dose: 1.25 g IV q6h via 30-minute infusion (500 mg imipenem + 500 mg cilastatin + 250 mg relebactam)
• Relebactam inhibits AmpC → restores imipenem activity vs P. aeruginosa
• Emerging role: difficult-to-treat P. aeruginosa
• AmpC drives resistance to imipenem more than meropenem
• Can also be used for KPC-producing CRE (less clinical data)

PK/PD of the BLI components

• Vaborbactam: %fT>CT is the PK/PD driver; target threshold ~8 μg/mL
• Relebactam: AUC/MIC ratio drives efficacy
• Both BLIs require renal dose adjustment
• 3-hour infusion for meropenem-vaborbactam optimizes both components

MIC₉₀ comparison: Gram-positive cocci

Comparative Activity of Ertapenem, Imipenem, and Meropenem (MIC₉₀, μg/mL)^a

MIC₉₀ Comparison: Gram-negative cocci & enterobacterales (1)

MIC₉₀ Comparison: Enterobacterales (2) & Non-fermenters

MIC₉₀ comparison: anaerobes

Gram-positive activity

• S. pneumoniae: MIC <0.03 μg/mL (penicillin-susceptible), ~0.5 μg/mL (penicillin-resistant)
• β-Hemolytic streptococci: exquisitely susceptible
• MSSA: MIC <0.5 μg/mL; MRSA: resistant (PBP2a)
• E. faecalis: susceptible to imipenem (MIC ≤2); resistant to ertapenem/meropenem
• E. faecium: resistant to all carbapenems (PBP5)

Gram-negative activity: Enterobacterales

• Most inhibited at MIC ≤1 μg/mL for imipenem/meropenem
• Ertapenem MICs typically ≤0.1 μg/mL (including ESBL-producers)
• Exceptions for imipenem: Morganella, Providencia, Proteus — higher MICs, CLSI has no breakpoints; relebactam does not restore activity
• KPC-producing K. pneumoniae: MIC ≥8 μg/mL → resistant
• KPC-producing E. coli: often lower MICs (0.5–4 μg/mL)

Gram-negative activity: Non-fermenters

• P. aeruginosa: susceptible to imipenem and meropenem but NOT ertapenem
• A. baumannii: variable susceptibility; OXA-type carbapenemases common
• S. maltophilia: intrinsically resistant (chromosomal MBL-L1)
• Burkholderia cepacia: variable

Anaerobic activity

• Ertapenem and meropenem: excellent anaerobic coverage
• Broad activity against Bacteroides fragilis group, Clostridium spp.
• Imipenem: good but may have slightly higher MICs for some Bacteroides
• No carbapenem active against Clostridioides difficile

Other notable activity

• Neisseria gonorrhoeae: highly susceptible; ertapenem activity against ceftriaxone-resistant strains
• N. meningitidis: MIC <0.1 μg/mL
• H. influenzae: susceptible including β-lactamase producers
• Nocardia spp.: imipenem has best activity
• Mycobacteria: imipenem active against some NTM and M. tuberculosis

Ertapenem: Key features

• Once-daily dosing (1 g IV q24h) — ideal for OPAT
• Long half-life (~4 hours) due to high protein binding (92%–95%)
• No activity against: P. aeruginosa, Acinetobacter, Enterococcus
• Excellent ESBL-producer coverage
• Preferred for community-acquired polymicrobial infections

Ertapenem: Hypoalbuminemia concern

• 92%–95% protein bound → sensitive to albumin levels
• Hypoalbuminemia → increased free drug → faster renal clearance
• Clinical consequence: subtherapeutic levels despite “adequate” dosing
• Consider alternative carbapenem or TDM in ICU patients with low albumin

Imipenem-cilastatin: Key features

• Must be coadministered with cilastatin (DHP-I inhibitor)
• Most frequent dosing: q6h (less convenient)
• Highest seizure risk among carbapenems
• Unique activity: E. faecalis, Nocardia, mycobacteria
• Decreased infusion stability vs. meropenem

Imipenem: Seizure risk

• Reported rates: 1%–3% general; up to 10% with risk factors
• Risk factors: renal impairment, CNS pathology, high doses
• Mechanism: GABA receptor antagonism
• Dose reduction in renal impairment is critical
• Meropenem preferred when CNS infection or seizure risk exists

Meropenem: Key features

• Most versatile carbapenem for serious infections
• Extended infusion (3 hours) optimizes PK/PD target
• ~2% protein binding → nearly all drug is free
• Half-life ~1 hour with normal renal function
• Good CSF penetration → carbapenem of choice for meningitis
• Can combine total daily dose in 2 bags, infuse each over 12 hours

Meropenem: Extended infusion strategy

• Standard: 1–2 g IV q8h over 30 minutes
• Extended: 1–2 g IV q8h over 3 hours
• Rationale: increases %fT>MIC from ~60% to >90% at standard dose
• Most beneficial for organisms with elevated MICs (4–8 μg/mL)
• Not stable for continuous infusion — use 2 bags over 12h each as alternative

PK parameters at a glance

Renal dose adjustment

• All carbapenems require dose reduction in renal impairment
• Critical for seizure prevention (especially imipenem)
• Ertapenem: no adjustment until CrCl <30 mL/min
• Imipenem: reduce dose AND frequency as CrCl decreases
• Meropenem: extend interval; consider extended infusion maintained

Common adverse effects

Valproic acid interaction

• Class effect — ALL carbapenems cause precipitous VPA decrease
• Onset: within 24 hours of coadministration
• Mechanism: increased VPA glucuronidation + decreased intestinal absorption
• VPA levels often drop 50%–90%
• Clinical recommendation: avoid concomitant use; use alternative anticonvulsant or alternative antibiotic

β-Lactam cross-allergenicity

• Carbapenems share the β-lactam core with penicillins
• Cross-reactivity rate: approximately 1%
• Carbapenems generally safe in penicillin-allergic patients
• Use caution with history of severe (anaphylactic) penicillin allergy
• Aztreonam: no cross-reactivity with penicillins/carbapenems
  • Exception: shares side chain with ceftazidime

Treatment algorithm: Carbapenem selection

• Empiric/broad-spectrum: Meropenem (extended infusion)
• Step-down/OPAT: Ertapenem
• Mixed GN + E. faecalis: Imipenem
• KPC-producing CRE: Meropenem-vaborbactam
• DTR P. aeruginosa: Imipenem-relebactam
• MBL producers: Aztreonam + ceftazidime-avibactam
• Severe β-lactam allergy + GN coverage: Aztreonam

ESBL-producing enterobacterales

• Carbapenems remain agents of choice for serious ESBL infections
• MERINO trial: meropenem superior to piperacillin-tazobactam for ESBL bacteremia
• Ertapenem suitable for step-down therapy and less severe infections
• Once-daily dosing facilitates OPAT transition

KPC-producing CRE: Preferred agents

• First-line: Meropenem-vaborbactam (IDSA 2023 guidance)
• Alternative: Ceftazidime-avibactam
• Vaborbactam designed specifically for KPC binding
• Early clinical data: improved outcomes vs. best available therapy
• Imipenem-relebactam: less clinical data for KPC infections

Difficult-to-Treat P. aeruginosa

• DTR-PA: resistant to all traditional first-line agents
• Imipenem-relebactam: key agent (relebactam inhibits AmpC → restores imipenem activity)
• AmpC overproduction is a major driver of imipenem resistance in P. aeruginosa
• Alternative: ceftolozane-tazobactam, ceftazidime-avibactam
• For MBL-producing P. aeruginosa: cefiderocol

MBL-producing organisms

• No available BLI inhibits MBLs
• Aztreonam: stable to MBL hydrolysis
• Aztreonam + ceftazidime-avibactam: synergistic combination
  • Avibactam protects aztreonam from serine β-lactamases
  • Aztreonam resists MBL hydrolysis
• Cefiderocol: alternative for MBL-producers

Aztreonam: Unique monobactam

Aztreonam: Dosing and PK

• Adult dose: 2 g IV q8h (consider extended infusion over 3 hours)
• Pediatric dose: 30 mg/kg IV q6–8h (max 120 mg/kg/day)
• Higher doses for cystic fibrosis patients
• Adverse effects: rash, diarrhea, transaminase elevation, neutropenia, phlebitis

Aztreonam side chain similarity

• Similar R1 side chain to ceftazidime and cefiderocol
• This side chain provides activity vs P. aeruginosa
• Cross-allergenicity possible with ceftazidime (but not other cephalosporins)
• Stability to MBLs is due to the monobactam ring, not the side chain

Summary: Choosing the right carbapenem

Class-wide reminders

• ALL carbapenems: reduce dose in renal impairment
• ALL carbapenems: precipitous decrease in VPA levels
• ALL carbapenems: time-dependent kill → optimize infusion duration
• ALL carbapenems: no activity vs MRSA or VRE
• ALL carbapenems (except ertapenem): Pseudomonas activity
• Neither BLI: covers MBLs or OXA-48