Carbapenems and Aztreonam

Chemistry and Classification

Beta-lactam classification

Carbapenems and monobactams are both members of the beta-lactam family of antibiotics. They are all cell-wall synthesis inhibitors. Members of the beta-lactam family include:

• Penicillins
• Cephalosporins
• Carbapenems:
  • Imipenem
  • Doripenem
  • Meropenem
  • Ertapenem
• Monobactams: 
  • Aztreonam

Carbapenem structure

Carbapenems consist of:

• A beta-lactam ring: a 4-member ring containing 2 carbons (the α and β carbons), a nitrogen, and a carbonyl group (carbon double-bonded to oxygen)
  • The antibacterial portion of the structure
  • Can be hydrolyzed (i.e., broken) by beta-lactamases, which are produced by certain resistant bacteria
  • If this ring is broken, the medication loses its antibacterial properties.
  • All beta-lactams contain a beta-lactam ring.
• A side chain known as the R group: 
  • Bound to the α-carbon in the beta-lactam ring
  • Differentiates different carbapenems from one another
  • Responsible for their unique pharmacokinetics and spectrums of activity
  • Certain structures can sterically inhibit the hydrolysis of the beta-lactam ring by beta-lactamase. 
• A 5-member amide ring with a second R group

Monobactam structure

Monobactams are also beta-lactam antibiotics. Their structure is different enough from penicillin that there is no cross-allergy with penicillins. Azetreonam is the only marketed monobactam. Monobactam structures include:

• The beta-lactam ring
• A side chain with an R group
• A -SO₃H group

Mechanisms of Action and Resistance

All beta-lactams, including carbapenems and monobactams, work by inhibiting bacterial cell wall synthesis.

Background: Understanding cell walls

• Bacterial cell walls contain peptidoglycan chains (large, thick layers in gram-positive organisms, and relatively smaller/thinner layers in gram-negative organisms)
• The peptidoglycan chains are made up of:
  • A sugar backbone with 2 alternating sugars: 
    • N-acetylmuramic acid (NAM) 
    • N-acetylglucosamine (NAG)
  • Short peptide side chains off the NAM sugars
• These short peptides form cross-linked bridges between adjacent peptidoglycan chains, creating a fishnet-like structure.
  • These bridges are necessary for the peptidoglycan (and thus cell wall) structure.
  • PBPs are the enzymes that create these cross-linked bridges.

Mechanism of action

All beta-lactams work by irreversibly binding to and inhibiting the PBPs → beta-lactam antibiotics inhibit cell wall synthesis

Bactericidal activity

Beta-lactams, including the carbapenems and monobactams, are bactericidal (rather than bacteriostatic). 

• The bacterial cell wall is necessary for its survival → without it, cell death is initiated
• When bacteria attempt to replicate, they shed their cell walls.
• In the presence of beta-lactams, however, they are unable to form new cell walls.
• The bacteria are unable to effectively divide, and the remaining cell autocatalyzes and dies.

Mechanisms of resistance

Bacteria employ 3 primary mechanisms to resist beta-lactams:

• Beta-lactamase resistance: 
  • Beta-lactamase is an enzyme that cleaves the beta-lactam ring and inactivates the antibiotic.
  • Although most carbapenems and monobactams are resistant to beta-lactamases, there is increasing resistance, especially among gram-negative organisms.
  • Most common type of resistance
• PBP-mediated resistance (↓ binding to PBPs): 
  • Mutations in the PBPs → result in ↓ affinity of the beta-lactams to the PBP 
  • Despite the mutations, these PBPs are still able to produce a cell wall.
• ↓ Membrane permeability 
  • Carbapenems enter cells through specialized channels. 
    • Evidence suggests carbapenems do not use the porin channels used by other beta-lactams; they use a different channel.
    • Although less common, this channel can be altered to ↓ carbapenem permeability
  • ↓ Permeability → ↓ antibiotic within the cell → antibiotic resistance
  • A common mechanism of resistance against carbapenems in Pseudomonas aeruginosa

Mechanism of imipenem degradation

• Renal dehydropeptidase: a different type of enzyme produced by the kidney, which is capable of inactivating imipenem
• Cilastatin is a dehydropeptidase inhibitor and is always given in combination with imipenem.

Beta-lactamase inhibitors

Due to the increasing problem of resistance from beta-lactamases, beta-lactamase inhibitors have been developed and are often combined with different beta-lactam antibiotics. Available carbapenem and monobactam/beta-lactamase inhibitor combinations include:

• Meropenem/vaborbactam
• Imipenem/cilastatin/relebactam
• Aztreonam/avibactam

Carbapenems

Pharmacokinetics

• Distribution: penetrates well into all bodily fluids and tissues, including the peritoneal fluid, pulmonary fluid, bone, bile, and urine
• Protein binding: 
  • < 20%: meropenem, imipenem, doripenem
  • > 85%: ertapenem
• Metabolism:
  • Imipenem: metabolized in the proximal renal tubule by renal dehydropeptidase I
  • Others: 
    • Stable against renal dehydropeptidase I, so can be administered without cilastatin
    • Hepatic hydrolysis of the beta-lactam ring to inactive metabolites
• Half-life:
  • Ertapenem: approximately 4 hours → once daily dosing
  • Others: 1–2 hours; require more frequent dosing
• Excretion: 
  • Primarily in the urine as unchanged drug
  • Some have very small levels of fecal excretion.

Indications

• Considered to be very broad-spectrum antibiotics with activity against:
  • Gram-positive organisms:
    • Streptococcus spp.
    • Staphylococcus (not active against MRSA)
    • Enterococcus faecalis
    • Listeria spp.
  • Most Enterobacteriaceae: 
    • Escherichia coli
    • Klebsiella 
    • Proteus
    • Serratia 
    • Enterobacter
    • Citrobacter 
  • Beta-lactamase-producing H. influenzae and N. gonorrhoeae
  • Pseudomonas aeruginosa
  • Anaerobes:
    • Bacteroides
    • Fusobacterium
    • Clostridium 
    • Peptostreptococcus
• Typically reserved for:
  • Serious and/or life-threatening infections 
  • MDR infections
  • Hospital-acquired infections (HAIs)
• Common clinical uses include:
  • Severe intra-abdominal and pelvic infections (e.g., ruptured appendicitis, septic abortions)
  • Complicated skin and soft-tissue infections
  • Bacterial meningitis
  • Intracranial and spinal abscesses
  • Osteomyelitis
  • Complicated and/or healthcare-associated pneumonia (HCAP)
  • Complicated urinary tract infections (UTIs)
  • Sepsis
  • Neutropenic fever
• The carbapenems cross the placenta but generally are considered safe in pregnancy if they are otherwise thought to be required.

Adverse effects

• CNS toxicity (especially in patients with underlying CNS disease or impaired renal function):
  • Mental status changes
  • Myoclonus
  • Seizures (especially imipenem)
• Hematologic effects:
  • Anemia
  • Thrombocytopenia
• GI upset
• ↑ Serum transaminases
• Rash
• Superinfection:
  • Fungal infections
  • Clostridioides difficile/pseudomembranous colitis

Contraindications

• Beta-lactam allergies
• Use in caution with patients who have:
  • Underlying CNS disease
  • Impaired renal function
• Imipenem is contraindicated in pediatric CNS infections due to seizure potential.

Monobactams: Aztreonam

Pharmacokinetics

• Distributed widely in body tissues, CSF, bronchial secretions, peritoneal fluid, bile, and bone
• Protein binding: approximately 50%
• Metabolism: 
  • Minor hepatic metabolism
  • Not degraded by certain types of beta-lactamases
• Half-life: 1–2 hours with normal renal function
• Excretion:
  • 60%–70% in the urine as unchanged drug
  • Approximately 10% in feces

Indications

• Narrower spectrum than carbapenems
• Typically used for aerobic gram-negative rod infections in patients with serious beta-lactam allergies who require beta-lactam therapy:
  • Lower respiratory tract infections (LRTIs)
  • UTIs
  • Skin and soft-tissue infections
  • Intra-abdominal and pelvic infections
  • Bacterial meningitis
• Have activity against:
  • Enterobacteriaceae that do not produce beta-lactamase
  • Pseudomonas aeruginosa
• Not active against:
  • Gram-positive bacteria
  • Anaerobes
• Synergistic with aminoglycosides

Adverse effects

• ↑ Serum transaminases
• Neutropenia in children
• Rash
• GI upset
• Vertigo, headaches

Contraindications

• Allergy to aztreonam
• Cross-allergenicity with other beta-lactams is extremely rare, though possible.

Comparison of Antibiotic Coverage

Comparison based on mechanisms of action

Antibiotics can be classified in several ways. One way is to classify them by mechanism of action:

Comparison based on coverage

Different antibiotics have varying degrees of activity against different bacteria. The table below outlines which antibiotics have activity against 3 important classes of bacteria, including gram-positive cocci, gram-negative bacilli, and anaerobes.