Carbapenems and Aztreonam

The carbapenems and aztreonam are both members of the bactericidal beta-
lactam family of antibiotics (similar to penicillins). They work by preventing
bacteria from producing their cell wall, ultimately leading to bacterial cell
death. There are 4 available carbapenems, all ending in “-penem,” and 1
available monobactam, which is aztreonam. The carbapenems are all broad-
spectrum antibiotics used for a variety of serious, often MDR and/or hospital-
acquired infections (HAIs) that can occur throughout the body. Aztreonam has
a narrower spectrum and is typically used for aerobic gram-negative bacilli
infections in patients who have a serious beta-lactam allergy but require beta-
lactam therapy, as there is no significant cross-allergenicity between
aztreonam and the other beta-lactams.

Last updated: October 6, 2022

CONTENTS

Chemistry and
Classification
Mechanisms of
Action and
Resistance
Carbapenems
Monobactams:
Aztreonam
Comparison of
Antibiotic
Coverage
References

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
 Structure of beta-lactams:
All beta-lactam antibiotics contain the same core 4-member
“beta-lactam” ring (highlighted in red). This ring is responsible
for the antibacterial properties of these medications because it
is the region that binds to and inhibits the penicillin-binding
proteins (PBPs). The PBPs catalyze formation of the cell wall by
forming cross-links between peptide chains in peptidoglycan
molecules; the PBPs form these cross-links between acyl-D-
Ala-D-Ala peptides, which have a similar structure to the beta-
lactam ring.

Image by Lecturio. License: CC BY-NC-SA 4.0

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
 Structure of aztreonam, the only marketed monobactam in the
United States

Image: “Chemical structure of aztreonam” by Mysid. License: Public

Domain

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.

Structure of bacterial cell walls

Image by Lecturio. License: CC BY-NC-SA 4.0

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.

Bacterium attempting to divide in the presence of penicillin:

The bacterium ends up shedding its wall and becoming a
spheroplast. The spheroplast is unable to survive and
autocatalyzes (dies).

Image by Lecturio. License: CC BY-NC-SA 4.0

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.
Most common type of resistance
Although most carbapenems and
monobactams are resistant to beta-
lactamases, there is increasing resistance,
especially among gram-negative organisms.
Carbapenemases are beta-lactamases that
can hydrolyze carbapenems and other
beta-lactam antibiotics (e.g., penicillin,
cephalosporins).
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
To prolong drug activity, imipenem is
combined with cilastatin, a
dehydropeptidase inhibitor.
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
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
Superinfection

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:
 Table: Antibiotics classified by primary
mechanism of action

Mechanism Classes of
antibiotics

Bacterial cell wall Penicillins

synthesis Cephalosporins
inhibitors Penems
Miscellaneous

Bacterial protein Tetracyclines

synthesis Macrolides
inhibitors Ketolide
Lincosamides
Streptogramins
Linezolid

Agents acting Sulfonamides

against DNA Trimethoprim
and/or folate Fluoroquinolones

Antimycobacterial Tuberculosis
agents agents
Leprosy agents
Atypical
mycobacterium
agents

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.
 Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics
for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

1. McCormack, J, Lalji, F. (2019). The “best” antibiotic sensitivity

chart. Retrieved July 12, 2021, from
https://therapeuticseducation.org/sites/therapeuticseducation.or
g/files/Antibiotic_Sensitivity_FINAL_Nov_2019.pdf

2. Letourneau, AR. (2019). Beta-lactam antibiotics: Mechanisms of

action and resistance and adverse effects. In Bloom, A. (Ed.),
Uptodate. Retrieved May 20, 2021, from
https://www.uptodate.com/contents/beta-lactam-antibiotics-
mechanisms-of-action-and-resistance-and-adverse-effects
3. Letourneau, AR. (2019). Combination beta-lactamase inhibitors,
carbapenems, and monobactams. In Bloom, A. (Ed.), Uptodate.
Retrieved July 12, 2021, from
https://www.uptodate.com/contents/combination-beta-
lactamase-inhibitors-carbapenems-and-monobactams
4. Pandey, N. (2021). Beta Lactam Antibiotics. StatPearls. Retrieved
July 12, 2021, from
https://www.statpearls.com/articlelibrary/viewarticle/18243/
5. Werth, BJ. (2020). Carbapenems. Merck Manual. Retrieved July
12, 2021, from
https://www.merckmanuals.com/professional/infectious-
diseases/bacteria-and-antibacterial-drugs/carbapenems

6. Werth, BJ. (2020). Monobactams. Merck Manual. Retrieved July

12, 2021, from
https://www.merckmanuals.com/professional/infectious-
diseases/bacteria-and-antibacterial-drugs/monobactams?
query=aztreonam

7. Lexicomp, Inc. (2021). Drug Information Sheets, UpToDate,

Retrieved July 12, 2021, from:
Meropenem,
https://www.uptodate.com/contents/meropenem-drug-
information

Imipenem and cilastatin,

https://www.uptodate.com/contents/imipenem-and-
cilastatin-drug-information

Ertapenem,
https://www.uptodate.com/contents/ertapenem-drug-
information

Doripenem,
https://www.uptodate.com/contents/doripenem-drug-
information

Aztreonam, systemic,
https://www.uptodate.com/contents/aztreonam-systemic-
drug-information