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 Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." 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 Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
- 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 Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics 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.
Monobactam structure
Monobactams are also beta-lactam antibiotics. Their structure is different enough from penicillin that there is no cross-allergy with penicillins Penicillins Beta-lactam antibiotics contain a beta-lactam ring as a part of their chemical structure. Drugs in this class include penicillin G and V, penicillinase-sensitive and penicillinase-resistant penicillins, cephalosporins, carbapenems, and aztreonam. 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 DomainMechanisms 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
- A sugar backbone with 2 alternating 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that create these cross-linked bridges.
Structure of bacterial cell walls
Image by Lecturio. License: CC BY-NC-SA 4.0Mechanism of action
All beta-lactams work by irreversibly binding to and inhibiting the PBPs → beta-lactam antibiotics inhibit cell wall synthesis
(1) Penicillin-binding protein (PBP) forming cross-linked bridges between adjacent peptidoglycan chains
Image by Lecturio. License: CC BY-NC-SA 4.0(2) Penicillin-binding protein (PBP) forming cross-linked bridges between adjacent peptidoglycan chains
Image by Lecturio. License: CC BY-NC-SA 4.0(3) Penicillin-binding protein (PBP) forming cross-linked bridges between adjacent peptidoglycan chains
Image by Lecturio. License: CC BY-NC-SA 4.0
Presence of a beta-lactam antibiotic, which irreversibly binds to and inhibits the PBP, preventing it from forming new cross-links:
Image by Lecturio. License: CC BY-NC-SA 4.0
This effectively inhibits further cell wall synthesis, which ultimately leads to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death.
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 Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death is initiated
- When bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview 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 Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview 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).
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 Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa
- Carbapenems enter cells through specialized channels.
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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, 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 Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus spp.
- Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus (not active against MRSA)
- Enterococcus Enterococcus Enterococcus is a genus of oval-shaped gram-positive cocci that are arranged in pairs or short chains. Distinguishing factors include optochin resistance and the presence of pyrrolidonyl arylamidase (PYR) and Lancefield D antigen. Enterococcus is part of the normal flora of the human GI tract. Enterococcus faecalis
- Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes Infections spp.
- Most Enterobacteriaceae:
- Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli
- Klebsiella Klebsiella Klebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species. Klebsiella
- Proteus Proteus Proteus spp. are gram-negative, facultatively anaerobic bacilli. Different types of infection result from Proteus, but the urinary tract is the most common site. The majority of cases are caused by Proteus mirabilis (P. mirabilis). The bacteria are part of the normal intestinal flora and are also found in the environment. Enterobacteriaceae: Proteus
- Serratia
- Enterobacter
- Citrobacter
- Beta-lactamase-producing H. influenzae and N. gonorrhoeae
- Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa
- Anaerobes:
- Bacteroides Bacteroides Bacteroides is a genus of opportunistic, anaerobic, gram-negative bacilli. Bacteroides fragilis is the most common species involved in human disease and is part of the normal flora of the large intestine. Bacteroides
- Fusobacterium
- Clostridium
- Peptostreptococcus
- Gram-positive organisms:
- 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 Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis, septic abortions)
- Complicated skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and soft-tissue infections
- Bacterial meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
- Intracranial and spinal abscesses
- Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
- Complicated and/or healthcare-associated pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (HCAP)
- Complicated urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections (UTIs)
- Sepsis
- Neutropenic fever Neutropenic fever Neutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Neutropenic Fever
- The carbapenems cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity but generally are considered safe in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (especially imipenem)
- Hematologic effects:
- Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
- Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
- GI upset
- ↑ Serum transaminases
- Rash
- Superinfection:
- Fungal infections
- Clostridioides difficile/ pseudomembranous colitis Pseudomembranous colitis Pseudomembranous colitis is a bacterial disease of the colon caused by Clostridium difficile. Pseudomembranous colitis is characterized by mucosal inflammation and is acquired due to antimicrobial use and the consequent disruption of the normal colonic microbiota. C. difficile infections account for the most commonly diagnosed hospital-acquired diarrheal illnesses. 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones
- 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 Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
- Have activity against:
- Enterobacteriaceae that do not produce beta-lactamase
- Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa
- Not active against:
- Gram-positive bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
- Anaerobes
- Synergistic with aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides
Adverse effects
- ↑ Serum transaminases
- Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia in children
- Rash
- GI upset
- Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. 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:
| Mechanism | Classes of antibiotics |
|---|---|
| Bacterial cell wall synthesis inhibitors |
|
| Bacterial protein synthesis inhibitors |
|
| Agents acting against DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and/or folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 |
|
| Antimycobacterial agents Antimycobacterial Agents Antimycobacterial agents represent a diverse group of compounds that have activity against mycobacterial infections, including tuberculosis, leprosy and Mycobacterium avium complex (MAC) disease. The 1st-line agents for tuberculosis are rifampin, isoniazid, pyrazinamide, and ethambutol. Antimycobacterial Agents |
|
Comparison based on coverage
Different antibiotics have varying degrees of activity against different bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview. The table below outlines which antibiotics have activity against 3 important classes of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, 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.
References
- McCormack, J, Lalji, F. (2019). The “best” antibiotic sensitivity chart. Retrieved July 12, 2021, from https://therapeuticseducation.org/sites/therapeuticseducation.org/files/Antibiotic_Sensitivity_FINAL_Nov_2019.pdf
- 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
- 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
- Pandey, N. (2021). Beta Lactam Antibiotics. StatPearls. Retrieved July 12, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/18243/
- Werth, BJ. (2020). Carbapenems. Merck Manual. Retrieved July 12, 2021, from https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/carbapenems
- 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
- 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
