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. Beta-lactam antibiotics block bacterial transpeptidase (penicillin-binding protein) and, therefore, inactivate peptidoglycan crosslinking in the cell wall. All beta-lactam antibiotics are bactericidal. Common mechanisms of resistance include beta-lactamase production or mutation in the penicillin-binding protein gene. The common side effects include hypersensitivity reactions, GI upset, and hemolytic anemia.

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Chemistry

Penicillins are members of the beta-lactam family of drugs and consist of:

  • A beta-lactam ring: a 4-membered ring containing 2 carbons (α and β carbons), a nitrogen, and a carbonyl group (a carbon double-bonded to oxygen)
    • The beta-lactam group in the compound is responsible for antibacterial activity.
    • Can be hydrolyzed (i.e., broken down) by beta-lactamases, which are produced by certain resistant bacteria
    • If the beta-lactam ring is broken, the drug loses its antibacterial properties.
    • All beta-lactams contain a beta-lactam ring.
  • Thiazolidine ring: a 5-membered ring containing both sulfur and nitrogen
  • Side chain: 
    • Bound to the α-carbon in the beta-lactam ring
    • Differentiates penicillins from each other
    • Responsible for their unique pharmacokinetics and spectra of activity
    • Certain structures can sterically inhibit the hydrolysis of the beta-lactam ring by beta-lactamases. 
    • Certain compounds can be more readily taken up by gram-negative bacteria than others.
Structure of beta-lactams

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

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

Penicillins

Image: “Strukturen verschiedener Penicillinen” by Roland Mattern. License: Public Domain

Mechanism of Action and Resistance

All beta-lactams, including penicillins, exert their effects 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).
  • Peptidoglycan chains are composed of:
    • A sugar backbone with 2 alternating sugars: 
      • N-acetylmuramic acid (NAM) 
      • N-acetylglucosamine acid (NAG)
    • Short peptide side chains branching off the NAM sugars
  • The short peptides form crosslinked bridges between adjacent peptidoglycan chains and create a fishnet structure:
    • Crosslinked bridges are necessary for the peptidoglycan (and thus cell wall) structure.
    • Penicillin-binding proteins (PBPs) are enzymes that create these crosslinked bridges. 
Structure of bacterial cell walls

Structure of bacterial cell walls

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

Mechanism of action

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

Presence of a beta-lactam antibiotic, irreversibly binding and inhibiting PBP

Presence of a beta-lactam antibiotic, which irreversibly binds to and inhibits the PBP, preventing it from forming new crosslinks:
The beta-lactam antibiotic effectively inhibits further cell wall synthesis, ultimately leading to cell death.

NAM: N-acetylmuramic acid
NAG: N-acetylglucosamine
Image by Lecturio. License: CC BY-NC-SA 4.0

Bactericidal activity

Beta-lactams, including penicillins, exert a bactericidal (rather than a bacteriostatic) effect. 

  • Bacterial cell wall is necessary for its survival → if lacking, cell death is initiated
  • When bacteria attempt to replicate, they shed their cell walls.
  • In the presence of penicillins, however, bacteria are unable to form a new cell wall.
  • Bacteria are unable to effectively divide, and the remaining cell autocatalyzes and dies.
Bacteria attempting to divide in the presence of penicillin

Bacterium attempting to divide in the presence of penicillin:
The bacterium sheds its wall and becomes 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 use 3 primary mechanisms to resist penicillins:

  • Beta-lactamase resistance (penicillins are inactivated): 
    • Beta-lactamase is an enzyme that cleaves the beta-lactam ring and inactivates the antibiotic.
    • In the case of penicillin resistance, the enzymes are often called penicillinases.
    • Can be produced by both gram-positive and gram-negative organisms
    • Usually secreted
    • May be secreted only in the presence of a beta-lactam antibiotic
    • Most common type of resistance
    • Most gram-negative bacilli possess a beta-lactamase gene.
  • PBP-mediated resistance (↓ penicillin binding to PBPs): 
    • Mutations in PBPs → ↓ affinity of penicillins to PBPs 
    • Despite the mutations, the PBPs are still able to produce a cell wall.
  • Porin-mediated resistance (↓ penicillin uptake): 
    • Penicillins enter bacteria through channels called porins in the cell walls.
    • Bacteria can ↓ production of porins → ↓ antibiotic levels within the cell → antibiotic resistance
    • Common mechanism of resistance in Pseudomonas aeruginosa

Penicillinase-resistant medications

  • Some drugs can help overcome penicillinase by acting as penicillinase inhibitors.
  • Penicillinase-resistant medications are often combined with penicillinase-sensitive penicillins to enhance activity.
  • Penicillinase inhibitors include:
    • Clavulanic acid 
    • Sulbactam
    • Tazobactam

Classification

Penicillins can be classified as natural penicillins, antistaphylococcal penicillins, and broad-spectrum penicillins. Penicillins can also be classified as penicillinase-sensitive or penicillinase-resistant compounds.

Penicillinase-sensitive penicillins

  • Natural penicillins: chemicals that are naturally produced:
    • Penicillin G
    • Penicillin V
  • Broad-spectrum penicillins: much better activity against gram-negative bacilli:
    • 2nd generation (aminopenicillins):
      • Ampicillin (IV/oral)
      • Amoxicillin (oral)
    • 3rd-generation drugs (carbenicillin and ticarcillin) are not available in the U.S.
    • 4th generation (also known as antipseudomonal penicillins):
      • Piperacillin
      • Mezlocillin

Penicillinase-resistant penicillins

Penicillinase-resistant penicillins have a large R group next to the beta-lactam ring, which prevents the degradation of drugs by penicillinase. Penicillinase-resistant penicillins are effective against methicillin-susceptible staphylococci; thus, they are commonly referred to as antistaphylococcal penicillins.

  • Dicloxacillin
  • Cloxacillin
  • Oxacillin
  • Nafcillin
  • Methicillin (rarely used due to resistance and the risk of interstitial nephritis)

Penicillin-penicillinase inhibitor combinations

  • Ampicillin-sulbactam (Unasyn)
  • Amoxicillin-clavulanate (Augmentin)
  • Piperacillin-tazobactam (Zosyn)

Pharmacokinetics

Distribution

  • All penicillins are distributed in:
    • Pleural cavity/lungs
    • Pericardial fluid
    • Peritoneal fluid/ascites
    • Synovial fluid
    • Urine
    • Bile (especially mezlocillin)
  • Poor penetration across the blood-brain barrier (exception: during inflammation in meningitis)

Protein binding

  • Varies based on the drug
  • Penicillinase-resistant penicillins (nafcillin, oxacillin, cloxacillin): > 90% is protein bound.
  • Penicillin V: > 80% is protein bound.
  • Amoxicillin, ampicillin, and piperacillin: 15%–20% is protein bound.

Half-life

  • Relatively short for all penicillins (generally < 1 hour)
  • Parenteral agents are typically administered every 4 hours.
  • Exception: Piperacillin has a longer half-life when administered at higher doses.

Metabolism

  • Penicillinase-resistant penicillins (nafcillin, oxacillin, cloxacillin) undergo hepatic metabolism.
  • Most others are not extensively metabolized.

Excretion

  • Most are excreted primarily in the urine:
    • Most are excreted unchanged.
    • Ampicillin and piperacillin require dose adjustments in patients with renal insufficiency.
  • Some are excreted primarily in the bile/feces, including:
    • Penicillinase-resistant penicillins (nafcillin, oxacillin, and cloxacillin)
    • Mezlocillin

Indications

Table: Spectrum of activity and clinical uses of penicillins
Drug (route of administration)Spectrum of activityClinical uses
Penicillin G (IV/IM) and penicillin V (oral)Narrow:
  • Gram-positive cocci:
    • Streptococcus pyogenes
    • S. pneumoniae
    • S. agalactiae (GBS)
  • Gram-positive bacilli:
    • Listeria monocytogenes
    • Actinomyces Israelii
  • Gram-negative cocci:
    • Neisserria meningitidis
    • N. gonorrhoeae
  • Spirochetes:
    • Treponema pallidum
    • Leptospira spp.
  • Streptococcal pharyngitis (i.e., strep throat)
  • Endocarditis
  • Toxic shock syndrome caused by Streptococcus spp.
  • Rheumatic fever prophylaxis
  • Bacterial meningitis caused by L. monocytogenes or N. meningitidis
  • Gonorrhea
  • S. agalactiae (GBS) infections in pregnancy
  • Syphilis (penicillin G)
  • Leptospirosis
  • Anthrax
  • Botulism (adjunct)
  • Diphtheria (adjunct)
  • Tetanus (adjunct)
Cloxacillin and dicloxacillinNarrow:
Gram-positive cocci:
  • Staphylococcus spp. (excluding MRSA)
  • Streptococcus spp.
  • Skin and soft tissue infections
    • Impetigo
    • Cellulitis
    • Mastitis
  • Otitis externa
  • Septic arthritis
  • Pneumonia due to susceptible bacteria
Ampicillin (IV/oral) and amoxicillin (oral)Wider:
  • Gram-positive bacteria:
    • Streptococcus spp.
    • L. monocytogenes
  • Gram-negative bacteria:
    • Helicobacter pylori
    • Haemophilus influenzae
    • Escherichia coli
    • Proteus mirabilis
    • Salmonella spp.
    • Shigella spp.
  • Activity is enhanced with the use of clavulanate.
  • ENT infections:
    • Pharyngitis
    • Tonsillitis
    • Otitis media
    • Rhinosinusitis
  • GI infections:
    • H. pylori eradication
    • Salmonella
    • Complementary with aminoglycosides for enterococcal infections
  • Community-acquired pneumonia
  • Endocarditis prophylaxis
  • Bacterial meningitis
  • Sepsis
  • Genitourinary infections:
    • Urinary tract infections (not 1st line)
    • Intra-amniotic infections
    • Postpartum endometritis
    • Tubo-ovarian abscess
Piperacillin (only available as piperacillin/tazobactam in the US)Widest:
  • Gram-positive bacteria:
    • Streptococcus spp.
    • Staphylococcus spp. (excluding MRSA)
  • Gram-negative bacteria:
    • P. aeruginosa
    • Many Enterobacteriaceae
  • Paired with the penicillinase inhibitor tazobactam to enhance activity.
  • Sepsis
  • Neutropenic fever in high-risk patients
  • Intra-abdominal/pelvic infections:
    • Appendicitis
    • Pelvic inflammatory disease
    • Postpartum endometritis
  • Skin and soft tissue infections:
    • Cellulitis
    • Abscesses
    • Ischemic/diabetic foot infections
MezlocillinWide: good gram-negative coverageBiliary tract infections (e.g., biliary cholangitis)
GBS: group B Streptococcus

Adverse Effects and Contraindications

Adverse effects

The most common effects are related to allergic reactions.

  • IgE-mediated allergic reactions:
    • Present with pruritis, urticaria, angioedema, hypotension, and/or anaphylaxis
    • Symptoms typically appear within 4 hours of administration (often within minutes).
  • Serum sickness:
    • A late allergic reaction due to circulating immune complexes
    • Characterized by fever, urticaria, adenopathy, arthritis, and occasionally glomerulonephritis
  • Dermatologic reactions:
    • Morbilliform rash: a maculopapular eruption due to a hypersensitivity reaction
    • Erythema multiforme: target lesions developing with acute onset
    • Stevens-Johnson syndrome: a desquamating skin condition involving mucosal surfaces
  • Neurologic reactions:
    • Encephalopathy
    • Penicillin neurotoxicity: 
      • Decreased level of consciousness (e.g., somnolence, coma)
      • Generalized hyperreflexia
      • Myoclonus
      • Seizures
  • GI and hepatic reactions:
    • Diarrhea (especially with ampicillin and amoxicillin)
    • Clostridioides difficile colitis 
    • Suppression of gut flora leading to vitamin K deficiency
    • Hypersensitivity hepatitis (especially with oxacillin and nafcillin)
  • Renal reactions:
    • Glomerulonephritis (occurring in association with allergic reactions)
    • Allergic interstitial nephritis (especially with nafcillin and methicillin)
    • AKI (associated with the concomitant use of piperacillin-tazobactam and vancomycin)
  • Hematologic reactions:
    • Neutropenia due to immune-mediated destruction of polymorphonuclear (PMN) leukocytes
    • Hemolytic anemia
    • Immune thrombocytopenia, especially with ticarcillin
    • Suppression of gut flora leading to vitamin K deficiency

Contraindications

  • Hypersensitivity reactions
  • Serious skin reactions (e.g., Stevens-Johnson syndrome)

Comparison of Antibiotic Coverage and Classification

Comparison based on mechanisms of action

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

Table: Antibiotics classified by primary mechanism of action
MechanismClasses of antibiotics
Bacterial cell wall synthesis inhibitors
  • Penicillins
  • Cephalosporins
  • Penems
  • Miscellaneous
Bacterial protein synthesis inhibitors
  • Tetracyclines
  • Macrolides
  • Ketolide
  • Lincosamides
  • Streptogramins
  • Linezolid
Agents acting against DNA and/or folate
  • Sulfonamides
  • Trimethoprim
  • Fluoroquinolones
Antimycobacterial agents
  • Anti-TB agents
  • Antileprosy agents
  • Atypical mycobacterial agents

Comparison based on coverage

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

Antibiotic sensitivity chart

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. Letourneau, A.R. (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
  2. Letourneau, A.R. (2019). Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins. In Bloom, A. (Ed.), UpToDate. Retrieved July 8, 2021, from https://www.uptodate.com/contents/penicillin-antistaphylococcal-penicillins-and-broad-spectrum-penicillins 
  3. Letourneau, A.R. Cephalosporins. UpToDate. Retrieved May 20, 2021, from https://www.uptodate.com/contents/cephalosporins
  4. Penicillin G Benzathine. Medscape. Retrieved May 20, 2021, from https://reference.medscape.com/drug/bicillin-la-permapen-penicillin-g-benzathine-999573
  5. Abraham, E.P. (1987). Cephalosporins 1945-1986. In: The Cephalosporin Antibiotics. Williams, J.D. (Ed.). Adis Press.
  6. Bodey, G.P. (1990). Penicillins, monobactams and carbapenems. Tex Heart Inst J. 17(4), 315-329.
  7. Deck, D.H., Winston, L.G. (2012). Beta-lactam & other cell wall- & membrane-active antibiotics (Chapter 43). In: Basic and Clinical Pharmacology. 12e. Katzung, B.G., Masters, S.B., Trevor, A.J. (Editors). McGraw-Hill/Lange.
  8. Hauser, A.R. (2013). Antibiotic basics for clinicians. The ABCs of choosing the right antibacterial agent. 2nd Ed. Lippincott Williams & Wilkins. ISBN-13: 978-1-4511-1221-4

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