Lincosamides

The lincosamides, lincomycin and clindamycin, are inhibitors of bacterial protein synthesis. Drugs in this class share the same binding site as that of macrolides and amphenicols; however, they differ in chemical structure. Lincosamides target the 50S ribosomal subunit and interfere with transpeptidation. The antimicrobial coverage of lincosamides encompasses gram-positive cocci (including MRSA) and anaerobes. Clindamycin can also be used to treat toxic shock syndrome and necrotizing fasciitis owing to its antitoxin effect. Diarrhea is a common adverse effect, and clindamycin is often associated with a higher risk of Clostridioides difficile colitis.

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Chemistry and Pharmacodynamics

Chemical structure

  • The chemical structure consists of amino acid and sugar moieties.
  • Lincomycin is the protype drug.
  • Clindamycin is a chlorinated derivative.
chemical structure of clindamycin Lincosamides

Chemical structure of clindamycin

Image: “Clindamycin” by Jü. License: Public Domain

Mechanism of action

  • Inhibits bacterial protein synthesis by binding reversibly to the 50S ribosomal subunit: 
    • Binds near the peptidyltransferase center → prevents peptidyltransferase from adding amino acids to the growing peptide (prevents transpeptidation)
    • Similar binding site as that of macrolides and chloramphenicol
  • Limits bacterial growth → bacteriostatic
  • Can exert a time-dependent killing effect for some bacteria
  • Additional effect: inhibits the production of staphylococcal and streptococcal toxins
Site of action Clindamycin Lincosamides

Site of action of clindamycin at the 50S ribosomal subunit

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

Pharmacokinetics

Since lincomycin is rarely used, the pharmacokinetics of clindamycin are have been listed:

Absorption and distribution

  • Rapid absorption
  • Protein bound
  • Taken up by phagocytic cells
  • Widely distributed in body fluids, bone, and tissues
  • Crosses placenta
  • Does not cross the blood-brain barrier

Metabolism and excretion

  • Metabolism: primarily by CYP3A4
  • Excretion:
    • Urine
    • Feces/bile

Indications

Antimicrobial coverage

  • Gram-positive microbes:
    • Streptococcus
    • Staphylococcus (including MRSA)
  • Anaerobes:
    • Bacteroides
    • Clostridium perfringens
    • Fusobacterium
    • Prevotella melaninogenicus
    • Peptostreptococcus

Type of infections

  • Skin and soft tissue infections:
    • Acne
    • Cellulitis
  • Respiratory infections:
    • Oral infections
    • Pneumonia 
    • Lung abscess
  • Bone and joint infections:
    • Osteomyelitis
    • Prosthetic joint infection
    • Septic arthritis
  • Intraabdominal infections
  • Gynecologic infections:
    • Bacterial vaginosis
    • Pelvic inflammatory disease
    • Endometritis
  • Used as part of combination therapy for:
    • Babesiosis
    • Toxoplasmosis
    • Pneumocystis jirovecii pneumonia
    • Toxic shock syndrome and necrotizing fasciitis (antitoxin effect)

Adverse Effects and Contraindications

Adverse effects

  • Topical:
    • Pruritis
    • Xeroderma
    • Erythema
    • Exfoliation
  • Vaginal:
    • Candidiasis
    • Vulvovaginitis
  • Systemic:
    • GI upset and diarrhea
    • Pseudomembranous colitis (Clostridioides difficile)
    • Esophagitis
    • Metallic taste
    • Azotemia
    • Agranulocytosis
    • Allergic reactions:
      • Erythema multiforme
      • Stevens-Johnson syndrome
      • Anaphylaxis

Contraindications

  • History of C. difficile infections
  • History of lincosamide allergy

Drug interactions

  • Inducers of CYP3A4: ↓ clindamycin concentrations
  • Neuromuscular blocking agents: ↑ neuromuscular blocking effect
  • Should not be used in combination with macrolides or chloramphenicol (due to the same ribosomal target site)

Mechanisms of Resistance

There are 3 main routes of resistance:

  • Target site modification: 
    • Ribosomal methylation or mutation prevents the binding of the antibiotic to its ribosomal target. 
    • Most prevalent mechanism of resistance to lincosamides
  • Efflux pumps
  • Enzymatic inactivation (uncommon, mostly seen in Staphylococcus)

Comparison of Antibiotics

The following table compares several classes of bacterial protein synthesis inhibitor antibiotics:

Table: Comparison of several classes of bacterial protein synthesis inhibitor antibiotics
Drug classMechanism of actionCoverageAdverse effects
Amphenicols
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • GI upset
  • Optic neuritis
  • Aplastic anemia
  • Gray baby syndrome
Lincosamides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram-positive cocci:
    • MSSA
    • MRSA
    • Streptococcus
  • Anaerobes
  • GI upset
  • Allergic reactions
  • Pseudomembranous colitis
Macrolides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • Mycobacterium avium complex
  • GI upset
  • QT prolongation
  • Hepatotoxicity
  • Myasthenia gravis exacerbation
Oxazolidinones
  • Bind to the 23S rRNA of the 50S subunit
  • Prevent initiation complex formation
Gram-positive cocci:
  • MSSA
  • MRSA
  • VRE
  • Streptococcus
  • Myelosuppression
  • Neuropathy
  • Lactic acidosis
  • Serotonin syndrome
rRNA: ribosomal RNA
VRE: vancomycin-resistant Enterococcus
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. Deck, D.H., Winston, L.G. (2012). Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, & oxazolidinones. In Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 809-819). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  2. Leclercq, R. (2002). Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clinical Infectious Diseases, 34(4), 482-492. https://academic.oup.com/cid/article/34/4/482/412492
  3. Johnson, M. (2020). Clindamycin: An overview. In Bond, S. (Ed.), UpToDate. Retrieved June 30, 2021, from https://www.uptodate.com/contents/clindamycin-an-overview
  4. Murphy, P.B., Bistas, K.G., Le, J.K. (2020). Clindamycin. StatPearls. Retrieved June 30, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK519574/
  5. Werth, B.J. (2020). Clindamycin. MSD Manual Professional Version. Retrieved June 30, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/clindamycin

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