Lincosamides Notes

Bacteriostatic.
Inhibits protein synthesis by interfering with:
- Formation of initiation complexes.
- Aminoacyl translocation reactions.
The ribosomal binding site for clindamycin overlaps with that of macrolides and chloramphenicol.
Chloramphenicol binds to the 50S ribosomal subunit at the peptidyltransferase site and inhibits transpeptidation.
Clindamycin and macrolides can interfere with the binding of chloramphenicol, potentially interfering with each other's actions if given concurrently.

Several mechanisms of bacterial resistance to clindamycin:
- Modification of the target.
- Inactivation of the drug.
- Efflux.
Resistance mechanisms are the same as those for erythromycin, leading to cross-resistance with clindamycin.
Resistance can be conferred by plasmid- and chromosomally-mediated mechanisms.
Macrolide resistance due to ribosomal methylation can produce resistance to clindamycin.
Clindamycin does not induce the methylase, so cross-resistance occurs only if the enzyme is produced constitutively.
Erm encodes methylases that modify the macrolide binding of the ribosome.
If expression of the erm is constitutive, then cross-resistance occurs because macrolides, lincosamides, and streptogramin B share the same ribosomal binding site.
If expression of the erm is inducible, there is resistance to macrolides (which induce erm) but not to lincosamides (which do not induce erm).

Alternative in patients with severe allergy to penicillins and cephalosporins.
- Endocarditis prophylaxis (clindamycin).
- Aspiration pneumonia (clindamycin).
- Dental infections.
- Skin infections.
- Soft tissue infections.
- Bone infections.
- Anaerobic infections.
- Malaria (with quinine) (clindamycin).
- Bacterial vaginosis (clindamycin).
- Acne (topical clindamycin).
Clindamycin has good activity against aerobic & anaerobic Gram-positive cocci and good oral bioavailability, making it an alternative agent for treating skin & soft tissue infections in patients allergic to beta-lactams.

Absorption:
- Well absorbed orally.
- Oral absorption is not depressed or delayed by food.
- Capsules contain clindamycin HCl (has a very bitter taste).
- Clindamycin phosphate is more soluble at neutral pH and less irritating than the HCl, used parenterally.
- The phosphate salt is hydrolyzed to clindamycin.
Distribution:
- Widely distributed in many fluids & tissues, including bone.
- CSF concentrations are low even when meninges are inflamed.
- >= 90% bound to plasma proteins.
- Accumulates in polymorphonuclear leukocytes, alveolar macrophages & in abscesses.
Metabolism:
- Metabolized in the liver by CYP3A4 (lesser extent by CYP3A5) to:
  - Clindamycose.
  - Desmethyl clindamycin (minor metabolite).
  - Clindamycin sulfoxide (major metabolite).
- Accumulation can occur in severe liver failure.
Excretion:
- Only $∼10$ % is excreted unaltered in urine.
- Antimicrobial activity persists in faeces for >= 5 days after parenteral therapy with clindamycin is stopped.
Half-life: $∼ 2.9$ hours.
Has some antibacterial activity.
Growth of clindamycin-sensitive organisms in the colon may be suppressed for up to 2 weeks.

Common:
- Diarrhoea (mild to severe).
- Nausea, vomiting, abdominal pain or cramps.
- Rash, itch, contact dermatitis (topical use).
Infrequent:
- Clostridioides difficile-associated disease (CDAD, pseudomembranous colitis).
Rare:
- Raised liver enzymes, hepatotoxicity (high doses).
  - Monitor liver function during prolonged treatment.
- Anaphylaxis.
- Polyarthritis.
- Serious skin reactions (SJS, TENs).
- Blood dyscrasia (e.g., thrombocytopenia).
- Hypotension or cardiac arrest (rapid IV injection).

Up to 30% of patients experience diarrhoea, especially with oral treatment.
In a small percentage of cases, leads to pseudomembranous colitis
Risk factors include:
- Increasing age (> 60).
- Severe disease.
- Long hospital stay.
- Long antibacterial course.
Community-acquired infection is increasingly recognised, where patients may be young with no exposure to antibacterials or hospitals.
Caused by the toxin from $C. difficile$ .
CDAD may also be associated with other antibiotics, including cephalosporins, ampicillin & fluoroquinolones.
$Clostridioides$ $difficile$ is a Gram-positive, anaerobic, spore-forming bacillus that produces toxins.
Characterised by:
- Mild to severe diarrhoea.
- Malaise, anorexia, nausea.
- Dehydration, fever (30-50% of patients).
- Abdominal pain & cramping.
- Colitis, toxic megacolon.
Proctoscopic examination shows white – yellow plaques on the mucosa of the colon.
Most patients develop diarrhea during or shortly after starting antibiotics.
25-40% of patients may not become symptomatic for as many as 10 weeks after completing antibiotic therapy.