3. Antibiotics - Lincosamides

1. 3.Antibiotics - Lincosamides Pharmacology II DSX 455 Dr/ Abdulaziz Saeedan Pharmacy College

2. Lincosamides • Lincosamides are a group of bacteriostatic OR bactericidal antibiotics that inhibit the synthesis of bacterial protein and are particularly active against aerobic, gram-positive bacteria and most anaerobes. Classification: • Lincosamides include: 1- Naturallincosamides: Lincomycin- isolated from Streptomyces lincolnensis. 2- Semi-synthetic lincosamides:Clindamycin(derivative of lincomycin).

3. Lincosamides : Pharmacokinetics 1- Absorption • Oral: • Lincosamides are non-polar compounds so absorbed from the healthy GI tract • Lincomycinis incompletely absorbed from the GI tract (about 30 - 40% of the oral dose is absorbed - Presence of food decreases absorption rate). • Clindamycin is absorbed well from the GI tract (about 90% of the oral dose is absorbed - not affected by food). • I/M injection: • Lincosamides are rapidly absorbed after intramuscular injection. • IM injection results in peak blood levels after about 30 minutes. • The peak blood level of IM lincosamides is double the level following oral administration of the same dose.

4. 2- Distribution • Lincosamides are characterized by their high lipid solubility, so they are widely distributed in the body including soft tissues, bones and skin. • Clindamycin penetrates bone well and is therefore effective for dental infections that might have bony involvement. • They have the ability to diffuses through the placenta if used in pregnant patients. • It diffuses into milk and reaches a concentration equal to plasma concentration. • They do not penetrate into the brain very well; therefore, they should not be used for CNS infections. • Clindamycin penetrates well into abscesses. 3- Metabolism (Biotransformation) • Lincosamides are metabolized in the liver. • 50% of lincomycin dose and 80-90% of clindamycin dose are metabolized in the liver. Metabolites often retain the same antibacterial activity. • Liver disease impairs the biotransformation of lincosamides

5. 4- Elimination • Both unchanged lincosamidesand their active metabolites are excreted in bile (into feces), urine and milk. • Fecal levels of lincosamides remain high for several days after administration and microorganisms in the colon may be suppressed for up to 2 weeks. • About 10 % of lincosamides dose is excreted unchanged in urine. • Antibacterial activity of lincosamidespersists in the urine for up to 4 days due to slow release from tissues. NOTE: • The liver plays a significant role in the metabolism and elimination of the lincosamide antibiotics.

6. Antimicrobial spectrum • Lincosamides are moderate spectrum antimicrobial drugs. • They are active against aerobic, gram-positive bacteria (Staphylococci, Streptococci, Pneumococci) and most anaerobic bacteria (Clostridium perfringens, Clostridium tetani). • They are also active against some protozoa (Toxoplasma gondii). • Lincosamides are mostly ineffective against aerobic Gram-negative bacteria. NOTE: • Clindamicyn is more active than lincomycin especially against Staphylococci andanaerobes.

7. Action and Mechanism of action • Lincosamides have bacteriostatic or bactericidal activity depending on: A- Concentration of the antibiotic at the site of infection. B- Susceptibility of the microorganism. • The main site of action of lincosamides is the bacterial ribosomes through which they interfere with the ability of bacteria to produce important proteins necessary for them to survive. • Lincosamides works by binding to the 50s ribosomal subunit of bacteria so interfere with the process of amino acidspolymerization and result in synthesis of non-functional or defective protein. • Defective protein fails to function correctly. NOTES: • Lincosamides do not interfere with protein synthesis in human cells (or those of other eukaryotes) because human ribosomes are structurally different from those of bacteria. • Erythromycinand chloramphenicol antibiotics acts also on the 50s ribosomal subunit of bacteria. Due to the shared site of activity, lincosamides, erythromycin and chloramphenicol can be antagonistic to each other SO lincosamides should not be administered concurrently with erythromycin and chloramphenicol.

8. Side Effects: 1- Allergic reactions in the form of skin rash and itching: • Rashes occur in about 10% of patients. 2- Vaginal and Oral thrush: (Candidiasis) • Occurs due to prolonged use. 3- Diarrhea and pseudomembranous colitis: • Oral administration of lincosamides alters the normal flora of the colon that may result in overgrowth of non-susceptible organisms such as Clostridium difficile and yeasts. • Clostridium difficile produces toxins A and B which result in inflammation of the colon and diarrhea (Clostridium difficile associated diarrhea). This is a major problem and requires a second antibiotic (usually metronidazole or vancomycin) to treat the diarrhea, which range in severity from mild diarrhea to fatal pseudomembranous colitis.

9. NOTES: • Pseudomembranous colitisis a severe form of bloody, mucus-filled diarrhea. • Pseudomembranous colitisis not common with the dental use of clindamycin. • Pseudomembranous colitisoccurs more in: • Patients over 60 years of age. • Patients with a history of colitis. • Patients using lincosamidesfor a long time. • In case of diarrhea: • Administration of lincosamides should be stopped. • A different antibiotic should be used.

10. Lincosamides cautions 1- Pregnancy: • Lincosamides can pass through the placenta. 2- Breastfeeding: • Lincosamides penetrate into breast milk and may affect intestinal flora of infants. 3- Pediatric use: • Lincosamides are contraindicated in neonates due to their decreased ability to metabolize drugs.

11. Clinical Uses: • Lincosamides are not indicated in the treatment of viral infections such as the common cold or flu. • Lincomycin: • Because lincomycin therapy has been associated with severe colitis which may end fatally, it should be indicated for serious infections due to staphylococci,streptococci and pneumococci. Its use should be reserved for penicillin-allergic patients. • Clindamycin: • Clindamycin is usually preferred to lincomycin as it is more active, better absorbed and less toxic. 1- Used for penicillin-allergic patients to treat infections caused by susceptible aerobic bacteria as: • Streptococcal tonsillitis. • Bacterial infections of the respiratory tract particularly those caused by Pneumococci. • Bone and joint infections, particularly those caused by Staphylococcus aureus. 2- Used before dental procedures or surgery in patients with certain heart conditions (e.g., artificial heart valves) to prevent bacterial endocarditis which is a serious infection of the heart.

12. 3- Used for treatment of some anaerobic infections: • Dental infections and dental abscesses. • Serious respiratory tract infections such as empyema and lung abscess. • Intra-abdominal infections such as peritonitis and intra-abdominal abscess. • Pelvic abscess and abscess of the fallopian tubes. 4- Used for the treatment of some protozoal diseases: • Toxoplasmosis (clindamycin in combination with pyrimethamine). • Malaria (clindamycin in combination with primaquine). 5- Topical application of clindamycin can be used to treat mild to moderate acne. NOTES: • Empyema is a collection of pus (dead cells and infected fluid) inside the pleural cavity. • Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. • Cats are the primary source of infection to human hosts (fecal contamination of hands, food, drinks). • Individuals at risk for toxoplasmosis include fetuses, newborns, and immunologically impaired patients. • Clindamycin cannot be used for CNS infections because penetration into the brain and CSF is poor.