Macrolides antibiotics (with lincosamide)

macrolides antibiotics

1. MACROLIDE ANTIBIOTICS Dr. Rupendra K Bharti Asst. Professor Late BRKM GMC Jagdalpur

2. Macrolide antibiotics contain a many membered lactone ring known as macrocyclic ring to which one or more deoxy-sugars are attached. They are: Erythromycin Clarithromycin Roxithromycin Azithromycin

3. Erythromycin is the first member of this group, and was isolated from a strain of Streptomyces erythreus in 1952. Clarithromycin, Roxithromycin and Azithromycin are semi-synthetic derivatives of erythromycin and these are also called newer macrolides . Some other macrolides are dirithromycin, oleandomycin and troleandomycin .

4. Mechanism of action Macrolide antibiotics are bacteriostatic agents and inhibit the protein synthesis by binding reversibly to 50s ribosomal subunit of sensitive micro-organism and interferes with ‘ translocation ’ step in the protein synthesis. The Gram-positive bacteria accumulate about 100 times more erythromycin than the Gram-negative bacteria, hence G+ve bacteria are more sensitive than the G- ve ones. Macrolides behave as bactericidal at very high concentrations.

5. Bacteriostatic effect at low concentration and bactericidal at high concentrations Antimicrobial spectrum These antibiotics are more active against G+ve cocci and inactive against most of the aerobic and enteric G- ve bacilli. Also chlamydia, mycoplasma, spirochetes and toxoplasma

6. Mechanism of Resistance

7. Pharmacokinetics Absorption: Destroyed by the gastric juice so better given as enteric coated tablet or in stearate form. Distribution: Distributed all over the body except in CSF Macrolides are concentrated in the phagocytes and therefore enhance phagocyte killing of bacteria Metabolism: Occurs in liver by zero order kinetics → So the half-life increases with increased dose → Contra-indicated in hepatic dysfunction Excretion: Mainly excreted through the bile Renal excretion is only 5%

8. Clinical uses Diphtheria Pertussis (=whooping cough) Tetanus Bacterial diarrheas as caused by campylobacter jejuni Clarithromycin is also used in peptic ulcer for the eradication of H. Pylori bacteria, MAC (atypical mycobacteria) infections and topically in acne Genital infections like gonorrhea, syphilis, chancroid and infections caused by chlamydia Mycoplasma pneumonia (DOC in children as tetracyclines, DOC in adults, are contraindicated) & Legionnaire’s pneumonia (DOC) Penicillin alternative in penicillin allergic patients as in Respiratory & ENT infections (Can be remembered by names of the vaccines: DPT , BCG , M easles & P olio) D P T B C G M P

9. Drugs

10. Drug properties Erythromycin Dose 250-500 mg QID Route Oral Duration of treatment 7-14 days Antibiotics spectrum Narrow Oral bioavailability Low t½ 1.5 hr Special properties Acid labile, given as enteric coated tablets. Poorly absorbed when given empty stomach. Has poor tissue penetration. Indications As drug of choice in atypical pneumonia, whooping cough, and chancroid. As an alternative to Penicillin in Streptococcal pharyngitis, tonsillitis, mastoiditis, leptospirosis and prophylaxis of rheumatic fever SABE. Skin and soft tissue infections, Susceptible infections, Acne. Prophylaxis of streptococcal infections in patients with evidence of rheumatic fever or heart disease. Treatment and prophylaxis of ophthalmic infections and neonatal conjunctivitis. Side effects Epigastric distress causing nausea, vomiting and diarrhoea. Allergic reaction such as fever and skin eruption Cholestatic hepatitis (especially by erythromycin estolate ). Prolongation of QTc interval. Interactions Erythromycin + benzodiazepines= increase sedation. Erythromycin + calcium channel blockers = Hypotension, Brady arrhythmia

11. Drug properties Clarithromycin Dose 250-500 mg BD Route Oral Duration of treatment 7-14 days Antibiotics spectrum Wide Oral bioavailability Good t½ 3-6 hr at low dose 3-9 hr at high dose Special properties Acid stable , good absorption occurs when given empty stomach. Has good tissue penetration. Indications Upper and lower respiratory tract infections, sinusitis, otitis media, atypical pneumonia , skin and skin structure infections As a component of triple drug regimen it eradicates H. pylori in 1–2 weeks. It is a first line drug in combination regimens for MAC infection in AIDS patients. Side effects Side effects same as erythromycin but has better gastric tolerance. Reversible hearing loss at high doses. Interactions Clarithromycin + zidovudine = Decreased concentration of zidovudine

12. Drug properties Azithromycin Dose 500 mg OD Route Oral Duration of treatment 3-5 days Antibiotics spectrum Wide Oral bioavailability Good t½ >50 hr Special properties Acid stable, good absorption occurs when given empty stomach. Has good tissue penetration. Indications Pharyngitis, tonsillitis, sinusitis, otitis media, pneumonias, acute exacerbations of chronic bronchitis, skin and soft tissue infections. In the prophylaxis and treatment of MAC in AIDS patients. In multidrug resistant typhoid fever (patients allergic to cephalosporins). Toxoplasmosis. As drug of choice : Legionnaires, Chlamydia trachomatis, Donovanosis and Chancroid. Side effects Nausea, vomiting, diarrhoea, and abdominal pain. Interactions Increases serum concentrations of digoxin, ciclosporin, hexobarbital and phenytoin

13. Drug properties Roxithromycin Dose 150 mg BD Route Oral Duration of treatment 7-14 days Antibiotics spectrum Wide Oral bioavailability Good t½ 12 hr Special properties Acid stable, good absorption occurs when given empty stomach. Has good tissue penetration.   Indications It is an alternative to erythromycin for respiratory, ENT, skin and soft tissue and genital tract infections with similar efficacy. Side effects Nausea, vomiting, diarrhoea, and abdominal pain.

14. Effect on Motilin receptors Erythromycin stimulates motilin receptors in the GIT which induces gastric contractions. This leads to early gastric emptying and increased intestinal motility without significantly affecting the colonic motility. Due to this property, it is also used in diabetic gastroparesis and post operatively to promote the peristalsis in the cases of post-operative paralytic ileus.

15. Spiramycin Spiramycin is also a macrolide antibiotic. It resembles erythromycin in spectrum of activity and properties. Its specific utility is for toxoplasmosis and recurrent abortions in pregnant women. It limits risk of transplacental transmission of Toxoplasma gondii infection.

16. Cont … It is given in a dose of 3 million units (MU) BD/TDS for 3 weeks . ( Three week course is to be repeated after 2 weeks gaps till delivery) . Other indications are similar to erythromycin with a dose of 6 MU per day for 5 days. Common side effects are: Gastric irritation, Nausea, Diarrhoea and Rashes.

17. ketolies Telithromycin, Cethromycin & Solithromycin

18. Telithromycin It is a semi-synthetic derivative of erythromycin and also called as Ketolide , due to a keto group in its structure. It blocks protein synthesis by binding to domains II and V of 23S ribosomal RNA of the 50S ribosome subunit. It may also inhibit the assembly of nascent ribosomal units. Due to this changed structure, it is more active against the Macrolide resistant G+ve micro-organisms.

19. Cont.. It is given orally as once daily dosage schedule in a dose of 400 mg OD. The half-life is 10 hrs. Telithromycin is used as treatment of respiratory tract infections including: Acute exacerbation of chronic bronchitis, Acute bacterial sinusitis and Community acquired pneumonia.

20. Cont … The major side effects are: Reversible hepatic dysfunction, Prolongation of QTc interval and Transient visual disturbances. Interactions: Additive effect on QT interval prolongation w/ class 1A (e.g. quinidine, procainamide) or class III (e.g. dofetilide) antiarrhythmic agents).

21. Cethromycin More potent than telithromycin Used against macrolide resistant Streptococci and Enterococci Resistance: Ribosomal modification via inducible or constitutive methylation. Ribosomal modification via point mutation- H. pylori Drug efflux- S. pyogenes Adverse reactions Diarrhoea, nausea Drug interaction Prolonged QT interval (cisapride, terfenadine) Increased blood levels of theophylline, midazolam

22. Indicated in: Community acquired pneumonia Prevention of post exposure inhalational anthrax It is discovered as orphan drug. Now under Phase III clinical trial.

23. Solithromycin MOA: Solithromycin inhibits bacterial translation by binding to the  23S ribosomal RNA , preventing the offending bacteria from synthesizing proteins. Abs spectrum: G+ve respiratory tract pathogens, macrolide-resistant strains. Indicated in Community acquired pneumonia. M/C ADR: hepatotoxicity.

24. Other indications of Macrolides Diffuse pan-bronchiolitis Cystic fibrosis Acute bacterial sinusitis Asthma Chronic obstructive pulmonary disease (COPD) Bronchiectasis Chronic bronchitis

25. LINCOSAMIDE ANTIBIOTICS

26. Clindamycin Clindamycin is a Lincosamide antibiotic. Its mechanism of action and spectrum of activity is similar to erythromycin. It also inhibits protein synthesis by binding to 50S ribosome. Clindamycin inhibits most G+ve cocci and may anaerobes.

27. Cont.. It is well absorbed orally. It attains good concentration in neutrophils, macrophages, skeletal and soft tissues. It is metabolised in liver with a t½ of 3 hr and excreted in urine and bile.

28. Mechanism of Resistance Alteration of 50s ribosomal subunit by adenine methylation. Chromosomal mutation of 50s ribosomal protein. Drug inactivation.

29. Indications Anaerobic and mixed infections (abdominal, pelvic and lung abscess). Skin and soft tissue infections. Prophylaxis of SABE in penicillin allergic patients, who undergo dental procedures. Alternative to doxycycline for supplementing quinine/ artesunate in treating multi-drug resistant malaria. Topically for infected acne vulgaris.

30. Indications Acute or chronical suppurative osteomyelitis , Arthritis caused by susceptive organisms especially Staphylococci aureus Aerobic G+ cocci infection Combination with pyrimethamine for AIDS-related toxoplasmosis (600, 75) Combination with primaquine for AIDS-related pneumocystis carinii pneumonia Dose: Adults: oral dose is 150–300 mg QID, 200–600 mg i.v. 8 hourly Children: oral dose is 3–6 mg/kg QID.

31. ADRs.. rashes, urticaria, abdominal pain and diarrhoea. Superinfection due to Clostridium difficile can occur. It causes pseudomembranous enterocolitis which can be fatal if not treated timely. ( The treatment should be done by promptly stopping the drug and giving oral metronidazole (alternatively vancomycin) to treat it. Higher IV dose –neuromuscular blockade Other :Impaired liver function , neutropenia, hypersensitivity

32. Lincomycin Lincomycin has similar antibiotic and toxic properties to clindamycin with higher incidence of diarrhoea and fatal colitis. It was used extensively before the introduction of clindamycin. Rarely used nowadays.