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Macrolides

- Macrolides are a class of antibiotics that are produced by Streptomyces bacteria and contain a macrocyclic lactone ring. Erythromycin was the first macrolide discovered in 1952. - Macrolides work by attaching to the 50S subunit of bacterial ribosomes and inhibiting protein synthesis. They are bacteriostatic and have selectivity for bacterial over mammalian cells. - Common macrolides include erythromycin, clarithromycin, roxithromycin, and azithromycin. They are effective against many gram-positive bacteria and some gram-negatives. Azithromycin has the broadest spectrum of activity.

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By Dr. Mohammed Yaqub Pasha
Introduction The term Macrolide was originally given to antibiotics produced by species of Streptomyces. Erythromycin was discovered in 1952 by McGuire and coworkers from a strain of Streptomyces erythreus.
General Structure O O O CH3 R1 H3C CH3 CH3 O H3C OH H3C CH3 OH O O HO CH3 N CH3 CH3 O OH CH3 CH3 OR2 1 3 5 9 12 1` 1`` Erythromycin Glycon Aglycone They all contain three characteristics parts in the molecule:  A highly substituted macrocyclic lactone: aglycone.  A ketone group.  An amino desoxysugar: glycon, and in some of the macrolides, a neutral desoxysugar which are glycosisically attached to the aglycone ring.
Mechanism of Action  Macrolides - bacteriostatic agents  Attach to the P site of 50s portion of bacterial ribosomes and inhibit the protein synthesis  Prevent translocation during elongation of protein synthesis  Do not inhibit the 60s/40s subunits of mammalian cells – selective toxicity
Mechanism of action
Resistance From one of four mechanisms  Drug efflux by an active pump mechanism  Modification of receptor sites on 50s ribosome – decreased binding of the drug  Macrolide hydrolysis by esterases produced by Enterobacteriaceae  Failure to permeate through bacterial cell membrane
Spectrum of Antibacterial Activity Macrolides are similar to penicillins regarding their spectrum of activity They are effective against penicillin-resistant strains Macrolides are effective against most of the G(+) bacteria, cocci or bacillus, they have antibiotic activity against G(-) cocci ,especially Neisseria Species
Typical therapeutic applications of macrolides.
ERYTHROMYCIN Antimicrobial spectrum: Mostly gram-positive  Highly sensitive: Str. pyogenus, Str. pneumoniae, N. gonorrhoeae, C. diphtheriae, Listeria, Campylobacter, Legionella, Branhamella catarrhalis, Gardnerella vaginalis, Mycoplasma  Moderately sensitive: H. ducreyi, H. influenzae, B. pertussis, Chlamydia trachomatis, Str. Viridans, N.meningitidis, Rickettsiae  Not sensitive: Enterobacteriaceae, B. fragilis
Pharmacokinetics:  Acid labile  Incomplete absorption  Food delays absorption  Inactivated by gastric acid – Enteric coated tablets/ester salts  Widely distributed, 70-80% plasma protein bound  Does not cross blood brain barrier  t-1.5 hr, persists longer in tissues  No need of dose alteration in renal failure
USES As an alternative to penicillin:  Streptococcal pharyngitis, tonsillitis, mastoiditis, community acquired pneumonia  Prophylaxis of rheumatic fever and SABE  Diphtheria  Tetanus  Syphilis and gonorrhoea  Leptospirosis
1st choice in  Atypical pneumonia (mycoplasma pneumonia)  Whooping cough  Chancroid 2nd choice in  Campylobacter gastroenteritis  Legionnaires pneumonia  Chlamydia trachomatis
ROXITHROMYCIN  Semisynthetic longer-acting acid stable macrolide  More potent against Branhamella catarrhalis, Gardnerella vaginalis, Legionella  Less potent against B. pertussis  Similar efficacy, better gastric tolerability
 Spectrum includes MAC, Mycobacterium leprae  More active against H. pylori, Moraxella, Legionella, Mycoplasma pneumonia  More acid stable, rapidly absorbed
CLARITHROMYCIN  Absorbed rapidly from the GI tract  Can be given with or without food  saturation kinetics  active metabolite  Bioavailability - 50-55%  T1/2 6-7 hrs, excreted through kidney
 Spectrum includes MAC, Mycobacterium leprae  More active against H. pylori, Moraxella, Legionella, Mycoplasma pneumonia
USES  200-500 mg BD  Clarithromycin or azithromycin - first-line therapy for prophylaxis and treatment of disseminated infection caused by M. avium- intracellulare in AIDS patients  Clarithromycin + minocycline used in lepromatous leprosy  Clarithromycin 500mg + omeprazole 20mg + amoxycillin 1gm BD (14 days) – PUD
AZITHROMYCIN  Expanded spectrum – H. influenza, Mycoplasma, Chlamydia pneumoniae, Legionella, Moraxella, MAC, Campylobacter, Ch. Trachomatis, H. ducreyi, N.gonorrhoeae, penicillinase producing Staph. Aureus  Higher efficacy
 Improved pharmacokinetics – acid-stability, rapid oral absorption, intracellular penetration, high concentrations inside macrophages and fibroblasts  Better gastric tolerability  Fewer drug interactions  Convenient once daily dosing
Administration and fate of the macrolide antibiotics
1st choice in  Legionnaire pneumonia  Clamydia trachomatis  Donovanosis  Chancroid  PPNG  Single 1gm dose – chlamydia cervicitis & urethritis  500mg OD – disseminated infection by MAC in AIDS  Excellent action against Toxoplasma gondii
 Other uses – Pharyngitis, otitis media, skin and soft tissue infections, prophylaxis and treatment of MAC in AIDS patients
Adverse effects 1. Hepatotoxicity  Cholestatic hepatitis - erythromycin estolate  Nausea, vomiting, intestinal cramps  Hypersensitivity reaction 2. GI toxicity  Erythromycin- epigastric distress  Dose related  Reduced by prolonging the infusion time to 1 hr/ pretreatment with glycopyrrolate
3. Cardiac toxicity  Cardiac arrythmias, QT prolongation, ventricular tachycardia 4. Toxic and irritative effects  Fever, eosinophilia, skin eruptions  Transient auditory impairment- erythromycin  i.v erythromycin – thrombophlebitis
DRUG INTERACTIONS  Erythromycin, clarithromycin- inhibit CYP3A4. may increase concentrations of: Theophylline Digoxin, Disopyramide Carbamazepine Valproic acid Cyclosporine Terfenadine, Astemizole Phenytoin Cisapride Warfarin Ergot alkaloids  Azithromycin - no drug interactions
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