Macrolides & Ketolides

Drugs:

The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached e.g Erythromycin, clarithromycin, azithromycin, Telithromycin roxithromycin and spiramycin**

• Prevpac

Therapeutic Uses

1. Gram +ve infections treatment & prevention of (Staph, Strept, Pneumococci) 2nd line after penicillin if they are hypersensitive

2. Eradication of C. Diphtheria from pharyngeal carriers (1st choice)

3. Atypical (Calm My Leg)

   • Mycoplasma Pneumonia infants
   • Chlamydial infections in pregnancy and infants

4. Clarithromycin: has activity against Toxoplasma. It is also effective against helicobacter pylori in peptic ulcer

5. Azithromycin: is effective in pelvic infections, urethritis and cervicitis caused by chlamydia and gonococci.

6. Others: It is a second line drug for the treatment of gonorrhea and syphilis and also Treatment of middle ear and sinus infections , since the causative agents, H. influenza and Strep. pneumonia are usually sensitive

Preparation

Erythromycin was the first of these drugs to find clinical application, both as a drug of first choice and as an alternative to penicillin in individuals with an allergy to β-lactam antibiotics

Spectrum

• Gram +ve Mainly
• Gram –ve Neisseria, H.Influenza
• Intracellular Gram –ve: (Chlamydia and Mycoplasma)

MOA:

Binds with 50s Ribosome with weak reversible bond Static in low doses & Cidal in high doses The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus preventing the ribosomes from shuffling along and adding a new amino acid to the elongating protein chain (inhibiting translocation steps of protein synthesis) Generally considered to be bacteriostatic, they may be bactericidal at higher doses. Their binding site is either identical to or in close proximity to that for clindamycin and chloramphenicol.

Pharmacokinetics (Prototype relevant)

Absorption: Poor orally and even decreased with food Erythromycin base is destroyed by gastric acid thus, either enteric-coated tablets or esterified forms of the antibiotic are administered. Clarithromycin, azithromycin, and telithromycin are stable in stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin. Erythromycin and azithromycin are available in IV formulations.

Distribution: • BBB: Not Significant • Placenta : it passes but pregnancy safe (Erythromycin and Azithromycin) • Highly concentrated in Neutrophils and PNL Erythromycin distributes well to all body fluids except the CSF . It is one of the few antibiotics that diffuses into prostatic fluid, and it also accumulates in macrophages. All four drugs concentrate in the liver. Azithromycin concentrates in neutrophils, macrophages, and fibroblasts, and serum levels are low. Azithromycin has the longest half-life and the largest volume of distribution of the four drugs

Metabolism: Liver

Excretion: 5-28% only excreted in urine (Cannot be used for UTI) • Excreted by liver (Bile) (Entero-Hepatic Circulation) • Can cause cholestatic jaundice

Side Effects

1. GIT Upset Gastric upset is the most common adverse effect of the macrolides i.e Significant (nausea, vomiting, diarrhea) and this may lead to poor patient compliance (especially with erythromycin). have been associated with the macrolides. Erythromycin is the worst Clarithromycin and azithromycin seem to be better tolerated .

   Higher doses of erythromycin lead to smooth muscle contractions that result in the movement of gastric contents to the duodenum, an adverse effect sometimes used therapeutically for the treatment of gastroparesis or postoperative ileus (prokinetics).

2. Liver : A) Cholestatic Jaundice/hepatitis his side effect occurs especially with the estolate form of erythromycin; however, it has been reported with other formulations

   B) CYP 450 Inhibition

   C) ototoxicity Transient deafness has been associated with erythromycin, especially at high dosages. Azithromycin has also been associated with irreversible sensorineural hearing loss

3. Prolonged QT Interval (Arrythmia) has been seen with the macrolides, again most commonly with erythromycin.

4. Resistance if it is used more than one week (so erythromycin should be combined with another antibiotic if used more than one week)

5. Others: Hypersensitivity; (fever & rashes, Thrombophlebitis;(may follow intravenous administrations), Transient hearing impairment

Contraindication

Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver. Severe hepatotoxicity with telithromycin has limited its use, given the availability of alternative therapies. Additionally, macrolides and ketolides may prolong the QTc interval and should be used with caution in those patients with pro-arrhythmic conditions or concomitant use of pro-arrhythmic agents

Interactions

1. Combination of the therapeutic dose of (Erythromycins) Macrolides with Penicillin antagonizes penicillin bactericidal effect.

2. Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulation of these compounds

3. An interaction with digoxin may occur. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of the drug from the enterohepatic circulation