Macrolide, Lincosamide, Glycopeptide

Sunday, June 4, 2023 17:38

Written by Mariama F

Macrolide refers to the structure that having a macrocyclic lactone ring with attached sugars
1st member : erythromycin
Newer : Roxithromycin, Clarithromycin, Telithromycin and Azithromycin
Erythromycin
• Water solubility of erythromycin is limited, and the solution remains stable only when kept in cold
• The nonionized (penetrable) form of the drug is favoured at higher pH (alkali)
• It is narrow spectrum, highly active against Str. pyogenes and Str. pneumoniae, N. gonorrhoeae,
Clostridia, C. diphtheriae and Listeria
• Erythromycin base is acid labile so it's given as enteric coated tablets to protect it from gastric acid
Mechanism of action
It is bacteriostatic at low but cidal (for certain bacteria only) at high concentrations
Static : inhibiting bacterial protein synthesis by combines with 50S ribosome subunits
Cidal : depends on the organism concerned and its rate of multiplication
Resistance
• All cocci develop resistance mostly by acquiring the capacity to pump it out
• Resistant Enterobacteriaceae have been found to produce an erythromycin esterase enzyme
• Change in the 50S ribosome by chromosomal mutation reducing macrolide binding affinity, so it cross
resistant with Clindamycin and chloramphenicol
Pharmakokinetics
Absorption: incomplete and food delays absorption by retarding gastric emptying
Distribution: widely distributed, enters cells and into abscesses, crosses serous membranes and placenta, but
not BBB, 70–80% plasma protein bound
Metabolism: partly metabolized and excreted primarily in bile in the active form, plasma t½ is 1.5 hr
Excretion: Renal excretion is minor; dose need not be altered in renal failure
Dose
Adult: 250–500 mg 6 hourly (max. 4 g/day)
Children 30–60 mg/kg/day
Adverse Effect
• G.I. : epigastric pain, nausea, anorexia on oral ingestion
• Reversible hearing impairment at very high dose
• Hypersensitivity Rashes, eosinophilia and fever are infrequent
Interaction
Erythromycin inhibit CYP3A4 resulting in high blood levels of terfenadine/astemizole/cisapride causing
serious ventricular arrhythmias and death
The clinically significant interactions ar rise in plasma levels of theophylline, carbamazepine, ergotamine and
warfarin
Indication
• As an alternative to penicilin
a. Streptococcal pharyngitis, respiratory infections caused by pneumococci and H. influenzae
b. Diphtheria : Some prefer erythromycin over penicillin.
c. Tetanus: Erythromycin maybe used as an adjuvant
d. Syphilis and gonorrhoea: Erythromycin is indicated only if other alternative drugs, including
tetracyclines also cannot be used
• As 1st choice drug
a. pneumonia caused by Mycoplasma pneumoniae
b. Batuk rejan: 1–2 week course of erythromycin is the most effective treatment for eradicating B.
pertussis from upper respiratory tract
• As 2nd choice : Chlamydia trachomatis infection of urogenital tract: erythromycin 500 mg 6 hourly for
7 days is an effective alternative

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Clarithromycin
Pharmakokinetics
Absorption: rapidly absorbed, food delays but does not decrease absorption, acid stable
Distribution: slightly larger tissue distribution than erythromycin
Metabolism: oral bioavailability is ~50% due to first pass metabolism, active metabolite is produced so that
clarithromycin can be given twice daily, t½ is prolonged from 4–6 hr at lower doses to 6–9 hr at higher doses
Excretion: 1/3 of an oral dose is excreted unchanged in urine, no dose modification is needed in liver disease
or in mild to moderate kidney failure.
Indication
Used 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
A second line drug for other atypical mycobacterial diseases as well as leprosy
Dose
250 mg BD for 7 days; severe cases 500 mg BD up to 14 days
Side effect
High doses can cause reversible hearing loss.
Its safety in pregnancy, gastric tolerance is better than erythromycin
Clarithromycin inhibits CYP3A4, and the drug interaction potential is similar to erythromycin

Azithromycin
more active than other macrolides against H. influenzae, acid-stable, better gastric tolerance
Pharmakokinetics
Absorption: rapid oral absorption (from empty stomach)
Distribution: larger tissue distribution, Vd is ~30 L/kg
Metabolism: t½ of >50 hr so the dosing is once a day
Excretion: largely excreted unchanged in bile, renal excretion is ~ 10%
Indication
as first choice drug for infections such as: Legionnaires’ pneumonia, Chlamydia trachomatis, Donovanosis
Other potential uses are in multidrug resistant typhoid fever in patients allergic to cephalosporins; and in
toxoplasmosis.
Dose
Adult: 500 mg once daily 1 hour before or 2 hours after food (food decreases bioavailability);
children above 6 month : 10 mg/kg/day) for 3 days is sufficient for most infections
Side effect
mild gastric upset, abdominal pain (less than erythromycin), headache and dizziness.
Azithromycin has been found not to affect hepatic CYP3A4 enzyme

Roxithromycin
Longer acting acid stable macrolide
Good enteral absorption and an average plasma t½ of 12 hr makes it suitable for twice daily dosing
Dose: 150–300 mg BD 30 min before meals, children 2.5–5 mg/kg BD

Telithromycin
Oral telithromycin is ~ 60% bioavailable, has good tissue penetration, eliminated in both urine and bile with a
t½ of 12 hours.
It inhibits CYP3A4 the drug interaction potential is similar to that of erythromycin.
Dose: 800 mg OD for not more than 7–10 days.

Spiramycin
Its specific utility is for toxoplasmosis and recurrent abortion in pregnant women;
3 week courses of 3 MU 2–3 times a day are repeated after 2 week gaps till delivery.

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Lincosamide
Clindamycin
Mechanism of action : inhibits protein synthesis by binding to 50S ribosome
Pharmakokinetics
Absorption: Oral absorption of clindamycin is good
Distribution: penetrates into most skeletal and soft tissues, but not in brain and CSF
Metabolism and excretion: It is largely metabolized and metabolites are excreted in urine and bile. t½ is 3 hr
Side effect: the major problem is diarrhea and pseudomembranous enterocolitis due to Clostridium difficile
superinfection
Indications
• It is a first line drug for pelvic and lung abscesses, septic abortion, penetrating injuries
• Skin and soft tissue infections in patients allergic to penicillins can be treated with clindamycin.
• Topically it is used for infected acne vulgaris
• Clindamycin is an alternative to doxycycline for supplementing quinine/artesunate in treating multidrug
resistant falciparum malaria
Dose: 150–300 mg (children 3–6 mg/kg) QID oral; 200–600 mg i.v. 8 hourly

Glycopeptide
Vancomycin
Bactericidal action is exerted only on gram positive cocci, Neisseria, Clostridia and diphtheroids
Mechanism of action: acts by inhibiting bacterial cell wall synthesis, binds to the terminal dipeptide ‘DAla D-
Ala’ sequence of peptidoglycan units
Pharmakokinetics
Absorption: not absorbed orally
Distribution: widely distributed after i.v. administration, penetrates serous cavities
Excretion: excreted mainly unchanged by glomerular filtration with a t½ of 6 hours. Dose reduction is needed
in renal insufficiency
Toxicity
• It can cause concentration dependent nerve deafness
• Kidney damage is also dose related
• has the potential to release histamine by direct action on mast cells.
• Rapid i.v. injection has caused chills, fever, urticaria and intense flushing— called ‘Red man syndrome’
Indications
• second choice drug to metronidazole for enterocolitis caused by C. difficile and staphylococcal
Given orally (125–500 mg 6 hourly)
• serious MRSA infections, Penicillin-resistant pneumococcal infections, also used in dialysis patients and
those undergoing cancer chemotherapy
Systemic use (500 mg 6 hourly or 1 g 12 hourly infused i.v. over 1 hr)

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