Macrolide Antibiotics

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Chapter: Essential pharmacology : Macrolide, Lincosamide, Glycopeptide And Other Antibacterial Antibiotics; Urinary Antiseptics

These are antibiotics having a macrocyclic lactone ring with attached sugars. Erythromycin is the first member discovered in the 1950s, Roxithromycin, Clarithromycin and Azithromycin are the later additions.


MACROLIDE ANTIBIOTICS

 

These are antibiotics having a macrocyclic lactone ring with attached sugars. Erythromycin is the first member discovered in the 1950s, Roxithromycin, Clarithromycin and Azithromycin are the later additions.

 

ERYTHROMYCIN

 

It was isolated from Streptomyces erythreus in 1952. Since then it has been widely employed, mainly as alternative to penicillin. Water solubility of erythromycin is limited, and the solution remains stable only when kept in cold.

 

Mechanism Of Action

 

Erythromycin is bacteriostatic at low but cidal (for certain bacteria) at high concentrations. Cidal action depends on the organism concerned and its rate of multiplication. Sensitive gram-positive bacteria accumulate erythromycin intracellularly by active transport which is responsible for their high susceptibility to this antibiotic. It is several fold more active in alkaline medium, because the nonionized (penetrable) form of the drug is favoured at higher pH.

 

Erythromycin acts by inhibiting bacterial protein synthesis. It combines with 50S ribosome subunits and interferes with ‘translocation’. After peptide bond formation between the newly attached amino acid and the nacent peptide chain at the acceptor (A) site the elongated peptide is translocated back to the peptidyl (P) site, making the A site available for next aminoacyl tRNA attachment. This is prevented by erythromycin and the ribosome fails to move along the mRNA to expose the next codon. As an indirect consequence, peptide chain may be prematurely terminated: synthesis of larger proteins is especifically suppressed.

 

Antimicrobial Spectrum

 

It is narrow, includes mostly gram-positive and a few gram-negative bacteria, and overlaps considerably with that of penicillin G. Erythromycin is highly active against Str. pyogenes and Str. pneumoniae, N. gonorrhoeae, Clostridia, C. diphtheriae, Listeria. Most penicillin-resistant Staphylococci and Streptococci were initially sensitive, but have now become resistant to erythromycin also.

 

In addition, Campylobacter, Legionella, Branhamella catarrhalis, Gardnerella vaginalis and Mycoplasma, that are not affected by penicillin, are highly sensitive to erythromycin. Few others, including H. influenzae, H. ducreyi, B. pertussis, Chlamydia trachomatis, Str. viridans, N. meningitides and Rickettsiae are moderately sensitive. Enterobacteriaceae, other gram-negative bacilli and B. fragilis are not inhibited.

 

Resistance

 

All cocci readily develop resistance to erythromycin, mostly by mechanisms which render them less permeable to erythromycin or acquire the capacity to pump it out. Resistant Enterobacteriaceae have been found to produce an erythromycin esterase. Alteration in the ribosomal binding site for erythromycin by plasmid encoded methylase enzyme is an important mechanism in gram-positive bacteria. All the above types of resistance are plasmid mediated, while change in the 50S ribosome by chromosomal mutation has also been found.

 

Bacteria that develop resistance to erythromycin are resistant to other macrolides as well. Cross resistance with clindamycin and chloramphenicol also occurs, because the ribosomal binding sites for all these are proximal to each other.

 

Pharmacokinetics

 

Erythromycin base is acid labile. To protect it from gastric acid, it is given as enteric coated tablets, from which absorption is incomplete and food delays absorption by retarding gastric emptying. Its acid stable esters are better absorbed.

 

Erythromycin is widely distributed in the body, enters cells and into abscesses, crosses serous membranes and placenta, but not bloodbrain barrier. It attains therapeutic concentration in the prostate. It is 70–80% plasma protein bound, partly metabolized and excreted primarily in bile in the active form. Renal excretion is minor; dose need not be altered in renal failure. The plasma t½ is 1.5 hr, but erythromycin persists longer in tissues.

 

 

Preparations and dose

 

Dose: 250–500 mg 6 hourly (max. 4 g/day), children 30– 60 mg/kg/day.

 

1. Erythromycin (base): ERYSAFE 250, mg tabs, EROMED 333 mg tab, 125 mg/5 ml susp.

 

2. Erythromycin stearate: blood levels produced are similar to those after erythromycin base. ERYTHROCIN 250, 500 mg tab, 100 mg/5 ml susp., 100 mg/ml ped. drops. ETROCIN, ERYSTER 250 mg tab, 100 mg/5 ml dry syr, EMTHRO 250 mg tab, 125 mg/5 ml susp.

 

3. Erythromycin estolate (lauryl sulfate): it is relatively acid stable and better absorbed after oral administration. However, concentration of free and active drug in plasma may be the same as after administration of erythromycin base. Certain organisms hydrolyse it to liberate the free form intracellularly and are more susceptible to it.

 

ALTHROCIN 250, 500 mg tab, 125 mg kid tab, 125 mg/ 5 ml and 250 mg/5 ml dry syr, 100 mg/ml ped. drops, EMYCIN 100, 250 mg tab, 100 mg/5 ml dry syr; ERYCS 250 mg tab, 125 mg/5 ml dry syr.

 

4. Erythromycin ethylsuccinate: well absorbed orally; ERYNATE 100 mg/5 ml dry syr, ERYTHROCIN 100 mg/ ml drops, 125 mg/5 ml syr.

 

A 30% ointment (GERY OINTMENT) is marketed for topical treatment of boils, carbuncles and skin infections, but efficacy is doubtful.

 

Adverse Effects

 

Erythromycin base is a remarkably safe drug.

 

1. Gastrointestinal: Mildtosevere epigastric pain is experienced by many patients, especially children, on oral therapy. Diarrhoea is occasional.

Erythromycin stimulates motilin receptors in the g.i.t.— thereby induces gastric contractions, hastens gastric emptying and promotes intestinal motility. However, contribution of this action to the g.i. side effects is not known.

 

2. Very high doses of erythromycin have caused reversible hearing impairment.

 

3. Hypersensitivity: Rashes and fever are infrequent. Other allergic manifestations are rare with erythromycin base or esters other than estolate.

 

Hepatitis with cholestatic jaundice resembling viral hepatitis or extrahepatic biliary obstruction occurs with the estolate ester (rarely with ethyl succinate or stearate ester) after 1–3 weeks. Incidence is higher in pregnant women. It clears on discontinuation of the drug, and is probably due to hypersensitivity to the estolate ester; erythromycin base or other esters can be given to these patients without recurrence. Though the estolate is acid stable, tasteless and better absorbed, it has been banned in some countries (but not in India).

 

Interaction

 

Erythromycin inhibits hepatic oxidation of many drugs. The clinically significant interactions are—rise in plasma levels of theophylline, carbamazepine, valproate, ergotamine and warfarin.

 

Several cases of QT prolongation, serious ventricular arrhythmias and death have been reported due to inhibition of CYP3A4 by erythromycin/clarithromycin resulting in high blood levels of concurrently administered terfenadine/astemizole/cisapride (see p. 158 and 645).

 

Uses

 

A. As An Alternative To Penicillin

 

1.  Streptococcal pharyngitis, tonsillitis, mastoiditis and community acquired respiratory infections caused by pneumococci and H. influenzae respond equally well to erythromycin. It is an alternative drug for prophylaxis of rheumatic fever and SABE. However, many bacteria resistant to penicillin are also resistant to erythromycin.

 

2.   Diphtheria: acute stage as well as for carriers—7 day treatment. Some prefer it over penicillin. Antitoxin is the primary treatment.

 

3.   Tetanus: as an adjuvant to antitoxin, toxoid therapy.

 

4. Syphilis and gonorrhoea: only if other alternative drugs, including tetracyclines also cannot be used: relapse rates are higher.

 

5.   Leptospirosis: 250 mg 6 hourly for 7 days in patients allergic to penicillins.

 

B. As A First Choice Drug For

 

1.   Atypical pneumonia caused by Mycoplasma pneumoniae: rate of recovery is hastened.

 

2.   Whooping cough: a 1–2 week course of erythromycin is the most effective treatment for eradicating B. pertussis from upper respiratory tract. However, effect on the symptoms depends on the stage of disease when treatment is started.

 

·        Prophylactic: during the 10 day incubation period—disease is prevented.

·   Catarrhal stage: which lasts for about a week—erythromycin may abort the next stage or reduce its duration and severity.

·       Paroxysmal stage: lasting 2–4 weeks—no effect on the duration and severity of ’croup’ despite eradication of the causative organism.

·     Convalescent stage: during which ‘croup’ gradually resolves (4–12 weeks)—is not modified.

 

Azithromycin, clarithromycin, and chloramphenicol are the alternative antimicrobials. Cough sedatives are not very effective. Corticosteroids may reduce the duration of paroxysmal stage but increase the risk of superinfections and carrier stage; should be reserved for severe cases only. Adrenergic β2 stimulants may reduce the severity of paroxysms; more useful in infants.

 

3. Chancroid : erythromycin 2 g/day for 7 days is one of the drugs of choice, as effective as azithromycin or ceftriaxone.

 

C. As A Second Choice Drug In

 

1.     Campylobacter enteritis: duration of diarrhoea and presence of organisms in stools is reduced. However, fluoroquinolones are superior.

 

2.   Legionnaires’ pneumonia: 3 week erythromycin treatment is effective, but azithromycin/ ciprofloxacin are preferred.

 

3. Chlamydia trachomatis infection of urogenital tract: erythromycin 500 mg 6 hourly for 7 days is an effective alternative to single dose azithromycin.

 

4.   Penicillin-resistant Staphylococcal infections: its value has reduced due to emergence of erythromycin resistance as well. It is not effective against MRSA.

 

 

NEWER MACROLIDES

 

In an attempt to overcome the limitations of erythromycin like narrow spectrum, gastric intolerance, gastric acid lability, low oral bioavailability, poor tissue penetration and short halflife, a number of semisynthetic macrolides have been produced, of which roxithromycin, clarithromycin and azithromycin have been marketed.

 

Roxithromycin

 

It is a semisynthetic long-acting acid-stable macrolide whose antimicrobial spectrum resembles closely with that of erythromycin. It is more potent against Branh. catarrhalis, Gard. vaginalis and Legionella but less potent against B. pertussis. Good enteral absorption and tissue penetration, an average plasma t½ of 12 hr making it suitable for twice daily dosing, as well as better gastric tolerability are its desirable features.

 

Though its affinity for cytochrome P450 is lower, drug interactions with terfenadine, cisapride and others are not ruled out. Thus, it is an alternative to erythromycin for respiratory, ENT, skin and soft tissue and genital tract infections with similar efficacy.

 

Dose: 150–300 mg BD 30 min before meals, children 2.5–5 mg/kg BD;

 

ROXID, ROXIBID, RULIDE 150, 300 mg tab, 50 mg kid tab, 50 mg /5 ml liquid; ROXEM 50 mg kid tab, 150 mg tab.

 

Clarithromycin

 

The antimicrobial spectrum of clarithromycin is similar to erythromycin; in addition, it includes Mycobact. avium complex (MAC), other atypical mycobacteria, Mycobact. leprae and some anaerobes but not Bact. fragilis. It is more active against sensitive strains of gram-positive cocci, Moraxella, Legionella, Mycoplasma pneumoniae and Helicobacter pylori. However, bacteria that have developed resistance to erythromycin are resistant to clarithromycin also.

 

Clarithromycin is more acid-stable than erythromycin, and is rapidly absorbed; oral bioavailability is ~50% due to first pass metabolism; food delays but does not decrease absorption. It has slightly greater tissue distribution than erythromycin and is metabolized by saturation kinetics—t½ is prolonged from 3–6 hours at lower doses to 6–9 hours at higher doses. An active metabolite is produced. About 1/3 of oral dose is excreted unchanged in urine, but no dose modification is needed in liver disease or in mild-to-moderate kidney failure.

 

Clarithromycin is indicated in upper and lower respiratory tract infections, sinusitis, otitis media, whooping cough, atypical pneumonia, skin and skin structure infections due to Strep. pyogenes and some Staph. aureus. Used as a component of triple drug regimen (see p. 637) it eradicates H. pylori in 1–2 weeks. It is a first line drug in combination regimens for MAC infection in AIDS patients and 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.

 

CLARIBID 250, 500 mg tabs, 250 mg/5 ml dry syr; CLARIMAC 250, 500 mg tabs; SYNCLAR 250 mg tab, 125 mg/5 ml dry syr.

 

Side effects of clarithromycin are similar to erythromycin, but gastric tolerance is better. High doses can cause reversible hearing loss. Few cases of pseudomembranous enterocolitis, hepatic dysfunction or rhabdomyolysis are reported. Its safety in pregnancy and lactation is not known. The drug interaction potential is also similar to erythromycin.

 

Azithromycin

 

This new azalide congener of erythromycin has an expanded spectrum, improved pharmacokinetics, better tolerability and drug interaction profiles. It is more active than other macrolides against H. influenzae, but less active against gram-positive cocci. High activity is exerted on respiratory pathogens—Mycoplasma, Chlamydia pneumoniae, Legionella, Moraxella and on others like Campylobacter, Ch. No. trachomatis, H. ducreyi, Calymm, granulomatis, N. gonorrhoeae. However, it is not active against erythromycin-resistant bacteria. Penicillinase producing Staph. aureus are inhibited but not MRSA. Good activity is noted against MAC.

 

The remarkable pharmacokinetic properties are acid-stability, rapid oral absorption, marked tissue distribution and intracellular penetration. Concentration in most tissues exceeds that in plasma. Particularly high concentrations are attained inside macrophages and fibroblasts; volume of distribution is ~30 L/kg. Slow release from the intracellular sites contributes to its long terminal t½ of >50 hr. It is largely excreted unchanged in bile, renal excretion is ~ 10%.

 

Because of higher efficacy, better gastric tolerance and convenient once a day dosing, azithromycin is now preferred over erythromycin as first choice drug for infections such as: Legionnaires’ pneumonia: 500 mg OD oral/ i.v. for 2 weeks. Erythromycin or a FQ are the alternatives.

 

a) Chlamydia trachomatis: nonspecific urethritis and genital infections in both men and women — 1 g single dose is curative, while 3 weekly doses are required for lymphogranuloma venereum. It is also the drug of choice for chlamydial pneumonia and is being preferred over tetracycline for trachoma in the eye.

 

b)  Donovanosis caused by Calymmatobacterium granulomatis: 500 mg OD for 7 days or 1.0 g weekly for 4 weeks is as effective as doxycycline.

 

c)   Chancroid and PPNG urethritis: single 1.0 g dose is highly curative.

 

The other indications of azithromycin are pharyngitis, tonsillitis, sinusitis, otitis media, pneumonias, acute exacerbations of chronic bronchitis, streptococcal and some staphylococcal skin and soft tissue infections. In combination with at least one other drug it is effective in the prophylaxis and treatment of MAC in AIDS patients. Other potential uses are in typhoid, toxoplasmosis and malaria.

 

Dose: 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.

 

AZITHRAL 250, 500 mg cap and 250 mg per 5 ml dry syr; AZIWOK 250 mg cap, 100 mg kid tab, 100 mg/5 ml and 200 mg/5 ml susp. AZIWIN 100, 250, 500 mg tab, 200 mg/5 ml liq. Also AZITHRAL 500 mg inj.

 

Side effects are mild gastric upset, abdominal pain (less than erythromycin), headache and dizziness. Azithromycin has been found not to affect hepatic CYP3A4 enzyme. Interaction with theophylline, carbamazepine, warfarin, terfenadine and cisapride is not likely.

 

Spiramycin

 

This macrolide antibiotic, though available for more than a decade, has been employed only sporadically. It resembles erythromycin in spectrum of activity and properties. Distinctively, it has been found to limit risk of transplacental transmission of Toxoplasma gondii infection. 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. Other indications are similar to erythromycin, for which 6 MU/day is given for 5 days. Side effects are gastric irritation, nausea, diarrhoea and rashes.

 

ROVAMYCIN 1.5 MU, 3 MU tabs, 0.375 MU/ 5 ml susp.

 

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