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Erythromycin, 400 mg tablets

Drug formTablets

ATC categoryAntibacterials

ATC subcategoryMacrolides (for systemic use)

Brand nameErythromycin

Generic nameErythromycin

Composition

Each tablet contains:

active ingredient: Erythromycin (as ethylsuccinate) – 400 mg (468 mg);

excipients: microcrystalline cellulose, povidone, maize starch, magnesium stearate, sodium starch glycolate.

Pharmacological group and ATC code
Antibacterial; J01FA01.

Chemical name and CAS number
Erythromycin 2´-(ethylsuccinate); 41342-53-4.

Pharmacology

Erythromycin is a macrolide antibacterial with a broad and essentially bacteriostatic action against many Gram-positive and to a lesser extent some Gram-negative bacteria, as well as other organisms including some Mycoplasma spp., Chlamydiaceae, Rickettsia spp., and spirochaetes.

Mechanism of action. Erythromycin binds reversibly to the 50S subunit of the ribosome, resulting in blockage of the transpeptidation or translocation reactions, inhibition of protein synthesis, and hence inhibition of cell growth. Its action is predominantly bacteriostatic, but high concentrations are slowly bactericidal against the more sensitive strains. Because macrolides penetrate readily into white blood cells and macrophages there has been some interest in their potential synergy with host defence mechanisms in vivo. The actions of erythromycin are increased at moderately alkaline pH (up to about 8.5), particularly in Gram-negative species, probably because of the improved cellular penetration of the nonionised form of the drug.

Spectrum of activity. Erythromycin has a broad spectrum of activity. The following pathogenic organisms are usually sensitive to erythromycin.

Gram-positive cocci, particularly streptococci such as Streptococcus pneumoniae and Str. pyogenes are sensitive. Most strains of Staphylococcus aureus remain susceptible, although resistance can emerge rapidly, and some enterococcal strains are also susceptible.

Many other Gram-positive organisms respond to erythromycin, including Bacillus anthracis, Corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, and Listeria monocytogenes. Anaerobic Clostridium spp. are also usually susceptible, as is Propionibacterium acnes. Nocardia spp. vary in their susceptibility.

Gram-negative cocci including Neisseria meningitidis and N. gonorrhoeae, and Moraxella catarrhalis (Branhamella catarrhalis) are usually sensitive.

Other Gram-negative organisms vary in their susceptibility, but Bordetella spp., some Brucella strains, Flavobacterium, and Legionella spp. are usually susceptible. Haemophilus ducreyi is reportedly susceptible, but H. influenzae is somewhat less so. The Enterobacteriaceae are usually resistant, although some strains may respond at alkaline pH. Helicobacter pylori and most strains of Campylobacter jejuni are sensitive (about 10% of the latter are reported to be resistant).

Among the Gram-negative anaerobes most strains of Bacteroides fragilis and many Fusobacterium strains are resistant.

Other organisms usually sensitive to erythromycin include Actinomyces, Chlamydiaceae, rickettsias, spirochaetes such as Treponema pallidum and Borrelia burgdorferi, some mycoplasmas (notably Mycoplasma pneumoniae), and some of the opportunistic mycobacteria: Mycobacterium scrofulaceum and M. kansasii are usually susceptible, but M. intracellulare is often resistant and M. fortuitum usually so.

Fungi, yeasts, and viruses are not susceptible to erythromycin.

Activity with other antimicrobials. As with other bacteriostatic antimicrobials, the possibility of an antagonistic effect if erythromycin is given with a bactericide exists, and some antagonism has been shown in vitro between erythromycin and various penicillins and cephalosporins or gentamicin. However, in practice the results of such concurrent use are complex, and depend on the organism; in some cases synergy has been seen. Because of the adjacency of their binding sites on the ribosome, erythromycin may competitively inhibit the effects of chloramphenicol or lincosamides such as clindamycin. A synergistic effect has been seen when erythromycin was combined with a sulfonamide, notably against Haemophilus influenzae. Erythromycin has also been reported to enhance the antiplasmodial actions of chloroquine.

  • Several mechanisms of acquired resistance to erythromycin have been reported of which the most common is a plasmid-mediated ability to methylate ribosomal RNA, resulting in decreased binding of the antimicrobial drug. This can result in cross-resistance between erythromycin, other macrolides, lincosamides, and streptogramin B, because they share a common binding site on the ribosome and this pattern of resistance is referred to as the MLSB phenotype. It is seen in staphylococci, and to a somewhat lesser extent in streptococci, as well as in a variety of other species including Bacteroides fragilis, Clostridium perfringens, Corynebacterium diphtheriae, Listeria, and Legionella spp.
  • Decreased binding of antimicrobial to the ribosome may also occur as a result of a chromosomal mutation, resulting in an alteration of the ribosomal proteins in the 50S subunit, which conveys one-step high-level erythromycin resistance. This form of resistance has been demonstrated in Escherichia coli and some strains of Str. pyogenes, and probably occurs in Staphylococcus aureus.

    Other forms of erythromycin resistance may be due to the production of a plasmid-determined erythromycin esterase which can inactivate the drug, or to decreased drug penetration. The latter may be partly responsible for the intrinsic resistance of Gram-negative bacteria like the Enterobacteriaceae, but has also been shown to be acquired as a plasmid-mediated determinant in some organisms; production of a protein which increases drug efflux from the cell is thought to explain the MS form of resistance, in which organisms are resistant to 14-carbon ring macrolides and streptogramins, but retain sensitivity to 16-carbon ring macrolides and lincosamides.

    The incidence of resistance varies greatly with the area and the organism concerned and, although the emergence of resistance is rarely a problem in the short-term treatment of infection, it is quite common in conditions requiring prolonged treatment such as endocarditis due to Staph. aureus. The incidence of resistance in streptococci is generally lower than in Staph. aureus but shows geographical variation and may be increasing in some countries, including the UK. In addition, localised outbreaks of resistant strains may occur and produce a much higher incidence of resistance.

    Pharmacokinetics

    Absorption

    Erythromycin ethylsuccinate is generally more reliably and quickly absorbed, than erythromycin base, and its absorption is little affected by food, obviating any need to take them before food. Erythromycin ethylsuccinate is partially dissociated in the intestine where both erythromycin and the undissociated ester are absorbed; in the blood, the ester is partially hydrolyzed to release free erythromycin. Higher total concentrations are achieved after oral doses of the erythromycin ethylsuccinate, but only about 20 to 30% of 55% of ethyl succinate is present as the active base, the rest being present as the inactive ester.

    Single oral doses of the erythromycin ethylsuccinate generally produce peak serum concentrations within 1–4 hours. Peak concentrations of about 500 nanograms/ml of erythromycin base have been reported following 500 mg of the ethylsuccinate. Mean peak serum concentrations of about 0.6 mcg/mL reportedly occur 1.5–2 hours after a single 50-mg IM dose of erythromycin ethylsuccinate in children, or 1–4 hours after a single 100-mg IM dose in adults.

    Distribution

    Erythromycin is widely distributed throughout body tissues and fluids, although it does not cross the blood-brain barrier well and concentrations in CSF are low. Relatively high concentrations are found in the liver and spleen, and some is taken up into polymorphonuclear lymphocytes and macrophages. Around 70 to 75% of the base is protein bound. Erythromycin crosses the placenta: fetal plasma concentrations are variously stated to be 5 to 20% of those in the mother. Erythromycin is distributed into milk in concentrations about 50% of plasma concentrations.

    Elimination

    Erythromycin is excreted in high concentrations in the bile and 2 to 5% of an oral dose is excreted unchanged in the urine. Erythromycin is partly metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 in the liver by N-demethylation to inactive, unidentified metabolites.

    The half-life of erythromycin is usually reported to be about 1.5 to 2.5 hours, although this may be slightly longer in patients with renal impairment. Only small amounts of erythromycin are removed by hemodialysis.

    Uses
    Erythromycin is a macrolide antibacterial with a wide spectrum of activity, that has been used in the treatment of a wide variety of infections caused by susceptible organisms.

    Its uses have included bronchitis, severe campylobacter enteritis, chancroid, diphtheria, legionnaires’ disease and other Legionella infections, neonatal conjunctivitis, pertussis, pneumonia (mycoplasmal and other atypical pneumonias as well as streptococcal), sinusitis, and trench fever, and, combined with neomycin, for the prophylaxis of surgical infection in patients undergoing bowel surgery.

    Erythromycin is used as an alternative to penicillin in penicillin-allergic patients with various conditions including anthrax, actinomycosis, leptospirosis, listeriosis, mouth infections, otitis media (usually with a sulfonamide such as sulfafurazole), pelvic inflammatory disease caused by Neisseria gonorrhoeae, pharyngitis, the prevention of perinatal streptococcal infections, rheumatic fever, and infections in splenectomised patients, and staphylococcal and streptococcal skin infections. It has also been used in the treatment of penicillin-allergic patients with syphilis, but there are doubts about its efficacy. In penicillin-allergic patients in the early stages of Lyme disease, erythromycin may be used as an alternative to a tetracycline; this use is generally restricted to pregnant women and young children, since it is less effective than other drugs. It is also used as an alternative to the tetracyclines in patients with Chlamydia or Chlamydophila infections (such as epididymitis, lymphogranuloma venereum, nongonococcal urethritis, pneumonia, psittacosis, and trachoma), in Q fever, and in spotted fevers.

    Oral erythromycin may be used as an alternative to a tetracycline in moderate acne.

    Dosage and administration
    The usual oraldose for adult and child over 8 years is the equivalent of erythromycin 1 to 2 g daily in 2 to 4 divided doses (the BNF recommends a doses of 250–500 mg every 6 hours or 0.5–1 g every 12 hours); for severe infections this may be increased to up to 4 g daily in divided doses. Daily doses higher than 1 g should be given in more than 2 divided doses. Doses may need to be reduced in patients with renal impairment.

    For children the dose is usually about 30 to 50 mg/kg daily in divided doses although it may be doubled in severe infections; based on age, children of 2 to 8 years may be given 1 g daily in divided doses and infants and children up to 2 years of age may be given 500 mg daily in divided doses.

    The BNF for Children recommends the following doses:

    Neonate: 12.5 mg/kg every 6 hours.

    Child 1 month–2 years: 125 mg 4 times daily; dose doubled in severe infections.

    Child 2–8 years: 250 mg 4 times daily; dose doubled in severe infections.

    Early syphilis: for adult and child 12–18 years: 500 mg 4 times daily for 14 days.

    For the prevention of streptococcal infections in patients with evidence of rheumatic fever or heart disease, who are unable to take penicillin or sulfonamides, a dose of 250 mg twice daily may be given.

    Prophylaxis against pneumococcal infection (BNF for Children)

    Child 1 month–2 years: 125 mg twice daily.

    Child 2–8 years: 250 mg twice daily.

    Child 8–18 years: 500 mg twice daily.

    For the management of acne, maintenance doses as low as 250 mg daily have been used in adults but resistant strains of propionibacteria are widespread; the BNF recommends a dose of 500 mg twice daily.

    Precautions and contraindications

    Erythromycin should be avoided in those known to be hypersensitive to it, or in those who have previously developed jaundice. Erythromycin should be used with care in patients with existing liver disease or hepatic impairment. Erythromycin may aggravate muscle weakness in patients with myasthenia gravis. Erythromycin should be used with care in patients with a history of arrhythmias or a prolonged QT interval.

    Erythromycin may interfere with some diagnostic tests including measurements of urinary catecholamines and 17-hydroxycorticosteroids. It has also been associated with falsely-elevated serum aspartate aminotransferase values when measured colorimetrically, although genuine elevations of this enzyme, due to hepatotoxicity, also occur, particularly with the estolate.

    Breast feeding: because erythromycin is distributed into milk, the drug should be used with caution in nursing women.

    Pregnancy: pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

    Overdosage

    Symptoms: hearing loss, severe nausea, vomiting and diarrhoea.

    Treatment: gastric lavage, general supportive measures.

    Drug interactions
    Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

    Erythromycin, apparently through inhibition of cytochrome P-450 (CYP) microsomal enzyme systems, can reduce the hepatic metabolism of some drugs including carbamazepine, cyclosporine, hexobarbital, phenytoin, alfentanil, disopyramide, lovastatin, and bromocriptine, thereby decreasing elimination and increasing serum concentrations of these drugs. In patients receiving concomitant erythromycin, serum concentrations of drugs metabolized by cytochrome P-450 microsomal enzyme systems should be monitored closely and dosage adjusted if necessary.

    Erythromycin is metabolized by CYP3A and concomitant use with drugs that inhibit the CYP3A isoenzyme may result in increased erythromycin plasma concentrations. There is some evidence that concomitant use of oral erythromycin with drugs that inhibit CYP3A (i.e., fluconazole, ketoconazole, itraconazole, diltiazem, verapamil) is associated with an increased incidence of sudden death from cardiac causes, presumably because of increased plasma erythromycin concentrations resulting in an increased risk of QT prolongation (a dose-associated effect of erythromycin) and serious ventricular arrhythmias. Therefore, it has been suggested that concomitant use of erythromycin and drugs that are potent inhibitors of CYP3A should be avoided.

    Antifungal Agents

    Concomitant use of oral erythromycin and drugs that inhibit CYP3A (i.e., fluconazole, ketoconazole, itraconazole) was associated with an increased incidence of sudden death from cardiac causes. Concomitant use of erythromycin and these drugs presumably increases plasma erythromycin concentrations resulting in an increased risk of QT prolongation (a dose-associated effect of erythromycin) and serious ventricular arrhythmias. Concomitant use of erythromycin and fluconazole, ketoconazole, or itraconazole should be avoided.

    Astemizole and Terfenadine

    Erythromycin may interact with astemizole and terfenadine, resulting in potentially serious adverse cardiovascular effects. Some evidence indicates that erythromycin may alter the metabolism of astemizole and terfenadine, probably via inhibition of the cytochrome P-450 microsomal enzyme system.

    Other interactions

    Other mechanisms by which Erythromycin causes interactions include suppression of the gastrointestinal flora responsible for the intraluminal metabolism of digoxin and possibly oral contraceptives.

    Cimetidine is one of the few drugs reported to affect erythromycin.

    Adverse effects
    Erythromycin are generally well tolerated and serious adverse effects are rare. Gastrointestinal disturbances such as abdominal discomfort and cramp, nausea, vomiting, and diarrhoea are fairly common after oral use, probably because of the stimulant activity of erythromycin on the gut. Gastrointestinal effects are dose-related and appear to be more common in young than in older subjects. Supra-infection with resistant organisms may occur and pseudomembranous colitis has been reported.

    Hypersensitivity reactions appear to be uncommon, having been reported in about 0.5% of patients, and include pruritus, urticaria and skin rash as well as occasional cases of anaphylaxis. Hypersensitivity or irritation may occur following topical application of erythromycin.

    A hypersensitivity reaction may also be responsible for the hepatotoxicity sometimes reported in patients receiving erythromycin or its derivatives. Symptoms indicative of cholestasis, including upper abdominal pain (sometimes very severe), nausea and vomiting, abnormal liver function values, raised serum bilirubin and usually jaundice, may be accompanied by rash, fever, and eosinophilia. Symptoms usually occur initially in patients who have been receiving the drug for more than 10 days, although they may develop more quickly in patients given the drug previously. Erythromycin may interfere with tests for serum aspartate aminotransferase, which might make diagnosis of hepatotoxicity more difficult.

    The majority of reports of liver dysfunction have been in patients receiving the estolate, and it has been suggested that the propionyl ester linkage is particularly associated with hepatotoxicity, but symptoms have been reported in patients receiving the base and most of the other derivatives, both by mouth and parenterally. Hepatic dysfunction seems to be rare in children. The effects of erythromycin on the liver are generally reversible on discontinuing treatment.

    A generally reversible sensorineural deafness, sometimes with tinnitus, has been reported in patients receiving erythromycin and appears to be related to serum concentration, with an increased likelihood of such effects in patients given doses of 4.68 g or more daily of ethylsuccinate, in those with renal or hepatic impairment.

    Other adverse effects that have been reported in patients receiving erythromycin include agranulocytosis, prolongation of the QT interval and other arrhythmias, central neurotoxicity including psychotic reactions and nightmares, a myasthenia-like syndrome, and pancreatitis.

    Pregnancy and Breast feeding

    Erythromycin has been in widespread use for a number of years without apparent ill consequence. Animal studies have shown no hazard. Erythromycin has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low. Erythromycin is excreted in breast milk, therefore, caution should be exercised when erythromycin is administered to a nursing mother.

    Identification

    White or off white biconvex, scored tablets with a few small darker spots.

    Presentation

    1 blister packet with 10 tablets in the cardboard box.

    Expiry date

    3 years. Do not use after the expiration date.

    Prescription status

    To be dispensed with prescription.

    Storage conditions

    Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.