Common side effects include abdominal cramps, vomiting, and diarrhea.[1] More serious side effects may include
Clostridium difficile colitis, liver problems,
prolonged QT, and
allergic reactions.[1] It is generally safe in those who are
allergic to penicillin.[1] Erythromycin also appears to be safe to use during pregnancy.[2] While generally regarded as safe during
breastfeeding, its use by the mother during the first two weeks of life may increase the risk of
pyloric stenosis in the baby.[5][6] This risk also applies if taken directly by the baby during this age.[7] It is in the
macrolide family of antibiotics and works by decreasing bacterial protein production.[1]
Erythromycin can be used to treat bacteria responsible for causing infections of the skin and upper respiratory tract, including Streptococcus, Staphylococcus, Haemophilus and
Corynebacterium genera. The following represents MIC susceptibility data for a few medically significant bacteria:[12]
Haemophilus influenzae: 0.015 to 256 μg/ml
Staphylococcus aureus: 0.023 to 1024 μg/ml
Streptococcus pyogenes: 0.004 to 256 μg/ml
Corynebacterium minutissimum: 0.015 to 64 μg/ml
It may be useful in treating
gastroparesis due to this promotility effect. It has been shown to improve feeding intolerances in those who are critically ill.[13] Intravenous erythromycin may also be used in
endoscopy to help clear
stomach contents to enhance endoscopic visualization, potentially improving diagnostic accuracy and subsequent management.[14]
Available forms
Erythromycin is available in
enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, enteric-coated capsules, non enteric-coated tablets, non enteric-coated capsules, and injections.
The following erythromycin combinations are available for oral dosage:[15]
erythromycin base (capsules, tablets)
erythromycin estolate (capsules, oral suspension, tablets), contraindicated during pregnancy[16]
Studies have shown evidence both for and against the association of
pyloric stenosis and exposure to erythromycin prenatally and postnatally.[19] Exposure to erythromycin (especially long courses at antimicrobial doses, and also through
breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants.[20][21] Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.[20]
Erythromycin estolate has been associated with reversible hepatotoxicity in pregnant women in the form of elevated serum glutamic-oxaloacetic transaminase and is not recommended during pregnancy. Some evidence suggests similar hepatotoxicity in other populations.[22]
Erythromycin is metabolized by enzymes of the
cytochrome P450 system, in particular, by
isozymes of the
CYP3A superfamily.[24] The activity of the CYP3A enzymes can be induced or inhibited by certain drugs (e.g., dexamethasone), which can cause it to affect the
metabolism of many different drugs, including erythromycin. If other CYP3A substrates — drugs that are broken down by CYP3A — such as
simvastatin (Zocor),
lovastatin (Mevacor), or
atorvastatin (Lipitor) — are taken concomitantly with erythromycin, levels of the substrates increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for
rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for
migraine such as
ergotamine and
dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated.[23]
Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin,
ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like
verapamil or
diltiazem) by interfering with CYP3A4.[25] Hence, erythromycin should not be administered to people using these drugs, or drugs that also prolong the
QT interval. Other examples include
terfenadine (Seldane, Seldane-D),[26]astemizole (Hismanal),[27]cisapride[28] (Propulsid, withdrawn in many countries for prolonging the QT time) and
pimozide (Orap).[29] Interactions with
theophylline, which is used mostly in asthma, were also shown.[30]
Erythromycin and
doxycycline can have a synergistic effect when combined and kill bacteria (E. coli) with a higher potency than the sum of the two drugs together. This synergistic relationship is only temporary. After approximately 72 hours, the relationship shifts to become antagonistic, whereby a 50/50 combination of the two drugs kills less bacteria than if the two drugs were administered separately.[31]
It may alter the effectiveness of
combined oral contraceptive pills because of its effect on the gut flora. A review found that when erythromycin was given with certain oral contraceptives, there was an increase in the maximum serum concentrations and
AUC of
estradiol and
dienogest.[32][33]
Erythromycin is an inhibitor of the cytochrome P450 system, which means it can have a rapid effect on levels of other drugs metabolised by this system, e.g.,
warfarin.[34]
Pharmacology
Mechanism of action
Erythromycin displays
bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations.[35] By binding to the 50s subunit of the bacterial
rRNA complex, protein synthesis and subsequent structure and function processes critical for life or replication are inhibited.[35] Erythromycin interferes with aminoacyl translocation, preventing the transfer of the
tRNA bound at the
A site of the rRNA complex to the
P site of the rRNA complex.[36] Without this translocation, the A site remains occupied, thus the addition of an incoming tRNA and its attached
amino acid to the nascent
polypeptide chain is inhibited.[medical citation needed] This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action.[medical citation needed]
Erythromycin increases gut motility by binding to
motilin receptor, thus it is a motilin receptor agonist in addition to its antimicrobial properties. It can be therefore administered intravenously as a stomach emptying stimulant.[37]
Pharmacokinetics
Erythromycin is easily inactivated by gastric acid; therefore, all orally administered formulations are given as either enteric-coated or more-stable salts or
esters, such as erythromycin
ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and
phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active
phagocytosis, large concentrations of erythromycin are released.[38]
Metabolism
Most of erythromycin is metabolised by
demethylation in the
liver by the hepatic enzyme CYP3A4. Its main elimination route is in the
bile with little renal excretion, 2%–15% unchanged drug. Erythromycin's
elimination half-life ranges between 1.5 and 2.0 hours and is between 5 and 6 hours in patients with end-stage renal disease. Erythromycin levels peak in the serum 4 hours after dosing; ethylsuccinate peaks 0.5–2.5 hours after dosing, but can be delayed if digested with food.[39]
Erythromycin crosses the placenta and enters breast milk. The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding.[40] Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients.[41][19]
Chemistry
Composition
Standard-grade erythromycin is primarily composed of four related compounds known as erythromycins A, B, C, and D. Each of these compounds can be present in varying amounts and can differ by lot. Erythromycin A has been found to have the most antibacterial activity, followed by erythromycin B. Erythromycins C and D are about half as active as erythromycin A.[12][42] Some of these related compounds have been purified and can be studied and researched individually.
Synthesis
Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were made to synthesize it in the laboratory. The presence of 10 stereogenic carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task.[43] Complete syntheses of erythromycins’ related structures and precursors such as 6-deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials.[44]Woodward successfully completed the synthesis of erythromycin A, which was published in 1981.[45][46][47]
History
In 1949
Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer at
Eli Lilly.[48] Aguilar managed to isolate erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to Saccharopolyspora erythraea) found in the samples. Aguilar received no further credit or compensation for his discovery.[49]
The scientist was allegedly promised a trip to the company's manufacturing plant in Indianapolis, but it was never fulfilled. In a letter to the company's president, Aguilar wrote: “A leave of absence is all I ask as I do not wish to sever my connection with a great company which has given me wonderful breaks in life.” The request was not granted.[50]
Aguilar reached out to Eli Lilly again in 1993, requesting royalties from sales of the drug over the years, intending to use them to put up a foundation for poor and sickly Filipinos. This request was also denied. He died in September of the same year.[50]
Lilly filed for patent protection on the compound which was granted in 1953.[51] The product was launched commercially in 1952 under the brand name Ilosone (after the
Philippine region of
Iloilo where it was originally collected). Erythromycin was formerly also called Ilotycin.
The antibiotic
clarithromycin was invented by scientists at the Japanese drug company
Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.[52]
In the United States, in 2014, the price increased to seven dollars per tablet.[53]
The price of erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015.[54] In 2017, a Kaiser Health News study found that the per-unit cost of dozens of generics doubled or even tripled from 2015 to 2016, increasing spending by the Medicaid program. Due to price increases by drug manufacturers, Medicaid paid on average $2,685,330 more for Erythromycin in 2016 compared to 2015 (not including rebates).[55] By 2018, generic drug prices had climbed another 5% on average.[56]
Erythromycin is also used in fishcare for the "broad spectrum treatment and control of bacterial disease". Body slime, mouth fungus, furunculosis, bacterial gill illness, and hemorrhagic septicaemia are all examples of bacterial diseases in fish that may be treated and controlled with this therapy. The usage of Erythromycin in fishcare is mainly limited to therapies targeting gram-positive bacteria.[57]
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