Chemistry:Erythromycin

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Short description: Antibiotic medication
Erythromycin
Erythromycin A skeletal.svg
Erythromycin 3d structure.png
Clinical data
Trade namesEryc, Erythrocin, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa682381
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous, intramuscular, topical, eye drops
Drug classMacrolide antibiotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
BioavailabilityDepends on the ester type; between 30% and 65%
Protein binding90%
MetabolismLiver (under 5% excreted unchanged)
Elimination half-life1.5 hours
ExcretionBile
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC37H67NO13
Molar mass733.937 g·mol−1
  (verify)

Erythromycin is an antibiotic used for the treatment of a number of bacterial infections.[1] This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis.[1] It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn,[1] and to improve delayed stomach emptying.[3] It can be given intravenously and by mouth.[1] An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.[4]

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 was first isolated in 1952 from the bacteria Saccharopolyspora erythraea.[1][8] It is on the World Health Organization's List of Essential Medicines.[9] In 2021, it was the 259th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10][11]

Medical uses

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.

Available forms

Enteric-coated erythromycin capsule from Abbott Labs

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:[14]

  • erythromycin base (capsules, tablets)
  • erythromycin estolate (capsules, oral suspension, tablets), contraindicated during pregnancy[15]
  • erythromycin ethylsuccinate (oral suspension, tablets)
  • erythromycin stearate (oral suspension, tablets)

For injection, the available combinations are:[14]

  • erythromycin gluceptate
  • erythromycin lactobionate

For ophthalmic use:

  • erythromycin base (ointment)

Adverse effects

Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are very common because erythromycin is a motilin agonist.[16]

More serious side effects include arrhythmia with prolonged QT intervals, including torsades de pointes, and reversible deafness. Allergic reactions range from urticaria to anaphylaxis. Cholestasis and Stevens–Johnson syndrome are some other rare side effects that may occur.[17]

Studies have shown evidence both for and against the association of pyloric stenosis and exposure to erythromycin prenatally and postnatally.[18] 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.[19][20] Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.[19]

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.[21]

It can also affect the central nervous system, causing psychotic reactions, nightmares, and night sweats.[22]

Interactions

Erythromycin is metabolized by enzymes of the cytochrome P450 system, in particular, by isozymes of the CYP3A superfamily.[23] 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.[22]

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.[24] 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),[25] astemizole (Hismanal),[26] cisapride[27] (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap).[28] Interactions with theophylline, which is used mostly in asthma, were also shown.[29]

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.[30]

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.[31][32]

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.[33]

Pharmacology

Mechanism of action

Erythromycin displays bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations.[34] 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.[34] 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.[35] 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. This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action.

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.[36]

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.[37]

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.[38]

Erythromycin crosses the placenta and enters breast milk. The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding.[39] Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients.[40][18]

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][41] 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.[42] 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.[43] Woodward successfully completed the synthesis of erythromycin A.[44][45][46]

History

In 1949 Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer at Eli Lilly.[47] 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.[48]

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.[49]

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.[49]

Lilly filed for patent protection on the compound which was granted in 1953.[50] The product was launched commercially in 1952 under the brand name Ilosone (after the Philippines 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.[51]

Society and culture

Economics

It is available as a generic medication.[5]

In the United States, in 2014, the price increased to seven dollars per tablet.[52]

The price of erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015.[53] 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).[54] By 2018, generic drug prices had climbed another 5% on average.[55]

Brand names

Brand names include Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, E.E.S.-400, E.E.S.-400 Filmtab, Erymax, Ery-Tab, Eryc, Ranbaxy, Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin Stearate Filmtab, Erythrocot, E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, PCE Dispertab, Stiemycine, Acnasol, and Tiloryth.

Veterinary uses

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. It mainly attacks gram-positive bacteria in fish.[56]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Erythromycin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/erythromycin.html. 
  2. ↑ 2.0 2.1 "Prescribing medicines in pregnancy database". Australian Government. 23 August 2015. http://www.tga.gov.au/hp/medicines-pregnancy.htm. 
  3. ↑ "Clinical guideline: management of gastroparesis". The American Journal of Gastroenterology 108 (1): 18–37; quiz 38. January 2013. doi:10.1038/ajg.2012.373. PMID 23147521. 
  4. ↑ "Treatment and prevention of ophthalmia neonatorum". Canadian Family Physician 59 (11): 1187–90. November 2013. PMID 24235191. 
  5. ↑ 5.0 5.1 Tarascon pocket pharmacopoeia (2013 delux lab-coat ed., 14th ed.). [Sudbury, Mass.]: Jones & Bartlett Learning. 2013. p. 72. ISBN 9781449673611. https://books.google.com/books?id=zJay-fZCFGgC&pg=PA72. Retrieved 9 September 2017. 
  6. ↑ "Treatment of acne vulgaris during pregnancy and lactation". Drugs 73 (8): 779–87. June 2013. doi:10.1007/s40265-013-0060-0. PMID 23657872. 
  7. ↑ "Are young infants treated with erythromycin at risk for developing hypertrophic pyloric stenosis?". Archives of Disease in Childhood 92 (3): 271–3. March 2007. doi:10.1136/adc.2006.110007. PMID 17337692. PMC 2083424. http://adc.bmj.com/content/92/3/271. 
  8. ↑ Biosynthesis : polyketides and vitamins. Berlin [u.a.]: Springer. 2000. p. 52. ISBN 9783540669692. https://books.google.com/books?id=XUuFPxvfWgAC&pg=PA52. Retrieved 9 September 2017. 
  9. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  10. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Erythromycin - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Erythromycin. 
  12. ↑ 12.0 12.1 "Erythromycin Susceptibility and Minimum Inhibitory Concentration (MIC) Data". TOKU-E. http://www.toku-e.com/Assets/MIC/Erythromycin.pdf. 
  13. ↑ "The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials". Critical Care 20 (1): 259. August 2016. doi:10.1186/s13054-016-1441-z. PMID 27527069. 
  14. ↑ 14.0 14.1 "Erythromycin Oral, Parenteral Advanced Patient Information". Drugs.com. https://www.drugs.com/cons/erythromycin-oral-parenteral.html. 
  15. ↑ "Sexually transmitted diseases treatment guidelines, 2006". MMWR: Recommendations and Reports 55 (RR-11): 1–94. August 2006. PMID 16888612. https://www.cdc.gov/std/treatment/2006/toc.htm. 
  16. ↑ "Erythromycin: a motilin agonist and gastrointestinal prokinetic agent". The American Journal of Gastroenterology 88 (4): 485–90. April 1993. PMID 8470625. 
  17. ↑ Aronson, J.K., ed (2016). "Erythromycin". Meyler's Side Effects of Drugs (Sixteenth ed.). Elsevier. pp. 99–108. doi:10.1016/B978-0-444-53717-1.00698-3. ISBN 9780444537164. https://www.sciencedirect.com/science/article/abs/pii/B9780444537171006983. 
  18. ↑ 18.0 18.1 "Erythromycin". Drugs in pregnancy and lactation : a reference guide to fetal and neonatal risk (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2011. ISBN 978-1-60831-708-0. https://books.google.com/books?id=OIgTE4aynrMC&q=erythromycin&pg=PA512. Retrieved 20 October 2021. 
  19. ↑ 19.0 19.1 "Are young infants treated with erythromycin at risk for developing hypertrophic pyloric stenosis?". Archives of Disease in Childhood 92 (3): 271–3. March 2007. doi:10.1136/adc.2006.110007. PMID 17337692. 
  20. ↑ "Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study". BMJ 348: g1908. March 2014. doi:10.1136/bmj.g1908. PMID 24618148. 
  21. ↑ "Hepatotoxicity of erythromycin estolate during pregnancy". Antimicrobial Agents and Chemotherapy 12 (5): 630–5. November 1977. doi:10.1128/AAC.12.5.630. PMID 21610. 
  22. ↑ 22.0 22.1 "Erythromycine". Belgisch Centrum voor Farmacotherapeutische Informatie. http://www.bcfi.be/GGR/MPG/MPG_KABA.cfm. 
  23. ↑ "Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol". Clinical Pharmacology and Therapeutics 51 (1): 18–23. January 1992. doi:10.1038/clpt.1992.3. PMID 1732074. https://deepblue.lib.umich.edu/bitstream/2027.42/109905/1/cptclpt19923.pdf. Retrieved 29 August 2019. 
  24. ↑ "Oral erythromycin and the risk of sudden death from cardiac causes". The New England Journal of Medicine 351 (11): 1089–96. September 2004. doi:10.1056/NEJMoa040582. PMID 15356306. 
  25. ↑ "Drug Interactions between erythromycin and terfenadine". https://www.drugs.com/drug-interactions/erythromycin-with-terfenadine-1009-0-2164-0.html?professional=1. 
  26. ↑ "Drug Interactions between astemizole and erythromycin". https://www.drugs.com/drug-interactions/astemizole-with-erythromycin-271-0-1009-0.html?professional=1. 
  27. ↑ Landrum Michalets, E.; Williams, C. R. (2000). "Drug interactions with cisapride: clinical implications". Clinical Pharmacokinetics 39 (1): 49–75. doi:10.2165/00003088-200039010-00004. PMID 10926350. https://pubmed.ncbi.nlm.nih.gov/10926350/. 
  28. ↑ "Erythromycin Interactions". 20 December 2020. https://gpnotebook.com/pages/ear-nose-and-throat/erythromycin/interactions. 
  29. ↑ "Drug Interactions between erythromycin and theophylline". https://www.drugs.com/drug-interactions/erythromycin-with-theophylline-1009-0-2177-0.html?professional=1. 
  30. ↑ "When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition". PLOS Biology 11 (4): e1001540. 23 April 2013. doi:10.1371/journal.pbio.1001540. PMID 23630452. 
  31. ↑ "Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women" (in en). Contraception 86 (4): 337–44. October 2012. doi:10.1016/j.contraception.2012.01.010. PMID 22445438. https://www.contraceptionjournal.org/article/S0010-7824(12)00041-8/abstract. Retrieved 2 August 2019. 
  32. ↑ "Drug interactions between non-rifamycin antibiotics and hormonal contraception: a systematic review" (in en). American Journal of Obstetrics and Gynecology 218 (1): 88–97.e14. January 2018. doi:10.1016/j.ajog.2017.07.003. PMID 28694152. https://www.ajog.org/article/S0002-9378(17)30845-1/abstract. Retrieved 2 August 2019. 
  33. ↑ Westphal, Jean Frédéric (2000). "Macrolide – induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin". British Journal of Clinical Pharmacology 50 (4): 285–295. doi:10.1046/j.1365-2125.2000.00261.x. PMID 11012550. 
  34. ↑ 34.0 34.1 "Section VIII: Chemotherapeutic Drugs; Chapter 44: Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, & Streptogramins". Katzung & Trevor's Pharmacology: Examination & Board Review (9th ed.). New York: McGraw-Hill Medical. 2010. pp. 389–396. ISBN 978-0-07-170155-6. 
  35. ↑ "Erythromycin". https://www.sigmaaldrich.com/SE/en/product/sial/e6376. 
  36. ↑ Parkman, Henry P. (2021). "Chapter 24 - Prokinetic agents for gastroparesis". Gastroparesis: Pathophysiology, Clinical Presentation, Diagnosis and Treatment. Academic Press. pp. 323–339. doi:10.1016/B978-0-12-818586-5.00024-7. ISBN 9780128185865. https://www.sciencedirect.com/science/article/abs/pii/B9780128185865000247. "Erythromycin has prokinetic effects because it is a motilin receptor agonist in addition to being an antibiotic. [...] When given intravenously, erythromycin is a potent stimulant of gastric emptying among the available prokinetic drugs." 
  37. ↑ "Pharmacokinetic properties of clarithromycin: A comparison with erythromycin and azithromycin". The Canadian Journal of Infectious Diseases 4 (3): 148–152. May 1993. doi:10.1155/1993/168061. PMID 22346438. 
  38. ↑ "Chapter 61: Macrolides". Pharmacology for the primary care provider (Third ed.). Saint Louis, Missouri. 2009. pp. 658–662 (661). ISBN 978-0-323-06316-6. https://books.google.com/books?id=9JtgGU0fkggC&pg=PA661. Retrieved 3 March 2022. ; "Chapter 28: Erythromycin". The Macrolides. Oxford UK: Arnette-Blackwell. 1993. 
  39. ↑ American Academy of Pediatrics Committee on Drugs (September 2001). "Transfer of drugs and other chemicals into human milk". Pediatrics 108 (3): 776–89. doi:10.1542/peds.108.3.776. PMID 11533352. 
  40. ↑ "Erythromycin and clindamycin absorption and elimination in pregnant women". Clinical Pharmacology and Therapeutics 19 (1): 68–77. January 1976. doi:10.1002/cpt197619168. PMID 1245094. 
  41. ↑ "Antibacterial activities of erythromycins A, B, C, and D and some of their derivatives". Antimicrobial Agents and Chemotherapy 28 (5): 630–3. November 1985. doi:10.1128/aac.28.5.630. PMID 4091529. 
  42. ↑ "A journey across the sequential development of macrolides and ketolides related to erythromycin". Tetrahedron 62 (14): 3171–3200. 2006. doi:10.1016/j.tet.2005.11.064. 
  43. ↑ "Synthesis of 6-Deoxyerythronolide B. Implementation of a General Strategy for the Synthesis of Macrolide Antibiotics". Tetrahedron Lett. 38: 53–56. 1997. doi:10.1016/S0040-4039(96)02258-7. 
  44. ↑ "Asymmetric Total Synthesis of Erythromycin. 1. Synthesis of an Erythronolide A Seco Acid Derivative via Asymmetric Induction". Journal of the American Chemical Society 103 (11): 3210–3213. June 1981. doi:10.1021/ja00401a049. 
  45. ↑ "Asymmetric Total Synthesis of Erythromycin. 2. Synthesis of an Erythronolide A Lactone System". Journal of the American Chemical Society 103 (11): 3213–3215. 1981. doi:10.1021/ja00401a050. 
  46. ↑ "Asymmetric Total Synthesis of Erythromycin. 3. Total Synthesis of Erythromycin". Journal of the American Chemical Society 103 (11): 3215–3217. June 1981. doi:10.1021/ja00401a051. 
  47. ↑ "Drugs and rights" (in en). Philippine Daily Inquirer. 30 August 2019. https://opinion.inquirer.net/123626/drugs-and-rights. 
  48. ↑ Tan, Michael L. (30 August 2019). "Drugs and rights". Philippine Daily Inquirer. https://opinion.inquirer.net/123626/drugs-and-rights. 
  49. ↑ 49.0 49.1 "Remembering the battle of Dr. Abelardo Aguilar: Cure for millions, deprived of millions.". The News Today. https://www.thenewstoday.info/2005/05/03/iloilonews3.htm. 
  50. ↑ Bunch RL, Mcguire JM, "Erythromycin, its salts, and method of preparation", US patent 2653899, published 29 September 1953, assigned to Eli Lilly and Company.
  51. ↑ Greenwood, David (2008). Antimicrobial drugs: chronicle of a twentieth century medical triumph. New York: Oxford university press. pp. 239. ISBN 978-0-19-953484-5. https://books.google.com/books?id=i4_FZHmzjzwC&pg=PA239. 
  52. ↑ "Health: Generic Drugs Prices Increasing". CBS Philadelphia. 26 September 2014. http://philadelphia.cbslocal.com/2014/09/26/health-generic-drugs-prices-increasing/. 
  53. ↑ "Some Generic Drugs See Huge Price Increases". 15 September 2016. https://www.medscape.com/viewarticle/868812. 
  54. ↑ "Climbing cost of decades-old drugs threatens to break Medicaid bank". Kaiser Health News. 14 August 2017. http://www.philly.com/philly/health/health-cents/climbing-cost-of-decades-old-drugs-threatens-to-break-medicaid-bank-20170814.html. 
  55. ↑ "Are Drugs Really Getting More Expensive? Yes.". 27 February 2018. https://www.goodrx.com/blog/are-drugs-getting-more-expensive/. 
  56. ↑ "CIR 84/FA084: Use of Antibiotics in Ornamental Fish Aquaculture". https://edis.ifas.ufl.edu/publication/FA084. 



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