Chemistry:Chloramphenicol

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Short description: Antibiotic
Chloramphenicol
Chloramphenicol.svg
Chloramphenicol-from-xtal-3D-bs-17.png
Clinical data
Trade namesChloromycetin, Abeed, others[1]
Other namesC/CHL/CL[2]
AHFS/Drugs.comMonograph
MedlinePlusa608008
License data
Pregnancy
category
  • AU: A
Routes of
administration		Topical (eye drops), by mouth, intravenous therapy (IV), intramuscular injection (IM)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability75–90%
Protein binding60%
MetabolismLiver
Elimination half-life1.6–3.3 hours
ExcretionKidney (5–15%), faeces (4%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC11H12Cl2N2O5
Molar mass323.13 g·mol−1
3D model (JSmol)
  (verify)

Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections.[4] This includes use as an eye ointment to treat conjunctivitis.[5] By mouth or by injection into a vein, it is used to treat meningitis, plague, cholera, and typhoid fever.[4] Its use by mouth or by injection is only recommended when safer antibiotics cannot be used.[4] Monitoring both blood levels of the medication and blood cell levels every two days is recommended during treatment.[4]

Common side effects include bone marrow suppression, nausea, and diarrhea.[4] The bone marrow suppression may result in death.[4] To reduce the risk of side effects treatment duration should be as short as possible.[4] People with liver or kidney problems may need lower doses.[4] In young infants, a condition known as gray baby syndrome may occur which results in a swollen stomach and low blood pressure.[4] Its use near the end of pregnancy and during breastfeeding is typically not recommended.[6] Chloramphenicol is a broad-spectrum antibiotic that typically stops bacterial growth by stopping the production of proteins.[4]

Chloramphenicol was discovered after being isolated from Streptomyces venezuelae in 1947.[7] Its chemical structure was identified and it was first synthesized in 1949. It is on the World Health Organization's List of Essential Medicines.[8] It is available as a generic medication.[4]

Medical uses

The original indication of chloramphenicol was in the treatment of typhoid, but the presence of multiple drug-resistant Salmonella typhi has meant it is seldom used for this indication except when the organism is known to be sensitive.

In low-income countries, the WHO no longer recommends only chloramphenicol as first-line to treat meningitis, but recognises it may be used with caution if there are no available alternatives.[9]

During the last decade chloramphenicol has been re-evaluated as an old agent with potential against systemic infections due to multidrug-resistant gram positive microorganisms (including vancomycin resistant enterococci). In vitro data have shown an activity against the majority (> 80%) of vancomycin resistant E. faecium strains.[10]

In the context of preventing endophthalmitis, a complication of cataract surgery, a 2017 systematic review found moderate evidence that using chloramphenicol eye drops in addition to an antibiotic injection (cefuroxime or penicillin) will likely lower the risk of endophthalmitis, compared to eye drops or antibiotic injections alone.[11]

Spectrum

Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular infections such as conjunctivitis, blepharitis etc. caused by a number of bacteria including Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. It is not effective against Pseudomonas aeruginosa. The following susceptibility data represent the minimum inhibitory concentration for a few medically significant organisms.[12]

  • Escherichia coli: 0.015 – 10,000 μg/mL
  • Staphylococcus aureus: 0.06 – 128 μg/mL
  • Streptococcus pneumoniae: 2 – 16 μg/mL

Each of these concentrations is dependent upon the bacterial strain being targeted. Some strains of E. coli, for example, show spontaneous emergence of chloramphenicol resistance.[13][14]

Resistance

Three mechanisms of resistance to chloramphenicol are known: reduced membrane permeability, mutation of the 50S ribosomal subunit, and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permeability to chloramphenicol in vitro by serial passage of bacteria, and this is the most common mechanism of low-level chloramphenicol resistance. High-level resistance is conferred by the cat-gene; this gene codes for an enzyme called chloramphenicol acetyltransferase, which inactivates chloramphenicol by covalently linking one or two acetyl groups, derived from acetyl-S-coenzyme A, to the hydroxyl groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.

Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the ACCoT plasmid (A=ampicillin, C=chloramphenicol, Co=co-trimoxazole, T=tetracycline), which mediates multiple drug resistance in typhoid (also called R factors).

As of 2014 some Enterococcus faecium and Pseudomonas aeruginosa strains are resistant to chloramphenicol. Some Veillonella spp. and Staphylococcus capitis strains have also developed resistance to chloramphenicol to varying degrees.[15]

Adverse effects

Aplastic anemia

The most serious side effect of chloramphenicol treatment is aplastic anaemia ('AA'). This effect is rare but sometimes fatal. The risk of AA is high enough that alternatives should be strongly considered. Treatments are available but expensive. No way exists to predict who may or may not suffer this side effect. The effect usually occurs weeks or months after treatment has been stopped, and a genetic predisposition may be involved. It is not known whether monitoring the blood counts of patients can prevent the development of aplastic anaemia, but patients are recommended to have a baseline blood count with a repeat blood count every few days while on treatment.[16] Chloramphenicol should be discontinued if the complete blood count drops. The highest risk is with oral chloramphenicol (affecting 1 in 24,000–40,000)[17] and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions).[18]

Thiamphenicol, a related compound with a similar spectrum of activity, is available in Italy and China for human use, and has never been associated with aplastic anaemia. Thiamphenicol is available in the U.S. and Europe as a veterinary antibiotic, but is not approved for use in humans.[citation needed]

Bone marrow suppression

Chloramphenicol may cause bone marrow suppression during treatment; this is a direct toxic effect of the drug on human mitochondria.[19] This effect manifests first as a fall in hemoglobin levels, which occurs quite predictably once a cumulative dose of 20 g has been given. The anaemia is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia. Studies in mice have suggested existing marrow damage may compound any marrow damage resulting from the toxic effects of chloramphenicol.[20]

Leukemia

Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase of immature white blood cells. The risk of childhood leukemia is increased, as demonstrated in a Chinese case–control study,[21] and the risk increases with length of treatment.

Gray baby syndrome

Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome.[22] This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes (i.e. UDP-glucuronyl transferase), so chloramphenicol remains unmetabolized in the body.[23] This causes several adverse effects, including hypotension and cyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.[24][25][26]

Hypersensitivity reactions

Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. Herxheimer's reactions have occurred during therapy for typhoid fever.[27]

Neurotoxic reactions

Headache, mild depression, mental confusion, and delirium have been described in patients receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn.[27]

Pharmacokinetics

Chloramphenicol is extremely lipid-soluble; it remains relatively unbound to protein and is a small molecule. It has a large apparent volume of distribution and penetrates effectively into all tissues of the body, including the brain. Distribution is not uniform, with highest concentrations found in the liver and kidney, with lowest in the brain and cerebrospinal fluid.[27] The concentration achieved in brain and cerebrospinal fluid is around 30 to 50% of the overall average body concentration, even when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed.[citation needed]

Chloramphenicol increases the absorption of iron.[28]

Use in special populations

Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate (which is inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. No standard dose reduction exists for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma concentrations.

The majority of the chloramphenicol dose is excreted by the kidneys as the inactive metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is excreted by the kidneys unchanged. Plasma levels should be monitored in patients with renal impairment, but this is not mandatory. Chloramphenicol succinate ester (an intravenous prodrug form) is readily excreted unchanged by the kidneys, more so than chloramphenicol base, and this is the major reason why levels of chloramphenicol in the blood are much lower when given intravenously than orally.[29] Chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible.[30]

Dose monitoring

Plasma levels of chloramphenicol must be monitored in neonates and patients with abnormal liver function. Plasma levels should be monitored in all children under the age of four, the elderly, and patients with kidney failure. Because efficacy and toxicity of chloramphenicol are associated with a maximum serum concentration, peak levels (one hour after the intravenous dose is given) should be 10–20 µg/ml with toxicity > 40 µg/ml; trough levels (taken immediately before a dose) should be 5–10 µg/ml.[31][32]

Drug interactions

Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.[33]

Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and CYP3A4 in the liver.[34] Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, antidepressants, antiepileptics, proton-pump inhibitors, and anticoagulants if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, azole antifungals, tricyclic antidepressants, macrolide antibiotics, SSRIs, statins, cardiac antiarrhythmics, antivirals, anticoagulants, and PDE5 inhibitors.[27][35]

Drug antagonistic

Chloramphenicol is antagonistic with most cephalosporins and using both together should be avoided in the treatment of infections.[36]

Drug synergism

Chloramphenicol has been demonstrated a synergistic effect when combined with fosfomycin against clinical isolates of Enterococcus faecium.[37]

Mechanism of action

Chloramphenicol is a bacteriostatic agent, inhibiting protein synthesis. It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome. It specifically binds to A2451 and A2452 residues[38] in the 23S rRNA of the 50S ribosomal subunit, preventing peptide bond formation.[39] Chloramphenicol directly interferes with substrate binding in the ribosome, as compared to macrolides, which sterically block the progression of the growing peptide.[40][41][42]

History

Chloramphenicol was first isolated from Streptomyces venezuelae in 1947 and in 1949 a team of scientists at Parke-Davis including Mildred Rebstock published their identification of the chemical structure and their synthesis.[7]:26[43][44]

In 1972, Senator Ted Kennedy combined the two examples of the Tuskegee Syphilis Study and the 1958 Los Angeles Infant Chloramphenicol experiments as initial subjects of a Senate Subcommittee investigation into dangerous medical experimentation on human subjects.[45]

In 2007, the accumulation of reports associating aplastic anemia and blood dyscrasia with chloramphenicol eye drops led to the classification of “probable human carcinogen” according to World Health Organization criteria, based on the known published case reports and the spontaneous reports submitted to the National Registry of Drug-Induced Ocular Side Effects.[46]

Society and culture

Names

Chloramphenicol is available as a generic worldwide under many brandnames[47] and also under various generic names in eastern Europe and Russia, including chlornitromycin, levomycetin, and chloromycetin; the racemate is known as synthomycetin.[48]

Formulations

Pure chloramphenicol

Chloramphenicol is available as a capsule or as a liquid. In some countries, it is sold as chloramphenicol palmitate ester (CPE). CPE is inactive, and is hydrolysed to active chloramphenicol in the small intestine. No difference in bioavailability is noted between chloramphenicol and CPE.[citation needed]

Manufacture of oral chloramphenicol in the U.S. stopped in 1991, because the vast majority of chloramphenicol-associated cases of aplastic anaemia are associated with the oral preparation. No oral formulation of chloramphenicol is available in the U.S. for human use.[49]

In molecular biology, chloramphenicol is prepared in ethanol.[citation needed]

Intravenous

The intravenous (IV) preparation of chloramphenicol is the succinate ester. This creates a problem: Chloramphenicol succinate ester is an inactive prodrug and must first be hydrolysed to chloramphenicol; however, the hydrolysis process is often incomplete, and 30% of the dose is lost and removed in the urine. Serum concentrations of IV chloramphenicol are only 70% of those achieved when chloramphenicol is given orally.[50] For this reason, the dose needs to be increased to 75 mg/kg/day when administered IV to achieve levels equivalent to the oral dose.[51]

Oily

Oily chloramphenicol (or chloramphenicol oil suspension) is a long-acting preparation of chloramphenicol first introduced by Roussel in 1954; marketed as Tifomycine, it was originally used as a treatment for typhoid. Roussel stopped production of oily chloramphenicol in 1995; the International Dispensary Association Foundation has manufactured it since 1998, first in Malta and then in India from December 2004.[52]

Oily chloramphenicol was first used to treat meningitis in 1975[53] and numerous studies since have demonstrated its efficacy.[54][55][56] It is the cheapest treatment available for meningitis (US$5 per treatment course, compared to US$30 for ampicillin and US$15 for five days of ceftriaxone). It has the great advantage of requiring only a single injection, whereas ceftriaxone is traditionally given daily for five days. This recommendation may yet change, now that a single dose of ceftriaxone (cost US$3) has been shown to be equivalent to one dose of oily chloramphenicol.[57]

Eye drops

Chloramphenicol is used in topical preparations (ointments and eye drops) for the treatment of bacterial conjunctivitis. Isolated case reports of aplastic anaemia following use of chloramphenicol eyedrops exist, but the risk is estimated to be of the order of less than one in 224,716 prescriptions.[18] In Mexico, this is the treatment used prophylactically in newborns for neonatal conjunctivitis.[58]

Veterinary uses

Although its use in veterinary medicine is highly restricted, chloramphenicol still has some important veterinary uses.[59] It is currently considered the most useful treatment of chlamydial disease in koalas.[60][61] The pharmacokinetics of chloramphenicol have been investigated in koalas.[62]

References

  1. ↑ Delmar nurse's drug handbook. (2009 ed.). Clifton Park, N.Y.: Delmar. 2008. p. 296. ISBN 9781428361065. https://books.google.com/books?id=8MoIHiUja_oC&pg=PA296. 
  2. ↑ "Antibiotic abbreviations list". https://microbiologie-clinique.com/antibiotic-family-abbreviation.html. 
  3. ↑ "Chloramphenicol". PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/5959#section=Top. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 "Chloramphenicol". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/chloramphenicol.html. 
  5. ↑ (in en) Optometry: Science, Techniques and Clinical Management. Elsevier Health Sciences. 2009. p. 102. ISBN 978-0750687782. https://books.google.com/books?id=dv2g8aOIhhsC&pg=PA102. 
  6. ↑ "Chloramphenicol Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/chloramphenicol.html. 
  7. ↑ 7.0 7.1 "Chapter 3: Chloramphenicol". Mechanism of Action of Antibacterial Agents. Antibiotics Volume V Part 1. Berlin, Heidelberg: Springer Berlin Heidelberg. 1979. pp. 26–42. ISBN 978-3-642-46403-4. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  9. ↑ "WHO meningitis epidemic guidelines Africa". https://www.who.int/csr/resources/publications/HSE_GAR_ERI_2010_4/en/. 
  10. ↑ "Could chloramphenicol be used against ESKAPE pathogens? A review of in vitro data in the literature from the 21st century". Expert Review of Anti-Infective Therapy 12 (2): 249–264. February 2014. doi:10.1586/14787210.2014.878647. PMID 24392752. http://www.tandfonline.com/doi/full/10.1586/14787210.2014.878647. Retrieved 2021-07-02. 
  11. ↑ "Perioperative antibiotics for prevention of acute endophthalmitis after cataract surgery". The Cochrane Database of Systematic Reviews 2017 (2): CD006364. February 2017. doi:10.1002/14651858.CD006364.pub3. PMID 28192644. 
  12. ↑ "Chloramphenicol (Chloromycetin) | the Antimicrobial Index Knowledgebase - TOKU-E". http://antibiotics.toku-e.com/antimicrobial_507.html. 
  13. ↑ "High incidence of multiple antibiotic resistant cells in cultures of in enterohemorrhagic Escherichia coli O157:H7". Mutation Research 759: 1–8. January 2014. doi:10.1016/j.mrfmmm.2013.11.008. PMID 24361397. 
  14. ↑ "Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes". PLOS ONE 8 (11): e78822. 2013. doi:10.1371/journal.pone.0078822. PMID 24236055. Bibcode: 2013PLoSO...878822M. 
  15. ↑ "Chloramphenicol spectrum of bacterial susceptibility and Resistance". Product Data Safety Sheet. TOKU-E. December 2010. http://www.toku-e.com/Upload/Products/PDS/20120618001452.pdf. 
  16. ↑ "Laboratory guidelines for monitoring of antimicrobial drugs. National Academy of Clinical Biochemistry". Clinical Chemistry 44 (5): 1129–1140. May 1998. doi:10.1093/clinchem/44.5.1129. PMID 9590397. 
  17. ↑ "Statewide study of chloramphenicol therapy and fatal aplastic anemia". JAMA 208 (11): 2045–2050. June 1969. doi:10.1001/jama.208.11.2045. PMID 5818983. 
  18. ↑ 18.0 18.1 "Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database". BMJ 316 (7132): 667. February 1998. doi:10.1136/bmj.316.7132.667. PMID 9522792. 
  19. ↑ "Chloramphenicol toxicity: 25 years of research". The American Journal of Medicine 87 (3N): 44N–48N. September 1989. PMID 2486534. 
  20. ↑ "Residual marrow damage: possible explanation for idiosyncrasy to chloramphenicol". British Journal of Haematology 32 (4): 525–531. April 1976. doi:10.1111/j.1365-2141.1976.tb00955.x. PMID 1259934. 
  21. ↑ "Chloramphenicol use and childhood leukaemia in Shanghai". Lancet 2 (8565): 934–937. October 1987. doi:10.1016/S0140-6736(87)91420-6. PMID 2889862. 
  22. ↑ "Drug toxicity in the neonate". Biology of the Neonate 86 (4): 218–221. 2004. doi:10.1159/000079656. PMID 15249753. 
  23. ↑ "Liver". Pediatrics 113 (4 Suppl): 1097–1106. April 2004. doi:10.1542/peds.113.S3.1097. PMID 15060205. http://pediatrics.aappublications.org/content/113/Supplement_3/1097.full.pdf. Retrieved 2012-01-09. 
  24. ↑ "Chloramphenicol: what we have learned in the last decade". Southern Medical Journal 79 (9): 1129–1134. September 1986. doi:10.1097/00007611-198609000-00022. PMID 3529436. 
  25. ↑ "Chloramphenicol toxicity in neonates: its incidence and prevention". British Medical Journal 287 (6403): 1424–1427. November 1983. doi:10.1136/bmj.287.6403.1424. PMID 6416440. 
  26. ↑ "[Need for the determination of chloramphenicol levels in the treatment of bacterial-purulent meningitis with chloramphenicol succinate in infants and small children]" (in de). Monatsschrift Kinderheilkunde 133 (4): 209–213. April 1985. PMID 4000136. 
  27. ↑ 27.0 27.1 27.2 27.3 "Drug Insert from DailyMed". http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08c16a42-1ad4-400f-b1b0-75303eb86713. 
  28. ↑ "Iron Supplements". Pill Book, The (12th revised ed.). New York: Bantam Dell. 2006. pp. 593–596. ISBN 978-0-553-58892-7. 
  29. ↑ "Pharmacokinetic comparison of intravenous and oral chloramphenicol in patients with Haemophilus influenzae meningitis". Pediatrics 67 (5): 656–660. May 1981. doi:10.1542/peds.67.5.656. PMID 6973130. 
  30. ↑ "Drugs and Other Substances in Breast Milk". kidsgrowth.org. http://www.kidsgrowth.org/resources/articledetail.cfm?id=471. 
  31. ↑ "Laboratory guidelines for monitoring of antimicrobial drugs. National Academy of Clinical Biochemistry". Clinical Chemistry 44 (5): 1129–1140. May 1998. doi:10.1093/clinchem/44.5.1129. PMID 9590397. 
  32. ↑ "Chloramphenicol (Lexi-Drugs)". Lexi-Comp Online. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6582. 
  33. ↑ "Practice Guidance: OTC Chloramphenicol Eye Drops". Royal Pharmaceutical Society of Great Britain (RPSGB). June 2005. http://www.rpsgb.org.uk/pdfs/otcchlorampheneyedropsguid.pdf. 
  34. ↑ "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes". Antimicrobial Agents and Chemotherapy 47 (11): 3464–3469. November 2003. doi:10.1128/AAC.47.11.3464-3469.2003. PMID 14576103. 
  35. ↑ "Fakta för förskrivare" (in sv). FASS – Swedish National Drug Formulary. http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352. 
  36. ↑ "Antagonistic effect of chloramphenicol in combination with cefotaxime or ceftriaxone". Antimicrobial Agents and Chemotherapy 32 (9): 1375–8. September 1988. doi:10.1128/AAC.32.9.1375. PMID 3195999. 
  37. ↑ "Synergistic activity of fosfomycin and chloramphenicol against vancomycin-resistant Enterococcus faecium (VREfm) isolates from bloodstream infections". Diagnostic Microbiology and Infectious Disease 99 (2): 115241. February 2021. doi:10.1016/j.diagmicrobio.2020.115241. PMID 33130503. 
  38. ↑ "Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site". Proceedings of the National Academy of Sciences of the United States of America 110 (21): 8501–8506. May 2013. doi:10.1073/pnas.1222031110. PMID 23650345. Bibcode: 2013PNAS..110.8501S. 
  39. ↑ "Chloramphenicol". The Merck Manual. Rahway, NJ, USA: Merck & Co., Inc.. http://merck.com/mmpe/sec14/ch170/ch170d.html. 
  40. ↑ "Studies on the mechanism of action of chloramphenicol. I. The conformation of chlioramphenicol in solution". The Journal of Biological Chemistry 238 (7): 2498–2508. July 1963. doi:10.1016/S0021-9258(19)68000-2. PMID 13957484. http://www.jbc.org/content/238/7/2498.full.pdf. 
  41. ↑ "Mode of action of chloramphenicol IX. Effects of chloramphenicol upon a ribosomal amino acid polymerization system and its binding to bacterial ribosome". Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis 95: 146–155. January 1965. doi:10.1016/0005-2787(65)90219-4. PMID 14289020. 
  42. ↑ "Mode of action of chloramphenicol. III. Action of chloramphenicol on bacterial energy metabolism". Journal of Bacteriology 69 (2): 215–223. February 1955. doi:10.1128/JB.69.2.215-223.1955. PMID 14353832. 
  43. ↑ "Chloramphenicol (Chloromycetin).IV.Chemical Studies". Journal of the American Chemical Society 71 (7): 2458–2462. July 1949. doi:10.1021/ja01175a065. 
  44. ↑ "Chloramphenicol (Chloromycetin). V. Synthesis". Journal of the American Chemical Society 71 (7): 2463–2468. July 1949. doi:10.1021/ja01175a066. 
  45. ↑ ""Kennedy Says 45 Babies Died in a Test"". The New York Times (New York). October 12, 1972. https://timesmachine.nytimes.com/timesmachine/1972/10/12/91352284.html?pageNumber=22. 
  46. ↑ "Restricting topical ocular chloramphenicol eye drop use in the United States. Did we overreact?". American Journal of Ophthalmology 156 (3): 420–422. September 2013. doi:10.1016/j.ajo.2013.05.004. PMID 23953152. 
  47. ↑ "International listings for chloramphenicol". Drugs.com. https://www.drugs.com/international/chloramphenicol.html. 
  48. ↑ The Great Soviet Encyclopedia, 3rd Edition, 1970–1979 (3rd ed.). The Gale Group, Inc.. http://encyclopedia2.thefreedictionary.com/Levomycetin. Retrieved 10 July 2015. 
  49. ↑ "Chloramphenicol". June 23, 2023. https://go.drugbank.com/drugs/DB00446. 
  50. ↑ "Absorption and excretion of parenteral doses of chloramphenicol sodium succinate in comparison with per oral doses of chloramphenicol (abstract)". Clinical Pharmacological Therapy 21: 104. 1977. 
  51. ↑ "Chloramphenicol clearance in typhoid fever: implications for therapy". Indian Journal of Pediatrics 59 (2): 213–219. March–April 1992. doi:10.1007/BF02759987. PMID 1398851. 
  52. ↑ "Long-acting oily chloramphenicol for meningococcal meningitis". Lancet 352 (9130): 823. September 1998. doi:10.1016/S0140-6736(05)60723-4. PMID 9737323. 
  53. ↑ "Traitement minute de la méningite cérébrospinale épidémique par injection intramusculaire unique de chloramphénicol (suspension huileuse)" (in fr). Médecine et Maladies Infectieuses 6 (4): 120–124. 1976. doi:10.1016/S0399-077X(76)80134-5. 
  54. ↑ "Single injection treatment of meningococcal meningitis. 2. Long-acting chloramphenicol". Transactions of the Royal Society of Tropical Medicine and Hygiene 73 (6): 698–702. 1979. doi:10.1016/0035-9203(79)90024-5. PMID 538813. 
  55. ↑ "A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis". Transactions of the Royal Society of Tropical Medicine and Hygiene 78 (3): 399–403. 1984. doi:10.1016/0035-9203(84)90132-9. PMID 6464136. 
  56. ↑ "Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis". Lancet 338 (8771): 862–866. October 1991. doi:10.1016/0140-6736(91)91511-R. PMID 1681224. 
  57. ↑ "Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study". Lancet 366 (9482): 308–313. 2005. doi:10.1016/S0140-6736(05)66792-X. PMID 16039333. https://fieldresearch.msf.org/bitstream/10144/23232/1/187_Ceftriaxone_as_effective_as_long-acting_-_Lancet_9482_2005.pdf. Retrieved 2019-09-24. 
  58. ↑ "A Survey of Current Prophylactic Treatment for Ophthalmia Neonatorum in Croatia and a Review of International Preventive Practices". Medical Science Monitor 24: 8042–8047. November 2018. doi:10.12659/MSM.910705. PMID 30413681. "According to current health policy in Mexico, preventive treatment for ophthalmia neonatorum in neonates is a medico-legal requirement and consists of the application of a single drop of ophthalmic chloramphenicol in both eyes shortly after birth". 
  59. ↑ "Chloramphenicol and Congeners". Rahway, NJ, USA: Merck & Co., Inc.. March 2012. http://www.merckmanuals.com/vet/pharmacology/antibacterial_agents/chloramphenicol_and_congeners.html. 
  60. ↑ "Plasma concentrations of chloramphenicol after subcutaneous administration to koalas (Phascolarctos cinereus) with chlamydiosis". Journal of Veterinary Pharmacology and Therapeutics 35 (2): 147–154. April 2012. doi:10.1111/j.1365-2885.2011.01307.x. PMID 21569052. 
  61. ↑ "Diagnosis, treatment and outcomes for koala chlamydiosis at a rehabilitation facility (1995-2005)". Australian Veterinary Journal 90 (11): 457–463. November 2012. doi:10.1111/j.1751-0813.2012.00963.x. PMID 23106328. 
  62. ↑ "Pharmacokinetics of chloramphenicol following administration of intravenous and subcutaneous chloramphenicol sodium succinate, and subcutaneous chloramphenicol, to koalas (Phascolarctos cinereus)". Journal of Veterinary Pharmacology and Therapeutics 36 (5): 478–485. October 2013. doi:10.1111/jvp.12024. PMID 23157306. 

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