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Capreomycin

PubChem CID
3000502
Structure
Capreomycin_small.png
Molecular Formula
Synonyms
  • capreomycin
  • Capreomycin (INN)
  • CAPREOMYCIN [INN]
  • Capostatin
  • Capreomicin
Molecular Weight
1321.4 g/mol
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Component Compounds
Dates
  • Create:
    2005-08-01
  • Modify:
    2025-01-11
Description
Cyclic peptide antibiotic similar to viomycin. It is produced by Streptomyces capreolus.
Capreomycin is an injectable broad spectrum antibiotic used in the therapy of drug resistant tuberculosis as a second line agent, always in combination with other antituberculosis drugs. Capreomycin has not been linked to cases of clinically apparent liver disease.
Capreomycin is a cyclic polypeptide isolated from Streptomyces capreolus with antitubercular activity. Even though the exact mechanism by which capreomycin exerts its effect has yet to be fully elucidated, this agent may bind to the bacterial 50S subunit of the 70S ribosome. This leads to interference with the translational initiation complex, misreading of mRNA, and eventually leads to inhibition of protein synthesis. In addition, capreomycin also binds bacterial cell wall components thereby inhibiting cell wall synthesis.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Capreomycin.png

1.2 3D Status

Conformer generation is disallowed since too many atoms, too flexible, mixture or salt

2 Biologic Description

SVG Image
SVG Image
IUPAC Condensed
H-Dap(1)-Ala-Dap(2)-Dha(ureido)(ureido)-Arg-(1).H-Dap(3)-Ser-Dap(4)-Dha(ureido)(ureido)-Arg-(3).H-bLys(S)-(2).H-bLys(S)-(4)
HELM
PEPTIDE1{[Dpr].A.[Dpr].[*C(=O)C(=CNC(=O)N)N* |$_R2;;;;;;;;;;_R1$|].R}|PEPTIDE2{[Dpr].S.[Dpr].[*C(=O)C(=CNC(=O)N)N* |$_R2;;;;;;;;;;_R1$|].R}|PEPTIDE3{[*C(=O)C[C@H](CCCN)N |$_R2;;;;;;;;;$|]}|PEPTIDE4{[*C(=O)C[C@H](CCCN)N |$_R2;;;;;;;;;$|]}$PEPTIDE1,PEPTIDE1,1:R3-5:R2|PEPTIDE2,PEPTIDE2,1:R3-5:R2|PEPTIDE1,PEPTIDE3,3:R3-1:R2|PEPTIDE2,PEPTIDE4,3:R3-1:R2$$$

3 Names and Identifiers

3.1 Computed Descriptors

3.1.1 IUPAC Name

(3S)-3,6-diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(6R)-2-amino-1,4,5,6-tetrahydropyrimidin-6-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3S)-3,6-diamino-N-[[(2S,5S,8E,11S,15S)-15-amino-11-[(6R)-2-amino-1,4,5,6-tetrahydropyrimidin-6-yl]-8-[(carbamoylamino)methylidene]-2-methyl-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07)

3.1.2 InChI

InChI=1S/C25H44N14O8.C25H44N14O7/c26-4-1-2-11(27)6-17(41)32-8-14-20(43)35-15(9-34-25(30)47)21(44)39-18(13-3-5-31-24(29)38-13)23(46)33-7-12(28)19(42)37-16(10-40)22(45)36-14;1-11-19(41)36-15(9-32-17(40)7-12(27)3-2-5-26)21(43)37-16(10-34-25(30)46)22(44)39-18(14-4-6-31-24(29)38-14)23(45)33-8-13(28)20(42)35-11/h9,11-14,16,18,40H,1-8,10,26-28H2,(H,32,41)(H,33,46)(H,35,43)(H,36,45)(H,37,42)(H,39,44)(H3,29,31,38)(H3,30,34,47);10-15,18H,2-9,26-28H2,1H3,(H,32,40)(H,33,45)(H,35,42)(H,36,41)(H,37,43)(H,39,44)(H3,29,31,38)(H3,30,34,46)/b15-9+;16-10+/t11-,12-,13+,14-,16-,18-;11-,12-,13-,14+,15-,18-/m00/s1
Computed by InChI 1.0.6 (PubChem release 2021.05.07)

3.1.3 InChIKey

VCOPTHOUUNAYKQ-WBTCAYNUSA-N
Computed by InChI 1.0.6 (PubChem release 2021.05.07)

3.1.4 SMILES

C[C@H]1C(=O)N[C@H](C(=O)N/C(=C/NC(=O)N)/C(=O)N[C@H](C(=O)NC[C@@H](C(=O)N1)N)[C@H]2CCN=C(N2)N)CNC(=O)C[C@H](CCCN)N.C1CN=C(N[C@H]1[C@H]2C(=O)NC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N/C(=C/NC(=O)N)/C(=O)N2)CNC(=O)C[C@H](CCCN)N)CO)N)N
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

3.2 Molecular Formula

C50H88N28O15
Computed by PubChem 2.1 (PubChem release 2021.05.07)

3.3 Other Identifiers

3.3.1 CAS

3.3.2 DrugBank ID

3.3.3 Metabolomics Workbench ID

3.3.4 NCI Thesaurus Code

3.3.5 PharmGKB ID

3.3.6 Wikipedia

3.4 Synonyms

3.4.1 MeSH Entry Terms

  • Capastat
  • Capreomycin
  • Capreomycin Sulfate
  • Capromycin

3.4.2 Depositor-Supplied Synonyms

4 Chemical and Physical Properties

4.1 Computed Properties

Property Name
Molecular Weight
Property Value
1321.4 g/mol
Reference
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Property Name
Hydrogen Bond Donor Count
Property Value
27
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Hydrogen Bond Acceptor Count
Property Value
23
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Rotatable Bond Count
Property Value
19
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Exact Mass
Property Value
1320.69839421 Da
Reference
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Property Name
Monoisotopic Mass
Property Value
1320.69839421 Da
Reference
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Property Name
Topological Polar Surface Area
Property Value
737 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Heavy Atom Count
Property Value
93
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
2470
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
12
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
2
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2010.01.29)

4.2 Experimental Properties

4.2.1 Color / Form

White solid
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284

4.2.2 Solubility

Soluble in water as disulfate salt.
WHITE TO SLIGHTLY YELLOWISH WHITE, AMORPHOUS POWDER. ODORLESS. FREELY SOL IN WATER. PRACTICALLY INSOL IN MOST ORG SOLVENTS. /STERILE SULFATE SALT/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1135
Practically insol in most org solvents
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284

4.2.3 LogP

-9.609

4.2.4 Stability / Shelf Life

STABLE IN AQ SOLN @ PH 4-8; UNSTABLE IN STRONGLY ACIDIC OR STRONGLY BASIC SOLN /MIXT/
The Merck Index. 9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 223
SOLN DARKEN WITH NO LOSS OF POTENCY OR INCR IN TOXICITY; PROTECT FROM HEAT & MOISTURE /STERILE SULFATE SALT/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1135

4.2.5 Optical Rotation

CAS no. 37280-35-6. Mol wt: 669.71. MF: C25H44N14O8. MP 246-248 °C (dec). Specific optical rotation: -21.9 deg at 22 °C/D ( c 0.5 in water). UV max (0.1 N HCl): 269 nm (epsilon 2400); (H2O): 268 nm (epsilon 23900); (0.1 N NaOH): 287 nm (epsilon 15900) (all for hydrochloride ethanolate). /Capreomycin IA/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284
CAS no. 33490-33-4. Mol wt: 652.71. MF: C25H44N14O7. MP 253-255 °C (dec). Specific optical rotation: -44.6 deg at 22 °C/D ( c 0.5 in water). UV max (0.1 N HCl): 268 nm (epsilon 22700); (H2O): 268 nm (epsilon 22300); (0.1 N NaOH): 290 nm (epsilon 14400) (all for hydrochloride ethanolate). /Capreomycin IB/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284

4.2.6 Dissociation Constants

pKa in 66% aq dimethylformamide: 6.2, 8.2, 10.1, 13.3
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284

4.2.7 Other Experimental Properties

Soluble in water. In complete solution, it is almost colorless /Sulfate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1784

4.3 Chemical Classes

4.3.1 Drugs

4.3.1.1 Human Drugs
Breast Feeding; Lactation; Anti-Infective Agents; Antibacterial Agents; Antitubercular Agents

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Used in the treatment of tuberculosis in combination with other drugs.

7.2 LiverTox Summary

Capreomycin is an injectable broad spectrum antibiotic used in the therapy of drug resistant tuberculosis as a second line agent, always in combination with other antituberculosis drugs. Capreomycin has not been linked to cases of clinically apparent liver disease.

7.3 Drug Classes

Breast Feeding; Lactation; Anti-Infective Agents; Antibacterial Agents; Antitubercular Agents
Antituberculosis Agents

7.4 Clinical Trials

7.4.1 ClinicalTrials.gov

7.5 Therapeutic Uses

Antibiotics, Antitubercular; Antibiotics, Peptide
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Capreomycin is indicated in combination with other antituberculosis medications in the treatment of pulmonary tuberculosis caused by Mycobacterium tuberculosis after failure with the primary medications (streptomycin, isoniazid, rifampin, pyrazinamide, and ethambutol) or when these cannot be used because of toxicity or development of resistant tubercle bacilli. /Included in US product label/
Thomson.Micromedex. Drug Information for the Health Care Professional. 25th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2005., p. 726
Since bacterial resistance may develop rapidly when capreomycin is administered alone, it should only be administered concurrently with other antituberculosis medications in the treatment of tuberculosis. /NOT included in US product label/
Thomson.Micromedex. Drug Information for the Health Care Professional. 25th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2005., p. 726

7.6 Drug Warnings

Nephrotoxicity and ototoxicity are the most serious adverse effects of capreomycin. These effects are most likely to occur in patients with renal impairment, in geriatric patients, and in patients who are receiving other nephrotoxic and/or ototoxic drugs.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 565
Renal toxicity may be manifested by tubular necrosis, increases in BUN and nonprotein nitrogen, decreased creatinine clearance, proteinuria, and the presence of casts, erythrocytes, and leukocytes in the urine. The manufacturer states that BUN concentrations increased to greater than 20 mg/dL in 36% of 722 patients receiving capreomycin; BUN concentrations were greater than 30 mg/dL in 10% of patients. There also was depression of PSP excretion and abnormal urine sediment in many patients. Renal toxicity is usually reversible following discontinuation of the drug however, fatal toxic nephritis has occurred rarely. Fatal toxic nephritis was reported in one patient with tuberculosis and portal cirrhosis who had received one month of therapy with capreomycin (1 g daily) in conjunction with aminosalicylic acid; the patient developed renal insufficiency and oliguria and autopsy indicated subsiding acute tubular necrosis. Nephrotoxicity is most closely related to the area under the serum concentration-time curve. Geriatric patients, patients with abnormal renal function or dehydration, and patients receiving other nephrotoxic drugs are at increased risk of developing acute tubular necrosis during capreomycin therapy.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 565
Electrolyte disturbances including alkalosis and decreased serum concentrations of potassium, magnesium, and calcium have also occurred because of renal tubular dysfunction in patients receiving capreomycin. Electrolyte disturbances resembling Bartter's syndrome have been reported in at least one patient.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 565
Capreomycin may produce damage to both the auditory and vestibular portions of the eighth cranial nerve. Damage to auditory function may result in a hearing loss. Rarely, permanent deafness has occurred. Headache, tinnitus, and vertigo have occurred rarely from injury to the vestibular branch of the eighth cranial nerve. The manufacturer states that subclinical auditory loss (5- to 10-decibel loss in the 4000-8000 CPS range) was noted in approximately 11% of 722 patients receiving capreomycin; clinically apparent hearing loss occurred in 3% of patients. Some audiometric changes were reversible; hearing loss that was permanent was not progressive following discontinuance of capreomycin. Damage to the auditory and vestibular divisions of the eighth cranial nerve have generally been associated with capreomycin therapy in patients with impaired renal function or dehydration or those receiving other drugs with additive auditory toxicities; these patients often experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 565
For more Drug Warnings (Complete) data for CAPREOMYCIN (13 total), please visit the HSDB record page.

7.7 Drug Tolerance

Natural and acquired resistance to capreomycin have been demonstrated in vitro and in vivo in strains of M. tuberculosis. In vitro, resistance to the drug develops slowly and in a stepwise manner. Resistant strains of initially susceptible M. tuberculosis develop rapidly if capreomycin is used alone in the treatment of clinical tuberculosis. When capreomycin is combined with other antituberculosis agents in the treatment of the disease, emergence of resistant strains may be delayed or prevented. Frequent cross-resistance occurs between capreomycin and viomycin. Partial cross-resistance has been demonstrated between capreomycin and kanamycin or neomycin. There is no evidence of cross-resistance between capreomycin and other antituberculosis agents currently available in the US.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566
Capreomycin, an important drug for the treatment of multidrug-resistant tuberculosis, is a macrocyclic peptide antibiotic produced by Saccharothrix mutabolis subspecies capreolus. The basis of resistance to this drug was investigated by isolating and characterizing capreomycin-resistant strains of Mycobacterium smegmatis and Mycobacterium tuberculosis. Colonies resistant to capreomycin were recovered from a library of transposon-mutagenized M. smegmatis. The transposon insertion site of one mutant was mapped to an open reading frame in the unfinished M. smegmatis genome corresponding to the tlyA gene (Rv1694) in the M. tuberculosis H37Rv genome. In M. smegmatis spontaneous capreomycin-resistant mutants, the tlyA gene was disrupted by one of three different naturally occurring insertion elements. Genomic DNAs from pools of transposon mutants of M. tuberculosis H37Rv were screened by PCR by using primers to the tlyA gene and the transposon to detect mutants with an insertion in the tlyA gene. One capreomycin-resistant mutant was recovered that contained the transposon inserted at base 644 of the tlyA gene. Complementation with the wild-type tlyA gene restored susceptibility to capreomycin in the M. smegmatis and M. tuberculosis tlyA transposon mutants. Mutations were found in the tlyA genes of 28 spontaneous capreomycin-resistant mutants generated from three different M. tuberculosis strains and in the tlyA genes of capreomycin-resistant clinical isolates. In in vitro transcription-translation assays, ribosomes from tlyA mutant but not tlyA(+) strains resist capreomycin inhibition of transcription-translation. Therefore, TlyA appears to affect the ribosome, and mutation of tlyA confers capreomycin resistance.
Maus CE et al; Antimicrob Agents Chemother 49 (2): 571-7 (2005)
The cyclic peptide antibiotics capreomycin and viomycin are generally effective against the bacterial pathogen Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their tlyA gene. /It is/ showh here that tlyA encodes a 2'-O-methyltransferase that modifies nucleotide C1409 in helix 44 of 16S rRNA and nucleotide C1920 in helix 69 of 23S rRNA. Loss of these previously unidentified rRNA methylations confers resistance to capreomycin and viomycin. Many bacterial genera including enterobacteria lack a tlyA gene and the ensuing methylations and are less susceptible than mycobacteria to capreomycin and viomycin. We show that expression of recombinant tlyA in Escherichia coli markedly increases susceptibility to these drugs. When the ribosomal subunits associate during translation, the two tlyA-encoded methylations are brought into close proximity at interbridge B2a. The location of these methylations indicates the binding site and inhibitory mechanism of capreomycin and viomycin at the ribosome subunit interface.
Johansen SK et al; Mol Cell 23 (2): 173-82 (2006)

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Capreomycin is a member of the aminoglycoside family of antibiotics. These antibiotics have the ability to kill a wide variety of bacteria, including bacteria responsible for causing tuberculosis (TB).

8.2 MeSH Pharmacological Classification

Protein Synthesis Inhibitors
Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins. (See all compounds classified as Protein Synthesis Inhibitors.)
Anti-Bacterial Agents
Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)
Antibiotics, Antitubercular
Substances obtained from various species of microorganisms that are, alone or in combination with other agents, of use in treating various forms of tuberculosis; most of these agents are merely bacteriostatic, induce resistance in the organisms, and may be toxic. (See all compounds classified as Antibiotics, Antitubercular.)

8.3 ATC Code

J - Antiinfectives for systemic use

J04 - Antimycobacterials

J04A - Drugs for treatment of tuberculosis

J04AB - Antibiotics

J04AB30 - Capreomycin

8.4 Absorption, Distribution and Excretion

Absorption
Not absorbed in significant quantities from the gastrointestinal tract and must be administered parenterally.
Route of Elimination
When a 1–g dose of capreomycin was given intramuscularly to normal volunteers, 52% was excreted in the urine within 12 hours.
Capreomycin sulfate is not appreciably absorbed from the GI tract and therefore must be given parenterally. Following im administration of a single 1 g dose of capreomycin in healthy adults, peak plasma capreomycin concentrations ranging from 20-47 ug/mL are attained within 1-2 hours (averaging 28 and 32 ug/mL at 1 and 2 hours, respectively); plasma concentrations of the drug average 10 ug/mL at 6 hours and less than 1 ug/mL at 24 hours. Following administration of a single 1-g dose im or by iv infusion over 1 hour, the area under the serum concentration-time curve (AUC) was similar for both routes of administration. However, peak serum capreomycin concentrations after iv infusion were 30% higher than those following IM injection.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566
/Investigators/ examined the pharmacokinetics of single dose capreomycin (1.0 g) administered intramuscularly and by intravenous infusion (1 hour) in 6 healthy volunteers. The area under the serum concentration versus time curve was similar for the two routes of administration. Capreomycin peak concentrations after intravenous infusion were 30 +/- 47% higher than after intramuscular administration.
US Natl Inst Health; DailyMed. Current Medication Information. Capreomycin (01/2008). Available from, as of July 8, 2008: https://dailymed.nlm.nih.gov/dailymed/about.cfm
Capreomycin does not distribute into CSF. Information is not available on the distribution of capreomycin into other body tissue or fluids. It is not known if the drug crosses the placenta or is distributed into milk.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566
Capreomycin is excreted mainly unchanged in urine by glomerular filtration. Results of animal studies suggest that small amounts of the drug may also be excreted in bile. Following a single 1g IM dose of capreomycin in adults with normal renal function, approximately 52% of the dose is excreted in urine within 12 hours.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566
For more Absorption, Distribution and Excretion (Complete) data for CAPREOMYCIN (6 total), please visit the HSDB record page.

8.5 Metabolism / Metabolites

Paper chromatographic studies indicated that capreomycin is excreted essentially unaltered. Urine concentrations averaged 1.68 mg/mL (average urine volume, 228 mL) during the 6 hours following a 1-g dose.
US Natl Inst Health; DailyMed. Current Medication Information. Capreomycin (01/2008). Available from, as of July 8, 2008: https://dailymed.nlm.nih.gov/dailymed/about.cfm

8.6 Biological Half-Life

The plasma half-life of capreomycin in patients with normal renal function is 4-6 hours. Plasma concentrations of capreomycin are higher and the half-life is prolonged in patients with impaired renal function.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566

8.7 Mechanism of Action

Little is known about capreomycin's exact mechanism of action, but it is thought to inhibit protein synthesis by binding to the 70S ribosomal unit. Capreomycin also binds to components in the bacterial cell which result in the production of abnormal proteins. These proteins are necessary for the bacteria's survival. Therefore the production of these abnormal proteins is ultimately fatal to the bacteria.
Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 67
Capreomycin is an important drug used for TB with multi-drug resistance. A recent study also indicates that this drug possesses unique bactericidal activity against non-replicating TB bacilli among known anti-TB drugs. Thus, there is an urgent need for investigating the full-spectrum action of capreomycin. Here /investigators/ conduct the first microarray-based study on capreomycin using the high-resolution Affymetrix oligonucleotide GeneChip system. The results indicate that capreomycin primarily acts on the information pathways but it also significantly affects cell wall, cell processes, intermediate metabolism and respiration in Mycobacterium tuberculosis. This study not only transcriptionally validates the specific molecular target, 16S rRNA, but also discovers potential new targets of capreomycin, including genes operating at the DNA level, such as Rv0054 (ssb) and Rv3715c (recR), as well as genes involved in cell division like Rv3260c (whiB2). In addition, the nuo gene cluster and the ATP synthase gene cluster are repressed.
Fu L, Shinnick T; J Infect 54 (3): 277-84 (2007)

9 Use and Manufacturing

9.1 Uses

Active against strains of Mycobacterium tuberculosis found in humans
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1784
THERAP CAT: Antibacterial (tuberculostatic)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284
... second-line injectable anti-tuberculosis drug
Zager WM, McNerney R; BMC Infectious Diseases 8: 10 (2008). Available from, as of Apr 16, 2008: https://www.biomedcentral.com/content/pdf/1471-2334-8-10.pdf
MEDICATION

9.2 Methods of Manufacturing

... Produced by Streptomyces capreolus
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 227

9.3 Formulations / Preparations

Parenteral for injection: 1g (of capreomycin), Capastat Sulfate, Lilly
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566
/CAPREOMYCIN/...CONSISTS OF 4 ACTIVE COMPONENTS--CAPREOMYCIN IA, IB, IIA, & IIB... AGENT USED CLINICALLY CONTAINS PRIMARILY IA & IB; OTHER FRACTIONS MAKE UP ONLY 20% OF DRUG.
Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 1213
Sterile capreomycin sulfate, USP (capastat), is supplied in ampules containing 1 g of drug for solution in 2 mL of sodium chloride injection or sterile water.
Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 1213

9.4 General Manufacturing Information

Mixture of capreomycins IA, IB, IIA, and IIB in the approx percentages, 25%, 67%, 3%, and 6%.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284
Polypeptide antibiotic isolated from Streptomyces capreolus ... complex of 4 microbiologically active components which have been characterized in part; however, complete structural determination of all components has not been established /Sulfate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1784

10 Identification

10.1 Analytic Laboratory Methods

Analyte: capreomycin sulfate; matrix: chemical identification; procedure: reaction with barium chloride yields a white precipitate that is insoluble in hydrochloric acid and in nitric acid; reaction with lead acetate yields a white precipitate that is soluble in ammonium acetate (sulfate test) /capreomycin sulfate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.1623 (2008)
Analyte: capreomycin sulfate; matrix: chemical purity; procedure: turbidimetric method with comparison to standards /capreomycin sulfate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.1623 (2008)
Analyte: capreomycin sulfate; matrix: pharmaceutical preparation (solid for injection); procedure: turbidimetric method with comparison to standards (chemical purity) /capreomycin sulfate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.1623 (2008)

10.2 Clinical Laboratory Methods

Analyte: capreomycin; matrix: urine; procedure: high-performance capillary electrophoresis with ultraviolet detection at 280 nm; limit of detection: 150 ng/mL
hang SS et al; J Pharm Biomed Anal 17: 617-622 (1998). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)

11 Safety and Hazards

11.1 Accidental Release Measures

11.1.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.2 Handling and Storage

11.2.1 Storage Conditions

Capreomycin sulfate sterile powder should be stored at controlled room temperature (15-30 °C).
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566
Following reconstitution of the sterile powder with 0.9% sodium chloride injection or sterile water for injection, the manufacturer states that capreomycin sulfate solutions may be stored for up to 24 hours at 2-8 °C. Solutions of capreomycin sulfate may develop a pale straw color and darken with time; however, this is not associated with loss of potency or development of toxicity.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 566

11.3 Regulatory Information

11.3.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl capreomycin sulfate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Capreomycin Sulfate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 30, 2008: https://www.fda.gov/cder/ob/

12 Toxicity

12.1 Toxicological Information

12.1.1 Hepatotoxicity

Intramuscular therapy with capreomycin has not been definitely linked to liver injury, either in the form of asymptomatic elevations in serum enzymes or of clinically apparent liver injury. However, the agent is rarely used and is always used in combination with other antituberculosis medications, many of which are well known to cause liver injury. Nevertheless, in the few studies done, capreomycin has not been associated with an increase in the rate of serum enzyme elevations or in episodes of acute liver injury above or beyond what was reported in the comparator arm.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

12.1.2 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Developmental problems have been reported in two infants exposed to capreomycin in breastmilk; however, their mothers were also exposed to several drugs during pregnancy and during breastfeeding, so the problems cannot necessarily be attributed to capreomycin. Because capreomycin is not orally absorbed it is unlikely to adversely affect the breastfed infant.

◉ Effects in Breastfed Infants

Capreomycin was used as part of multidrug regimens to treat two pregnant women with multidrug-resistant tuberculosis, one throughout pregnancy and postpartum and the other postpartum only. The infants were breastfed (extent and duration not stated). At age 4.6 and 5.1 years, the children were developing normally except for a mild speech delay in one and hyperactivity in the other.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.3 Interactions

Concomitant and/or sequential use of an aminoglycoside and other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects (e.g. other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, certain cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) may result in additive toxicity and should be avoided, if possible. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 66
Because of the possibility of an increased risk of ototoxicity due to additive effects or altered serum and tissue aminoglycoside concentrations, aminoglycosides should not be given concomitantly with potent diuretics such as ethacrynic acid, furosemide, urea, or mannitol. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 66
It has been suggested that concomitant use of certain anti-emetics that suppress nausea and vomiting of vestibular origin and vertigo (e.g., dimenhydrinate, meclizine) may mask symptoms of aminoglycoside-associated vestibular ototoxicity. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 66
Concurrent use of an aminoglycoside with general anesthetics or neuromuscular blocking agents (e.g., succinylcholine, rocuronium, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 66
For more Interactions (Complete) data for CAPREOMYCIN (10 total), please visit the HSDB record page.

12.1.4 Antidote and Emergency Treatment

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with fluids to alleviate crystalluria ... Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Most antibiotics are excreted unchanged in the urine, so maintenance of adequate urine flow is important. The role of forced diuresis is unclear. Hemodialysis is not usually indicated, except perhaps in patients with renal dysfunction and a high level of a toxic agent. /Antibacterial agents/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 82
In the event of aminoglycoside overdosage or toxic reactions, hemodialysis may aid in removal of aminoglycosides, especially if renal function is (or becomes) compromised. Peritoneal dialysis may be less effective than hemodialysis. In neonates, exchange transfusions may also be considered. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 66

12.1.5 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ The use of Capreomycin for Injection in patients with renal insufficiency or preexisting auditory impairment must be undertaken with great caution, and the risk of additional cranial nerve VIII impairment or renal injury should be weighed against the benefits to be derived from therapy.
US Natl Inst Health; DailyMed. Current Medication Information. Capreomycin (01/2008). Available from, as of July 8, 2008: https://dailymed.nlm.nih.gov/dailymed/about.cfm
/SIGNS AND SYMPTOMS/ Limited information is available on acute overdosage of capreomycin. In general, overdosage may be expected to produce effects that are extensions of the drug's adverse effects, principally nephrotoxic and ototoxic effects. Hypokalemia, hypocalcemia, hypomagnesemia, and an electrolyte disturbance resembling Bartter's syndrome have been reported in patients with capreomycin toxicity. Because capreomycin is not appreciably absorbed from the GI tract, acute toxicity would be unlikely following accidental ingestion of the drug.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 565
/CASE REPORTS/ Marked renal potassium and magnesium wasting, alkalosis, and a progressive increase in plasma renin and eventual hyperaldosteronemia developed during a 15-month course of in-hospital capreomycin therapy that was necessary for drug-resistant pulmonary tuberculosis. A prominent feature of the present case was renal chloride wasting, a feature of the capreomycin syndrome that has previously received little attention. Similar potentially life-threatening metabolic abnormalities, which resemble those found in Bartter's syndrome, can occur during prolonged therapy with the antibiotic gentamicin. In the present case, electrolyte abnormalities were unaffected by three days of indomethacin therapy but were partially corrected by large doses of spironolactone. Capreomycin, viomycin (an antibiotic closely related to capreomycin), and gentamicin are highly basic polypeptide antibiotics that may induce strikingly similar and potentially fatal syndromes of renal tubular dysfunction that can feature multiple electrolyte abnormalities.
Steiner R, Omachi A; Am J Kidney Dis 7 (3): 245-9 (1986)
/CASE REPORTS/ /Investigators/ report a patient with tuberculosis treated with a five-drug regimen who experienced severe acid-base and electrolyte abnormalities including hypomagnesemia, hypokalemia, hypocalcemia, and a hypochloremic metabolic alkalosis. These disturbances are believed to be due to treatment with capreomycin, which produced renal magnesium wasting and possible tubular damage. /Investigators/ recommend frequent determinations of serum electrolytes, magnesium, and calcium in patients treated with capreomycin.
Darr M et al; South Med J 75 (5): 627-8 (1982)
/CASE REPORTS/ A case of toxic nephritis caused by administration of capreomycin, an antibiotic used in the treatment of tuberculosis /is reported/. / ... A 62-year-old woman, was admitted to the Glen Lake State Sanatorium on February 16, 1964, as a transfer from /another/ hospital... One month earlier, she had entered /that/ hospital for treatment of a right shoulder injury. A chest roentgenogram taken at that time showed a moderate infiltration in the right upper lung field and a smaller one on the left. Acid-fast bacilli were found in the cultures of three gastric specimens. ... On admission to the sanatorium ... the chest was clear to percussion and auscultation, except for the anterior apex, where there were occasional audible rhonchi. ...There was moderate tenderness over the left upper abdominal quadrant. The backs of both forearms were covered with ecchymosis. The admission roentgenogram, made on February 17, showed fibroid infiltrate at the level of the first anterior interspace on the left, and slightly more extensive infiltrate at the level of the first and second interspaces on the right lung. Sputum smears were negative for acid-fast bacilli, but cultures were positive for bacilli. ... Blood urea nitrogen was 5 mg per cent. Laboratory studies were repeated weekly with the following findings: Liver function tests showed no significant alteration; blood urea nitrogen remained at 7 or 8 mg per cent until March 24, when it rose to 25 mg per cent. ... On February 21, she was started on a daily regimen of capreomycin, 1 gram intramuscularly ...At first, she seemed to improve slowly; however, in the last week of March, she became restless, and experienced diarrhea, vomiting, and confusion. Her oral intake dropped to almost nothing. Capreomycin ... was discontinued on March 25. About March 28, her urine output dropped to approximately 120 mL and never again rose above 200 mL. She was treated with intravenous fluids and duodenal tube feedings. She became more and more stuporous and was in coma the 24 hours before her death, which occurred on April 1, 1964. At necropsy... the renal cortex was moderately thinned in focal areas. In these areas, there were completely hyalinized glomerular scars, lymphocytic infiltrates, and some tubular atrophy. In a few places, the glomeruli were partially hyalinized, suggesting the presence of fibrous crescents. Striking features, in the more intact areas of kidney, were the dilated proximal tubules with flat, proximal tubular epithelium, with the nuclei jutting into the dilated lumen. In the distal convoluted tubules were reddish-brown casts suggesting either hemoglobin or tubular cellular debris, and in some of the dilated tubules were vacuoles in the tubular cytoplasm. ...The appearance was that of some acute, toxic, tubular necrosis due to an exogenous source, accounting for her acute renal insufficiency with oliguria. ... Some evidence of tubular regeneration was noted and chronic pyelonephritis was present. The tubular changes observed in our patient were clearly similar to those found in studies of capreomycin toxicity in dogs. /The authors/ believe that this is an instance of renal tubular damage and irritation resulting from capreomycin administration. It is important, in the presence of a rising level of blood urea nitrogen or other signs of possible drug toxicity, that the capreomycin serum level be determined at once; a high concentration may be another warning of a toxic condition.
Yue W, Cohen S; Dis Chest 49 (5): 549-51 (1966)

12.1.6 Non-Human Toxicity Excerpts

/OTHER TOXICITY INFORMATION/ ...Prolonged admin to animals has appeared to cause injury of hearing and possibly development of cataracts in two out of twenty-four dogs, but not cats. It remains to be ascertained whether cataracts were due to advanced age of dogs or to toxic effect of drug.
Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 227

12.1.7 Populations at Special Risk

Capreomycin should be used with extreme caution in patients with renal insufficiency or auditory impairment, and the risk of additional renal impairment or eighth cranial nerve damage should be weighed against the possible benefits of capreomycin therapy.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 565
Geriatric patients may be at higher risk of aminoglycoside-associated nephrotoxicity and ototoxicity than younger adults. Aminoglycosides are substantially eliminated in urine and the risk of toxicity may be increased in patients with impaired renal function. Because of age-related decreases in renal function, dosage should be selected with caution and renal function closely monitored whenever aminoglycosides are used in geriatric patients. /Aminoglycosides/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 66

12.2 Ecological Information

12.2.1 Environmental Abiotic Degradation

Stable in aqueous solution at pH 4-8; unstable in strongly acidic or strongly basic solutions.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 284

12.2.2 Environmental Water Concentrations

While data specific to capreomycin were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Chemical Co-Occurrences in Literature

14.4 Chemical-Gene Co-Occurrences in Literature

14.5 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 Chemical Co-Occurrences in Patents

15.3 Chemical-Disease Co-Occurrences in Patents

15.4 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 WHO ATC Classification System

18 Information Sources

  1. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. DrugBank
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    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  3. Hazardous Substances Data Bank (HSDB)
  4. ClinicalTrials.gov
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    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  5. LiverTox
  6. NCI Thesaurus (NCIt)
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    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  7. Drugs and Lactation Database (LactMed)
  8. Metabolomics Workbench
  9. PharmGKB
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    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  10. Therapeutic Target Database (TTD)
  11. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  12. Wikipedia
  13. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
    Protein Synthesis Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68011500
  14. PubChem
  15. NCBI
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