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CAPREOMYCIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Capreomycin is a cyclic polypeptide antimicrobial agent produced by certain strains of Streptomyces capreolus.

Specific Substances

    1) Capreomycin IA, 1-de-(L-3,6-diaminohexanoic acid)-
    2) Capreomycin IB
    3) Capreomycin IIA
    4) Capreomycin IIB
    5) Capromycin
    6) 34977
    7) Kapreomycin
    8) Capreomycin sulfate
    9) CAS 11003-38-6 (Capreomycin)
    10) CAS 1405-37-4 (Capreomycin sulfate)
    1.2.1) MOLECULAR FORMULA
    1) CAPREOMYCIN IA: C25H44N14O8
    2) CAPREOMYCIN IB: C25H44N14O7

Available Forms Sources

    A) FORMS
    1) Capreomycin is available as a 1 gram powder in 10 mL vials for injection (Prod Info CAPASTAT(R) injection, 2008).
    B) USES
    1) Capreomycin is used concomitantly as part of a multidrug regimen to treat tuberculosis that is resistant to other therapy (Prod Info CAPASTAT(R) injection, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Capreomycin is used concomitantly as part of a multidrug regimen to treat tuberculosis that is resistant to other therapy.
    B) PHARMACOLOGY: Capreomycin is a cyclic polypeptide antimicrobial agent, isolated from Streptomyces capreolus, administered as a mixture of capreomycin IA and capreomycin IB, and active against strains of Mycobacterium tuberculosis.
    C) EPIDEMIOLOGY: Overdose is extremely rare.
    D) WITH THERAPEUTIC USE
    1) Renal dysfunction, electrolyte imbalances (ie, hypokalemia, hypocalcemia, hypomagnesemia), ototoxicity, leukocytosis, leukopenia, thrombocytopenia, injection site reaction, and hypersensitivity reactions are the most common adverse effects. Neuromuscular blockade and respiratory paralysis may occur with therapeutic use following rapid intravenous infusion and/or with large intravenous doses.
    E) WITH POISONING/EXPOSURE
    1) There have been no reports of capreomycin overdose; however, overdose effects are anticipated to be an exaggeration of the adverse effects associated with therapeutic doses.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever may occur.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Loss of visual acuity has been rarely reported with capreomycin therapy.
    2) Capreomycin may cause ototoxicity, which may result in vertigo, tinnitus, and hearing loss.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Respiratory paralysis may occur with therapeutic use.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Neuromuscular blockade may occur with therapeutic use.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Capreomycin may cause renal damage, associated with elevations in serum creatinine and blood urea nitrogen and changes in electrolyte balance.
    2) Severe renal tubular dysfunction and tubular necrosis have occurred.
    0.2.11) ACID-BASE
    A) WITH THERAPEUTIC USE
    1) Metabolic alkalosis may occur.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Capreomycin may cause electrolyte disturbances. Hypokalemia, hyponatremia, hypocalcemia, hypochloremia, and hypomagnesemia have been reported.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Eosinophilia, leukocytosis, leukopenia, and thrombocytopenia have been reported with therapeutic use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Urticaria and maculopapular rashes have been reported with capreomycin therapy.
    2) Capreomycin may cause pain at the site of injection, formation of sterile abscesses, induration, and excessive bleeding at the site of injection.
    0.2.20) REPRODUCTIVE
    A) Capreomycin is in pregnancy category C.

Laboratory Monitoring

    A) Monitor renal function, serum electrolytes, and acid-base balance.
    B) Monitor CBC and liver enzymes symptomatic patients.
    C) Perform auditory testing and vestibular function testing in patients with auditory symptoms.
    D) Perform an ophthalmologic examination in patients with visual symptoms (eye pain, changes in visual acuity, etc.).
    E) Serum capreomycin concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. Maintain good urine output (3 to 5 mL/kg/hr) with IV fluids. For mild allergic reactions, treat with antihistamines; if severe, airway management, epinephrine, ECG monitoring, IV fluids.
    B) DECONTAMINATION
    1) Gastrointestinal decontamination is not indicated as capreomycin is administered parenterally and is poorly absorbed orally (less than 1%).
    C) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions or respiratory paralysis (very rare).
    D) ANTIDOTE
    1) None
    E) ENHANCED ELIMINATION
    1) Hemodialysis clearance up to 2.6 L/hr has been reported, and may be useful following a massive overdose or in patients with significant renal impairment
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management as capreomycin is generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: Patients with significant overdose should have serum electrolyte and renal function monitoring and auditory testing performed.
    3) ADMISSION CRITERIA: Patients with worsening renal function may require in-patient monitoring and dialysis.
    4) CONSULT CRITERIA: Consult a toxicologist after large overdose or if effects are not consistent with the exposure.
    G) PHARMACOKINETICS
    1) Poorly absorbed following ingestion (<1%). Volume of distribution is 0.37 to 0.42 L/kg. Primarily excreted unchanged in the urine, and half-life varies according to creatinine clearance.
    H) DIFFERENTIAL DIAGNOSIS
    1) Other causes of nephrotoxicity and auditory dysfunction (eg, medications, infection).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: The usual recommended dose is 1 g daily (not to exceed 20 mg/kg/day) IV or IM for 60 to 120 days, followed by 1 g IV or IM 2 or 3 times weekly. PEDIATRIC: 15 to 30 mg/kg/day (maximum 1 g/day) IV or IM as a single daily or twice weekly dose.

Clinical Effects

Summary Of Exposure

    A) USES: Capreomycin is used concomitantly as part of a multidrug regimen to treat tuberculosis that is resistant to other therapy.
    B) PHARMACOLOGY: Capreomycin is a cyclic polypeptide antimicrobial agent, isolated from Streptomyces capreolus, administered as a mixture of capreomycin IA and capreomycin IB, and active against strains of Mycobacterium tuberculosis.
    C) EPIDEMIOLOGY: Overdose is extremely rare.
    D) WITH THERAPEUTIC USE
    1) Renal dysfunction, electrolyte imbalances (ie, hypokalemia, hypocalcemia, hypomagnesemia), ototoxicity, leukocytosis, leukopenia, thrombocytopenia, injection site reaction, and hypersensitivity reactions are the most common adverse effects. Neuromuscular blockade and respiratory paralysis may occur with therapeutic use following rapid intravenous infusion and/or with large intravenous doses.
    E) WITH POISONING/EXPOSURE
    1) There have been no reports of capreomycin overdose; however, overdose effects are anticipated to be an exaggeration of the adverse effects associated with therapeutic doses.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever may occur.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Capreomycin has been associated with drug fever (Levantine & Almeyda, 1972).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Loss of visual acuity has been rarely reported with capreomycin therapy.
    2) Capreomycin may cause ototoxicity, which may result in vertigo, tinnitus, and hearing loss.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Loss of visual acuity has been rarely reported with capreomycin therapy (JEF Reynolds , 1990). Occasionally patients will complain of transient flickering of vision, or of whiteness or black-outs (Grant & Schuman, 1993).
    2) When capreomycin was used in combination with ethambutol, 5% of 38 patients had visual disturbances. The contribution of capreomycin to this effect is uncertain (Holdiness, 1987).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Capreomycin may cause ototoxicity, which may result in vertigo, tinnitus, and hearing loss (Prod Info CAPASTAT(R) injection, 2008; Holdiness, 1987; Lien et al, 1983).
    2) Capreomycin has been associated with cranial nerve VIII damage resulting in both reversible and permanent auditory losses. Subclinical auditory loss (a 5- to 10-decibel loss in the 4000- to 8000-CPS range) has occurred in 11% and clinically apparent hearing loss in 3% of patients receiving capreomycin (n=722). Symptoms may include dizziness, tinnitus, vertigo, and a loss of high-tone acuity (Prod Info CAPASTAT(R) injection, 2008).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Respiratory paralysis may occur with therapeutic use.
    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY TRACT PARALYSIS
    1) WITH THERAPEUTIC USE
    a) Respiratory paralysis may occur following rapid intravenous infusion (Prod Info CAPASTAT(R) injection, 2008).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Neuromuscular blockade may occur with therapeutic use.
    3.7.2) CLINICAL EFFECTS
    A) CRANIAL NERVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Capreomycin has been associated with cranial nerve VIII damage resulting in both reversible and permanent auditory losses. Subclinical auditory loss (a 5- to 10-decibel loss in the 4000- to 8000-CPS range) has occurred in 11% and clinically apparent hearing loss in 3% of patients receiving capreomycin (n=722). Symptoms may include dizziness, tinnitus, vertigo, and a loss of high-tone acuity (Prod Info CAPASTAT(R) injection, 2008).
    B) ANTIBIOTIC-INDUCED NEUROMUSCULAR BLOCKING
    1) WITH THERAPEUTIC USE
    a) Partial neuromuscular blockade has been associated with capreomycin therapy following large intravenous doses and/or rapid intravenous infusions. This effect is enhanced by ether anesthetics and reversed by neostigmine (Prod Info CAPASTAT(R) injection, 2008).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal liver function tests have been reported with capreomycin use in combination with other antituberculin drugs (Prod Info CAPASTAT(R) injection, 2008).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Capreomycin may cause renal damage, associated with elevations in serum creatinine and blood urea nitrogen and changes in electrolyte balance.
    2) Severe renal tubular dysfunction and tubular necrosis have occurred.
    3.10.2) CLINICAL EFFECTS
    A) INJURY OF KIDNEY
    1) WITH THERAPEUTIC USE
    a) Capreomycin may cause renal injury and tubular necrosis, associated with elevations in serum creatinine and blood urea nitrogen (Prod Info CAPASTAT(R) injection, 2008).
    b) Elevations of BUN above 20 mg/100 mL have occurred in 36% of patients treated with capreomycin (n=722). In 10%, the BUN elevations exceeded 30 mg/100 mL. Prolonged capreomycin therapy has caused elevations of BUN and serum creatinine (Prod Info CAPASTAT(R) injection, 2008)
    c) In one study, capreomycin therapy had to be stopped in 6 of 82 patients, because of increased blood urea nitrogen; 3 of these patients had preexisting renal damage. About 66% of 82 patients developed mild proteinuria (Kropp et al, 1970).
    B) PSEUDOPRIMARY HYPERALDOSTERONISM
    1) WITH THERAPEUTIC USE
    a) BARTTER'S SYNDROME: Capreomycin has been reported to cause a condition resembling Bartter's Syndrome associated with renal tubulopathy. The condition occurred after 15 months of therapy with capreomycin and was characterized by hyperaldosteronism and renal loss of sodium, potassium, magnesium, and chloride (Steiner & Omachi, 1986).
    C) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) In a case report, the patient developed toxic nephritis, renal insufficiency, oliguria, and eventually died following treatment with capreomycin 1 g and aminosalicylic acid daily for one month, for the treatment of tuberculosis and portal cirrhosis. Subsiding acute tubular necrosis was discovered upon autopsy (Prod Info CAPASTAT(R) injection, 2008).

Acid-Base

    3.11.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Metabolic alkalosis may occur.
    3.11.2) CLINICAL EFFECTS
    A) ALKALOSIS
    1) WITH THERAPEUTIC USE
    a) The use of capreomycin has been associated with metabolic alkalosis (Darr et al, 1982).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Eosinophilia, leukocytosis, leukopenia, and thrombocytopenia have been reported with therapeutic use.
    3.13.2) CLINICAL EFFECTS
    A) WHITE BLOOD CELL COUNT ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Eosinophilia, leukocytosis, and leukopenia have been reported with therapeutic use of capreomycin. Eosinophilia exceeding 5% has occurred in patients receiving daily capreomycin therapy, which subsided following a dose reduction of 2 to 3 g weekly (Prod Info CAPASTAT(R) injection, 2008; Wykoff, 1986).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported rarely with capreomycin use (Prod Info CAPASTAT(R) injection, 2008).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urticaria and maculopapular rashes have been reported with capreomycin therapy.
    2) Capreomycin may cause pain at the site of injection, formation of sterile abscesses, induration, and excessive bleeding at the site of injection.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Urticaria and maculopapular rashes have been reported with capreomycin therapy (Prod Info CAPASTAT(R) injection, 2008).
    B) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) Capreomycin may cause pain at the site of injection. The formation of sterile abscesses, induration, and excessive bleeding at the site of injection have also been reported (Prod Info CAPASTAT(R) injection, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions including urticaria and maculopapular rashes, have been reported with capreomycin used concomitantly with other antituberculin drugs (Prod Info CAPASTAT(R) injection, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Capreomycin is in pregnancy category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of capreomycin in pregnant women. Use during pregnancy only if the potential benefit justifies the risk (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009).
    B) PREGNANCY CATEGORY
    1) Pregnancy Category C (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009).
    C) ANIMAL STUDIES
    1) Capreomycin was not teratogenic at doses 3.5 times the human dose (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if capreomycin is excreted into human breast milk. Use caution when administering to a nursing woman (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor renal function, serum electrolytes, and acid-base balance.
    B) Monitor CBC and liver enzymes symptomatic patients.
    C) Perform auditory testing and vestibular function testing in patients with auditory symptoms.
    D) Perform an ophthalmologic examination in patients with visual symptoms (eye pain, changes in visual acuity, etc.).
    E) Serum capreomycin concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Methods

    A) CHROMATOGRAPHY
    1) Capreomycin levels can be determined by ion exchange chromatography (Bloom, 1970).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with worsening renal function may require in-patient monitoring and dialysis.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management as capreomycin is generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a toxicologist after large overdose or if effects are not consistent with the exposure.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with significant overdose should have serum electrolyte and renal function monitoring and auditory testing performed.

Monitoring

    A) Monitor renal function, serum electrolytes, and acid-base balance.
    B) Monitor CBC and liver enzymes symptomatic patients.
    C) Perform auditory testing and vestibular function testing in patients with auditory symptoms.
    D) Perform an ophthalmologic examination in patients with visual symptoms (eye pain, changes in visual acuity, etc.).
    E) Serum capreomycin concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is unnecessary; Capreomycin is administered parenterally and less than 1% is absorbed following ingestion.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis clearance up to 2.6 L/hr has been reported, and may be useful following a massive overdose or in patients with significant renal impairment (Prod Info CAPASTAT(R) injection, 2008; Lehmann et al, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: The usual recommended dose is 1 g daily (not to exceed 20 mg/kg/day) IV or IM for 60 to 120 days, followed by 1 g IV or IM 2 or 3 times weekly. PEDIATRIC: 15 to 30 mg/kg/day (maximum 1 g/day) IV or IM as a single daily or twice weekly dose.

Therapeutic Dose

    7.2.1) ADULT
    A) 1 g/day (not to exceed 20 mg/kg/day) IV or IM for 60 to 120 days, followed by 1 g IV or IM 2 or 3 times/week (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009)
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (SUBCUTANEOUS)MOUSE:
    a) 514 mg/kg (Prod Info CAPASTAT(R) injection, 2008; RTECS , 2000)
    2) LD50- (SUBCUTANEOUS)RAT:
    a) 1191 mg/kg (Wells et al, 1966)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Capreomycin is a cyclic polypeptide antimicrobial agent, isolated from Streptomyces capreolus(Prod Info CAPASTAT(R) injection, 2008; Mandell et al, 1985). It is administered as a mixture of capreomycin IA and capreomycin IB (Nomoto et al, 1977).
    B) The mechanism of action of capreomycin is not well understood. Mycobacterial species that have become resistant to other agents are usually still sensitive to the action of capreomycin (Conte & Barriere, 1984). However, significant cross-resistance with viomycin and kanamycin occurs.
    C) MINIMUM INHIBITORY CONCENTRATION: The minimum inhibitory concentration of capreomycin is 2.5 micrograms/milliliter for Mycobacterium tuberculosis (Conte & Barriere, 1984). A concentration of 10 micrograms/milliliter inhibit 40% of strains of Mycobacterium scrofulaceum and 21% of strains of Mycobacterium fortuitum. The minimum inhibitory concentration of capreomycin for Mycobacterium szulgai was 10 micrograms/milliliter (Schaefer et al, 1973).
    D) RESISTANCE PATTERNS: Mycobacterium kansasii and intracellularis are resistant to capreomycin (Conte & Barriere, 1984). Mycobacterium szulgai has been shown to be slightly resistant (Schaefer et al, 1973).

Physicochemical

Physical Characteristics

    A) CAPREOMYCIN is a polypeptide mixture containing not less than 90% of capreomycin I, and a white to practically white amorphous powder that is freely soluble in water and practically insoluble in most organic solvents (Sweetman, 2014). Capreomycin injection is a powder for solution that is soluble in water; after complete dissolution the solution is almost colorless, but may darken and acquire a pale straw color over time without loss of potency or development of toxicity (Prod Info Capastat(R) Sulfate intramuscular intravenous injection, 2009).

Ph

    A) 4.5 to 7.5 (3% solution in water) (Sweetman, 2014)

Molecular Weight

    A) CAPREOMYCIN IA: 668.7 (Sweetman, 2014)
    B) CAPREOMYCIN IB: 652.7 (Sweetman, 2014)

References

General Bibliography

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