Capreomycin

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.

/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.

/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.

/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.

/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.

/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.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

capreomycin

DILI Negative

Intravenous

DOI:10.1016/j.drudis.2019.09.022

/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.

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.

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/

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).

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/

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/

232HYX66HC

CAPREOMYCIN

Established Pharmacologic Class [EPC] - Antimycobacterial

Capreomycin is an Antimycobacterial.

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.

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.

Substances that inhibit the growth or reproduction of BACTERIA.

Not absorbed in significant quantities from the gastrointestinal tract and must be administered parenterally.

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.

/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.

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.

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.