Kanamycin Sulfate
Indications: Infection
WARNING:
Patients treated with aminoglycosides by any route should be under close clinical observation because of the potential toxicity associated with their use. As with other aminoglycosides, the major toxic effects of kanamycin sulfate are its action on the auditory and vestibular branches of the eighth nerve and the renal tubules. Neurotoxicity is manifested by bilateral auditory toxicity which often is permanent and, sometimes, by vestibular ototoxicity. Loss of high frequency perception usually occurs before there is noticeable clinical hearing loss and can be defected by audiometric testing. There may not be clinical symptoms to warn of developing cochlear damage. Vertigo may occur and may be evidence of vestibular injury. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions. The risk of hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations and continues to progress after drug withdrawal.
Renal impairment may be characterized by decreased creatinine clearance, the presence of cells or casts, oliguria, proteinuria, decreased urine specific gravity, or evidence of increasing nitrogen retention (increasing BUN, NPN, or serum creatinine).
The risks of severe ototoxic and nephrotoxic reactions are sharply increased in patients with impaired renal function and in those with normal renal function who receive high doses or prolonged therapy.
Renal and eighth nerve function should be closely monitored, especially in patients with known or suspected reduced renal function at the onset of therapy, and also in those whose renal function in initially normal but who develop signs of renal dysfunction during therapy. Serum concentrations of parenterally administered aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels. Urine should be examined for decreases specific gravity, increased excretion of protein, and the presence of cells or casts. Blood urea nitrogen, serum creatinine, or creatinine clearance should be measured periodically. Serial audiograms should be obtained when feasible in patients old enough to be tested, particularly high risk patients. Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss) or nephrotoxicity requires dosage adjustment of discontinuance of the drug.
Neuromuscular blockade with respiratory paralysis may occur when kanamycin sulfate is instilled intraperitoneally concomitantly with anesthesia and muscle-relaxing drugs. Neuromuscular blockade has been reported following parenteral injection and the oral use of aminoglycosides. The possibility of the occurrence of neuromuscular blockade and respiratory paralysis should be considered it aminoglycosides are administered by any route, especially in patients receiving anesthetics, neuromuscular-blocking agents such as tubocurarine, succinylcholine, decamethonium or in patients massive transfusions of citrate-anticoagulated blood. It blockage occurs, calcium salts may reduce these phenomenal but mechanical respiratory assistance may be necessary.
The concurrent and/or sequential systemic, oral, or topical use of kanamycin and other potentially nephrotoxic, and/or neurotoxic drugs, particularly polymyxin B, bacitracin, colistin, amphotericin B, cisplatin, vancomycin, and all other aminoglycosides (including paromomycin) should be avoided because the toxicity may be additive. Other factors which may increase patient risk of toxicity are advanced age and dehydration.
Kanamycin sulfate should not be given concurrently with potent diuretics (ethacrynic acid, furosemide, meralluride sodium, sodium mercaptomerin or mannitol). Some diuretics themselves cause ototoxicity, and intravenously administered diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.
DESCRIPTION:
Kanamycin sulfate is an aminoglycoside antibiotic produced by Streptomyces kanamyceticus . It is C18H36N4O11Β·2H2SO4. D-Streptamine, 0-3-amino -3-deoxy-alpha -D-glucopyranosyl - (16)-o- (6-amino -6-deoxy- alpha-D-glucopyranosyl-(14))-2-deoxy, sulfate 1:2 (salt). It consists of two amino sugars glycosidically linked to deoxystreptamine.
Kanamycin sulfate injection, sterile solution for parenteral administration, contains respectively, kanamycin sulfate 75 mg, 500 mg, and 1.0 g; sodium bisulfite, an antioxidant, 0.099%, 0.66%, and 0.45%; and sodium citrate, 0.33%, 2.2%, and 2.2% with pH of each dosage form adjusted to 4.5 with sulfuric acid.
Vial headspace contains nitrogen.
CLINICAL PHARMACOLOGY:
The drug is rapidly absorbed after intramuscular injection and peak serum levels are generally reached within approximately one hour. Doses of 7.5 mg/kg given mean levels of 22 mcg/ml. At 8 hours following a 7.5 mg/kg dose, mean serum levels are 3.2 mcg/ml. The serum half-life is 2 1/2 hours. Intravenous administration kanamycin over a period of one hour resulted in serum concentrations similar to those obtained by intramuscular administration.
Kanamycin diffuses rapidly into most body fluids including synovial and peritoneal fluids and bile. Significant levels of the drug appear in cord blood and amniotic fluids following intramuscular administration to pregnant patients. Spinal fluid concentrations in normal infants are approximately 10 to 20 percent serum levels and may reach 50 percent when the meninges are inflamed.
Studies in normal adult patients have shown only trace levels of kanamycin in spinal fluid. No data are available on adults with meningitis.
The drug is excreted almost entirely by glomerular filtration and is not reabsorbed by the renal tubules. Hence, high concentrations are attained in the nephron, and the urine may contain levels 10 to 20 times higher than those in serum. Little, if any, metabolic transformation occurs. Renal excretion is extremely rapid. In patients with normal renal function, approximately one-half of the administered dose is cleared within 4 hours and excretion is complete with 24 to 48 hours. Patients with impaired renal function or with diminished glomerular filtration pressure excrete kanamycin more slowly. Such patients may build up excessively high blood levels which greatly increase the risk of ototoxic reactions. In severely burned patients half-life may be significantly decreased and resulting serum concentration may be lower than anticipated from the mg per kg dose.
Microbiology
Kanamycin sulfate is bactericidal antibiotic which acts by inhibiting the synthesis of protein in susceptible in susceptible microorganisms. Kanamycin sulfate is active in vitro against many strains of Staphylococcus aureus (including penicillinase and non penicillinase-producing strains), Staphylococcus epidermidis, N. gonorrhoeae, H. influenzae, E. coli, Enterobacter aerogenes, Shigella and Salmonella species, K. pneumoniae, Serratia marcescens, Providencia species, Acinetobacter species and Citrobacter freundii and Citrobacter species, and many strains of both indole-positive and indole-negative Proteus strains that are frequently resistant to other antibiotic.
Aminoglycosides have a low order of activity against most gram-positive organisms including Streptococcus pyogenes, Streptococcus pneumoniae and enterococci . In vitro studies have demonstrated that an aminoglycoside combined with an antibiotic which interferes with cell wall synthesis (i.e., Penicillin G or ampicillin) affects some Group D streptococcal strains synergistically. Bacteriological testing and tests for antibiotic synergism are necessary.
Enzymatic inactivation of deoxystreptamine is the principal mechanism of resistance.
Susceptibility Testing: Quantitative methods for susceptibility testing that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure has been recommended for use with discs to tests susceptibility to kanamycin. Interpretation involves correlation of the diameters obtained in the disc test that minimal inhibitory concentration (MIC) values of kanamycin.
Reports from the laboratory give results of the standardized single disc susceptibility tests (Bauer, et al. Am. J. Clin. Path. 1966; 45:493 and Federal Register 37:20529, 1972), using a 30-mcg kanamycin disc should be interpreted according to the following criteria:
Organisms producing zones of 18 mm or greater, or MIC's of 16 mcg or less are considered susceptible, indicating that the test organism is likely to respond to therapy.
Resistant organisms produce zones of 14 mm or less or MIC's of 16 mcg or greater. A report of "resistant" from the laboratory indicates that the infection organism is not likely to respond to therapy.
Zones greater than 14 mm and less than 18 mm, or MIC's of greater than 16 mcg and less than 65 mcg, indicate intermediate susceptibility. A report of "intermediate" susceptibility suggests that the organism would be susceptible if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained.
Control organisms are recommended for susceptibility testing. Each time the test is performed one or more of the following organisms should be included: Escherichia coli ATCC 15922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The control organisms should produce zones of inhibition with the following ranges:
Escherichia coli (ATCC 15922)--22-30 mm
Staphylococcus aureus (ATCC 25923)--22-31 mm
Pseudomonas aeruginosa (ATCC 27853)--17-23 mm
INDICATIONS AND USAGE:
Kanamycin is indicated in the short term treatment of serious infections caused by susceptible strains of the designated microorganisms below. Bacteriological studies to identify the causative organisms and to determine their susceptibility to kanamycin should be performed. Therapy may be instituted prior to obtaining the results of susceptibility testing.
Kanamycin may be considered as initial therapy in the treatment of infection where one or more of the following are the known or suspected pathogens. E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter species. The decision to continue therapy with the drug should be based on results of the susceptibility tests, the response of the infection to therapy, and the important additional concepts contained in the BOXED WARNING.
In serious infections when the causative organisms are unknown, kanamycin sulfate may be administered as initial therapy in conjunction with an penicillin or cephalosporin-type drug before obtaining results of susceptibility testing. If anaerobic organisms are suspected, consideration should be given to using other suitable antimicrobial therapy in conjunction with kanamycin.
Although kanamycin is not the drug of choice for staphylococcal infections, it may be indicated under certain conditions for the treatment of known or suspected staphylococcal disease. These situations include the initial therapy of server infections where the organism is thought to be either a Gram-negative bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and mixed staphylococcal/Gram-negative infections.
CONTRAINDICATIONS:
A history of hypersensitivity or toxic reactions to one aminoglycoside may also contraindicate the use of any other aminoglycoside, because of the known cross-sensitivity and cumulative effects of drugs in this category.
THIS DRUG IS NOT INDICATED IN LONG-TERM THERAPY (e.g., Tuberculosis) BECAUSE OF THE TOXIC HAZARD ASSOCIATED WITH EXTENDED ADMINISTRATION.
WARNINGS:
See BOXED WARNING.
Aminoglycosides can cause fetal harm when administered to pregnant women. Aminoglycoside antibiotics cross the placenta and there have been several reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to fetus or new born have not been reported in treatment of pregnant women with other aminoglycosides, the potential for harm exists.
Reproductive studies have been performed in rats and rabbits and have revealed no evidence of impaired fertility or teratogenic effects. Dosages of 200 mg/kg/day in pregnant rats and pregnant cayenne pigs led to hearing impairment in the off-spring. There are not well-controlled studies in pregnant women but clinical experience does not include any positive evidence of adverse effects on the fetus. However, if the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard on the fetus.
Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
PRECAUTIONS:
General
Neurotoxic and nephrotoxic antibiotics may be almost completely absorbed from body surfaces (except the urinary bladder) after local irrigation and after topical application during surgical procedures. The potential toxic effects of antibiotics administered in this fashion (oto-and nephrotoxicity, neuromuscular blockade, respiratory paralysis) should be considered. (See BOXED WARNING.)
Increased nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics with some cephalosporins.
Aminoglycosides should be used with caution in patients with neuromuscular disorders such as myasthenia gravis, Parkinsonism, or infant botulism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular junction.
Elderly patients may have a decrease in renal function which may not be evident in the results of routine screening tests, such as BUN or serum creatine levels. Measurement of creatinine clearance or an estimate based on published nomograms or equations may be more useful. Monitoring of renal function during treatment with kanamycin as with other aminoglycosides, is particularly important in such patients.
Because of high concentrations of kanamycin sulfate in the urinary excretory system, patients should be well hydrated before treatment to prevent irritation of the renal tubules.
NOTE: The risk of toxic reactions is low in well-hydrated patients with normal kidney function, who receive a total dose of 15 g of kanamycin or less. Treatment with kanamycin may result in overgrowth of nonsusceptible organisms. If this occurs kanamycin should be discontinued and appropriate therapy initiated.
Laboratory Tests
Tests of eighth cranial nerve functions: Serial audiometric tests are suggested, particularly when renal function is impaired and/or prolonged aminoglycoside therapy is required; such tests should also be repeated periodically after treatment if there is evidence of a hearing deficit or vestibular abnormalities before or during therapy or when consecutive or concomitant use of other potentially ototoxic drug is unavoidable.
Test of renal functio:n It should be emphasized that since renal function may after appreciably during therapy, renal function should be tested daily or more frequently. Urine should be examined for increased excretion of protein and for presence of cells and casts, keeping in mind the effects of the primary illness on these tests. One or more of the following laboratory measurements should be obtained at the onset of therapy, frequently during therapy, and at, or shortly after, the end of therapy:
Creatinine clearance rate (either carefully measured or estimated from published nomograms or equations based on patient's age, sex, body weight, and serial creatinine concentrations) (preferred over BUN).
Serum creatinine concentration (preferred over BUN).
Blood urea nitrogen (BUN).
More frequent testing is desirable if renal function is changing. If sings of renal irritation appear, such as casts, white or red cells, and albumin, hydration should be increased and a reduction in dosage may be desirable (see DOSAGE AND ADMINISTRATION.) These signs usually disappear when treatment is completed. However, if azotemia or a progressive decrease of urine output occurs, treatment should be stopped.
Laboratory Test Interactions
Concomitant cephalosporin therapy may spuriously elevate creatinine determinations.
The inactivation between aminoglycosides and beta-lactam antibiotics described in DRUG INTERACTIONS may continue in specimens of body fluids collected for assay, resulting in inaccurate, false low aminoglycoside readings. Such specimens should be properly handled, i.e. assayed promptly, frozen, or treated with beta-lactamase.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies have not been performed with kanamycin to determine its effect in carcinogenesis, mutagenesis, or impairment of fertility.
Pregnancy Category D
See WARNINGS.)
Nursing Mothers
Kanamycin sulfate is excreted in minute amounts in human milk. Because of the potential for serious adverse reactions from aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.
Pediatric Use
Aminoglycosides should be used with caution in prematures and neonates because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.
DRUG INTERACTIONS:
In vitro mixing of an aminoglycoside with beta-lactam-type antibiotics (penicillins or cephalosporins) may result in a significant mutual inactivation. Even when an aminoglycoside and a penicillin-type drug are administered separately by different routes, a reduction in aminoglycoside serum half-life or serum levels has been reported in patients with impaired renal function and in some patients with normal renal function. Usually, such inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function. (See Laboratory Test Interactions). See BOXED WARNING regarding concurrent use of potent diuretics, concurrent and/or sequential use of other neurotoxic and/or nephrotoxic antibiotics, and for other essential information.
ADVERSE REACTIONS:
Kanamycin has the potential to induce auditory and sometimes vestibular toxicity, renal toxicity, and neuromuscular blockade. The risks are higher for patients with a present or past history of renal impairment (especially if hemodialysis is required), for those receiving concomitant or sequential treatment with other ototoxic or nephrotoxic drugs or rapid acting diuretic agent