ins). serious central-nervous-system infections (meningitis) caused by susceptible organisms. intra-abdominal infections, including peritonitis, caused by e. coli , klebsiella sp, and enterobacter sp. skin, bone, and skin-structure infections caused by p. aeruginosa , proteus sp, e. coli , klebsiella sp, enterobacter sp, and s. aureus. complicated and recurrent urinary tract infections caused by p. aeruginosa , proteus sp (indole-positive and indole-negative), e. coli , klebsiella sp, enterobacter sp, serratia sp, s. aureus , providencia sp, and citrobacter sp. aminoglycosides, including tobramycin, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics having less potential toxicity. tobramycin may be considered in serious staphylococcal infections when penicillin or other potentially less toxic drugs are contraindicated and when bacterial susceptibility testing and clinical judgment indicate its use. bacterial cultures should be obtained prior to and during treatment to isolate and identify etiologic organisms and to test their susceptibility to tobramycin. if susceptibility tests show that the causative organisms are resistant to tobramycin, other appropriate therapy should be instituted. in patients in whom a serious life-threatening gram-negative infection is suspected, including those in whom concurrent therapy with a penicillin or cephalosporin and an aminoglycoside may be indicated, treatment with tobramycin sulfate may be initiated before the results of susceptibility studies are obtained. the decision to continue therapy with tobramycin should be based on the results of susceptibility studies, the severity of the infection, and the important additional concepts discussed in the warnings box above.

and may range in severity from mild diarrhea to fatal colitis. treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of c. difficile . c. difficile produces toxins a and b which contribute to the development of cdad. hypertoxin producing strains of c. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. cdad must be considered in all patients who present with diarrhea following antibiotic use. careful medical history is necessary since cdad has been reported to occur over two months after administration of antibacterial agents. if cdad is suspected or confirmed, ongoing antibiotic use not directed against c. difficile may need to be discontinued. appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of c. difficile , and surgical evaluation should be instituted as clinically indicated. risk of ototoxicity due to mitochondrial dna variants cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12s rrna gene (mt-rnr1), particularly the m.1555a>g variant. ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. mitochondrial dna variants are present in less than 1% of the general us population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. in case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial dna variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

ng usual dose for serious infections maximum dose for life- threatening infections (reduce as soon as possible) 1 mg/kg q8h (total, 3 mg/kg/day) 1.66 mg/kg q8h (total, 5 mg/kg/day) mg/dose ml/dose* mg/dose ml/dose* kg lb q8h q8h 120 264 120 mg 3 ml 200 mg 5 ml 115 253 115 mg 2.9 ml 191 mg 4.75 ml 110 242 110 mg 2.75 ml 183 mg 4.5 ml 105 231 105 mg 2.6 ml 175 mg 4.4 ml 100 220 100 mg 2.5 ml 166 mg 4.2 ml 95 209 95 mg 2.4 ml 158 mg 4 ml 90 198 90 mg 2.25 ml 150 mg 3.75 ml 85 187 85 mg 2.1 ml 141 mg 3.5 ml 80 176 80 mg 2 ml 133 mg 3.3 ml 75 165 75 mg 1.9 ml 125 mg 3.1 ml 70 154 70 mg 1.75 ml 116 mg 2.9 ml 65 143 65 mg 1.6 ml 108 mg 2.7 ml 60 132 60 mg 1.5 ml 100 mg 2.5 ml 55 121 55 mg 1.4 ml 91 mg 2.25 ml 50 110 50 mg 1.25 ml 83 mg 2.1 ml 45 99 45 mg 1.1 ml 75 mg 1.9 ml 40 88 40 mg 1 ml 66 mg 1.6 ml * applicable to all product forms except tobramycin injection, usp, 10 mg/ml (pediatric). pediatric patients (greater than 1 week of age): 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours). premature or full-term neonates 1 week of age or less: up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours. it is desirable to limit treatment to a short term. the usual duration of treatment is 7 to 10 days. a longer course of therapy may be necessary in difficult and complicated infections. in such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days. dosage in patients with cystic fibrosis in patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentration of aminoglycosides. measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose. in patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended. this dosing regimen is suggested only as a guide. the serum levels of tobramycin should be measured directly during treatment due to a wide interpatient variability. administration for patients with impaired renal function whenever possible, serum tobramycin concentrations should be monitored during therapy. following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals. both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly. they are based on either the creatinine clearance or the serum creatinine of the patient, because these values correlate with the half-life of tobramycin. the dosage schedules derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. neither method should be used when dialysis is being performed. reduced dosage at 8-hour intervals when the creatinine clearance rate is 70 ml or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from table 1 by the percent of normal dose from the accompanying nomogram. an alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine. normal dosage at prolonged intervals if the creatinine clearance rate is not available and the patient's condition is stable, a dosage frequency in hours for the dosage given in table 1 can be determined by multiplying the patient's serum creatinine by 6. dosage in obese patients the appropriate dose may be calculated by using the patient's estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg. intramuscular administration tobramycin injection, usp may be administered by withdrawing the appropriate dose directly from a vial. tobramycin sulfate in 0.9% sodium chloride is not intended for intramuscular administration. intravenous administration for intravenous administration, the usual volume of diluent (0.9% sodium chloride injection or 5% dextrose injection) is 50 to 100 ml for adult doses. for pediatric patients, the volume of diluent should be proportionately less than for adults. the diluted solution usually should be infused over a period of 20 to 60 minutes. infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/ml (see warnings box). tobramycin injection, usp should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. graphic reduced dosage nomogram

have been conducted to compare the nephrotoxic potential of tobramycin and gentamicin. in some of the clinical studies and in the animal studies, tobramycin caused nephrotoxicity significantly less frequently than gentamicin. in some other clinical studies, no significant difference in the incidence of nephrotoxicity between tobramycin and gentamicin was found. other reported adverse reactions possibly related to tobramycin include anemia, granulocytopenia, and thrombocytopenia; and fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhea, headache, lethargy, pain at the injection site, mental confusion, and disorientation. laboratory abnormalities possibly related to tobramycin include increased serum transaminases (ast, alt); increased serum ldh and bilirubin; decreased serum calcium, magnesium, sodium, and potassium; and leukopenia, leukocytosis, and eosinophilia. to report suspected adverse events, contact fda at 1-800-fda-1088 or www.fda.gov.

ormal adults. dosage for such patients must, therefore, be adjusted accordingly (see dosage and administration ). following parenteral administration, little, if any, metabolic transformation occurs, and tobramycin is eliminated almost exclusively by glomerular filtration. renal clearance is similar to that of endogenous creatinine. ultrafiltration studies demonstrate that practically no serum protein binding occurs. in patients with normal renal function, up to 84% of the dose is recoverable from the urine in 8 hours and up to 93% in 24 hours. peak urine concentrations ranging from 75 to 100 mcg/ml have been observed following the intramuscular injection of a single dose of 1 mg/kg. after several days of treatment, the amount of tobramycin excreted in the urine approaches the daily dose administered. when renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood levels. the serum half-life in normal individuals is 2 hours. an inverse relationship exists between serum half-life and creatinine clearance, and the dosage schedule should be adjusted according to the degree of renal impairment (see dosage and administration ). in patients undergoing dialysis, 25% to 70% of the administered dose may be removed, depending on the duration and type of dialysis. tobramycin can be detected in tissues and body fluids after parenteral administration. concentrations in bile and stools ordinarily have been low, which suggests minimum biliary excretion. tobramycin has appeared in low concentration in the cerebrospinal fluid following parenteral administration, and concentrations are dependent on dose, rate of penetration, and degree of meningeal inflammation. it has also been found in sputum, peritoneal fluid, synovial fluid, and abscess fluids, and it crosses the placental membranes. concentrations in the renal cortex are several times higher than the usual serum levels. probenecid does not affect the renal tubular transport of tobramycin. microbiology tobramycin is an aminoglycoside antibiotic with activity against gram-positive and gram-negative bacteria. mechanism of action tobramycin acts by inhibiting synthesis of protein in bacterial cells. in vitro tests demonstrate that tobramycin is bactericidal. resistance cross-resistance between aminoglycosides may occur. interactions with other antimicrobials although most strains of enterococci demonstrate in vitro resistance, some strains in this group are susceptible. in vitro studies have shown that an aminoglycoside combined with an antibiotic that interferes with cell-wall synthesis affects some enterococcal strains synergistically. the combination of penicillin g and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of enterococcus faecalis . however, this combination is not synergistic against other closely related organisms, e.g. enterococcus faecium . speciation of enterococci alone cannot be used to predict susceptibility. susceptibility testing and tests for antibiotic synergism are emphasized. antimicrobial activity tobramycin has been shown to be active against most strains of the following organisms both in vitro and in clinical infections: (see indications and usage ) aerobic and facultative gram-positive microorganisms staphylococcus aureus aerobic and facultative gram-negative microorganisms citrobacter sp pseudomonas aeruginosa enterobacter sp proteus mirabilis escherichia coli proteus vulgaris klebsiella sp providencia sp morganella morganii serratia sp aminoglycosides have a low order of activity against most gram-positive organisms, including streptococcus pyogenes, streptococcus pneumoniae , and enterococci. susceptibility testing for specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by fda for this drug, please see: https://www.fda.gov/stic.

ken the last dose of the antibiotic. if this occurs, patients should contact their physician as soon as possible.