DESCRIPCION

Mecanismo of Action: Despite many years of investigation, it is not clear how tobramycin and other aminoglycosides cause bacterial cell death. It is known that tobramycin binds irreversibly to one of two aminoglycoside binding sites on the 30 S ribosomal subunit, which, in turn, inhibits bacterial protein synthesis. However, inhibition of bacterial protein synthesis does not adequately explain tobramycin's bactericidal effects, since other non-aminoglycoside antibiotics that also inhibit protein synthesis are only bacteriostatic. One aspect essential to aminoglycoside lethality is the need to achieve intracellular concentrations in excess of extracellular. Anaerobic bacteria are not susceptible to aminoglycosides due, at least in part, to a lack of an active transport mechanism for aminoglycoside uptake. Against gram-negative aerobic rods, aminoglycosides exhibit "concentration-dependent killing" and a "post-antibiotic effect" (PAE). "Concentration-dependent killing" describes the principle that bactericidal effects increase as the concentration increases. PAE is where suppression of bacterial growth continues after the antibiotic concentration falls below the bacterial MIC. The post-antibiotic effect can be bacteria specific, as well as drug specific. The PAE of aminoglycosides is short for most gram-postive organisms (< 2 hours) and longer for gram-negative organisms (2�7 hours), such as E. coli, K. pneumoniae, and Ps. aeruginosa. Both of these phenomena are being exploited in designing dosage regimens that employ higher doses administered at longer intervals. A recent study of amikacin 20 mg/kg administered as a single daily dose versus three evenly spaced doses in granulocytopenic patients revealed less severe nephrotoxicity in the single-dose group with no difference in efficacy.[63] Tobramycin is active against Enterobacteriaceae organisms including Escherichia coli, Proteus, Klebsiella, Serratia, Enterobacter, and Citrobacter. In general, Pseudomonas aeruginosa is usually sensitive to aminoglycosides and frequently is more sensitive to tobramycin than to gentamicin; its susceptibility, however, is considerably variable. Other pseudomonal species also may be susceptible but are usually less so than Pseudomonas aeruginosa. Staphylococcus aureus is sensitive while Neisseria and Haemophilus genera are not. Although many strains of Streptococcus are sensitive, tobramycin is usually added to another antibiotic to treat these organisms. Against Enterococcus faecalis, aminoglycosides are used only in combination with a cell-wall active antibiotic such as a penicillin or vancomycin. Clinical conditions for which tobramycin is useful include: urinary tract infections such as pyelonephritis, gynecologic infections, peritonitis, endocarditis, pneumonia, bacteremia and sepsis, respiratory infections including those associated with cystic fibrosis, osteomyelitis, and diabetic foot and other soft-tissue infections. Because aminoglycosides do not penetrate appreciably into the CNS, they are not considered useful for treating meningitis. In all cases, specific organism susceptibility data should be reviewed before selecting an antibiotic for the treatment of gram-negative infections. Pharmacokinetics: Tobramycin is not absorbed orally, and serum concentrations are unpredictable after IM injection. Thus, IV infusion over 15�30 minutes is the usual mode of administration. A solution for inhalation is also available. Since penetration into the CNS is poor, tobramycin also has been given intrathecally or intraventricularly in conjunction with parenteral therapy for treating CNS infections. Peak serum concentrations following an intravenous infusion are proportional to the dose; a peak serum concentration of 6�8 �g/ml is usually achieved with an intravenous dose of 2 mg/kg infused over 30 minutes. Following inhalation of tobramycin 300 mg, the average concentration in sputum is 1237 �g/g (range: 35�7414 �g/g); tobramycin does not accumulate in sputum with repeated dosing. The mean serum tobramycin concentration one hour after inhalation of a single 300 mg dose by cystic fibrosis patients is 0.95 �g/ml; after repeated dosing for 20 weeks, the average serum concentration is 1.05 �g/ml. Tobramycin distributes into extracellular fluid; the volume of distribution is approximately 0.25�0.3 L/kg. However, critically-ill patients, and patients with burns, ascites, or heart failure usually have larger volumes of distribution, often in the range of 0.3�0.4 L/kg. Infants and neonates have volumes of distribution usually between 0.4�0.5 L/kg. Protein binding of tobramycin is negligible. Tobramycin is not metabolized. Elimination is almost exclusively via glomerular filtration. Thus, elimination half-life varies according to renal function. In adults with normal renal function, the plasma elimination half-life is about 2�3 hours. In patients with impaired renal function, the plasma elimination half-life can be 24 hours or longer. In infants, the half-life ranges from 3�11 hours and is inversely proportional to birth weight and gestational age.

INDICACIONES Y POSOLOGIA

ndications...Dosage The following organisms are generally considered susceptible to tobramycin in vitro: Acinetobacter sp.; Aeromonas sp.; Citrobacter sp.; Enterobacter aerogenes; Enterobacter sp.; Escherichia coli; Haemophilus influenzae (beta-lactamase negative); Haemophilus influenzae (beta-lactamase positive); Klebsiella sp.; Morganella morganii; Proteus mirabilis; Proteus vulgaris; Providencia rettgeri; Providencia sp.; Pseudomonas aeruginosa; Salmonella sp.; Serratia sp.; Shigella sp.; Staphylococcus aureus (MSSA); Staphylococcus epidermidis. NOTE: Enterococcus sp. are generally resistant to therapeutic concentrations of aminoglycosides. Aminoglycosides are only effective in clinical cure of enterococcus infections when used to provide synergistic bacteriocidal activity to penicillins or vancomycin. The degree of synergy is related to the level of aminoglycoside resistance of the specific enterococcus strain. For treatment of the following infections due to susceptible organisms: urinary tract infection (UTI) including pyelonephritis, endocarditis, bacteremia, septicemia, lower respiratory tract infections (e.g. pneumonia), bone and joint infections (e.g. osteomyelitis, infectious arthritis), gynecologic infections, skin and skin structure infections (e.g. cellulitis, burn wound infection), intraabdominal infections (e.g. peritonitis), meningitis, neonatal sepsis, and empiric anti-infective management of febrile neutropenia: NOTE: Tobramycin serum concentrations should be used to guide dosage adjustments. A "dosing" weight should be used to calculate initial dosages in patients weighing more than their ideal body weight (see Drug Monitoring on this dosage card). Parenteral dosage (Traditional dosing): Adults: 3�6 mg/kg/day IV/IM given in 2�3 divided doses. Lower doses can be used in uncomplicated, lower urinary tract infections. Higher doses may be required in pneumonia, gram-negative endocarditis, or in infections due to more resistant organisms. Children >= 5 years: 2�2.5 mg/kg IV/IM every 8 hours. Infants and children < 5 years: 2.5 mg/kg IV/ IM every 8 hours. Neonates postnatal age > 7 days > 2000 g: 2.5 mg/kg IV/IM every 8 hours. Neonates postnatal age > 7 days 1200�2000 g: 2.5 mg/kg IV/IM every 8�12 hours. Neonates postnatal age <= 7 days > 2000 g: 2.5 mg/kg IV/IM every 12 hours. Neonates postnatal age <= 7 days 1200�2000 g: 2.5 mg/kg IV/IM every 12�18 hours. Preterm neonates, 0�4 weeks, weighing < 1200 g: 2.5 mg/kg IV/IM every 18�24 hours. Preterm neonates < 1000 g: 3.5 mg/kg IV/IM every 24 hours. Intravenous dosage (Once daily or "pulse" dosing): Adults: Studies of once daily or "pulse" dosing have used doses of 4�7 mg/kg IV. Dosing intervals are often determined using a nomogram and are frequently based on a random level drawn 8�12 hours after the first dose; dosing intervals of 24 hours, 36 hours, and in some cases, 48�72 hours, are used. Some clinicians do not recommend this dosage regimen in immunocompromised patients. For the treatment of bronchiectasis in cystic fibrosis patients with Pseudomonas aeruginosa: Intravenous dosage: Adults, adolescents, and children: 2.5�3.3 mg/kg IV every 8 hours. Dosage should be adjusted, if necessary, to achieve a peak serum concentration of 8�12 �g/ml and trough concentration < 2 �g/ml. Nebulized dosage (TOBI�): Adults, adolescents, and children >= 6 years: 300 mg (one ampule) via inhalation twice daily for 28 days. Administer in alternating 28-day periods (i.e., administer for 28 days, the 28 days off therapy, then resume therapy for the next 28 days). In one study, tobramycin was administered at a dosage of 600 mg via inhalation three times daily for 28 days.[5] NOTE: Safety and efficacy have not been demonstrated in children < 6 years, patients with FEV1 < 25% or > 75% predicted, or in patients colonized with Burkholderia cepacia. For intrathecal administration in patients with meningitis due to susceptible organisms: Intrathecal dosage: Adults: 4�8 mg intrathecally once daily in combination with parenteral therapy. Children with normal renal function: 1�2 mg intrathecally once daily in combination with parenteral therapy. For intraperitoneal administration to treat systemic infections in patients with no IV access when IM administration is not acceptable: Intraperitoneal dosage: Adults and children: 1.5�2 mg/kg intraperitoneally. For the treatment of peritoneal dialysis-associated peritonitis in patients with end-stage renal disease: Intraperitoneal dosage: Adults and children: Intraperitoneal (IP) tobramycin can administered in each dialysate exchange bag at a dose of 4�8 mg/l; doses of 6�8 mg/l IP should be used in documented pseudomonas infections. Higher doses of 12 mg/l IP per exchange bag have also been used. Alternatively, an IP dose of 20 mg/l can be administered in one exchange bag per day.[1492] For the treatment of blepharitis, blepharoconjunctivitis, bacterial conjunctivitis, dacryocystitis, keratitis, keratoconjunctivitis, and acute meibomianitis caused by Staphylococcus aureus, Staphylococcus epidermidis, Proteus sp., Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Moraxella lacunata, Enterobacter aerogenes, and Neisseria species including N. gonorrhoeae: Ophthalmic dosage (ointment): Adults and children: Apply a thin strip to the conjunctiva (about 1 cm) every 8�12 hours. For severe infections, apply every 3�4 hours. Ophthalmic dosage (solution): Adults and children: Instill 1�2 drops onto the infected eye every 4 hours. For severe infections, instill 2 drops every 30�60 minutes initially, then reduce to less frequent intervals. Therapeutic Drug Monitoring: Dosing of aminoglycosides is highly variable. Factors such as patient size, renal function, site of infection, and organism susceptibility should all be considered. In patients who are overweight, the following equation should be used to determine the appropriate weight for dosage calculations: [(total body weight - ideal body weight) x 0.4] + ideal body weight. While dosing has traditionally been based on patient size, recently, importance has been placed on achieving peak concentrations in several-fold excess of the organism's MIC.[507] Most urinary tract infections may be adequately treated with lower peak serum concentrations, however pulmonary infections in general may require much higher peak serum concentrations to achieve adequate tissue penetration and killing.[1154] Serum trough concentrations of tobramycin should remain below 2 �g/ml to minimize potential toxicities. Individualization of dosage should be designed to achieve a peak serum concentrations in several-fold excess of the MIC, achieving optimal concentration-dependent bacterial activity. As the practice of dosing based on the organism's MIC becomes more widespread, traditional dosing methods will no longer be appropriate. Pulse dose intravenous therapy (often referred to as "single-daily dosing" or "once-daily dosing") satisfies the goal of producing serum concentrations that exceed the MIC by several-fold while simultaneously taking advantage of the PAE in susceptible gram-negative bacteria. This high-dose, extended interval dosing does not appear to increase the risk of toxicity and may actually reduce it.[1155] High-dose pulse therapy is not advocated in pregnancy, pediatrics, renal failure, and is usually unnecessary in the treatment of urinary tract infections. Patients with renal impairment: CrCl > 70 ml/min: reduce dose by multiplying maintenance dose by 0.85 and administer IV every 8�12 hours. Adjust doses based on serum concentrations and organism MIC. CrCl 50�69 ml/min: reduce dose by multiplying maintenance dose by 0.85 and administer IV every 12 hours. Adjust doses based on serum concentrations and organism MIC. CrCl 25�49 ml/min: reduce dose by multiplying maintenance dose by 0.85 and administer IV every 24 hours. Adjust doses based on serum concentrations and organism MIC. CrCl <25 ml/min: reduce dose by multiplying maintenance dose by 0.85 and administer IV doses based on serum concentrations. Intermittent hemodialysis: Adults: 1�1.7 mg/kg IV or IM after the initial hemodialysis session. Subsequent doses should be guided by serum tobramycin concentrations. Infants and Children: 1.25�1.75 mg/kg IV or IM after the initial hemodialysis session. Subsequent doses should be guided by serum tobramycin concentrations. �non-FDA-approved indication

Administration Parenteral Administration �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. �Reconstitute 1.2 g pharmacy bulk package with 30 ml of sterile or bacteriostatic water for injection to give a solution containing 40 mg/ml. FURTHER DILUTION IS REQUIRED. Intravenous infusion: �Withdraw appropriate dose from commercially available multi-dose vials, pharmacy bulk package injection, or reconstituted bulk package injection and dilute in 50�100 ml of a compatible IV infusion solution. �ADD-Vantage� vials may be used for IV infusion only and only if the dose is exactly 60 mg or 80 mg; reconstitute only with NS or D5W in the appropriate diluent container. �Premixed solutions in NS should be administered by IV infusion only. If required, additional tobramycin injection may be added to the container. �Infuse doses over 20�60 minutes. Volume of infusion solution for pediatric patients depends on the patient's needs and should be sufficient to allow infusion over 20�60 minutes. Intramuscular injection: �While intramuscular dosing is acceptable, absorption is erratic. The IM route is discouraged unless IV access cannot be obtained. �Do not use solutions prepared from commercially available bulk packages and ADD-Vantage� vials for IM administration. �Withdraw appropriate dose directly from the vial or use a prefilled syringe. No dilution necessary. Inject deeply into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel. Inhalation Administration �The solution for nebulization is administered by inhalation only. Do not administer subcutaneously, intravenously, or via intrathecally. �Administer via inhalation while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help the patient breath through the mouth. �The ampules should be refrigerated at 2�8 degrees C. However, upon removal from the refrigerator or if refrigeration is unavailable, TOBI� pouches (opened or unopened) may be stored at room temperature for up to 28 days. �The ampules should not be exposed to intense light. Nebulization of solution: �The dose should be inhaled over a 10�15 minute period, using a hand-held PARI LC PLUS� reusable nebulizer with a DeVilbiss Pulmo-Aide� compressor. �Do not dilute or mix with dornase alfa (Pulmozyme�) in the nebulizer. Ophthalmic Administration Injection: �Do not use commercially available ophthalmic solutions for subconjunctival injection or injections directly into the anterior chamber of the eye. A solution should be prepared from the sterile powder for IV injection. Ophthalmic injections should only be performed by clinicians skilled in such techniques. Ointment or solution: �Instruct patient on proper instillation of eye ointment and/or solution (see Patient Information). �Do not to touch the tip of the dropper to the eye, fingertips, or other surface.

CONTRAINDICACIONES

Tobramycin should be used cautiously in patients with renal impairment or dehydration. Tobramycin is eliminated via glomerular filtration and can accumulate in patients with renal dysfunction. Tobramycin also should be used cautiously in patients with other types of renal disease since it is nephrotoxic and may worsen the underlying condition. Although tobramycin is not absolutely contraindicated during pregnancy, it should not be considered free from risk. Streptomycin, a related aminoglycoside, is known to be ototoxic to the fetus. While tobramycin is less ototoxic than streptomycin, it still retains the potential of causing similar toxicity. Patients should be monitored for ototoxicity or nephrotoxicity if more than several days of therapy with tobramycin is anticipated (see Adverse Reactions). Ototoxicity can be manifest as vertigo or high-frequency hearing loss, since both cochlear and vestibular toxicity occur. Aminoglycosides should be used with caution in patients with hearing impairment, especially eighth-cranial-nerve impairment, because of the risk of ototoxicity. Nephrotoxicity may be manifest as renal insufficiency or acute renal failure. Neonates (age <1 month) and elderly patients (age >65 years) may be at increased risk. Aminoglycosides may cause severe neuromuscular weakness lasting hours to days because of their potential curare-like effect. Aminoglycosides may aggravate muscle weakness in patients with muscular disorders such as myasthenia gravis, infant botulism, or parkinsonism. Patients with aminoglycoside hypersensitivity should not receive tobramycin. Allergenic reactions to aminoglycosidesare generally uncommon, but hypersensitivity with one agent may demonstrate cross sensitivity with another aminoglycoside.

INTERACCIONES

Additive nephrotoxicity is possible if tobramycin is used with any of the following: acyclovir, amphotericin B, other aminoglycosides, carboplatin, cidofovir, cisplatin, cyclosporine, foscarnet, ganciclovir, salicylates, tacrolimus, or vancomycin. The combination of tobramycin and cidofovir is contraindicated. Tobramycin should be discontinued 7 days prior to beginning cidofovir. Indomethacin has been shown to increase serum aminoglycoside concentrations in premature infants receiving indomethacin for patent ductus arteriosus. Urine output decreased and serum creatinine increased in these infants during indomethacin administration. It is likely that other NSAIDs may cause a similar interaction with aminoglycosides. Although data regarding these interactions in adults are not available, serum aminoglycoside concentrations should be monitored carefully in patients receiving aminoglycosides and indomethacin concurrently. It is possible that additive nephrotoxicity may occur in patients who receive aminoglycosides and NSAIDs concomitantly. Dimenhydrinate and other antiemetics should be used carefully with tobramycin because they can mask symptoms of ototoxicity (e.g., nausea secondary to vertigo). Many pharmacy references mention neuromuscular blockade as an adverse reaction of aminoglycoside antibiotics, however, it appears this is only seen when aminoglycosides are used to irrigate the abdominal cavity during surgery, a practice which has been discouraged. It is believed that this problem is less likely to occur with parenteral aminoglycoside therapy since patients are exposed to smaller amounts of drug. Nevertheless, patients receiving depolarizing or nondepolarizing neuromuscular blockers and/or general anesthetics should be observed for exaggerated effects if they are receiving tobramycin. The effects of botulinum toxin type A or botulinum toxin type B can be potentiated by aminoglycosides or other drugs that interfere with neuromuscular transmission. Ethacrynic acid and, to a lesser extent, furosemide are ototoxic. Ototoxicity is additive when either of these loop diuretics are administered concomitantly with tobramycin. Bumetanide appears to be less of a risk. Certain penicillins, such as carbenicillin and ticarcillin, have been shown to bind to and inactivate tobramycin in vitro and in vivo. Phlebotomy samples for assaying tobramycin should be either assayed immediately or frozen if the patient is also receiving parenteral carbenicillin or ticarcillin. Some surfactant-anti-infective mixtures have been shown to affect the in vivo activity of exogenous pulmonary surfactants when they are administered via inhalation. Pulmonary surfactants (e.g., beractant, calfactant, poractant alfa, and colfosceril; cetyl alcohol; tyloxapol) should not be mixed with anti-infectives that are commonly administered via nebulization such as aminoglycosides, amphotericin B, ceftazidime, pentamidine, or vancomycin. [ Revised 2/15/01 ]

REACCIONES ADVERSAS

Nephrotoxicity is a well-known adverse reaction to systemic tobramycin and other aminoglycoside antibiotics. Some studies suggest tobramycin is less nephrotoxic than gentamicin. Aminoglycoside antibiotics are taken up by lysosomes in cells lining the proximal tubule, which, in turn, leads to necrosis and/or fibrosis. With continued exposure, interstitial fibrosis, renal tubular necrosis, and renal tubular acidosis occur. If aminoglycoside therapy is discontinued prior to this, renal dysfunction can be reversible. Although it is commonly believed that maintaining tobramycin serum concentrations within traditional ranges minimizes the risk of nephrotoxicity, some patients may still experience azotemia. Worsening of creatinine clearance, hyposthenuria (loss of concentrating ability), pyuria (increased WBCs), proteinuria, and cylindruria (cells or casts in the urine) are all manifestations of nephrotoxicity; oliguria occurs rarely. Various studies have identified risk factors for developing nephrotoxicity from aminoglycosides: excessive trough serum concentrations, other nephrotoxic agents, total dose or treatment duration, and preexisting renal disease. Finally, new approaches to clinical dosing of tobramycin can reduce the incidence of nephrotoxicity. Ototoxicity also can occur during tobramycin therapy. This effect can be manifest as high-frequency hearing loss, tinnitus, vertigo, dizziness, or nausea, since either cochlear or vestibular toxicity is possible. Although some believe that peak serum concentrations predict ototoxicity, a firm association has not been made. Uptake of drug into the inner ear can occur more readily in patients who develop ototoxicity. Factors that increase risk include total duration of exposure to the aminoglycoside and concomitant use of ototoxic drugs such as ethacrynic acid. Audiograms should be performed in patients who receive repeated or prolonged courses of therapy with tobramycin. Neuromuscular blockade causing myasthenia has occurred with neomycin intra-abdominal irrigation. Since tobramycin is chemically related, the possibility of this reaction should be considered, although the risk appears to be low after intravenous administration. Irritation after IM injection of tobramycin has also been reported. Patients should be observed for a local injection site reaction after IM administration of tobramycin. Tobramycin solution for inhalation (TOBI�) is generally well tolerated. In clinical studies in over 250 cystic fibrosis patients, dysphonia (13%) and tinnitus (3%) were the only adverse reactions reported more frequently in tobramycin-treated patients than in placebo-treated patients. All episodes of tinnitus were transient and resolved without discontinuation of the drug; no cases of hearing loss were identified. Increases in serum creatinine of at least 50% over baseline occurred in 3% of patients treated with tobramycin for inhalation and 3% of placebo-treated patients. Nevertheless, if nephrotoxicity occurs, inhalation therapy should be discontinued until serum concentrations fall below 2 �g/ml. Although bronchospasm was not reported during initial clinical trials of inhaled tobramycin, the potential for this adverse reaction exists

Tobramycin Nebcin�, TOBI�, Tobrex�, Tobramycin by Bristol-Myers | Tomycine�

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5. Ramsay BW, Dorkin HL, Eisenberg JD et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med 1993;328:1740�6.

1492. Keane WF, Everett ED, Golper TA et al. Peritoneal dialysis-related peritonitis treatment recommendations, 1993 update. Perit Dial Int 1993;13:21.

507. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio to peak concentration. J Infect Dis 1987;155:93�9.

1154. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 1984;77:657�62.

1155. Prins JM, Buller HR, Kuijper EJ et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993;341:335�9.