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PubMed1994

Ceftriaxone protects against tobramycin nephrotoxicity.

The effect of ceftriaxone on tobramycin-induced nephrotoxicity was investigated. Female Sprague-Dawley rats were treated during 4 and 10 days with saline (NaCl, 0.9%), ceftriaxone at a dose of 100 mg/kg of body weight/12 h subcutaneously, tobramycin at doses of 40 and 60 mg/kg/12 h intraperitoneally, or the combination ceftriaxone-tobramycin. Creatinine levels in serum were significantly higher in animals treated with tobramycin alone given at 60 mg/kg/12 h during 10 days, compared with control animals (P < 0.01) or animals receiving the combination tobramycin-ceftriaxone (P < 0.01). After 10 days of treatment, ceftriaxone did not accumulate in renal tissue but did reduce the renal intracortical accumulation of tobramycin (P < 0.05). Tobramycin given alone at either 40 or 60 mg/kg/12 h induced a significant inhibition of sphingomyelinase activity compared with control animals (P < 0.05). However, this enzyme activity was significantly less inhibited when tobramycin was injected in combination with ceftriaxone (P < 0.05). Ceftriaxone alone had no effect on the activity of this enzyme. The [3H]thymidine incorporation into the DNA of renal cortex was also significantly lower in animals treated with tobramycin-ceftriaxone compared with animals receiving tobramycin alone (P < 0.05). The 24-h urinary excretion of beta-galactosidase was significantly reduced in animals treated with the combination tobramycin-ceftriaxone compared with the administration of tobramycin alone at 40 and 60 mg/kg/12 h after 5 and 10 days (P < 0.05). Histologically, ceftriazone induced very few cellular alterations and reduced considerably the presence of typical signs of tobramycin nephrotoxicity. This investigation demonstrated that ceftriaxone protects animals against tobramycin-induced nephrotoxicity.

Animals↗
PubMed2004

In vitro tobramycin elution analysis from a novel beta-tricalcium phosphate-silicate-xerogel biodegradable drug-delivery system.

This in vitro research analyzed local tobramycin elution characteristics from a novel, biodegradable drug delivery system, consisting of a beta-TCP bone substitute, VITOSS trade mark, encapsulated with silicate xerogel prepared by the sol-gel process. Tobramycin elution from silicate-xerogel-encapsulated VITOSS was compared directly with non-silicate-xerogel-encapsulated VITOSS to assess whether xerogels are effective in delivering greater tobramycin quantities in a controllable, sustained manner crucial for microbial inhibition. Tobramycin elution characteristics indicate an initial release maximum during the first 24 h that diminishes gradually several days after impregnation. The copious tobramycin quantity eluted from the VITOSS/silicate-xerogel systems is attributed to various factors: the intrinsic ultraporosity and hydrophilicity of VITOSS, the ability of tobramycin to completely dissolve in aqueous media, tobramycin complexation with highly polar SO(4) (2-) salts that further assist dissolution, and ionic exchanges between VITOSS and the environment. Silicate-xerogel-encapsulated VITOSS eluted 60.65 and 61.31% of impregnated tobramycin, whereas non-silicate-xerogel-encapsulated VITOSS eluted approximately one-third less impregnated tobramycin, at 21.53 and 23.60%. These results suggest that silicate xerogel optimizes tobramycin elution because of its apparent biodegradability. This mechanism occurs through xerogel superficial acidic sites undergoing exchanges with various ions present in the leaching buffer. Tobramycin elution kinetics were evaluated, and demonstrate that first-order elution rate constants are considerably less when silicate xerogels are employed, following a more uniform exponential decay-type mechanism, thus bolstering controlled release. Overall, tobramycin elution rates adhere to linear-type Higuchi release profiles. Elution rate constants are initially first order, and taper into zero-order elution kinetics in the latter stages of release. Because VITOSS and silicate xerogel are completely biodegradable, essentially all impregnated tobramycin will be delivered to the surgical site after implantation.

Anti-Bacterial Agents↗
PubMed1985

Attenuation of experimental tobramycin nephrotoxicity by ticarcillin.

It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same doses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animals given tobramycin alone was 0.15 +/- 0.1 (mean +/- 2 standard errors) ml/min per 100 g of body weight as compared with 0.53 +/- 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 +/- 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 +/- 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Real histology confirmed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.

Animals↗
PubMed1986

Vancomycin enhancement of experimental tobramycin nephrotoxicity.

The influence of vancomycin on tobramycin nephrotoxicity was assessed in male Fischer rats. Treatment groups included controls receiving diluent and groups receiving vancomycin alone at a dosage of 200 mg/kg (body weight) per day, tobramycin alone at a dosage of 80 mg/kg per day, and a combination of vancomycin and tobramycin at the above dosages. All regimens were injected on a twice-a-day schedule. The animals were sacrificed on days 1, 3, 10, 14, 17, and 21. When compared with controls, animals receiving vancomycin alone exhibited no detectable renal toxicity. Compared with the case with controls, tobramycin alone was toxic, as manifested by lower mean animal weights, increased blood urea nitrogen concentrations on days 14 and 17 (P less than 0.005), increased serum creatinine concentrations on days 17 and 21 (P less than 0.005), and the presence of renal cortical tubular necrosis and regeneration. When compared with tobramycin alone, the combination of vancomycin and tobramycin caused earlier and more severe toxicity. By day 10, the magnitude of weight loss, the rise in blood urea nitrogen, and the increase in serum creatinine concentration were all greater in the rats given the combination of vancomycin plus tobramycin than in the animals given tobramycin alone (P less than 0.005). In addition, there was more proximal tubular necrosis and regeneration in rats given vancomycin plus tobramycin compared with those given tobramycin alone. In this animal model, vancomycin alone caused no detectable renal injury, tobramycin alone produced minimal proximal tubular damage, and the combination of vancomycin and tobramycin resulted in a greater degree of kidney injury than observed with tobramycin alone.

Animals↗
PubMed1990

Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats.

Daptomycin is a new biosynthetic antibiotic which belongs to a new class of drugs known as lipopeptides. The objective of this study was to evaluate the effects of daptomycin and vancomycin on tobramycin-induced nephrotoxicity. Female Sprague-Dawley rats were treated during 4 and 10 days with either saline (NaCl, 0.9%) or tobramycin at doses of 4 and 40 mg/kg per day (given every 12 h [q12h] intraperitoneally). Each treatment was combined with saline, daptomycin at a dose of 20 mg/kg per day (given q12h subcutaneously), and ancomycin at a dose of 50 mg/kg per day (given q12h subcutaneously). Daptomycin and vancomycin had no effect on the intracortical accumulation of tobramycin. Daptomycin did not accumulate in renal tissue even after 10 days of treatment. Tobramycin given at a dose of 40 mg/kg per day during 10 days induced a significant inhibition of sphingomyelinase activity in the renal cortex (P less than 0.01) and increased cellular regeneration (P less than 0.01), as measured by the incorporation of [3H]thymidine into DNA of the renal cortex. These changes were minimal when daptomycin was combined with tobramycin. Histologically, signs of tobramycin toxicity were also less severe in the presence of daptomycin. The intracortical accumulation of vancomycin was not modified by tobramycin. The sphingomyelinase activity was significantly more inhibited (P less than 0.01) when vancomycin was associated with tobramycin (4 and 40 mg/kg) without affecting the rate of [3H]thymidine incorporation into DNA. Histologically, signs of tobramycin toxicity were not affected by vancomuycin, but the cellular vacuolizations which were also observed in vancomycin-treated animals were still present in the proximal tubular cells of animals that were treated with the combination vancomycin-tobramycin. This study strongly suggests that daptomycin protects animals from tobramycin-induced nephrotoxicity but that vancomycin may enhance the effect of tobramycin. We conclude that daptomycin is safe and protects kidney cells from tobramycin-induced nephrotoxicity.

Animals↗
PubMed1986

Preparation and release characteristics of tobramycin-impregnated polymethylmethacrylate beads.

Preparation of tobramycin-impregnated polymethylmethacrylate (PMMA) bone cement beads and release of tobramycin from the beads in vitro and after implantation in a patient are described. Tobramycin sulfate powder 1.2 g was mixed with Palacos PMMA bone cement 40 g in a custom-made mold to produce 25 beads containing 3.26 mg tobramycin (as the sulfate salt) per bead. Chains of the beads, strung on stainless-steel suture, were sterilized with ethylene oxide. Three single beads were each placed in multiple-electrolyte solution (pH 7.4); the solution was removed and replaced with fresh solution every 24 hours for 28 days. The tobramycin content of each day's solution was determined by fluorescence polarization immunoassay. After day 28, solution was removed weekly for assay until day 84. Tobramycin concentrations were measured in drainage from the surgical wound after six chains of tobramycin-PMMA bone cement beads were implanted in the right acetabulum and femur of a patient whose hip prosthesis had been removed because of infection. Tobramycin concentrations in the dissolution medium averaged 34.3 micrograms/mL initially, and 7.5 micrograms/mL on day 2, gradually decreasing to 0.6 microgram/mL on day 28. Release of tobramycin followed a predictable pattern, and variation among samples was small. Over 12 weeks, less than 20% of the theoretically available tobramycin from a single bead was released. Tobramycin concentration in wound drainage was 90.0 micrograms/mL during the first 24 hours after surgery, while serum tobramycin concentrations were less than 0.5 microgram/mL. Extemporaneously prepared beads of bone cement are effective for delivering high concentrations of tobramycin to an infection site.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Cements↗
PubMed1985

In vitro inactivation of tobramycin by cephalosporins.

The in vitro inactivation of tobramycin when combined with each of six cephalosporins in samples of human serum was investigated. Each of six cephalosporins (cefazolin sodium, cefoxitin sodium, cefamandole nafate, moxalactam disodium, cefoperazone sodium, and cefotaxime sodium) was added to human serum samples containing tobramycin sulfate 8 micrograms/mL to produce final cephalosporin concentrations of approximately 250 and 1000 micrograms/mL. Duplicate solutions were prepared and stored at either 0 or 21 degrees C. Solutions containing tobramycin 8 micrograms/mL alone and with carbenicillin disodium in four concentrations were prepared as controls. Samples were assayed using a fluorescence polarization immunoassay (TDX) at 0, 2, 4, 8, 12, 24, and 48 hours to determine tobramycin concentration; two of the carbenicillin-tobramycin solutions were frozen immediately for assay 53 hours later. Tobramycin concentrations in the admixtures were compared with those in tobramycin reference samples. At both temperatures, samples containing tobramycin with cefamandole 250 micrograms/mL or cefotaxime 250 micrograms/mL showed less than 10% inactivation of tobramycin for at least 48 hours. At 0 degrees C, tobramycin retained greater than 90% activity when combined with cefoperazone 250 and 1000 micrograms/mL. In samples containing cefazolin 250 micrograms/mL at 0 degrees C and cefoperazone 250 micrograms/mL at 21 degrees C, tobramycin was stable for 24 hours. Only samples containing moxalactam stored at 21 degrees C showed greater than 16% inactivation of tobramycin at 48 hours. Under these study conditions, tobramycin is only moderately inactivated in vitro when combined with clinically achievable concentrations of the tested cephalosporins (excluding moxalactam) and then stored for up to 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Cephalosporins↗
PubMed2004

Are recombinant human bone morphogenetic protein-7 and tobramycin compatible? An experiment in rats.

OBJECTIVES: To evaluate the effects of local antibiotics on bone morphogenetic protein-induced new bone formation in vivo. DESIGN: In the research laboratory, inactive collagenous bone matrix was reconstituted with 1 microg of recombinant human bone morphogenetic protein-7 and implanted subcutaneously in the thorax bilaterally in 30 male Long-Evans rats. INTERVENTION: In group A (n = 2), the inactive collagenous bone matrix alone was implanted, bilaterally, and one of these pellets treated with either 500 microg tobramycin in aqueous solution or 3 tobramycin-impregnated polymethyl methacrylate beads. In group B (n = 4), the reconstituted pellets were not treated with tobramycin. In group C (n = 8), 1 reconstituted pellet in each rat was treated with 500 microg tobramycin in aqueous solution. In group D (n = 8), 3 tobramycin beads were placed in contact with 1 of the 2 reconstituted pellets in each rat. In group E (n = 8), 3 tobramycin beads were placed on the dorsal surface of 4 of the rats. All rats were killed on day 11. MAIN OUTCOME MEASUREMENT: Bone formation was evaluated by alkaline phosphatase assay and histology. Tobramycin elution from the beads after day 11 was measured by placing the explanted beads into a phosphate buffer solution to incubate for 24 hours. RESULTS: There was no difference in the alkaline phosphatase activity between the tobramycin treated and untreated implants. Histologic evaluation of the implants revealed areas of robust new bone formation in both the tobramycin treated and untreated implants. CONCLUSIONS: The results by both alkaline phosphatase assay and histologic evaluation in this rat model indicate that there is no inhibition of recombinant human bone morphogenetic protein-7-induced new bone formation by locally applied tobramycin. Recombinant human bone morphogenetic protein-7 is osteoinductive in the presence of locally applied tobramycin. A composite osteogenic device containing both tobramycin and recombinant human bone morphogenetic protein-7 may be developed that can simultaneously induce bone healing and decrease the risk for infection.

Administration, Topical↗
PubMed1991

Endotoxin-tobramycin additive toxicity on renal proximal tubular cells in culture.

Aminoglycoside-induced renal damage is enhanced in animals with Escherichia coli pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy. The toxic effect of endotoxin and tobramycin, alone or in combination, was investigated in primary cultures of rabbit proximal tubular cells grown to confluence in serum-free medium. Sodium-dependent uptakes of Pi and alpha-methylglucopyranoside (MGP) and enzymatic activities (lactate dehydrogenase [LDH] released as a marker of cell necrosis and gamma-glutamyltransferase [GGT] and N-acetyl-beta-D-glucosaminidase [NAG] present in the homogenate as markers of brush border membrane and lysosome integrity) were measured. Cells were exposed to (i) endotoxin (20 mg/liter), tobramycin (1 mM), or endotoxin plus tobramycin for 48 h, or (ii) endotoxin (100 mg/liter), tobramycin (4 mM), or endotoxin plus tobramycin for 72 h. Endotoxin alone did not alter Pi uptake, but tobramycin inhibited Pi uptake through a decrease in Vmax. The effect was not enhanced by the combination of endotoxin and tobramycin. Endotoxin and tobramycin alone exerted no significant effect upon MGP uptake, but strong inhibition of the Vmax was observed after exposure to a combination of endotoxin plus tobramycin, without alteration of the Km. Endotoxin decreased residual GGT activity in the cell homogenate. Tobramycin increased LDH release in the medium and NAG activity in the homogenate. Endotoxin plus tobramycin resulted in an additive effect upon LDH and NAG activities. In conclusion, by disturbing apical membrane integrity, endotoxin increased tobramycin toxicity in vitro in the absence of serum hormonal mediator.

Acetylglucosaminidase↗
PubMed1985

Cost savings associated with use of gentamicin versus tobramycin.

A hospital's use and costs of tobramycin sulfate versus gentamicin sulfate before and after a tobramycin use review were compared. Retrospective audits of 100 charts of adult patients in a 515-bed hospital were performed for two six-month periods in 1983-84. Tobramycin use was considered appropriate in patients with serum creatinine concentrations greater than 1.5 mg/dL or pre-existing renal disease, in any patient over 70 years of age, and in patients with neutropenia, documented pseudomonas infection, or infection with an organism shown to be resistant to gentamicin but sensitive to tobramycin. Tobramycin use was not justifiable in 37 (18.7%) of 198 patients whose charts were evaluable. Use of gentamicin in these 37 patients would have saved $14,300. The infection control committee was notified of the audit results; the audit results and recommendations for tobramycin use were included in a letter to all physicians; and the infectious disease service held educational conferences on tobramycin use. In the first six months after the corrective measures, mean monthly tobramycin use decreased by 38% and gentamicin use increased by 48.9%. Total aminoglycoside costs decreased 30.2% and total aminoglycoside use decreased 12.5%. In the second six months after intervention, mean monthly tobramycin use was 11% less than before intervention, and mean monthly gentamicin use was 13% greater than before intervention. Total aminoglycoside costs were 3.6% less and total aminoglycoside use was 4% less than before the audit. The tobramycin use audit and subsequent interventions with prescribers were effective in reducing tobramycin use and costs for approximately six months; decreases in tobramycin use and costs were smaller during the second six months after intervention.

Aged↗
PubMed2000

Transmucosal transport of tobramycin incorporated in SLN after duodenal administration to rats. Part I--a pharmacokinetic study.

Tobramycin-loaded solid lipid nanospheres (SLN) were prepared and administered to rats into the duodenum; their behaviour was compared to that of tobramycin-loaded SLN administered intravenously (i.v.). A tobramycin control solution was also administered to rats. Tobramycin in solution is not absorbed by the gastrointestinal route, while tobramycin incorporated in the SLN is absorbed. A high concentration of tobramycin is still present in plasma 24 hours after the duodenal administration of tobramycin-loaded SLN. Tobramycin-loaded SLN administered i.v. showed a prolonged circulation time compared to the i.v. administered tobramycin solution. The AUC of tobramycin in SLN administered duodenally is higher than those of tobramycin in SLN and in solution administered i.v.

Animals↗
PubMed2000

Bioavailability of tobramycin after oral delivery in FVB mice using CRL-1605 copolymer, an inhibitor of P-glycoprotein.

Tobramycin is an aminoglycoside used in the treatment of infection against gram-negative bacteria. Tobramycin cannot be delivered orally probably due to efflux of drug by a P-glycoprotein pump in the brush border of the small intestine. In this report we demonstrate oral delivery of tobramycin in FVB mice using CRL-1605 copolymer as a vehicle. This copolymer is known to inhibit P-glycoprotein. Two different doses of tobramycin (25 mg/kg and 200 mg/kg) were used. The concentration of CRL-1605 copolymer was 132 mg/kg. The liquid formulation was fed to mice by gavage and serum tobramycin concentrations were measured after one and two hours using the fluorescence polarization immunoassay. We observed significant increases in serum tobramycin concentrations when the drug was delivered orally with the copolymer compared to when the drug was delivered alone. We also performed a bioassay using Bacillus subtilis to confirm antibacterial effect of tobramycin in mice sera. This was to ensure that tobramycin did not undergo structural change during oral absorption when delivered in the copolymer vehicle. We observed minimal inhibition in growth of Bacillus subtilis in sera obtained from mice fed with tobramycin alone. In contrast, we observed almost complete inhibition of growth (most specimens) in sera obtained from mice fed with tobramycin in the presence of CRL-1605 copolymer. We conclude that tobramycin delivered orally in mice using copolymer 1605 is also bioactive.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets.

Calcium sulfate was used as a biodegradable delivery system for the administration of antibiotics in musculoskeletal infection. New Zealand white rabbits were infected with Staplylococcus aureus, debrided, and randomized to one of four treatment groups: calcium sulfate pellets with 10% tobramycin sulfate, placebo calcium sulfate pellets and IM tobramycin, placebo calcium sulfate pellets, or debridement. Serum and wound exudate tobramycin concentrations and serum calcium levels were measured. Radiographs, cultures, and histology were analyzed for efficacy and treatment. Rabbits treated with 10% tobramycin sulfate pellets showed a significantly higher eradication of infection (11/13) than rabbits treated with debridement only (5/12), placebo pellets and IM tobramycin (5/14). or placebo pellets (3/13). In the group receiving 10% tobramycin sulfate pellets, serum tobramycin concentrations peaked 3 h post-operatively at 5.87 microg/ml and were non-detectable after day 1. In the group receiving placebo pellets and IM tobramycin, serum concentrations peaked at 7.82 microg/ml 1 h post-operatively, fell to 6.12 microg/ml on day 2, and averaged 4.18 microg/ ml for the remainder of the treatment period. The wound exudate tobramycin concentrations in the animals treated with tobramycin sulfate pellets peaked at 11.9 mg/ml on day 1 and dropped to 2.5 microg/ml on day 7. There was no significant difference in the serum calcium levels in any of the treatment groups. Calcium sulfate containing tobramycin sulfate has potential utility as a biodegradable local antibiotic delivery system in the treatment of musculoskeletal infections.

Animals↗
PubMed1997

Calcium hydroxide ameliorates tobramycin toxicity in cultured chick tibiae.

Results from this laboratory have shown that bone metabolism is directly related to extracellular pH and that high concentrations of tobramycin released from impregnated polymethylmethacryrate (PMMA) beads has pH-dependent toxic effects on bone. In the present study, beneficial effects of calcium hydroxide-impregnated PMMA were investigated regarding tobramycin toxicity and bone metabolism in chick embryo tibiae in vitro. Also using Ca(OH)2 as a pH regulator, the antibiotic efficacy of tobramycin-impregnated PMMA was evaluated with respect to inhibition of Staphylococcus aureus growth. When Ca(OH)2 was added to PMMA beads containing tobramycin, the beads released hydroxyl and calcium ions into the culture medium and released more antibiotic than beads containing only tobramycin. Bone metabolism (glycolysis, total protein synthesis, and collagen synthesis) was enhanced by Ca(OH)2-impregnated beads with or without tobramycin. Additionally, bacterial growth was inhibited more strongly when S. aureus was incubated with tobramycin- and Ca(OH)2-impregnated PMMA disks than with disks containing only tobramycin. This study demonstrates the feasibility of adding Ca(OH)2 to tobramycin-impregnated PMMA beads as a regulator of local pH and a promoter of bone metabolism for protection of bone when high concentrations of tobramycin are used to treat osteomyelitis. It also suggests that lower concentrations of antibiotic may be effective if Ca(OH)2 and tobramycin are administered simultaneously.

Animals↗
PubMed1992

Effect of extracorporeal membrane oxygenation on tobramycin pharmacokinetics in sheep.

BACKGROUND AND METHODS: Critically ill infants undergoing extracorporeal membrane oxygenation (ECMO) therapy often receive multiple pharmacologic agents. Although the disposition of many drugs has been assessed in patients undergoing cardiopulmonary bypass and in patients receiving mechanical ventilation, only limited data exist for selected medications in patients undergoing ECMO. To evaluate the potential influence of ECMO on aminoglycoside pharmacokinetics, we studied the disposition of tobramycin in ten sheep before and during ECMO therapy. Each sheep received a single iv dose of tobramycin during a control period before ECMO and on a study day during ECMO. Identically timed serial blood samples over 4 hrs were obtained after each tobramycin dose. Paired serum tobramycin concentrations were obtained pre- and postmembrane oxygenator during ECMO in six sheep. RESULTS: Alterations in specific pharmacokinetic variables for tobramycin were observed as a result of ECMO. Estimates of elimination half-life and volume of distribution for tobramycin were significantly increased during ECMO as compared with control (pre-ECMO) values (1.8 +/- 0.3 vs. 2.7 +/- 0.8 [SD] hrs [p < .01] and 0.3 +/- 0.1 vs. 0.5 +/- 0.2 L/kg [p < .005], respectively). Tobramycin body clearance was unaffected by the procedure (1.8 +/- 0.8 vs. 1.7 +/- 0.4 mL/min/kg). Paired serum tobramycin concentrations obtained pre- and postmembrane oxygenator demonstrated no drug removal. CONCLUSIONS: These data suggest that ECMO circuitry does not sequester tobramycin and that the prolonged elimination half-life observed during ECMO therapy is not due to a change in drug clearance but is due to an ECMO-induced increase in tobramycin volume of distribution. To achieve and maintain preselected target tobramycin serum concentrations during ECMO, the usual dosage interval should remain unchanged, but the dose should be increased to compensate for the alteration in the drug's volume of distribution. The clinical applicability of these findings needs to be confirmed in carefully controlled clinical studies involving infants receiving ECMO therapy.

Animals↗
PubMed1983

Tobramycin inactivation by carbenicillin, ticarcillin, and piperacillin.

The in vitro and in vivo inactivation of tobramycin by carbenicillin, ticarcillin, or piperacillin was investigated by the enzyme immunoassay method in clinically employed dosages. After the addition of an 80-mg dose of tobramycin to 4- to 5-g doses of a penicillin in 100 ml of 0.9% saline or distilled water, the degradation profile of tobramycin appeared to follow a biexponential pattern of decay. Remarkable losses (30 to 40%) of tobramycin combined with carbenicillin or ticarcillin were observed within 1 h, as compared with the later decline. The combination of tobramycin with piperacillin was least inactivating. When the admixture of tobramycin with carbenicillin or piperacillin used in the in vitro study was infused to six volunteers over 1 h, the observed maximum concentrations of tobramycin were on the average 66 and 74% for carbenicillin and piperacillin, respectively, of that observed after tobramycin alone was given. In contrast, the value obtained for tobramycin in combination with piperacillin was close to 90% of the control value. The elimination half-lives of tobramycin combined with the penicillins were slightly shorter than those of tobramycin alone, indicating that the interaction occurs even in patients with normal renal function.

Adult↗
PubMed2005

Breakpoints for predicting Pseudomonas aeruginosa susceptibility to inhaled tobramycin in cystic fibrosis patients: use of high-range Etest strips.

Inhaled administration of tobramycin assures high concentrations in cystic fibrotic lungs, improving the therapeutic ratio over that of parenteral tobramycin levels, particularly against Pseudomonas aeruginosa. Conventional Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards) breakpoints only consider parenteral levels and do not take into account these high antimicrobial concentrations. The Spanish Antibiogram Committee (The MENSURA Group) has tentatively defined specific breakpoint values for inhaled tobramycin when testing P. aeruginosa isolates from cystic fibrosis (CF) patients (susceptible, < or =64 microg/ml; resistant, > or =128 microg/ml). The antimicrobial susceptibilities of 206 prospectively collected CF P. aeruginosa isolates were determined by the reference agar dilution method. For tobramycin, the performance of high range tobramycin Etest strips (AB Biodisk, Solna, Sweden) and conventional tobramycin disks were assessed with the same collection. Applying MENSURA proposed breakpoints, 95.1% of the strains were categorized as susceptible to tobramycin, either using agar dilution or Etest high-range strips (99% categorical agreement between both methods). With CLSI breakpoints, susceptibility rates decreased to 79.1 and 81.1% for agar dilution and Etest strips, respectively (83.5% categorical agreement). Minor, major, and very major errors for Etest strips (CLSI criteria) were 13.6, 1.2, and 14.8%, respectively. Upon applying the new proposed criteria for inhaled tobramycin, only one major and one very major error were observed with Etest strips. Whenever inhaled tobramycin is considered for therapy, we suggest that P. aeruginosa strains from CF patients categorized as intermediate or resistant to tobramycin according to the CLSI criteria should be retested with high-range Etest strips and recategorized using MENSURA interpretive criteria. CLSI breakpoints should still be followed when intravenous tobramycin is used in CF patients, particularly during the course of exacerbations.

Anti-Bacterial Agents↗
PubMed1990

Pharmacokinetics of intravitreally injected liposome-encapsulated tobramycin in normal rabbits.

Bacterial endophthalmitis, which is a devastating complication of intraocular surgery or eye trauma, has a poor prognosis. Intravitreal injection of antimicrobial agents has become a part of the standard treatment of endophthalmitis. The authors investigate the pharmacokinetics of intravitreal liposome-encapsulated tobramycin as a possible method of prolonging the duration of therapeutic concentrations. Tobramycin was encapsulated into liposomes of phosphatidylcholine, phosphatidic acid, and alpha-tocopherol by the reverse phase evaporation method. The final liposomal suspension contained tobramycin, 7.0 mg/ml, 60.5% encapsulated. One eye received an intravitreal injection of either liposome-encapsulated tobramycin (LET), tobramycin phosphated-buffered saline (TS) or a mixture of tobramycin and liposome-encapsulated saline (TEL), and the results were as follows: 1. Concentrations of free tobramycin were significantly lower with LET than with TS or TEL at 1 hour after intravitreal injection. 2. Concentrations of free and total tobramycin were significantly higher with LET than with TS or TEL at 5 and 8 days after intravitreal injection. Concentrations of free tobramycin with TS were lower than the minimal inhibitory concentration(MIC) of tobramycin for Pseudomonas aeruginosa at 8 days after intravitreal injection, while those with LET were higher than the MIC of tobramycin for Pseudomonas aeruginosa 18 days after injection.

Animals↗