The Influence of Tobramycin Dosage Regimens on Nephrotoxicity, Ototoxicity, and Antibacterial Efficacy in a Rat Model of Subcutaneous Abscess

Wood, C.; Norton, Debra R.; Kohlhepp, Sue J.; Kohnen, P. W.; Porter, George A.; Houghton, Donald C.; Brummett, Robert E.; Bennett, William M.; Gilbert, David N.

doi:10.1093/infdis/158.1.13

Cited by 86 publications

(34 citation statements)

References 29 publications

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“…These doses could double or quadruple the amount of drug, increasing toxicity without a parallel benefit from increased antibacterial activity. Increasingly, experience and opinion indicate that severe oto-and nephrotoxicities are primarily caused by duration of treatment with a persistent drug level and not by brief periods of high drug levels (3,8,31,32,36). Transient levels of amikacin and tobramycin higher than 300 and 40 ,ug/ml, respectively, in patients caused no evidence of neuromuscular blockade, nephrotoxicity, or ototoxicity (15,31).…”

Section: Discussionmentioning

confidence: 99%

First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use

Daikos

Lolans

Jackson

1991

Antimicrob Agents Chemother

145

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, 1990). The therapeutic implications were examined in netilmicin treatment of a Pseudomonas aeruginosa infection of normal and neutropenic mice. For 2 h after the first dose, the bactericidal rates were rapid, 0.75, 1.0, and 1.5 loglo CFU/h with doses of 10, 30, and 60 mg/kg, respectively. Each twofold increase in dosage reduced the number of surviving bacteria fivefold. Between 2 and 6 h, the second-phase bactericidal rate was slow, c0.3 loglo CFU/h, regardless of the dose. In a multiple-dose regimen, the same amount of netilmicin given in one dose was 70 and 90% more effective than two or three doses, respectively. Doses calculated to keep the drug level in plasma above the MIC were less effective than regimens giving first exposure to a high drug concentration. Adaptive resistance occurred when doses were given more than 2 h after the start of treatment. Temporary survival of bacteremic neutropenic mice was 60 to 70% greater with a second dose at 2 h than after a longer interval. In a thigh infection of neutropenic mice treated every 2 h, doses 4, 6, and 8 h after the first one showed no bactericidal effect. A drug-free interval of 8 h (20 times the drug half-life) renewed bacterial susceptibility to drug action. The results in vivo confirm the biphasic bactericidal action and induction of adaptive resistance that characterize first exposure of gram-negative bacilli to aminoglycoside antibiotics. The phenomena have meaning for the optimum clinical use of aminoglycosides.The rate of the bactericidal action of an aminoglycoside antibiotic on Pseudomonas aeruginosa and other aerobic gram-negative bacilli has been observed to be biphasic in vitro (23). An initial phase of rapid bacterial killing is induced by passive ionic binding of the drug to bacterial lipopolysaccharide (16,23,24,30). The killing rate is directly related to the initial drug concentration. A second phase of slower bacterial killing is associated with decreased energy-dependent uptake of the aminoglycoside, and the rate is independent of the initial or persistent drug level (6,14,23,28). Bacteria surviving the first exposure develop adaptive resistance, which is mediated by impermeability to all aminoglycosides (7, 22b). Adaptive resistance is unstable and is reversed during growth in drug-free media.If the same interactions between aminoglycosides and bacteria apply in the treatment of bacterial infections, the data are relevant to selection of the most effective dosing regimen for therapeutic use of these antibiotics. The investigations reported here were designed to determine whether the biphasic bactericidal action of aminoglycoside antibiotics observed in vitro also applies in the treatment of an experimental infection and whether the first-exposure effect includes the development of adaptive resistance. MATERIALS AND METHODSExperimental infection. Infection was produced in the thighs of normal or neutropenic female ICR mice weighing 23 to 28 g (Sprague Dawley Laboratory, Madison, Wis.) by injection of 0.1 ml of broth containing approxim...

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Section: Discussionmentioning

confidence: 99%

First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use

Daikos

Lolans

Jackson

1991

Antimicrob Agents Chemother

145

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“…It9s pharmacodynamic and pharmacokinetic properties, however, suggest that once-daily (o.d.) administration would be more effective and less toxic; bactericidal effects depend on peak drug concentration achieved [1], toxicity is related to the amount of drug that accumulates in susceptible end organs [2] and saturation of binding sites during o.d. administration may reduce tissue accumulation [3].…”

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confidence: 99%

Once-daily tobramycin in the treatment of adult patients with cystic fibrosis

Whitehead¹,

Conway²,

Etherington³

et al. 2002

Eur Respir J

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Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. A. Whitehead, S.P. Conway, C. Etherington, N.A. Caldwell, N. Setchfield, S. Bogle. #ERS Journals Ltd 2002. ABSTRACT: The aim of this study was to test the equivalence of once-and thrice-daily dosing with tobramycin by comparing efficacy and safety in adult patients with cystic fibrosis.Sixty adult patients with an acute respiratory exacerbation were randomized to receive either 10 mg?kg -1 tobramycin once-daily or 3.3 mg?kg -1 tobramycin thricedaily. Primary efficacy and safety endpoints were defined as changes in respiratory function and changes in renal function and hearing.Both groups showed a significant increase in respiratory function without a clinically significant change in renal function. For changes in forced vital capacity % predicted and serum potassium and magnesium levels, equivalence was demonstrated. For the variables forced expiratory volume in one second and forced mid-expiratory flow % pred and serum creatinine levels, there was insufficient power to demonstrate equivalence. One patient in each group showed bilateral impairment in pure tone audiogram after treatment.This study demonstrated significant clinical improvement with both once-and thricedaily tobramycin dosing. Equivalence between the two regimens was shown for some, but not all primary endpoints. Once-daily dosing should be used with careful monitoring of safety and efficacy until large multicentre studies confirm these encouraging results.

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“…However, their auditory and renal toxicities have also been well established (9,17). Animal studies have demonstrated that nephrotoxicity was lower when the daily dose was given in a single administration compared with multiple injections (2,22). A study in humans showed that once-daily dosing decreased renal accumulation of gentamicin and netilmicin (NT) (21).…”

mentioning

confidence: 99%

Fever and associated changes in glomerular filtration rate erase anticipated diurnal variations in aminoglycoside pharmacokinetics

Fauvelle

Perrin

Belfayol

et al. 1994

Antimicrob Agents Chemother

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Netilmicin (4.5 mg/kg of lean body weight) was administered intravenously once every 24 h at 10 a.m. to 23 patients (group I) and at 10 p.m. to 20 patients (group II) with severe infection. No significant differences (P > 0.05) in peak and trough concentrations in serum were found between groups I and II (peak, 12.9 ± 3.7 versus 12.8 ± 4.4 mg/liter, respectively; trough, 0.7 ± 0.6 versus 0.8 ± 0.6 mg/liter, respectively [

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The Influence of Tobramycin Dosage Regimens on Nephrotoxicity, Ototoxicity, and Antibacterial Efficacy in a Rat Model of Subcutaneous Abscess

Cited by 86 publications

References 29 publications

First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use

First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use

Once-daily tobramycin in the treatment of adult patients with cystic fibrosis

Fever and associated changes in glomerular filtration rate erase anticipated diurnal variations in aminoglycoside pharmacokinetics

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