Pharmacologic Factors Associated with Gentamicin Nephrotoxicity in Rabbits

Frame, Peter T.; Phair, John P.; Watanakunakorn, Chatrchai; Bannister, Thomas

doi:10.1093/infdis/135.6.952

Cited by 67 publications

(19 citation statements)

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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%

“…A fatal bacteremic infection was initiated in groups of neutropenic mice by intraperitoneal injection of 0.1 ml of broth containing approximately 108 CFU of bacteria. The survival record of the animals and the treatment schedule included observations after 2, 4,6,8,12, and 24 h. Antibiotic treatment. Netilmicin was made up fresh from a powder standard in a stock solution of 15 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

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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%

Section: Methodsmentioning

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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“…The doses given in the rabbit infection model portion of this study were insufficient to cause measurable serum gentamicin levels. Rats are a well-established model for evaluation of the pharmacokinetics and nephrotoxicity of free gentamicin [7,15,23,27]. Nephrotoxicity markers (blood urea nitrogen [BUN] and serum creatinine) were evaluated because both the PNDJ polymer and gentamicin are cleared by renal excretion.…”

Section: Maximum Tolerated Dosementioning

confidence: 99%

Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective

Overstreet

McLaren

Calara

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Local delivery can achieve the high antimicrobial concentrations necessary to kill biofilm-related microbes. Degradation times for resorbable carriers are too long. Hydrogels (gels of hydrophilic polymer in water) can degrade faster but release antimicrobials too quickly. We previously developed hydrogels based on the copolymer poly(N-isopropylacrylamide-co-dimethyl-c-butyrolactone acrylate-co-Jeffamine 1 M-1000 acrylamide) (PNDJ) with delivery times of several days with complete degradation in less than 6 weeks. Questions/purposes We asked: (1) What is the elution profile of gentamicin from PNDJ hydrogels? (2) Is gentamicin released from gentamicin-loaded PNDJ (G-PNDJ) hydrogel effective for treatment of orthopaedic infection? (3) Does local gentamicin delivery from G-PNDJ hydrogel cause renal dysfunction? Methods (1) Two formulations of G-PNDJ, lower dose (1.61 wt%) and higher dose (3.14 wt%), five samples each, were eluted in buffered saline under infinite sink conditions. (2) Infections were induced in 16 New Zealand White rabbits by inserting a Kirschner wire in a devascularized radius segment and inoculating with 7.5 9 10 6 colony-forming units Staphylococcus aureus. At 3 weeks, débridement was performed and a new Kirschner wire was placed in the dead space. Treatment was randomized to higher-dose G-PNDJ or no hydrogel. No systemic antimicrobials were used. Positive culture and acute inflammation on histology were used to determine the presence of infection 4 weeks postdébridement. (3) 3.14 wt% G-PNDJ, 0.75, 1.5, or 3.0 mL, was injected subcutaneously in nine Sprague-Dawley rats, three of each dose. Serum gentamicin, blood urea nitrogen, and creatinine were measured on Days 1, 3, 7, 14, and 28. Results (1) Gentamicin release was sustained over 7 days with the higher-dose formulation release profile similar to release from high-dose antimicrobial-loaded bone cement.(2) Four weeks postdébridement, infection was present in eight of eight no-hydrogel rabbits but zero of eight rabbits treated with G-PNDJ hydrogel (p \ 0.001). (3) Blood urea nitrogen and creatinine were transiently elevated

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“…However, data from in-vitro and experimental in-vivo studies suggest that once-daily dosing of aminoglycoside might be at least as efficacious and potentially less toxic (Frame et al, 1977;Blaser, Stone & Zinner, 1985a;Gerber et al, 1989;Mattie, Craig & Pechere, 1989). Single-daily dosing of aminoglycosides has also been studied clinically (Powell et al, 1983;Hollender et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of once- and thrice-daily dosing of aminoglycosides in in-vitro models of infection

Blaser¹

1991

Journal of Antimicrobial Chemotherapy

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The bactericidal efficacy of amikacin, isepamicin and netilmicin was studied against Pseudomonas aeruginosa and Serratia marcescens over a treatment period of 30 h using two one-compartment in-vitro models with differently designed culture compartments. High bacterial inocula were exposed to fluctuating drug concentrations, simulating human serum concentrations (t m -2 h) during clinical treatment. The same daily dose was administered as 1 h infusions given every 8 h or every 24 h, resulting in peak concentrations of 8 and 24 mg/1 for netilmicin, and 24 and 72 mg/1 for amikacin and isepamicin, respectively. Once-daily dosing was more bactericidal during initial treatment in the in-vitro models (P < 0-01) and at least as effective as thrice-daily dosing in preventing bacterial regrowth, despite a prolonged period of subinhibitory drug concentration before administration of the second dose. Lower ratios of peak concentration to MIC were needed to achieve bactericidal activity (> 99-9% reduction of cfu) after 24 h treatment against S. marcescens compared with P. aeruginosa (/> < 0-01). All nine regimens providing peaks of at least four times the MIC were bactericidal against S. marcescens after 24 h exposure. In contrast, a bactericidal effect against P. aeruginosa occurred only during two of six experiments with peaks of four to nine times the MIC. Similar results were obtained in both in-vitro models of infection. These data suggest insufficient intrinsic activity of the aminoglycosides studied for single drug treatment of P. aeruginosa in the absence of host-defence mechanisms.

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Pharmacologic Factors Associated with Gentamicin Nephrotoxicity in Rabbits

Cited by 67 publications

References 0 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

Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective

Efficacy of once- and thrice-daily dosing of aminoglycosides in in-vitro models of infection

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