Subacute Toxicity of Colistin Methanesulfonate in Rats: Comparison of Various Intravenous Dosage Regimens

Wallace, Stephanie Jean; Li, Jian; Nation, Roger L.; Rayner, Craig R.; Taylor, David A.; Middleton, Deborah; Milne, Robert W.; Coulthard, Kingsley; Turnidge, John

doi:10.1128/aac.01101-07

Cited by 68 publications

(58 citation statements)

References 13 publications

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“…Kidney of control rat treated with saline for 7 days showing normal renal cortex and glomeruli (HE Â 100). in line with those of Wallace et al 18 who showed no significant change in pCr level after 30 mg/kg/12 h of colistin over 7days.…”

Section: Discussionsupporting

confidence: 80%

Evaluation of colistin nephrotoxicity administered at different doses in the rat model

et al. 2013

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Objective: This study evaluated the usefulness of plasma Cystatin C (pCysC) along with urinary neutrophil gelatinase-associated lipocalin (NGAL), g-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate (AST) and alanine (ALT) aminotransferase to monitor colistin nephrotoxicity. Method: Male rats were given intramuscular (i.m.) injections of colistin in doses of 150,000 (G 1 ), 300,000 (G 2 ) and 450,000 IU/kg/day (G 3 ) or normal saline (Control), every 12 h for 7 days. After the 14th injection, animals were placed in metabolic cages and urine samples were collected in the next 12 h. Thereafter, animals were euthanized, blood samples were collected and kidneys were removed for histological assessment. Results: Nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were acute tubular necrosis in the tubules of G 3 . No significant change in pCr was observed in all treated groups, but pCysC increased in the G 3 compared to the control. In urinary markers, uNGAL level showed a dose dependant increase with significant change in the G2 and G3 groups compared to the control. However, there was no significant change in the AST, ALT, LDH or ALP activities but only GGT increased in the G 3 compared to the control. Conclusion: Based on colistin doses used in our experimental study on rat model, histopathologic assessment remains the most accurate way to diagnose colistin nephrotoxicity. pCysC appears to be more reliable than pCr, and uNGAL seems to be the most sensitive factor of colistin nephrotoxicity.

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Section: Discussionsupporting

confidence: 80%

Evaluation of colistin nephrotoxicity administered at different doses in the rat model

et al. 2013

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“…It is not known why the nephroprotective effect of melatonin against these drugs has not been examined clinically. A recent study in rats (37) reported that coadministration of N-acetylcysteine seemed to ameliorate CMS-induced oxidative stress in kidney cells; however, the daily dose of the prodrug, CMS, was very low based upon animal scaling considerations (48), and no differences in histological abnormalities were observed between groups, including the CMS group. Our study is the first to demonstrate the protective effect of melatonin against colistin-induced nephrotoxicity.…”

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confidence: 99%

“…Nephrotoxicity rates in patients receiving currently recommended CMS dosage regimens are often ϳ45 to 55% (8,10,11,14,19,20,22). Although the mechanism of colistin-induced nephrotoxicity still remains unknown, it appears to be related to total dose of CMS and duration of therapy and is usually reversible upon cessation of therapy (14,48). Notwithstanding its reversibility, nephrotoxicity is currently a major dose-limiting adverse effect impacting the clinical use of CMS.…”

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confidence: 99%

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Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats

Yousef

Chen

Hill

et al. 2011

Antimicrob Agents Chemother

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113

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Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n ‫؍‬ 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-␤-D-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P ‫؍‬ 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ؎ 0.26 ml/min/kg) was lower than in the colistin group (4.28 ؎ 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.

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“…Los autores proponen la primera fórmula para calcular la dosis de carga (basada en el peso corporal) y de mantención (que incorpora el aclaramiento de creatinina), además de hacer recomendaciones para pacientes en hemodiálisis intermitente y en terapias continuas de sustitución renal. Los autores, además, sugieren que la administración de CMS sea en tres dosis en pacientes con función renal normal, lo que se asociaría a menor toxicidad en modelos animales 41 , y a menor emergencia de resistencia en estudios in vitro 42 . Si aceptamos la recomendación de Garonzik y cols 40 , el objetivo plasmático de colistín a alcanzar es 2,5 mg/L, algo así como un punto intermedio entre eficacia y toxicidad.…”

Section: Farmacocinética-farmacodinámica (Pk/pd)unclassified