Acyclovir-induced renal failure in an obese patient

Hernandez, J.; Norstrom, Jeni; Wysock, Glenn

doi:10.2146/ajhp080307

Cited by 27 publications

(12 citation statements)

References 16 publications

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“…While previous data (10,11) have shown that using TBW for dose determination leads to excessive acyclovir exposure in obese patients, our study found that dosing by IBW will provide substantially lower exposure than in nonobese controls. Using patient-specific PK parameters in the MO patients, utilizing an AjBW to dose acyclovir would result in similar exposure (AUC 0 -ϱ) compared to our NW patients.…”

Section: Discussioncontrasting

confidence: 93%

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Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

Turner

Cumpston

Sweet

et al. 2016

Antimicrob Agents Chemother

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cThe current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normalweight patients were enrolled, with mean body mass indexes of 45. 2 ) in the United States and an additional 34% as overweight (BMI, Ͻ30 but Ն25 kg/m 2 ). Class III obesity (BMI, Ն40 kg/m 2 ) has risen from 1.3% in the 1980s to 6.6% currently (1). Body composition is a major factor influencing drug pharmacokinetics (PK) and can alter several parameters, including volume of distribution (V) and clearance (CL) (2). Unfortunately, published PK data specific to obese patients are limited. While biomarkers and surrogate endpoints can direct dosing of certain agents, such as antihypertensives and lipid-lowering drugs, no such biomarkers exist for antimicrobials; thus, clinicians must rely on published PK and pharmacodynamic (PD) data.Acyclovir is a nucleoside analogue that possesses activity against the herpes family of viruses, including herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV) (3). The efficacy of acyclovir for treating HSV has been linked to both area under the plasma concentration-time curve (AUC) and the time that drug concentration remains above the 50% inhibitory concentration (TϾIC 50 ) (4-7). The TϾIC 50 target that has been proposed is 50% of the dosing interval (4-9). Controversy exists regarding which of these PD parameters is most important in predicting clinical success.The manufacturer recommends calculation of intravenous (i.v.) acyclovir dose to be based on total body weight (TBW); however, in obese patients it recommends dosing by ideal body weight (IBW) (3). The only literature to support this recommendation is a single PK analysis comparing morbidly obese (MO) to normal-weight (NW) healthy females, presented as an abstract in 1991 by Davis and colleagues (10). All participants received doses based on TBW. Dosing by TBW in MO patients resulted in approximately 2-fold-higher maximum concentrations than in NW patients. The authors concluded that dosing by TBW in MO patients was inappropriate and recommended the use of IBW in this population (10). The conclusions of this study remain to be validated. The decision to not use TBW in dosing morbidly obese patients is supported by at least one case of an obese patient developing acyclovir-induced renal failure following i.v. acyclovir dosed by TBW (11). A prospective evaluation of IBW to dose a...

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Section: Discussioncontrasting

confidence: 93%

“…The decision to not use TBW in dosing morbidly obese patients is supported by at least one case of an obese patient developing acyclovir-induced renal failure following i.v. acyclovir dosed by TBW (11). A prospective evaluation of IBW to dose acyclovir in obese patients has not been published.…”

mentioning

confidence: 99%

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

Turner

Cumpston

Sweet

et al. 2016

Antimicrob Agents Chemother

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“…vancomycin) [77]Contrast administration12.2% for gentamicin in neonates [78]11.5-60% for aminoglycosides in adults [8, 74, 77, 79] Prevention: Once daily dosing [75]Consider using tobramycin instead of gentamicin since it has lower rates of nephrotoxicity [80, 81]Avoid midnight to 7 am administration [76]No difference in need for renal support in no gentamicin vs. gentamicin treated infection endocarditis, 8 vs. 6% respectively [82]4.6% mortality in a cohort of 201 critically ill patients [8]51% recovery within 21 days of AMG associated AKI [77]Cohort of critically ill patients, mortality in AKI vs. non-AKI group was 44.5 vs. 29.1%, respectively. [74]AcyclovirNephrolithiasis/AKIOlder children [83]Obesity [55, 84, 85]Volume depletionCKDRapid intravenous administrationDose dependentLonger duration of therapy [83]Length of hospital stay [83]Concomitant nephrotoxins [86]12-48% crystal nephropathy with rapid intravenous bolus administration0.27% AKI from oral acyclovir [87]3.1-10.3% children developed AKI from intravenous acyclovir Prevention: HydrationSlow intravenous administrationDose adjustment for CKD Treatment: DiscontinuationRehydrationHemodialysisCalcineurin Inhibitors [88]AKI/glomerularGenetic variations in CYP3A4, MDR1, ACE, TGF-β, and CCR5 [89–93]42% in non-renal allografts [88]Reduce doseCalcineurin minimizationCalcineurin replacement with mTor inhibitorsCisplatin [52, 94]AKI/tubularAgeAfrican AmericansCKDConcurrent nephrotoxins58% in pediatrics [52]43.5% in adults [94]Minimize concurrent nephrotoxin exposure49% with reduction in GFR, 71% with glucosuria, 67% with proteinuria over long term [95]Colistin [96]AKIAgeObesity48% in overweight or obese patients [96]Minimize concurrent nephrotoxin exposureConsider alternative agents80% developed failure by RIFLE category [96]No statistica...…”

Section: Riskmentioning

confidence: 99%

The 6R’s of drug induced nephrotoxicity

2017

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Drug induced kidney injury is a frequent adverse event which contributes to morbidity and increased healthcare utilization. Our current knowledge of drug induced kidney disease is limited due to varying definitions of kidney injury, incomplete assessment of concurrent risk factors and lack of long term outcome reporting. Electronic surveillance presents a powerful tool to identify susceptible populations, improve recognition of events and provide decision support on preventative strategies or early intervention in the case of injury. Research in the area of biomarkers for detecting kidney injury and genetic predisposition for this adverse event will enhance detection of injury, identify those susceptible to injury and likely mitigate risk. In this review we will present a 6R framework to identify and mange drug induced kidney injury – risk, recognition, response, renal support, rehabilitation and research.

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“…Hernandez et al . describe a 60‐year‐old obese male (BMI 37·6 kg/m 2 ) with suspected herpes encephalitis receiving acyclovir at roughly 9 mg/kg/dose ABW IV every 8 h. By day 3, serum creatinine and BUN significantly increased, which prompted a discontinuation of acyclovir.…”

Section: Review Of Antiviral Agentsmentioning

confidence: 99%

Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review

2014

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SUMMARYWhat is known and objective: Obesity is a significant burden on the healthcare system in the United States, and determining the appropriate antimicrobial dosing regimen in morbidly obese patients is challenging. Morbidly obese patients have documented differences in pharmacokinetic and pharmacodynamic properties compared to normal-weight patients, which impact antibiotic efficacy and toxicity. The Food and Drug Administration does not recognize obesity as a special population and does not require pharmaceutical companies to perform studies specific to obese patients. However, there are an increasing number of post-approval studies in obese patients, and this manuscript reviews available clinical and pharmacokinetic literature regarding weight-based antimicrobial agents. Additionally, we describe a single-centre approach to optimize dosing in morbidly obese patients. Methods: A comprehensive literature search was performed on 15 weight-based antimicrobials in the setting of obesity: acyclovir, aminoglycosides, amphotericin B, cidofovir, colistimethate, daptomycin, flucytosine, foscarnet, ganciclovir, quinupristin/ dalfopristin, trimethoprim/sulfamethoxazole, vancomycin and voriconazole. A weight-based antimicrobial dosing guideline for morbidly obese patients was developed. An analysis of guideline compliance and cost analysis were performed following guideline implementation. Results and discussion: This review describes the pharmacokinetic changes that occur in obese patients, including increased volume of distribution, altered hepatic metabolism, renal excretion and changes in protein binding. The majority of weightbased antimicrobials result in increased serum concentrations in morbidly obese patients compared to normal-weight patients when the calculated dose is based on actual body weight. What is new and conclusion: This review demonstrates different antibiotic pharmacokinetic properties are altered in obese patients that could impact efficacy and toxicity. A single-centre guideline for weight-based antimicrobial dosing in obesity was developed and provides recommendations for using ideal body weight, adjusted body weight or actual body weight when calculating antimicrobial doses. However, more research is needed to better elucidate optimal dosing of weight-based antimicrobials in obesity, with particular focus on efficacy and toxicity. WHAT IS KNOWN AND OBJECTIVEObesity is a major issue in the United States, with 78 million US adults and 12Á5 million children and adolescents classified as obese [body mass index (BMI) greater than or equal to 30].1 This equates to an obesity rate of 35% and 16Á9% in adults and children in the United States, respectively.1 Physiological changes in obesity can alter immunological pathways and increase the risk of central line infection, post-operative surgical site infections, intensive care unit length of stay and risk for severe pneumonia and influenza. [2][3][4][5] Additionally, changes in antimicrobial pharmacokinetic and pharmacodynamic properties are well docume...

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Acyclovir-induced renal failure in an obese patient

Abstract: An obese man receiving excessive doses of i.v. acyclovir developed acute but reversible renal failure.

Cited by 27 publications

References 16 publications

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

The 6R’s of drug induced nephrotoxicity

Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review

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