All posts by Jerry Fahrni

Cockcroft-Gault equation remains an effective way to estimate GFR

From The Annals of Pharmacotherapy Vol. 44, No. 6, pp. 1030-1037:

Evaluation of Aminoglycoside Clearance Using the Modification of Diet in Renal Disease Equation Versus the Cockcroft-Gault Equation as a Marker of Glomerular Filtration Rate

BACKGROUND: Accurate estimation of kidney function is essential for safe administration of renally cleared drugs. Current practice recommends adjusting renally eliminated drugs according to the Cockcroft-Gault (CG) equation as an estimation of glomerular filtration rate. Few data exist regarding the utility of the Modification of Diet in Renal Disease (MDRD) equation in drug dosing.

OBJECTIVE: To evaluate glomerular filtration rate based on creatinine clearance (CrCl) derived from the MDRD or the CG equation compared with patient-specific CrCl calculated from aminoglycoside peak and trough concentrations.

METHODS: Medical records of patients who received aminoglycoside antibiotics were reviewed over 1 year. Patients who received aminoglycosides via conventional dosing with peak and trough concentrations at steady state were included. Calculations based on standard pharmacokinetic equations were used to estimate CrCl from aminoglycoside serum concentrations. Patient-specific CrCl estimated from aminoglycoside concentrations was compared with estimated CrCl from the CG or MDRD equation.

RESULTS: Fifty-five patients were included in the final analysis. The primary outcome showed concordance between estimated and actual aminoglycoside clearance was 0.53 (95% CI 0.18 to 0.88) for the CG equation and 0.41 (95% CI 0.04 to 0.78) for the MDRD equation. Subgroup analysis also favored CG as a better predictor of CrCl. This signified a stronger correlation between the CG equation and aminoglycoside clearance.

CONCLUSIONS: Compared with the MDRD equation, the CG equation provided better correlation of estimated glomerular filtration rate for aminoglycoside antibiotics. Institutions should continue to use the CG equation as the standard of practice to safely adjust aminoglycoside doses in patients with renal dysfunction.

It appears that the Cockcroft-Gault (CG) equation remains an effective way to estimate GFR for aminoglycoside PK calculations. I’ve been using the CG equation since my pharmacy school days and have no immediate plans to make a change.

Evaluation of once-daily gentamicin dosing in children with febrile neutropenia

Once-Daily Gentamicin Dosing in Children with Febrile Neutropenia Resulting from Antineoplastic Therapy

Miriam Inparajah, B.Sc.Phm. | Cecile Wong, B.Sc.Phm. | Cathryn Sibbald, B.Sc.Phm. | Sabrina Boodhan, B.Sc.Phm. | Eshetu G. Atenafu, M.Sc. | Ahmed Naqvi, M.B.B.S., MCPS, MRCP | L. Lee Dupuis, M.Sc.Phm., FCSHP

Pharmacotherapy. 2010 Jan;30(1):43-51


Study Objectives. To evaluate an existing once-daily gentamicin dosing guideline in children with febrile neutropenia resulting from antineoplastic therapy and, if necessary, to develop a new simulated dosing guideline that would achieve pharmacokinetic targets more reliably after the first dose.

Design. Pharmacokinetic analysis of data froma retrospective medical record review.

Setting. Hematology-oncology unit of a university-affiliated pediatric hospital in Canada.

Patients. One hundred eleven patients aged 1–18 years who received once-daily gentamicin between April 2006 and January 2008 for the treatment of febrile neutropenia resulting from antineoplastic therapy, and who had plasma gentamicin concentrations determined after their first dose.

Measurements and Main Results. Demographic data, gentamicin dosing information, blood sampling times, and plasma gentamicin concentrations were noted. Plasma gentamicin concentrations were determined at approximately 3 and 6 hours after the start of the 30-minute infusion of the first dose. Pharmacokinetic parameters were calculated according to standard first-order, one-compartment equations. The proportion of children who achieved pharmacokinetic targets after the first gentamicin dose was used as a measure of dosing guideline performance; the guideline achieved maximum concentration (Cmax) values below the target range (20–25mg/L) in 51% of patients. Ideal dosing guidelines were then developed using the mean dose required to achieved a Cmax of 23 mg/L for each patient. Univariate analysis or the Student t test was used to determine the existence of significant relationships between pharmacokinetic parameters and patient age and sex. The recursive binary partitioningmethod was used to determine critical values of age for dosage guideline development; analysis of variance was then used to compare the different levels obtained after use of this technique. Simulated administration of once-daily gentamicin in the following doses achieved a Cmax within or above target in 73% of patients: 1 year to 6 years, 10.5mg/kg/dose; girls ≥ 6 years, 9.5mg/kg/dose; and boys ≥ 6 years, 7.5mg/kg/dose. Doses were based on actual body weight for children who weighed less than 125% of ideal body weight or based on effective body weight for children 125%ormore of ideal body weight.

Conclusion. The initial gentamicin dosing guidelines were not effective in achieving Cmax. The new proposed dosing guidelines are predicted to achieve a Cmax within or above the target range in almost three quarters of patients. Subsequent dosing should be tailored according to plasma gentamicin concentrations.

Summary of Consensus Recommendations for Vancomycin Monitoring in Adults

A recent article in November 2009 issue Pharmacotherapy summarizes the recommendations from the American Society of Health-System Pharmacists, the Infections Diseases Society of America, and the Society of Infectious Diseases Pharmacists on the monitoring of vancomycin in adults.

“The American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists published a consensus statement on therapeutic monitoring of serum vancomycin levels in adults. These organizations established an expert panel to review the scientific data and controversies associated with vancomycin monitoring and to make recommendations based on the available evidence. As the members of this panel, we summarize the conclusions and highlight the recommendations from the consensus statement. We determined that the area under the concentration-time curve (AUC):minimum inhibitory concentration (MIC) ratio is the most useful pharmacodynamic parameter to predict vancomycin effectiveness and suggested a target ratio of 400 or greater to eradicate S. aureus. In addition, trough serum concentration monitoring is the most accurate and practical method to monitor vancomycin serum levels. Increasing trough concentrations to 15–20 mg/L to attain the target AUC:MIC ratio may be desirable but is currently not supported by clinical trials. Alternative therapies should be considered in patients with S. aureus infections that demonstrate a vancomycin MIC of 2 mg/L or greater because the target AUC:MIC ratio ( 400) is unlikely to be achieved in this setting. Increasing the dosage to result in higher trough concentrations may increase the potential for toxicity; however additional clinical experience is required to determine the extent.”

While the article contains nothing new in terms of vancomycin monitoring and kinetics, the recommendation to consider alternate therapy for S. aureus infections with an MIC >/= 2 mg/L is important to note.

Can antibiotic choice be based on MIC alone?

This questions was recently addressed by Michael J. Postelnick, Senior Infectious Diseas Pharmacist of Northwestern Memorial Hospital in Chicago, Illinois in an Ask-the-Experts post on the Medscape website. Postelnick gives a good explanation of how various pharmacokinetic and pharmacodynamic principles are related to antibiotic choice for infectious pathogens. According to Postelnick “research into antimicrobial pharmacokinetics and pharmacodynamics has established surrogate relationships between the 2 that correlate with outcomes such [as] bacterial eradication or clinical cure. These relationships include the ratio of Cmax to the MIC, time above the MIC (defined as the amount of time during the dosing interval that the antimicrobial concentration in the blood or at the site of infection remains above the MIC of the organism), and the ratio of the AUC to the MIC. For concentration-dependent antimicrobial agents such as fluoroquinolones and aminoglycosides, Cmax/MIC or AUC/MIC most closely correlates with clinical and microbiological outcomes. For time-dependent antimicrobial agents such as beta-lactams, the percentage of time during the dosing interval that the drug concentration remains above the MIC of the organism is the measure that most closely predicts outcomes.” In other words, selection of an antibiotic requires more than the MIC. Knowledge of the organism in addition to pharmacokinetic and pharmacodynamic principles of the drug is necessary to make an informed choice.

Vancomycin and nephrotoxicity in hospitalized patients

An article on the possible link between vancomycin trough concentrations and nephrotoxicity appears in a recent issue of Clinical Infectious Diseases (2009;49:507-14) . The article describes a retrospective study of 166 patients treated at Albany Medical Center Hospital in Albany, New York between January 2005 and December 2006. The study found that patients in the ICU, those with a weight of >/= 101 kg, and those with prolonged exposure to elevated vancomycin troughs (> 20mg/L) were associated with a greater risk for developing nephrotoxicity. The authors conclude that the vancomycin trough value was the parameter that best described this risk of toxicity. Based on this information, it appears that successful treatment of serious methicillin-resistant S.aureus infections with higher minimum inhibitory concentrations (MIC) may place patients at a greater risk for developing nephrotoxicity. The findings in the article are significant as recent guidelines recommend higher vancomycin trough concentrations for complicated S.aureus infections.
Although interesting and possibly informative, the information contained in the study is based on a small observational study in a single facility. The findings cannot necessarily be extrapolated to any significant degree to other patient populations and further studies are necessary to confirm the results on a larger scale. For now it appears that aggressive vancomycin therapy in addition to cautious monitoring of renal function and patient status is prudent when trough levels are approaching 20mg/L.

Why I wanted RxCalc

Cross-post from Jerry is our resident PharmD and co-creator of RxCalc.

I have a couple of passions when it comes to pharmacy. The first is a love of pharmacy technology. Very few pharmacists have an appreciation for the “operations” side of pharmacy which includes automated dispensing cabinets, automated carousels, automated TPN compounders, Pharmacy Information System, etc. These tools are absolutely necessary if we want to get pharmacists out of the physical pharmacy and at the bedside where they belong. My second passion is a little less known discipline known as pharmacokinetics. I have no idea why I like pharmacokinetics; I just do. Some kids like PB&J and some don’t. It’s just the way it is.

Vancomycin and aminoglycoside (especially vancomycin) pharmacokinetics are very popular in hospitals, and are part of a select group of drugs that physicians prefer pharmacists to handle. Doing pharmacokinetic consults isn’t difficult per se, but can involve lots of numbers and equations. Many people find it a bit tedious and boring. There is also considerable variability in methods used for performing pharmacokinetic calculations. For example there are several existing pharmacokinetic models for vancomycin including Bauer, Matzke, Winter, Moellering, etc. Some of the models are more popular than others, but each has merit. As I’ve heard many times, “there are many roads to Rome.”

Pharmacists typically choose a favorite pharmacokinetic model and then alter the model to fit their needs based on years of clinical experience. I’m no different. Even though I was taught pharmacokinetics by Mike Winter at the UCSF School of Pharmacy, I prefer the vancomycin formulas derived by someone else. Please don’t tell Mike, he’s considered one of the best in the business and might revoke my alumni card if he found out.

Not all pharmacokinetic “starts” and adjustments require advanced calculations. Often times, years of experience and a good eye are all you need. However, there are times when you need a little more. Since the days of the Palm Pilot, I’ve always desired a portable pharmacokinetics program. It always made sense to me to use the technology at my finger tips to make my job easier. I’ve written several pharmacokinetic calculators, including simple Microsoft Excel spreadsheets and a little Java Script tied to a web front end, but I never got the opportunity to create a portable version. The iPhone (and iPod Touch) changed all that. The iPhone is a compelling device with a great user interface and unheard of popularity among healthcare professionals. My desire for a portable pharmacokinetics calculator, and the appearance of the iPhone, resulted in the creation of RxCalc.

RxCalc is designed for pharmacists based on my experiences over the past ten years. While not perfect, RxCalc does what I need. It’s clearly a work in progress. I don’t use it all the time because it’s simply not necessary. I still do a lot of “guess work” here and there, but rely onRxCalc when I need something to handle the more advanced calculations. Like every piece of software ever used, there is room for improvement. I have received lots of good, constructive feedback from several users. Combined with my desires, the feedback has created quite a list of future “enhancements” I’d like to see in RxCalc over the next several months. Among these include High Dose Extended Interval (a.k.a. once-daily) aminoglycoside dosing, single dose vancomycin kinetics, the option to change units (i.e. lbs, kg, cm, inches, etc), the ability to select different dosing models, alternate color schemes or themes and a more user friendly interface. Unfortunately, I don’t have the skill set to make the changes myself. That’s why God gave me a brother. I come up with the ideas and he does all the work to make it a reality. We make a great team.

I mentioned in a previous post that it may be time for me to put away my calculator in favor of newer technology. Pharmacokinetics was the last thing I really needed my calculator for. Well, with the creation of RxCalc I’ve finally put my calculator in the drawer and have been using pen, paper and my iPod Touch almost exclusively for a few weeks now. I must say, so far the results have been encouraging.

Guidelines for Monitoring Vancomycin against Staphylococus aureus Infection “The Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists have issued therapeutic guidelines for monitoring of vancomycin treatment for Staphylococcus aureus infection. The summary of consensus recommendations is published in the August 1 issue of Clinical Infectious Disease.

Some of the clinical recommendations include:

  • Dosing based on actual body weight, even for obese patients.
  • Measuring trough levels drawn just prior to the fourth dose.
  • Keeping trough concentrations greater than 10 mg/L and even higher, 15-20 mg/L, for complicated infections.
  • Consider alternate therapy for patients with CLcr 70-100 mL/minute and a targeted AUC/MIC > 400.

Additional clinical recommendations can be found in the guidelines, which are available for free in PDF format here.

Cockcroft-Gault remains standard for pharmacokinetic calculations, for now.

A recent article in Hospital Pharmacy presented a review of literature comparing various methods used for estimating renal function and how those equations are best used when applied to drug dosage adjustments. The article, “Drug Dosage Adjustment Using Renal Estimation equations: A Review of the Literature” discusses literature surrounding the Cockcroft-Gault (CG), the abbreviated Modification of Diet in Renal Disease equation (abbrMDRD), and to a lesser extent the original Modification of Diet in Renal Disease equation. Although promising, there simply isn’t enough literature to support the use of the abbrMDRD equation in pharmacy practice. The article concludes that “although the abbrMDRD equation has many advantages as compared with the CG equation, too little research has been completed at this time to recommend the clinical use of the abbrMDRD equation in pharmacy practice.”

RxCalc currently uses the Cockcroft-Gault equation to estimate renal function for all pharmacokinetic calculations. Apple Core Labs will continue to evaluate new and emerging data, and use this information to make changes to RxCalc when deemed appropriate.