Inmunologia

Use of Antibacterial A g e n t s i n R e n a l F a i l u re
Brett Gilbert, DOa,*, Paul Robbins, DOb, Lawrence L. Livornese Jr, MD, FIDSAc
KEYWORDS     Antibiotics  Renal failure  Volume of distribution  MDRD Dosing antibiotics with dialysis  Pharmacokinetics Dosing antibiotics with continuous renal replacement therapy Serum levels

The kidney is the major organ for maintaining fluidand electrolyte homeostasis. Changes in renal function, whether associated with normal aging or disease, can have profound effects on the pharmacology of antibacterial agents. It is imperative that clinicians have a basic understanding of these consequences to effectively prescribe antibacterial agents in the face of impaired or changing renal function. This article reviews the pharmacokinetics ofantibacterial agents in patients who have normal and decreased renal function. The concepts of volume of distribution, rate of elimination, loading and maintenance doses, and therapeutic drug monitoring are delineated. The recent controversy in the literature regarding proper vancomycin levels is reviewed. An updated formula to determine the glomerular filtration rate (GFR) is discussed. Commentis made about the use of intermittent dosing of cefazolin for patients who are receiving high-flux hemodialysis. The utility of once-daily aminoglycoside administration is reviewed. Newer and traditional methods of extracorporeal circulation and the resultant changes in the pharmacokinetics of antibacterial agents are discussed.

A version of this article appeared in the 23:4 issue of theInfectious Disease Clinics of North America. B.G. is on the speakers’ bureaus for Merck and Pfizer. No other potential conflicts of interest exist. a Division of Infectious Diseases, Department of Medicine, Thomas Jefferson University Hospital, Lankenau Hospital, Lankenau Medical Building, Suite 164, Wynnewood, PA 19096, USA b Division of Nephrology, Department of Medicine, Lankenau Hospital, LankenauMedical Building, Suite 130, Wynnewood, PA 19096, USA c Division of Infectious Diseases, Department of Medicine, Drexel University College of Medicine, Lankenau Hospital, Lankenau Medical Building, Suite 164, Wynnewood, PA 19096, USA * Corresponding author. E-mail address: santorow@mlhs.org Med Clin N Am 95 (2011) 677–702 doi:10.1016/j.mcna.2011.03.010 medical.theclinics.com 0025-7125/11/$ – seefront matter Ó 2011 Elsevier Inc. All rights reserved.

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PHARMACOKINETICS Bioavailability and Metabolism

Bioavailability refers to the degree that a drug is absorbed into the systemic circulation after extravascular administration. Relatively few studies have addressed this issue in patients who have renal failure. In chronic renal failure, numerous factors, such asnausea, vomiting, diabetic gastroparesis, and intestinal edema, may decrease gastrointestinal absorption. The conversion of urea to ammonia by gastric urease, antacids, or the use of alkalating agents such as bicarbonate and citrate increases gastric pH, thereby reducing the levels of drugs that require an acidic milieu for absorption.1 Some drugs are bound by antacids and phosphate binders, which arecommonly used in renal failure.2 In chronic renal failure, bioavailability is further reduced as the result of decreased small bowel absorption.3 First-pass hepatic metabolism may also be diminished in uremia, leading to increased serum levels of oral antibacterial agents. Impaired plasma protein binding increases the level of free drug; this permits more of a drug to bind to the site of actionand, conversely, increases the amount of a drug available for elimination by dialysis or hepatic metabolism. Of note, the rates of glucuronidation, sulfated conjugation, and oxidation are generally unchanged in the presence of uremia.4
Distribution and Elimination

Plasma levels for a given drug are a function of the dose, bioavailability, volume of distribution, and rate of metabolism and...