Antibiotic Adjustment in Continuous Renal Replacement Therapy

Bioavailability

BA refers to the degree that a drug is absorbed into the systemic circulation after extravascular administration: when the drug is administered by the IV route, 100% of the dose is bioavailable, whereas a drug administered by the PO route has to cross further barriers (absorption by gastric or intestinal mucosa or metabolism in liver, also known as first-passage effect) to reach the systemic circulation, which can reduce significantly the final extent of a drug in the bloodstream. In renal failure, numerous pathologic factors and the clinical use of antacids or alkalinizing agents may decrease gastrointestinal absorption. First-pass hepatic metabolism also may be diminished in uremia, leading to increased serum levels of oral antibacterial agents.

Plasma Protein Binding

PPB influences the V _D , the CL, and the drug clearance during renal replacement therapy (RRT) of many antibiotics. Exclusively, the protein-free (unbound) moiety of drugs is able to diffuse in the body and to be cleared off from plasma by kidney, liver, or extracorporeal clearance.

Plasma Drug Concentration (C _max , C _min , AUC)

After PO, at the time when the rate of the drug entering the plasma (absorption) and the rate of the drug disappearing from the plasma (distribution and elimination) are equal, or at completion of IV infusion, the maximal concentration (C _max ) is reached. Thereafter, the rate of distribution or elimination of the drug exceeds the rate of drug absorption, and the plasma concentration starts to decline to a minimal concentration (C _min ). The AUC is a PK measure that indicates the exposure to a drug during the full dosing interval ( Fig. 175.1 ).

When starting an antibiotic drug therapy, the clinician administers the loading dose (LD) to rapidly achieve therapeutically effective concentrations, whereas the maintenance doses (MD) are administered to maintain the effective levels over time by replacing the amount eliminated from the body during the dosing interval. Plasma levels for a given drug (C _max , C _min ) are a function of the dose, BA, V _D , and rate of metabolism and excretion. Therefore PK changes affect the antibiotic concentration at the target site and, finally, the clinical outcome.

Volume of Distribution

Distribution is the process by which a drug diffuses from the intravascular to extravascular compartments. It is described by the drug's V _D , which represents the volume of body fluid into which a drug's dose is dissolved. The V _D is important in calculating the plasma half-life (T _1/2 ) of a drug and also may be used to determine the loading dose. The presence of ascites or edema may necessitate a larger dose, whereas dehydration may require a reduction in the dose.

The V _D is calculated by dividing the amount of drug in the body by the plasma concentration. Usually, highly protein-bound or hydrophilic drugs are found mainly in the vascular compartment and have a small V _D , whereas poorly PPB or lipophilic drugs have a large V _D because they are able to penetrate body tissues. A V _D of about 0.06 L/kg of body weight corresponds to the plasma compartment, a V _D of about 0.2 L/kg corresponds to the extracellular fluid compartment, and a V _D of about 0.4 L/kg corresponds to the intracellular fluid compartment. If the V _D exceeds the total body water (>0.6 L/kg), the drug likely is sequestered in the intracellular fluid of certain tissues.

Clearance

Drug clearance from the body is the result of elimination by renal excretion and by extrarenal pathways (no renal clearance), usually by liver metabolism. The unbound moiety of the drug can be eliminated, so an increase in the plasma level of free drug, commonly observed in critically ill patients, may significantly reduce the clearance mainly for highly protein-bound antibiotics, such as ceftriaxone. In patients treated with extracorporeal treatment (e.g., RRT), total clearance is the sum of extracorporeal clearance, no renal clearance, and residual renal clearance, and this situation further complicates calculations of dose modification.

Half-Life

It is common that the rate of plasma clearance is expressed as the time required for the plasma concentration of a drug to decline by 50% (i.e., the T _1/2 ). After rapid IV administration, the decline in plasma drug levels may follow a biphasic curve. The T _1/2 of the initial phase (alpha-phase T _1/2 ) represents distribution of the drug, and the T _1/2 of the second phase (beta-phase T _1/2 ) represents elimination of the drug from the body. The T _1/2 that usually is reported is the beta-phase T _1/2 . The T _1/2 remains constant at all times for all drugs that follow first-order kinetics because of concentration decreased, as does the rate of plasma clearance. Drug elimination T _1/2 is related directly to CL and V _D . It follows that an increased drug CL is likely to reduce T _1/2 , whereas an increased V _D is likely to increase T _1/2 . T _1/2 is the PK parameter most changed with renal dysfunction in particular for hydrophilic antibiotics ( Fig. 175.2 ).