In 1998, the FDA recommended using the Cockcroft–Gault equation to
estimate kidney function when designing pharmacokinetic clinical trials and drug
dosing regimens. The Cockcroft–Gault equation has been the standard method to
estimate renal function to determine if drug dosage adjustments are necessary. In
2010, the FDA released a draft guidance that included both the Cockcroft–Gault and
MDRD equations to determine renal function. It also should be noted that the units for
the Cockcroft–Gault equation for CrCl is mL/minute, while the units for the MDRD
equation for eGFR is mL/minute/1.73m2
. The manufacturer’s prescribing information
and available literature should be evaluated to determine the appropriate dosage
regimen based on the patient’s renal function.
Gentamicin has a MW of about 500 and a relatively low Vd (averaging 0.25 L/kg),
and is about 10% bound to proteins, all favoring effective removal by conventional
44 For a given patient, the observed dialysis clearance of gentamicin
using conventional methods also depends on factors such as the physical properties
of the dialysis filter, the blood and dialysate
flow rates, and the length of dialysis. Studies indicate that dialysis clearance of
gentamicin averages 45 mL/minute compared with an average plasma clearance of 5
mL/minute in patients with ESRD.
55,56 Therefore, G.G.’s gentamicin dose must be
adjusted to compensate for the amount of drug that will be removed by dialysis.
Because drug removal represents a combination of drug elimination by the body and
dialysis, the following equation can be used:
is the total clearance of the drug during dialysis, Cldial
by dialysis, and Cl is plasma clearance. If dialysis clearance is high relative to
plasma clearance, drug removal will be enhanced by the dialysis procedure. The
total clearance of gentamicin in a patient with severe renal dysfunction during
dialysis is 50 mL/minute (45 mL/minute + 5 mL/minute) or 10 times the clearance
while off dialysis. Plasma clearance and dialysis clearance are related to the
elimination half-life by the following equation:
Thus, assuming a constant Vd of 17.5 L (i.e., 0.25 L/kg × 70 kg), the elimination
half-life on dialysis is approximately 4 hours compared with 40 hours off dialysis. In
addition, the extent (fraction) of drug removal (FD) during a timed dialysis run can
be predicted from the following equation:
where t is the duration of dialysis. Therefore, the fraction of gentamicin removed
(FD) during a 4-hour conventional dialysis procedure is approximately 50%. If
specific data are not available for dialysis and plasma clearance, the following
equation will predict fraction removed using the elimination half-life data alone
The estimated value of 50% removal is consistent with literature values indicating
that 50% to 70% of a dose of gentamicin is removed during a 4-hour dialysis
procedure. A limitation of this equation, however, is that it does not consider the
redistribution of drug from the tissues back into the plasma after the dialysis
It generally is difficult to calculate an appropriate maintenance dose for patients
having hemodialysis that will maintain peak and trough concentrations similar to
patients with normal renal function, in part because of the large variability found in
aminoglycoside pharmacokinetic parameters.
56,57 Sustained plasma concentrations
greater than 2 mg/L can increase the risk of toxicity; however, dosing gentamicin to
achieve trough concentrations of less than 2 mg/L may lead to prolonged periods of
subtherapeutic peak concentrations because one would have to use smaller doses
with lower peak concentrations to allow the troughs to decrease before the next dose.
Another practical consideration is that unless one expects the patient to recover renal
function in the future, renal toxicity of the drug is less of a concern. As a compromise
in patients receiving hemodialysis, gentamicin doses are given to achieve a
predialysis trough concentration of approximately 3 mg/L. This can generally be
achieved with a loading dose of 2 mg/kg, followed by a maintenance dose of 1 mg/kg
CASE 31-1, QUESTION 6: Why does the dose of ceftazidime in G.G. have to be adjusted because of her
hemodialysis when this drug has such a large therapeutic window?
Because only 21% of ceftazidime is protein bound and its Vd is 0.2 L/kg, it should
be readily removed by hemodialysis. The mean dialysis clearance of ceftazidime is
55 mL/minute, with 55% of the drug removed during 4 hours of conventional
58 A supplemental dose of ceftazidime should be given to G.G. after
each hemodialysis session to maintain a therapeutic concentration. Half of the daily
ceftazidime dose should be administered after each dialysis session.
and ceftazidime differ with high-flux hemodialysis compared with conventional hemodialysis?
High-flux hemodialysis is more effective than conventional dialysis at removing
certain pharmacologic agents (see Chapter 30, Renal Dialysis) because the
membranes are more efficient and the blood flow through the dialyzer is increased.
Although limited data are available, a greater fraction of drugs, such as
aminoglycosides, ceftazidime, and vancomycin, are removed by high-flux versus
59,60 Approximately 50% to 70% of gentamicin is removed
during a 2.5-hour, high-flux dialysis session.
59 Thus, further dosage adjustments for gentamicin and ceftazidime may
be necessary if G.G. is converted from conventional hemodialysis to high-flux
CONTINUOUS VENOVENOUS HEMOFILTRATION
CASE 31-1, QUESTION 8: What changes would be necessary in G.G.’s gentamicin dosing if she were to
Because of the continuous nature of CVVH, the extent of drug eliminated by
CRRTs will differ from intermittent modes such as hemodialysis. The clearance of a
drug in a patient receiving CVVH can be described in a fashion similar to Equation
from Equation 31-15 can be used for the plasma clearance
(Cl). The clearance by CVVH can be described by the following equation:
where Fu is the fraction of drug unbound and UFR is the ultrafiltration rate.
Gentamicin exhibits low plasma protein binding (Fu = 0.95). Typical ultrafiltration
rates for CVVH are approximately 1 L/hour, but can vary.
Because the clearance of gentamicin approximates that of CrCl, G.G.’s total
clearance is approximately one-third the normal
clearance of 100 mL/minute. Therefore, the gentamicin dose should be
approximately one-third of the normal dose. G.G. should be given 1.5 mg/kg/day or
100 mg of gentamicin as a single daily dose (normal dose is approximately 5
mg/kg/day). Gentamicin trough concentrations should be monitored, and her dose
adjusted to maintain a trough concentration of less than 2 mg/L.
CONTINUOUS AMBULATORY PERITONEAL DIALYSIS
QUESTION 1: J.J., a 24-year-old man with ESRD, is maintained with CAPD. He presents to the ED with a
Management of dialysis-related peritonitis can vary from one institution to another.
Antibiotics often are administered IP with or without systemic antibiotic therapy. For
less severe cases, IP administration is often considered sufficient. With IP
administration, the goal is to deliver a concentration of drug similar to the desired
plasma concentration for the treatment of systemic infections. Therefore, 8 mg of
gentamicin into each liter of dialysate (or 16 mg into a 2-L bag of dialysate) is
recommended. Once equilibrium or steady state is achieved, the dialysate
concentration will be comparable to the concentration of gentamicin in the plasma.
Despite a more rapid transfer of drug into the plasma because of increased
permeability of the peritoneal membrane in patients with peritonitis, there will still
be a substantial lag time before steady state is reached. For more serious cases of
peritonitis, concomitant systemic antibiotics should be given.
CASE 31-2, QUESTION 2: Is gentamicin eliminated by CAPD?
In general, most drugs are not well removed via CAPD. This is particularly true
for drugs that are highly protein bound or for drugs with a large Vd. Gentamicin and
other aminoglycosides, on the other hand, are effectively removed by CAPD because
they have low protein binding and a small Vd. It is estimated that 10% to 50% of
gentamicin is removed by CAPD.
QUESTION 1: D.M., a 28-year-old man with acquired immune deficiency syndrome, presents with a severe
herpetic infection requiring IV acyclovir. Because of other complications associated with his human
D.M. now, and also if he requires dialysis?
Acyclovir is used to prevent or treat a variety of viral infections, such as those
caused by herpes simplex and varicella zoster viruses.
It is cleared primarily by the
kidneys, with approximately 70% to 80% excreted unchanged in the urine. Dosage
adjustment is necessary in patients with renal disease.
19,63 Renal tubular secretion in
addition to filtration contributes to the elimination of acyclovir, which explains why
the renal clearance of acyclovir is about 3 times greater than the estimated CrCl.
Acyclovir also can precipitate in the renal tubules and exacerbate D.M.’s renal
failure. This is more likely to occur when high doses are infused too rapidly to
patients with renal dysfunction.
63 To minimize nephrotoxicity, the patient should be
adequately hydrated to maintain good urine flow, and the acyclovir dose should be
infused over the course of 1 hour. Nephrotoxicity is usually reversible on
discontinuation of the drug or reduction of the dose. In addition, acyclovir-associated
neurotoxicity correlates with elevated plasma concentrations, and further underscores
the need for adequate dosage adjustments in patients with renal dysfunction.
The clearance of acyclovir correlates with the CrCl according to the following
In patients with normal renal function, the clearance of acyclovir ranges from 210
to 330 mL/minute; in patients with ESRD, the clearance is 29 to 34 mL/minute.
Although this change in clearance primarily results from decreased renal clearance of
the drug, nonrenal clearance of acyclovir also decreases in these patients.
result, the elimination half-life increases significantly from approximately 3 hours in
patients with normal kidney function to 20 hours in patients with ESRD. Therefore,
doses should be reduced proportionately from a normal daily dose of 15 mg/kg body
weight (5 mg/kg given every 8 hours) for serious herpes simplex infections to doses
as low as 2.5 mg/kg/day (given as a single daily dose) in patients with ESRD.
Because D.M. has a CrCl of 20 mL/minute and an estimated Clacyclovir of 97
Acyclovir is moderately removed by conventional hemodialysis, with plasma
concentrations decreasing by 60% after 6 hours of dialysis.
clearance averages 80 mL/minute. Therefore, a supplemental dose of 2.5 mg/kg after
dialysis is recommended to replace the amount of drug removed by hemodialysis. No
data are available on the removal of acyclovir by high-flux hemodialysis.
EFFECT OF RENAL DYSFUNCTION ON METABOLISM
CASE 31-3, QUESTION 2: Does D.M.’s renal dysfunction affect the metabolism of acyclovir? Are there
other drugs that are affected similarly?
Approximately 20% of acyclovir is cleared by nonrenal mechanisms.
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