significant metabolite that has been isolated is 9-carboxymethoxymethylguanine,
which accounts for 9% to 14% of an administered dose. It is believed that this
metabolite is a product of hepatic metabolism; however, the kidney may also play an
19 Whether renal dysfunction alters hepatic metabolism or metabolic
enzymes are present within the kidney is unclear. Renal tissue contains many of the
same metabolic enzymes found in the liver. Mixed-function oxidases have been found
in segments of the proximal tubule, whereas other metabolic processes, such as
glucuronidation, acetylation, and hydrolysis, also occur within the kidney.
Renal failure can affect hepatic metabolic enzyme activity and drug transporter
69,70 Most of these investigations were carried out in animals that had
diminished microsomal, mitochondrial, and cytosolic enzyme activities. Renal
dysfunction substantially alters the nonrenal clearance of certain antibiotics, such as
ceftizoxime, cefotaxime, and imipenem,
71–74 as well as the benzodiazepines,
diazepam and desmethyldiazepam.
HIV disease. Will his tenofovir doses need to be adjusted?
Tenofovir is a nucleotide analog of adenosine monophosphate. Tenofovir undergoes
activation by phosphorylation to the active form, tenofovir diphosphate. Tenofovir
diphosphate inactivates HIV reverse transcriptase and HBV DNA polymerase by
It is used as part of an antiretroviral regimen in the
treatment of HIV infection and can also be used for the treatment of chronic hepatitis
78 Approximately 70% to 80% of tenofovir is excreted unchanged in the
urine. The elimination half-life is approximately 17 hours, and the clearance is
significantly reduced in the setting of renal dysfunction. Nephrotoxicity, including
cases of acute renal failure and Fanconi syndrome (renal tubular injury and
hypophosphatemia) have been reported. Organic transporters in the proximal tubule
are believed to mediate nephrotoxicity.
79 The dose of tenofovir must be adjusted in
the setting of kidney dysfunction to prevent accumulation, and the potential to worsen
renal dysfunction. Tenofovir is also available in combination with other
antiretrovirals in a single dose formulation for the treatment of HIV infection. The
specific dosing recommendation should be consulted in the setting of renal
dysfunction for tenofovir or the combination products.
CASE 31-3, QUESTION 4: Is tenofovir significantly removed by dialysis?
Tenofovir is effectively removed by hemodialysis, with an extraction coefficient
of approximately 54%. Approximately 10% of a 300 mg tenofovir dose is removed
after 4 hours of hemodialysis. The recommended dose of tenofovir is 300 mg orally
every 7 days (after approximately 12 hours of hemodialysis or three 4-hour dialysis
analysis reveals the following:
WBC count, 22,000/μL with 89% neutrophils
A lumbar puncture yields cerebrospinal fluid (CSF) with a WBC count of
2,000/μL (90% polymorphonuclear neutrophils), a glucose concentration of 36
mg/dL, and a protein concentration of 280 mg/dL. Gram-positive diplococci are seen
on CSF smear. A diagnosis of meningococcal meningitis is made, and potassium
penicillin G is ordered. What dose should be used?
Meningococcal meningitis can be treated with 20 to 24 million units of IV
penicillin G in patients with normal renal function. As with many β-lactam
antibiotics, penicillin is primarily excreted unchanged in the urine with little or no
hepatic metabolism. Thus, the elimination half-life, which averages less than 1 hour
in patients with normal kidney function, increases to 4 to 10 hours in patients with
Methods to modify the dose of penicillin in renal insufficiency have been
developed by numerous investigators. The clearance of penicillin correlates closely
with CrCl according to the following equation
This correlation is based on data from patients with varying degrees of renal
An equation to estimate the total daily dose for patients with renal failure to
achieve serum levels similar to those produced by high-dose penicillin (20–24
million units/day) in patients with normal renal function has been developed for
patients with an estimated CrCl of less than 40 mL/minute. The dose for T.H. should
be given in equal divided doses at 6- or 8-hour intervals:
Using the Cockcroft–Gault method, T.H.’s CrCl is approximately 20 mL/minute.
Therefore, his daily dose of penicillin should be 6 million units. A dose of 1 million
units every 4 hours would be appropriate for T.H. Penicillin G is often given as the
potassium salt (penicillin G potassium), which contains approximately 1.7 mEq of
potassium per 1 million units of penicillin. Accumulation of potassium due to renal
impairment may lead to hyperkalemia. Penicillin G sodium is an alternative
formulation that would be appropriate.
As is true for many agents, these dosing recommendations are empiric and based
on pharmacokinetic principles for patients in renal failure. These recommendations
have not been subjected to carefully designed clinical trials that establish therapeutic
efficacy. Therefore, other factors that can influence host response also should be
considered when designing an individualized therapeutic regimen. These include the
host’s immune status, the presence of other medical conditions, microbial sensitivity
patterns, and changes in pharmacokinetic disposition (e.g., concomitant liver disease,
PENICILLIN-INDUCED NEUROTOXICITY
CASE 31-4, QUESTION 2: The prescriber fails to consider T.H.’s renal dysfunction when he orders
T.H. is experiencing signs of neurotoxicity that are consistent with elevated
penicillin concentrations in the plasma and CSF. Penicillin usually produces few
serious adverse effects. When large doses are used in patients with renal impairment,
toxic symptoms such as those exhibited by T.H. can result. Signs and symptoms of
penicillin-induced CNS toxicity include myoclonus, complex or generalized seizure
activity, and encephalopathy progressing to coma.
T.H.’s renal dysfunction predisposes him to penicillin-induced neurotoxicity. In a
review of 46 cases of penicillin-associated neurotoxicity, decreased renal function
40 Several possible explanations for this observation exist.
Penicillin accumulates in patients with renal failure. The binding of acidic drugs
(such as penicillin) to albumin is decreased, resulting in an increased fraction of free
or active drug that can pass into the CSF. Alterations in the blood–brain barrier have
been observed in uremic patients, which can lead to further increases in CSF drug
39 High plasma concentrations of penicillin per se may contribute to changes in
the blood–brain barrier permeability of this drug.
39 All these factors, together with
the increased sensitivity of patients with renal failure to centrally acting agents, make
CNS toxicity more likely. Previous neurotrauma, history of seizures, elderly age, and
concurrent drugs that lower the seizure threshold can also contribute to neurotoxicity.
As with penicillin, the carbapenem antibiotic combination, imipenem–cilastatin, is
associated with a higher incidence of seizures in patients with renal dysfunction.
O t h e r β-lactam antibiotics such as ceftazidime, cefepime, and
piperacillin/tazobactam have also been associated with seizures.
QUESTION 1: M.H., a 44-year-old, 70-kg woman with acute nonlymphocytic leukemia, was admitted to the
lymphocytes, and 22% monocytes). Her platelet count is 16,000/μL. M.H. also has renal dysfunction as
Piperacillin is an antipseudomonal penicillin that is often used with an
aminoglycoside to treat serious infections caused by gram-negative organisms.
Piperacillin is commonly given as a combination with tazobactam, a β-lactamase
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