19,65 The only

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

important role.

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.

17,18,68

p. 672

p. 673

Renal failure can affect hepatic metabolic enzyme activity and drug transporter

function.

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.

75,76

Tenofovir

CASE 31-3, QUESTION 3: D.M. also is being treated with tenofovir as part of antiretroviral regimen for his

HIV disease. Will his tenofovir doses need to be adjusted?

DOSAGE ADJUSTMENT

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

causing chain termination.

77

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

B infection.

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.

HEMODIALYSIS

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

sessions).

78,80

Penicillin

DOSAGE ADJUSTMENT

CASE 31-4

QUESTION 1: T.H., a 57-year-old, 85-kg man with chronic kidney disease secondary to poorly controlled

hypertension, presents to the ED with a 24-hour history of fever (39°C), altered mental status, nausea, and

vomiting. On physical examination he is found to have nuchal rigidity and a positive Brudzin´ski sign. Laboratory

analysis reveals the following:

WBC count, 22,000/μL with 89% neutrophils

BUN, 45 mg/dL

SCr, 4.4 mg/dL

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

ESRD.

81–83

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

83

:

This correlation is based on data from patients with varying degrees of renal

impairment.

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,

fluid overload, dehydration).

PENICILLIN-INDUCED NEUROTOXICITY

CASE 31-4, QUESTION 2: The prescriber fails to consider T.H.’s renal dysfunction when he orders

penicillin, and begins a dose of 4 million units every 4 hours. Four days later, T.H. is encephalopathic (confused,

disoriented, and difficult to arouse), with some twitching noted on the right side of his face. Are these toxic

symptoms associated with high-dose penicillin? What predisposing factors may contribute to this neurotoxicity?

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.

39,40

p. 673

p. 674

Predisposing Factors

T.H.’s renal dysfunction predisposes him to penicillin-induced neurotoxicity. In a

review of 46 cases of penicillin-associated neurotoxicity, decreased renal function

was present in 35 patients.

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

levels.

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.

84,85

O t h e r β-lactam antibiotics such as ceftazidime, cefepime, and

piperacillin/tazobactam have also been associated with seizures.

86,87

Antipseudomonal Penicillins

PIPERACILLIN

CASE 31-5

QUESTION 1: M.H., a 44-year-old, 70-kg woman with acute nonlymphocytic leukemia, was admitted to the

oncology ward for placement of a Hickman catheter for her chemotherapy. Seven days after treatment with

cytarabine and daunorubicin, her temperature spiked to 39.4°C. Other physical findings consistent with sepsis

included a blood pressure of 102/68 mm Hg, pulse rate of 112 beats/minute, and a respiratory rate of 27

breaths/minute. M.H. is neutropenic with a WBC count of 1,400/μL (3% polymorphonuclear leukocytes, 70%

lymphocytes, and 22% monocytes). Her platelet count is 16,000/μL. M.H. also has renal dysfunction as

reflected by an SCr and BUN of 2.6 and 38 mg/dL, respectively. Empiric therapy for sepsis is started with

tobramycin, piperacillin/tazobactam, and vancomycin. How should piperacillin/tazobactam be dosed in M.H.?

Piperacillin is an antipseudomonal penicillin that is often used with an

aminoglycoside to treat serious infections caused by gram-negative organisms.

88

Piperacillin is commonly given as a combination with tazobactam, a β-lactamase

inhibitor.