Page 918 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 70: Fungal Infections 649

Management of Central Venous Catheters: Both the guidelines for the TABLE 70-6 Characteristics of Azoles Used in the ICU
management of candidiasis and those for the management of central
venous catheters recommend removing a central venous catheter Fluconazole Voriconazole
when a patient develops candidemia. 15,82 These recommendations are Formulation IV and oral IV and oral
based on data showing faster clearance of candidemia and better out-
comes when the catheter is removed. 86,93,94 However, there is a school Dosage 12 mg/kg loading dose, 6 mg/kg bid on first day, then
of thought that believes that for many patients, especially those who then 6 mg/kg once daily 3-4 mg/kg bid
are neutropenic, the source of candidemia is the gut, and the catheter Bioavailability (%) >90 >90
should remain in place. 95,96 It is further argued that removal of cath- Effect of food No effect Decreases absorption; give on
eters, many of which are tunneled catheters, in neutropenic patients empty stomach
is not without risk. At the crux of this debate is the problem that
there are no sensitive and specific tests that will unequivocally reveal Protein binding (%) 11-12 58
the source of candidemia to be either the catheter or the gut and Distribution (L/kg) 0.7-1 4.6
there have been no controlled trials aimed specifically at addressing Half-life (h) 22-31 6
the issue of catheter retention. After consideration of these data, the
IDSA Guidelines Panel strongly recommended removal of catheters Substrate/inhibitor of Inhibitor of CYP 2C9, Substrate and inhibitor of CYP
in nonneutropenic patients and suggested that catheter removal be CYP450 2C19, and 3A4 2C9, 2C19, and CYP 3A4
considered for those who are neutropenic. 82 Metabolism Minimal Hepatic CYP 450 2C19, 2C9, 3A4
■ INTRA-ABDOMINAL CANDIDIASIS CSF penetration (%serum) 50-94 42-67
Elimination
Urine as active drug
Urine and feces after metabolized,
Treatment is similar to that of candidemia in regard to the antifungal <1% active drug in urine
agent selected. Except for cases of peritonitis and phlegmon without a Dosage adjustment in Cr Cl >50 mL/min: none None; cannot use IV formulation
discrete abscess, drainage of purulent material is necessary and can be renal impairment if Cr Cl <50 mL/min
accomplished by either interventional radiologic or surgical procedures.
Longer therapy is often required than that needed for candidemia in Cr Cl <50 mL/min: reduce
order to ensure complete resolution of the intra-abdominal infection. by 50%
■ URINARY TRACT INFECTIONS Dosage adjustment in None Child-Pugh <7: none
hepatic impairment
The most important steps in treating candiduria are to remove indwell- Child-Pugh >7: 6 mg/kg bid
ing bladder catheters, stop broad-spectrum antibiotics, and be sure there loading dose, then 2 mg/kg bid
is no obstruction to urine flow. For many patients in the ICU, catheters CSF, cerebrospinal fluid; IV, intravenous.
must remain in place and antibiotics must continue. It is important to Adapted from references 99 and 100.
not treat every patient who has asymptomatic candiduria, but to treat
only those in whom there is some proof of infection.
If infection has been documented, then fluconazole is the drug of CYP2C19, CYP2C9, and CYP3A4 enzymes, to varying degrees. This
choice. No other azoles and no echinocandins achieve concentrations inhibition can lead to significant drug-drug interactions with resultant
in the urine that are adequate to treat Candida infection. Although C increased serum concentrations of drugs, such as warfarin, phenytoin,
97
albicans infections are usually readily treated (as long as all obstructing calcineurin inhibitors, and agents that can increase the QT interval. 99
lesions are removed or bypassed), C glabrata and C krusei infections Adverse events are uncommonly reported with fluconazole. However,
can be extremely recalcitrant to treatment. Amphotericin B remains an as is true of all azoles, hepatotoxicity can occur and liver enzymes should
effective agent for these infections, and low-dose therapy (0.3-0.6 mg/kg be monitored. Generally, mild elevations in transaminases are noted,
daily) for a few days is adequate usually. 82,97 The standard deoxycholate and these resolve when the drug is stopped. Nausea and vomiting can
formulation rather than a lipid formulation must be used, as the lipid occur but are uncommon.
formulations do not achieve adequate concentrations in the kidney. Other Azoles: The only azole other than fluconazole to have use in the
Nephrostomy drainage or placement of stents is often required to manage ICU for treating invasive Candida infections is voriconazole. This
obstructing lesions, such as fungus balls. agent has been shown to be as effective as amphotericin B followed
■ USE OF SPECIFIC ANTIFUNGAL AGENTS IN THE ICU by fluconazole for treating candidemia. It has activity against all
92
strains of C krusei, but cross-resistance between fluconazole and
Fluconazole: Fluconazole is active against C albicans and most, but not voriconazole occurs with C glabrata. 98,101 Voriconazole is used mostly
all, other species of Candida. C krusei, an uncommon species infecting for step-down oral therapy for organisms shown to be susceptible to
ICU patients, is inherently resistant to fluconazole. C glabrata, which is fluconazole, rather than primary therapy. 82
increasingly isolated from ICU patients, has decreased susceptibility to Voriconazole is available in both oral and intravenous formulations
fluconazole. Even when reported as susceptible, the minimum inhibi- and distributes to most tissues, including cerebrospinal fluid and vitre-
102
tory concentration (MIC) is higher than that noted in other species, and ous body (Table 70-6). Active drug is not excreted in the urine. The
many C glabrata isolates are resistant to fluconazole. 98 oral formulation is well absorbed on an empty stomach, but serum
Fluconazole is available as both oral and intravenous formulations levels are highly variable, in part because voriconazole is metabolized
(Table 70-6). The pharmacokinetics of this agent are ideal; it has excel- by three different CYP 450 pathways and has many drug-drug interac-
99
lent bioavailability, distributes to most tissues, including cerebrospinal tions. If given intravenously, a loading dose of 6 mg/kg intravenously
fluid and vitreous body, is excreted in the urine as intact drug, and has twice daily for 1 day should be given, after which the dose is usually
a long half-life allowing once daily dosing. For patients who have nor- 3 to 4 mg/kg twice daily. If given orally, the loading dose is 400 mg twice
99
mal renal function, a loading dose of 800 mg (12 mg/kg) should always daily, followed by 200 mg twice daily thereafter. Voriconazole cannot
be given, followed by the daily dose of 400 mg (6 mg/kg). The dosage is be given intravenously if the creatinine clearance is <50 mL/min because
adjusted for those who have renal insufficiency (Table 70-6). of toxicity of the cyclodextrin vehicle in which it is solubilized, but the
100
Fluconazole is not metabolized extensively by the cytochrome P450 oral formulation can be given safely in renal failure and there is no
(CYP450) system, as are many azole agents; however, it does inhibit dose reduction needed.

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