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648 PART 5: Infectious Disorders

noncomparative study in patients who had recurrent gastrointestinal TABLE 70-5 Treatment Recommendations for Candidemia in Nonneutropenic
perforation/ anastomotic leakage or acute necrotizing pancreatitis found Patients
that caspofungin was effective in preventing invasive candidiasis in 18 of
19 patients. Results should soon be available from a randomized, pla- • Fluconazole, loading dose 800 mg (12 mg/kg), then 400 mg (6 mg/kg) daily or
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cebo-controlled study of caspofungin in ICUs that had rates of invasive • Echinocandin: caspofungin 70 mg load, then 50 mg daily; anidulafungin 200 mg load,
candidiasis of approximately 10% and that targeted only those patients then 100 mg daily; micafungin 100 mg daily
that were deemed at high risk of invasive infection for prophylaxis. • Echinocandin recommended for patients with moderately severe to severe disease and
Several meta-analyses have attempted to establish whether there recent azole exposure
is benefit from prophylaxis in the ICU setting. 75,76,80,81 Results varied • Fluconazole recommended for patients with less severe disease and no recent azole use
depending on the different methodologies used, the trials that were • Transition from echinocandin to fluconazole recommended when organism shown to be
included, the azoles used, and the patient populations studied. All of susceptible to fluconazole and in patients who are clinically stable
these studies showed that rates of invasive candidiasis and/or candidemia • For C glabrata, echinocandins preferred
were significantly reduced by the use of prophylactic fluconazole. One of • For C parapsilosis, fluconazole preferred
these meta-analyses noted a concomitant reduction in mortality, but • Amphotericin B, 0.5-1.0 mg/kg daily, or lipid formulation amphotericin B, 3-5 mg/kg
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three found no change in mortality. 76,80,81 None of these analyses assessed daily, can be used if intolerant to other antifungal agents
the important issue of changes in the epidemiology of Candida species • Voriconazole, 6 mg/kg (400 mg) twice daily for two doses, then 3 mg/kg (200 mg) twice
brought about by the broad use of azole prophylaxis in an ICU setting. daily, is an option for step-down therapy for C krusei or voriconazole-susceptible C glabrata,
Given the association of increasing C glabrata infections in hematology but not initial therapy
units in which fluconazole is widely used, there is great concern that • Recommended duration of therapy 2 weeks after first negative blood culture assuming
widespread use of fluconazole prophylaxis in ICUs will contribute to resolution of symptoms and no secondary site of infection, such as endophthalmitis
selection of C glabrata in that setting. In 2009, the IDSA Guidelines Panel • Intravenous catheter removal strongly recommended
concluded that a beneficial effect of fluconazole prophylaxis outweighed Data from Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candi-
the risk of selection for increasingly resistant Candida species only for diasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. March 1, 2009;48(5):503-535.
those ICUs that had high rates (about 10%) of invasive candidiasis. In
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other units, use of prophylaxis was discouraged. ■ CANDIDEMIA
■ PREEMPTIVE THERAPY All patients with documented candidemia should be treated with an
Preemptive therapy targets those patients who are colonized with antifungal agent. Even if it is thought that an intravascular catheter was
Candida and have certain risk factors for developing invasive infection the source of the Candida, removal of the catheter alone is not adequate
and treats before actual infection occurs. The Candida Colonization therapy. The sooner that antifungal therapy is started, the better the
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Index and the Candida Score were both developed with the goal of uti- outcome, and thus, preemptive or empirical therapy is appropriate
lizing effective preemptive therapy. 68,72 One prospective study enrolled for severely ill patients who have not responded to broad-spectrum
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478 patients, and then treated preemptively, with 400 mg fluconazole for antimicrobial therapy and who are at risk for candidemia.
2 weeks, the 96 patients who had a Candida Colonization Index >0.4. Antifungal Agent: Three randomized controlled trials have shown the
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The rate of invasive candidiasis in this group was only 3.8%. This rate efficacy of fluconazole when compared with amphotericin B, 84-86 and
was significantly less than the 7% rate noted previously in this ICU, but five trials have shown the efficacy of echinocandins for candidemia. 87-91
the use of historical controls weakens this study. Unfortunately, there The echinocandins have been shown to be as efficacious as ampho-
are no randomized blinded placebo-controlled trials that show this tericin B, 87,88 and in one study, anidulafungin appeared to be superior
approach is helpful. to fluconazole. When candidemia is due to C glabrata or C krusei, it is
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■ EMPIRICAL THERAPY recommended that echinocandins, and not fluconazole, be used. When
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Empirical antifungal therapy is given when patients have signs of systemic candidemia is due to C parapsilosis, it is recommended that fluconazole,
and not an echinocandin, be used. Voriconazole has been shown to
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infection but before the laboratory identifies the causative organism. be as effective as amphotericin B followed by fluconazole, but it is not
A blinded placebo-controlled trial assessed this approach in 270 ICU recommended as first-line therapy for candidemia. 92
patients who had the following: fever while on broad-spectrum antibi- Most times, the clinician has to start therapy before the infecting yeast
otics, a central venous catheter, and an APACHE II score >16; patients has been identified to species level. In this case, in an ICU in which
were randomized to receive either fluconazole, 800 mg daily, or placebo C glabrata is a commonly isolated organism, it is prudent to begin with
for 2 weeks. Six patients receiving fluconazole versus 11 patients receiv- an echinocandin. Echinocandins are also recommended for patients
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ing placebo developed invasive candidiasis, a difference that was not sig- who are clinically unstable and for those who had been on an azole prior
nificant. Because the rate of development of candidemia in the placebo to the onset of candidemia. If the patient is stable, has not been treated
arm was only 1.6%, the study was markedly unpowered to show any with azoles previously, and historically, the specific ICU has had few
benefit of empiric therapy. As is true of prophylaxis, it appears that the infections caused by C glabrata, then fluconazole should be the initial
empirical use of antifungal agents is unlikely to have any benefit unless choice. After the organism has been identified, therapy can be switched
the rate of invasive candidiasis is close to 10%. 82 to the most appropriate agent. Switching to fluconazole allows oral dos-
ing and is considerably cheaper than continuing with an echinocandin.
TREATMENT OF FUNGAL INFECTIONS
Follow-up Studies: Follow-up to evaluate the response to antifungal therapy
The treatment of Candida infections in ICU patients has changed mark- is essential. Blood cultures should be obtained daily until it is documented
edly over the last decade. Amphotericin B is now rarely used, and most that candidemia has cleared. It is recommended that antifungal therapy con-
patients are treated with an azole, usually fluconazole, or an echinocandin. tinue for 2 weeks, starting from the time of the first negative blood culture.
Toxicity is much less than that seen with amphotericin B formulations. All patients who have documented candidemia should have a dilated eye
The Infectious Diseases Society of America (IDSA) has published guide- examination to determine whether metastatic infection is present in the
lines for the management of various forms of candidiasis that are helpful eye. Many patients in an ICU cannot tell their caregivers that they have eye
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for directing antifungal therapy, as well as other aspects of management. complaints, so routine consultation with an ophthalmologist is essential.
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Treatment of only the most common types of invasive candidiasis that are The presence of endophthalmitis requires longer therapy with drugs that
frequently seen in the ICU will be discussed (Table 70-5). achieve adequate levels within the posterior compartment of the eye.

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