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618 PART 5: Infectious Disorders

those agents involved in the pathogenesis of infections among immu- The combination of a triazole and a polyene antifungal may be poten-
nocompromised patients with damaged mucosal and integumental tially antagonistic given that both classes act upon the fungal cell mem-
surfaces. This has been recently reviewed. 345 brane. 364,365 Azoles interfere with the 14-demethylation of lanosterol in
Invasive candidiasis encompasses deep infections of various organ the synthetic pathway of ergosterol, the predominant sterol in the fungal
sites. 272,346,347 C albicans is the most commonly observed; however, C trop- cell membrane to which polyene antifungal agents such as amphotericin
icalis, C glabrata, C parapsilosis, C krusei, and C guilliermondii are seen B bind to produce their fungicidal effects. Clinical reports suggest that
in neutropenic patients as well. When multiple organ sites are involved, sequential treatment with lipophilic azoles such as itraconazole followed
the term disseminated candidiasis is more appropriate. The most com- by amphotericin B may be deleterious. This effect may not be as
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mon forms of invasive candidiasis encountered in neutropenia are prominent with the more lipophobic azoles such as fluconazole with less
candidemia with or without associated central venous catheter infection, accumulation of the agent in the lipid-rich environment of the cell mem-
chronic systemic candidiasis (hepatosplenic candidiasis), endophthal- brane. In one randomized, blinded placebo-controlled trial comparing
mitis, hematogenously spread skin infection, and renal candidiasis. The the safety and efficacy of fluconazole with or without amphotericin B
pathogenesis is invasion of damaged integumented surfaces by coloniz- for the treatment of candidemia in severely ill nonneutropenic patients,
ing yeasts during immunosuppression. the response rates were higher in the combination group with no
Candidemia without evidence of metastatic infection is frequently evidence of antagonism. Treatment failure increased in those with
355
associated with indwelling central venous catheters. Such patients high APACHE II scores, and decreased in those with C parapsilosis. 355
should have the catheter removed where possible 347,348 and should Most episodes of candidemia are caused by C albicans 272,367 ; how-
receive at least a 14-day course of antifungal therapy starting from the ever, there is an increasing incidence of non-albicans candidemia.
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day of the first negative blood culture with intravenous amphotericin In a multicenter prospective, observational study of candidemia in 427
B deoxycholate 0.6 to 1.0 mg/kg per day or an intravenous lipid for- consecutive patients from four tertiary care hospitals during the early
mulation of amphotericin B 3 mg/kg per day, intravenous fluconazole 1990s, C albicans accounted for 52% of the bloodstream isolates over-
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800 mg initially followed by 400 mg daily, or an echinocandin (intra- all. However, over the course of the 3.5-year study, the proportion of all
venous anidulafungin 200 mg loading dose followed by 100 mg daily, bloodstream isolates that were non-albicans candidal species increased
micafungin 100 mg daily, or caspofungin 70 mg on day 1 followed by from 40% to 53%. Risk factors for candidemia due to C albicans included
50 mg daily). 148,349 Step-down to fluconazole 400 mg to 800 mg daily may no prior use of antifungal therapy, solid organ transplant recipient,
be considered for stable patients with susceptible organisms and nega- and having a wound as portal of entry. This same epidemiological pattern
tive follow-up blood cultures. When the central venous access device has been observed from 2004 to 2008. Risk factors for non-albicans
349
367
cannot be removed, chronic suppressive therapy with fluconazole or infections include neutropenia, prior use of amphotericin B or fluconazole,
voriconazole may be considered. 272,349 hemodialysis, and an abdominal portal of entry. These observations
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Patients with dissemination to other end organs may be treated with have important implications for neutropenic patients in whom agents such
fluconazole 400 mg/day (6 mg/kg/day) if clinically stable, or with ampho- as fluconazole are used widely for prophylaxis 279,280 and therapy. 356
tericin B deoxycholate or a lipid-based formulation of amphotericin B Chronic systemic candidiasis, also referred to as granulomatous hepa-
or an echinocandin if clinically unstable 272,349 until the clinical foci have titis, focal hepatic candidiasis, or hepatosplenic candidiasis, has emerged
resolved (often several weeks to months) . The overall response rates for as a significant problem among recipients of high-dose cytotoxic
349
amphotericin B in candidemia have been as high as 70%. 350-353 Patients therapy. 346,369-373 The typical clinical presentation is a leukemia patient
with CNS involvement probably also should receive 5- flucytosine (5-FC) who has received HDARA-C, with persistent fever despite broad-
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and be treated until all signs, symptoms, cerebrospinal fluid, and radio- spectrum antimicrobial therapy and neutrophil recovery. The incidence
logical abnormalities have resolved. Imidazoles (eg ketoconazole or has been reported to range from 3.8% to 7.4% in acute leukemia patients
349
miconazole) are not recommended under these circumstances. receiving cytotoxic therapy and somewhat higher in autopsied HSCT
In a systematic review of the five clinical trials 351-355 comparing flu- recipients, 7.3% to 11.5%. 375-380 There may be associated right upper
conazole and amphotericin B deoxycholate in patients with invasive quadrant tenderness, hepatomegaly, splenomegaly, and elevated serum
candidiasis, a meta-analysis suggested the superiority of amphotericin B alkaline phosphatase and γ-glutamyl transferase levels. The diagnosis
deoxycholate with respect to defervescence-based response. Moreover, may be established by ultrasonography, CT, or MRI 381,382 showing mul-
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there was evidence of a greater risk for persistent fungemia among flu- tiple abscesses in the liver and splenic parenchyma (Fig. 68-6). Where
conazole recipients. These differences notwithstanding, there were possible, a tissue biopsy should be considered for histopathologic and
356
no differences in the all-cause mortality. Observations such as these microbiologic confirmation. Liver biopsy is the most reliable means of
356
raise the question of the clinical relevance of the concept of the use of definitively establishing the diagnosis, either by CT-guided transhepatic
agents such as the polyenes that are “cidal” for Candida spp compared to biopsy, transjugular hepatic biopsy, or open biopsy. Biopsy of these
383
fluconazole, which is felt to be “static.” 357,358 That said, voriconazole, an lesions demonstrates the presence of necrotizing granulomata, frequently
extended-spectrum triazole, was shown to be noninferior to amphoteri- (but not uniformly) containing budding yeasts and pseudohyphal ele-
cin B deoxycholate followed by a step-down to fluconazole in patients ments. Liver biopsy specimens should be submitted in a dry, sterile con-
with candidemia and invasive candidiasis. 359 tainer to the clinical microbiology laboratory and processed for pyogenic
The echinocandins (caspofungin, micafungin, and anidulafungin) have bacteria, mycobacteria, viruses, and fungi. Specimens for histopathologic
been effective and safer alternatives to the polyenes for the treatments evaluation may be submitted to the pathology laboratory in fixative
of invasive candidiasis. 272,360 Moreover, this class of antifungal agents and processed for staining with hematoxylin and eosin, with periodic
has been considered fungicidal against Candida spp. Mora-Duarte acid-Schiff (PAS), with an acid-fast stain, and with methenamine silver.
361
and colleagues demonstrated similar response rates of caspofungin and Multiple sections through the paraffin-embedded tissue fragments may
amphotericin B deoxycholate, yet caspofungin recipients experienced be necessary to detect the pathogens. The pathogen is often not grown
fewer adverse drug effects, particularly nephrotoxicity. Similarly, Kuse despite appropriate culture of the tissue specimen. The determination
350
and colleagues demonstrated noninferiority of micafungin and liposo- of a correct diagnosis becomes an important factor contributing to the
mal amphotericin B. In contrast, anidulafungin, a fungicidal agent for planning of potentially curative post-remission therapeutic strategies.
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Candida spp, was associated with higher global response rates than flu- The antifungal regimen choices for the treatment of chronic sys-
conazole. Further, the rates of persistent infection were higher among temic candidiasis involving the liver or spleen are as for candidemia
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fluconazole recipients than for anidulafungin recipients providing (vide supra). The duration of therapy, however, may be significantly
363
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additional evidence for the importance of considering the “cidality” of an longer. Response outcomes include resolution of fever, cholestasis, and
antifungal agent in severely ill patients with invasive candidiasis. radiologically detectable hepatosplenic microabscesses. 381,382 Resolution

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