Generally, IDSA guideline divided antifungal therapy in cancer patients with FN into two stragetries: empirical antifungal therapy and preemptive antifungal therapy. The former refers to initiation of an antifungal agent at the first possible clinical evidence of fungal infection, which is usually persistent or recrudescent fever or after day 4 of empirical antibiotic therapy. While preemptive antifungal therapy refers to more-targeted, less broad treatment of only those patients with additional findings suggestive of invasive fungal infection, such as serologic test results or chest CT findings.
Due to that clinical manifestations are nonspecific in the early stages of incubating infection, the diagnosis of invasive fungal infection is especially difficult.
High-risk patients who have received intensive cytotoxic chemotherapy are at risk for invasive fungal infection. These fungal pathogens include different kinds of Candida species, molds such as aspergillosis, zygomycosis, and fusariosis. The profound and prolonged neutropenia is a risk factor for invasive fungal infections (IFIs). Patients treated for acute myeloid leukemia are at greatest risk for IFIs with molds, which is 20 times greater than patients with lymphoma and multiple myeloma.
Since that clinical manifestations are nonspecific in the early stages of incubating infection, the diagnosis of invasive fungal infection is especially difficult, and a delay to initiation of therapy might be dangerous, empirical antifungal therapy for persistent or recrudescent neutropenic fever syndrome has been the standard approach for many decades.
Generally, empirical antifungal therapy is instituted for the treatment of “occult” fungal infection presenting as persistent neutropenic fever despite 4-7 days of empirical antibiotic therapy. By this criteria approximately 22%-34% of neutropenic patients with cancer will receive an antifungal drug, but only ~4% have a demonstrated invasive fungal infection. Given that fever is an especially nonspecific surrogate for invasive fungal infection, the true utility of requiring empirical antifungal therapy for every neutropenic patient on the basis of persistent fever alone must be questioned.
The choice of empirical antifungal therapy is basd on likely fungal pathogens, toxicities, and cost. If antifungal prophylaxis has not been given, then candidemia is initially the greatest concern, while of note if fluconazole prophylaxis had been given before, fluconazole-resistant Candida infections, such as Candida krusei or Candida glabrata, or an invasive mold infection would be more likely. If patients have receiving mold-active prophylaxis, there has been insufficient data upon which to base a specific empirical antifungal choice, but a switch to an IV anti-mold agent within a different antifungal class seems prudent.
Amphotericin B desoxycholate has been the standard empirical choice for over 3 decades; clinical trials have identified roles for other antifungal agents, such as liposomal amphotericin B, itraconazole, voriconazole, caspofungin, and so on. But none of these alternatives have proven to have an efficacy advantage, while they have generally been less toxic than amphotericin B desoxycholate.
Several new technologies facilitate the early detection of fungal infections, which have prompted a critical re-assessment of whether empirical antifungal therapy is mandatory for all persistently febrile neutropenic patients. These new technologies include serum tests for fungal antigens such as β-(1-3)-D glucan test and the galactomannan test, DNA tests such as polymerase chain reaction (PCR) assays for fungal detection, and high-resolution chest CT.
The β-(1-3)-D glucan test detects most of the relevant fungal pathogens, including Candida species, Aspergillus species, Pneumocystis species, and Fusarium species (but not the zygomycetes agents or Cryptococcus species). A positive test result preceded clinical symptoms of IFI in many patients. However, hemodialysis, hemolysis, serum turbidity, hyperlipidemia, visible bilirubin, use of blood products including immunoglobulin and albumin, bacteremia, and the specimen’s exposure to gauze may confound interpretation of the test.
The galactomannan assay detects only Aspergillus species and Penicillium species. But the performance of the galactomannan assay may be confounded by concomitant use of β-lactam/β-lactamase combinations, such as piperacillin-tazobactam (false positives) or anti-mold antifungal agents (false negatives).
PCR assays for fungal detection in blood and BAL (bronchoalveolar lavage) fluid are also being developed and tested, but none are yet commercially available.
CT may reveal abnormalities in either the lungs or the sinuses. Macronodules with or without a halo sign are the most typical findings associated with invasive aspergillosis on chest CT at the initial diagnosis and are evident during neutropenia. The halo sign represents edema or blood surrounding the nodule. Other later manifestations include nodular,wedge-shaped, peripheral, multiple, or cavitary lesions. An aircrescent sign is insensitive and generally appears late, if at all.
Preemptivemanagement, using a combination of clinical, serologic, and CT evidence to initiate antifungal therapy, has been evaluated in several trials. Remember that approximately 22%-34% of neutropenic patients with cancer will receive an antifungal drug, but only ~4% have a demonstrated invasive fungal infection. In a 2005 pilot study serial serum galactomannan tests and early CT were applied prospectively in a preemptive treatment algorithm that lead to nearly 78% reduction (from 35% to 8%) in the use of antifungals among 41 neutropenic patients who would otherwise have qualified for empirical antifungal treatment on the basis of persistent or recurrent fever, without compromising outcomes.
While preemptive antifungal therapy refers to more-targeted, less broad treatment of only those patients with additional findings suggestive of invasive fungal infection, if those tests described above (serologic, DNA, CT) suggested a IFI, then antifungal therapy that covers a broader range of fungal pathogens, including molds should be quickly applied using one of the broad-spectrum antifungals that has documented efficacy in the empirical setting.
At last, a number of important issues about preemptive therapy require further study, which limit the expanding application of this approach.