A patient with athletes foot asks the nurse about the pathogenesis of fungal infections

passenger attempted to ignite his shoes with either matches or a cigarette lighter, already prohibited. Unless I am terribly mistaken, one's flora are being mixed with that of several hundreds of thousand of passengers who have passed through the same lines. The floors are rarely cleaned (evidently) and never disinfected. Has

simple hygiene been forfeited in the US in the name of "security?" When the TSA finally answered a query, they told me that OSHA had approved the cross contamination of hundreds of thousands of feet. The CDC, NIH, WHO, or state or local health departments were not consulted. National Security indeed. Though a disgusting and unaesthetic procedure, the people at highest risk must obviously be airport security staff. Studies documenting increased risk of dermatophytes and/or tinea pedis, and increased risk of respiratory tract symptoms like asthma or allergic alveolitis, is clearly highly needed
Invasive fungal infections (IFIs) are continuing threats to patients with hematologic malignancies. Factors associated with greater susceptibility for IFIs include:

• prolonged neutropenia
• graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)
  
• the use of antineoplastic therapies that cause intense and prolonged deficiency of T cell immune responses

Definitions of IFIs in patients with cancer and recipients of HSCT :

Candida and Aspergillus are the major fungal pathogens that cause infection. New antifungal agents have been developed and new fungal diagnostics are now licensed. It is hoped that incorporation of these new tools into antifungal strategies will result in improved outcomes.

• Candida infections : for years, the mainstay of treatment for Candida infections has been the use of amphotericin B, a polyene that binds to ergosterol in the fungal cell membrane, given in a dose of 0.6�1.0 mg/kg/day. Alternatively, fluconazole, an azole that inhibits ergosterol biosynthesis, given in a dose of 400�800 mg/day intravenously or orally, is also acceptable. Amphotericin B is active against most Candida species. Exceptions include variable susceptibility by C lusitaniae and C guillermondi strains and rare resistant C albicans strains. Fluconazole is also active against many Candida species, with the notable exceptions of C krusei, C dubliniensis, and some strains of C glabrata. Many strains of C glabrata are susceptible dose-dependent, meaning that the agent is clinically useful for infections due to such strains but higher doses (e.g., 800 mg/day rather than the usual 400 mg/day) are needed; approximately 15% of C glabrata isolates are fully resistant to fluconazole even at higher doses. The lower sensitivity of C glabrata to fluconazole and the widespread use of fluconazole in critical care and oncology units have been associated with a rise in the proportion of C glabrata in numerous hospital fungal surveys (especially of colonizing isolates) in recent years. Notwithstanding, worldwide surveys have been consistent in showing no rise in rates of resistance to fluconazole of Candida bloodstream isolates over timeref. Randomized trials in patients with systemic candidiasis comparing amphotericin B and fluconazole have shown comparable response rates and less toxicity with fluconazole. Amphotericin B in lipid complex has been compared to amphotericin B deoxycholate and found to have comparable response and survival rates, but the lipid formulation was associated with less nephrotoxicity (Anaissie EJ, White M, Ozun O, et al. Amphotericin B lipid complex versus amphotericin B for treatment of invasive candidiasis: a prospective, randomized, multicenter trial. (Poster Session). In: Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: ASM Press. 1995: Abstract #330). It is important to note that most trials that have evaluated fluconazole were conducted in non-neutropenic patients, and some experts believe that its use in neutropenic patients is not yet firmly establishedref. Since susceptibility to fluconazole is well predicted by species, some experts suggest use of fluconazole can be guided by knowledge of the species of infecting pathogenref. Susceptibility testing can also be used to guide therapy, but it is not widely available. While both the azoles and polyenes exert their antifungal activity through actions on ergosterol in the fungal cell membrane, a new class of drugs, the echinocandins, acts on the fungal cell wall through inhibition of biosynthesis of �-1,3-glucan, a major constituent of the cell wall. This action is exerted by inhibition of �-1,3-glucan synthase. The echinocandins have potent in vitro activity against all of the Candida species. The first licensed member of this family was caspofungin. Other members of the echinocandin class in clinical trials include anidulofungin and micafungin. Caspofungin�s half-life is 12�16 hours, permitting once daily dosing. Bioavailability is poor, necessitating administration by intravenous route. In adults, a loading dose of 70 mg on the first day is given, followed by a once daily dose of 50 mg. No dose adjustment is needed for renal impairment; however, the maintenance dose should be reduced to 35 mg/day for patients with moderate hepatic impairment (Child-Pugh score 7�9) and there are no published data in patients with severe hepatic insufficiency. Data on dosing for children younger than 12 years of age are under evaluation. When caspofungin was given to volunteers concomitantly with cyclosporine, a rise in hepatic transaminases was seen, which raises a concern about a potential deleterious interaction; however, two recent series suggest that patients treated with the two drugs concomitantly have not suffered ill effects (Marr K, Hachem R, Papanicolaou G, et al. Retrospective study of concomitant use of caspofungin with cyclosporine A in patients treated during marketed use [abstract]. Blood. 2003;102:471a) ref. Caspofungin�s clinical activity was noted in case series of systemic Candida infections, in a randomized comparative trial (compared with fluconazole) of esophageal candidiasis in human immunodeficiency virus (HIV)�infected patients, and more recently in a randomized comparison with amphotericin B for systemic candidiasisref. In this latter study, caspofungin had comparable response and survival rates to amphotericin B. In secondary analyses, in evaluable patients, the response rate in those given caspofungin was significantly higher. Response rates were comparable across different Candida species. This trial was mostly in non-neutropenic patients, but in the small subset of neutropenic patients, response rates were lower but comparable. Caspofungin was well tolerated and considerably less toxic than amphotericin B. Anidulafungin has been evaluated for treatment of candidiasis in a case seriesref. A randomized trial comparing voriconazole, an extended spectrum azole, with amphotericin B has been completed and is being analyzed. Practical use of current anti-Candida agents : For patients with serious Candida infections, caspofungin or one of the amphotericin B formulations is most appropriate, providing proven efficacy against practically all Candida species. Safety considerations give an edge to caspofungin over amphotericin B, including the lipid formulations (Walsh TJ, Sable C, DePauw B, et al. A randomized, double-blind, multicenter trial of caspofungin vs liposomal amphotericin B for empirical antifungal therapy of persistently febrile neutropenic patients [Abstract M1761]. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago). Washington, DC: American Society for Microbiology, 2003). Once the infection is stabilized, then fluconazole can be substituted for continued therapy, provided the Candida species is a fluconazole susceptible species. For less serious Candida infections due to fluconazole-susceptible species, fluconazole is appropriate, especially in non-neutropenic patients.
• Aspergillus infections : amphotericin B administered in a dose of at least 1.0 mg/kg/day has been the treatment of choice for decades. Unfortunately, prolonged courses of amphotericin B in this dose schedule are poorly tolerated in many patients, especially those with antecedent renal impairment or those receiving concomitant nephrotoxins. Lipid formulations are much better tolerated even when given in higher doses and are more advantageous as salvage therapy, but no trial has convincingly shown them to produce significant improvements in response or survival rates as primary therapyref. Although one trialref suggested that 1 mg/kg/day of liposomal amphotericin B was as effective as 4 mg/kg/day, it was so underpowered as to make its conclusions moot, and most experts believe higher doses of the lipid formulations are optimal (4�6 mg/kg/day). Nephrotoxicity rates are substantially less with the lipid formulations, and that consideration alone makes them the only reasonable choice for a polyene therapy for most patients with aspergillosis. The extended spectrum azoles, including itraconazole, voriconazole, posaconazole, and ravuconazole, have excellent activity against Aspergillus in vitro and case series demonstrate clinical utility for all of them. Only one, voriconazole, has been tested in a randomized trial (compared with amphotericin B) for first line therapy for aspergillosisref. Patients included in the study were immunocompromised patients who were documented to have proven or probable acute invasive aspergillosis. Both response and survival rates were significantly better for voriconazole in comparison with amphotericin B. Voriconazole was better tolerated than amphotericin B with less nephrotoxicity and fewer switches to alternative therapies due to toxicity. Voriconazole�s half-life is 6 hours and is administered every 12 hours. It is available in both intravenous and oral formulations. The oral formulation is well absorbed with a 96% bioavailability, generally better absorbed and more palatable than itraconazole. The intravenous formulations of both voriconazole and itraconazole have cyclodextrin excipients. Although the azole is not excreted renally, the excipient is; thus, use of the intravenous formulation of both of these azoles should be avoided in patients with severe renal impairment to avoid potential accumulation of the cyclodextrin. This is not a concern with the oral formulation. The kinetics are nonlinear for individuals over the age of 12: doubling of the dose leads to a 4-fold increase in the blood area under the curve (AUC). In contrast, in children under the age of 12, the kinetics are linear: doubling of dose results in doubling of exposure. In children younger than 12, the clearance is higher, and higher doses are necessary. For example, exposure is comparable for a child given a dose of 4 mg/kg and an adult given a dose of 3 mg/kg. For Aspergillus infections in adults, 2 loading doses of 6 mg/kg are given intravenously on the first day and, subsequently, a dose of 4 mg/kg is given twice daily. When the patient stabilizes, the drug can be switched from intravenous to the oral formulation and dosed at 200 mg twice daily. In clinical studies, voriconazole has been associated with infrequent hepatotoxicity and nephrotoxicity. However, two unique toxicities are notable: visual disturbances occur in approximately 30%; these tend to be self-limited and not associated with severe or enduring sequelae and rarely require discontinuation of the drug. Dermatologic reactions occur in 6%, often in sun-exposed areas. These are mostly mild to moderate and generally do not necessitate alteration of the treatment course. Both itraconazole and voriconazole are metabolized by cytochrome P450 enzymes. The interaction with cytochrome P450 isoenzymes results in alteration of the metabolism of other drugs metabolized by this enzyme. Multiple important drug interactions can occur. Two interactions of particular relevance to hematologists include (1) an increase of cyclophosphamide toxic metabolites (thus, clinicians should avoid concomitant use of these azoles when high doses of cyclophosphamide are used) and (2) a predictable increase in blood concentrations of calcineurin inhibitors (thus, clinicians should reduce the dose of cyclosporine by about 50% and reduce the dose of tacrolimus by about 65% when these azoles are instituted and adjust the calcineurin inhibitor doses based on blood level monitoring). Caspofungin has been evaluated in patients intolerant of first-line therapy or where the infection progressed on first-line therapy. As "salvage" therapy, responses were seen in approximately 40% (Maertens J, Raad I, Sable CA, et al. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin B, AMB lipid formulations or azole. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: ASM Press. Abstract #1103. 2000). This is comparable to response rates seen with lipid formulations of amphotericin B and voriconazole used in the salvage setting. To date there are no published data as to caspofungin�s efficacy as first-line therapy for aspergillosis. Practical use of current anti-Aspergillus agents : voriconazole is currently the drug of choice for first line therapy. For allergic, intolerant, or non-responsive patients, one of the lipid formulations of amphotericin B is an excellent alternative. Caspofungin is yet another option for salvage therapy.

Combination therapy : few controlled trials of combination therapy have been performed, despite this approach being evaluated in numerous in vitro and animal model studies. Combination antifungal therapy (amphotericin B + flucytosine) is well established for cryptococcal meningitis. In a recent trial, the combination of fluconazole and amphotericin B was compared to fluconazole in high doses (800 mg/day) as therapy for candidemiaref: overall, the response rate was higher and time to bloodstream clearance was shorter in the group receiving the combination. This advantage was offset by greater nephrotoxicity in the combination arm. Despite considerable interest in this concept, there are no controlled trials for aspergillosis. Although several case series suggest benefitref1, ref2, the majority of Aspergillus cases in which combination therapy was evaluated were only "possible" infections. There are pitfalls with the use of combination therapy including potential antagonism, greater toxicity, and costref1, ref2. Thus, controlled trials are clearly needed.
Adjunctive measures : for catheter-related candidemia, removal of a central venous catheter, if possible, should be strongly consideredref. More rapid clearance of fungemia with catheter removal has been seen in several studies. For Aspergillus infections, consideration should be given for surgical excision of infarcted tissue, especially if the patient faces additional antineoplastic therapy. The role of cytokines such as myeloid growth factors and interferon gamma are supported by preclinical data, but there is a paucity of clinical trial data. Similarly, the use of granulocyte transfusions for neutropenic patients not responding to antimicrobial therapy is intuitively sensible, but this strategy is not without complications, is difficult to implement, and lacks convincing clinical data.
Duration of therapy : the duration of therapy has not been defined in clinical trials but generally lasts for several weeks to months.

• In general, treatment of Candida infections should continue for at least 2 weeks beyond the time when cultures become negative, signs and symptoms of infection have improved, and preferably host defenses have improvedref
• For Aspergillus infections, treatment should continue until resolution of symptoms and signs, clearance of cultures at previously culture-positive sites, improvement and stabilization of radiological findings, and improvement of underlying host defenses and control of the hematologic malignancy. In the largest trial to date, the planned course of therapy was 12 weeksref

Prophylaxis : fluconazole, itraconazole, and low doses of amphotericin B have been shown in randomized trials to be effective as prophylaxis. More recently, micafungin has also been shown to be effective as prophylaxis (Van Burik J-A, Ratanatharathorn V, Lipton J, et al. Randomized, double-blind trial of micafungin versus fluconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplant. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego). [Abstract M1238]. Washington, DC: American Society for Microbiology, 2002). In general, from meta-analyses of randomized trial data, the benefit appears to be meaningful when the risk of IFI is at least 15% in the patient group treatedref. Most of the antifungal benefit seen in clinical trials has been in the prevention of Candida infection. Trials of itraconazole during neutropenia have been mostly conducted in patient groups at low risk for aspergillosis, and thus no clear benefit against aspergillosis has been shown. A recent meta-analysisref showed that itraconazole given in oral solution at adequate doses (at least 400 mg/day) was associated with fewer Aspergillus infections. 2 randomized trials of prolonged prophylaxis comparing itraconazole to fluconazole after allogeneic HSCT provide an unclear message: although an anti-Aspergillus benefit for itraconazole was suggested (but not definitely shown), issues of excess toxicity were also raisedref1, ref2. High rates of recurrence of IFI occur if the once-infected patient is subjected to subsequent antineoplastic treatment cycles or undergoes hematopoietic stem cell transplantation, and thus "secondary" prophylaxis or chronic maintenance is necessary until the underlying disease is controlled and the full treatment course is completed. Several published case series indicate that hematopoietic stem cell transplantation can be successfully performed in patients given secondary prophylaxisref. After completion of therapy the patient should be observed to monitor for possible exacerbation.
Empirical therapy for neutropenic patients with persistent fever : early trials demonstrated that rates of IFIs were 15�30% in neutropenic patients with fever persisting 4�7 days despite antibiotics; fungal morbidity could be reduced by empirical amphotericin B. Subsequent trials with lipid formulations of amphotericin B, itraconazole, voriconazole and caspofungin have been performed. In each study, the test agent was compared with either amphotericin B or liposomal amphotericin B. Since all patients had an active agent, the rates of IFIs in both groups were anticipated to be small and thus a surrogate endpoint of "success" was used as the primary endpoint. Success was judged by defervescence, resolution of an IFI if found at baseline, absence of breakthrough IFI, survival to neutrophil recovery, and no toxicity that necessitated withdrawal of study drug. None of these agents were found to be superior to amphotericin B in the primary endpoint and, in one case, voriconazole failed to meet its protocol-specified non-inferiority bounds. However, a strong trend in favor of itraconazole was noted for the primary endpoint of success (P = 0.055), and differences in secondary endpoints, in terms of rates of breakthrough IFIs (in favor of voriconazole over liposomal amphotericin B) and response of baseline IFIs (in favor of caspofungin over liposomal amphotericin B), were noted in these various trialsref. Considerable differences in toxicity were demonstrated with the various agents. Indeed, tolerability should be considered in the choice of a specific agent for a given patient.
What the future holds : several studies indicate early treatment is key in determining the outcome of IFI treatment. Conventional diagnostic methods are either too slow or fraught with considerable imprecision, and use of invasive procedures is not practical for many patients with aspergillosis. Two rapid diagnostic tests using serum have been licensed. The serum galactomannan assay, testing for a constituent of Aspergillus cell wall released into blood early during the course of invasive Aspergillus infection, has been found to have sensitivity and specificity both exceeding 80% (US Food and Drug Administration [FDA] package insert). This assay used twice weekly detected two-thirds of Aspergillus infections in advance of conventional diagnostic testingref. This assay clearly has promise. However, concerns as to its performance in children, non-neutropenic patients, patients receiving anti-mould antifungal prophylaxis, and in patients with antibody have been raisedref. Recent reports indicate that false-positive test results can often occur in patients receiving piperacillin-tazobactamref. More recently, another serum assay, the glucan assay, detecting a cell wall constituent in a wide range of fungal pathogens (rather than limited to only Aspergillus), has received FDA approval. It was found to have high levels of sensitivity and specificityref. The development of PCR assays also appears promising, and one trial showed that sampling of serum twice weekly accurately identified patients with IFIref, often earlier than known using conventional diagnostic criteria. It is hoped that such assays can assist the clinician to better distinguish febrile patients with fungal infections from those who are febrile but not infected. Further experience is needed for all of these assays to determine if and how these assays can assist us in making diagnoses more accurately, earlier, and allow the targeting of antifungal therapy to replace empirical trials in patients suspected of infection. Ultimately, successful resolution of any IFI is dependent on restoration of the compromised host defenses that led to susceptibility for infection in the first place. Indeed, it can be argued that without immune recovery no IFI can be adequately or durably controlled. There has been substantial progress in our understanding of how host immune responses interact with fungal pathogensref. These insights are leading to new therapeutic strategies. Cytokines such as IL-12 show promise as adjunctive therapy in preclinical studies. Efforts to enhance Th1 immune responses (or decrease polarization to Th2 responses) also offer promise from preclinical studies. Infusions of common myeloid progenitors provide protection against lethal infection in animal modelsref. New fungal molecular structures are being identified that may prove to be novel targets for antifungal drugs or can elucidate crucial cellular receptors, such as the TLRs, that can be exploited. Vaccine strategies using dendritic cells pulsed with fungal antigens are also under developmentref1, ref2.

Which patients are susceptible to developing severe systemic fungal infections?

What are the common primary tissues that are affected by infection with the Trichophyton spp?

What antifungal would be appropriate for the nurse to administer to treat a patient with an oropharyngeal candidiasis?

Which antifungal drug is applied topically for the treatment of Candida diaper rash?