Azole resistance in Aspergillus species: promising therapeutic options.

INTRODUCTION: Azoles are the first-line antifungal agents used for the treatment of Aspergillus infection. There is an increasing concern for azole resistance all over the world mainly from agricultural fungicide use. Choosing safe and effective antifungal regimens has become a challenge. AREAS COVERED: Here, the authors review the epidemiology, mechanisms, and detection of azole resistance along with management options for azole-resistant Aspergillus infection, including new antifungal agents under development. EXPERT OPINION: Routine global epidemiological surveillance is required to understand azole resistance prevalence. Azole-resistant Aspergillus infections are associated with high mortality. No good therapeutic options are currently available. High index of suspicion of resistance is required if a patient is not responding to 4-7 days of azole therapy, particularly in the areas of resistance. Susceptibility testing for Aspergillus is not routinely available in many parts of the world, which makes it difficult to diagnose azole resistance in Aspergillus infection. There are several new antifungal classes with novel mechanisms of action; clinical trials are ongoing.

Successful treatment of primary cutaneous Aspergillus ustus infection with surgical debridement and a combination of voriconazole and terbinafine.

Aspergillus ustus infections are associated with a high mortality in immunocompromised hosts, and the mold has decreased susceptibility to most antifungal drugs, especially azoles. We report primary cutaneous A. ustus infection in a patient who failed itraconazole therapy and was switched to voriconazole (VRC). During VRC therapy, the MICs of VRC, amphotericin B (AMB), caspofungin (CFG), and terbinafine (TBF) were 4, 2, 64, and 0.13 microg/mL, respectively. Because the MIC to VRC was high, TBF was added to VRC for synergy based on anecdotal data from other mycoses. After treatment with VRC and TBF for 5 months, MICs of VRC, AMB, CFG, and TBF of A. ustus were 8, 1, 64, and 4 microg/mL respectively. Although the MICs of VRC and TBF increased during antifungal therapy, the patient responded well to the combination antifungal therapy with surgical debridement. With a successful outcome despite high MICs and with limited therapeutic options currently available, we investigated the in vitro activity of posaconazole (PCZ) and VRC individually and in combination with AMB, CFG, or TBF using the fractional inhibitory concentration index (FICI) method. Combination of VRC with TBF showed synergistic activity (FICI = 0.5). Therefore, combination of VRC and TBF with surgical debridement, when appropriate, may be a viable treatment option for refractory A. ustus infections.

Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation.

In this multicenter, randomized study, cytomegalovirus (CMV)-seropositive patients who received an allogeneic bone marrow transplant were provided high-dose intravenous acyclovir (500 mg/m(2) q8h) from the day of transplantation until engraftment. The patients were then randomly assigned to receive either oral valacyclovir, 2 g q.i.d. (n=83), or intravenous ganciclovir, 5 mg/kg q12h for 1 week, then 6 mg/kg once daily for 5 days per week (n=85), until day 100 after transplantation. CMV infection occurred in 12% of the patients who received valacyclovir and in 19% of the patients who received ganciclovir (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.391-2.778; P=.934). CMV disease developed in only 2 patients who received valacyclovir and in 1 patient who received ganciclovir (HR, 1.943; 95% CI, 0.176-21.44; P=.588). Oral valacyclovir can be an effective alternative to intravenous ganciclovir for prophylaxis of CMV disease after bone marrow transplantation.

Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis.

Emergence of resistance to antifungal drugs during therapy for invasive aspergillosis has received scant attention. We recovered Aspergillus isolates from six patients with invasive aspergillosis, who were receiving amphotericin B before fungal isolation. Although isolates were susceptible to amphotericin B in vitro, none of the patients survived. The MIC of amphotericin B for isolates was similar to that for isolates from 35 patients with no prior exposure to amphotericin B. Laboratory attempts to produce amphotericin B resistance in Aspergillus were unsuccessful. These data indicate that emergence of resistance to amphotericin B is uncommon during therapy for invasive aspergillosis.