Ans. A. Liposomal amphotericin B. (Ref H- 17th/chapter 198)Mucormycosis: Rx# Three factors are key to a successful outcome of therapy for mucormycosis:- (1) Reversal of the underlying predisposition;- (2) Aggressive surgical debridement; and- (3) Aggressive antifungal therapy, with early initiation and high drug doses.# Traditionally, high-dose conventional Amphotericin B has been used for the Rx of mucormycosis, but doses have been limited to <1.5 mg/kg per day because of the nearly universal development of nephrotoxicity.# Use of lipid formulations at doses of 15-20 mg/kg per day (AmBisome) or 15 mg/kg per day (Abelcet) maximizes the amount of amphotericin B delivered to the tissues as well as the speed of its delivery. At these doses, nephrotoxicity occurs in <50% of patients.# The optimal duration of therapy for mucormycosis is not known precisely. If possible, antifungal administration should be continued for at least 3 months after- (1) all clinical abnormalities resolve or stabilize, leaving no clinical evidence of infection at the involved site(s); and (2) scans, x-rays, and laboratory studies yield normal or stable results. Careful follow-up should continue for at least 1 year to confirm that there is no evidence of recurrent infection.Additional Educational points:Harrison's Internal Medicine 17th / Chapter 191.......Voriconazole# Like fluconazole, voriconazole is available in both oral and IV formulations.# Voriconazole has a broader spectrum than fluconazole against- Candida species (including C. glabrata and C. krusei) and- is active against Aspergillus, Scedosporium, and Fusarium.# It is generally considered the first-line drug of choice for Rx of aspergillosis. Q# This agent is not recommended for Rx of the endemic mycoses.# Among the disadvantages of voriconazole (compared with fluconazole) are its more numerous interactions with many of the drugs used in patients predisposed to fungal infections.# Hepatotoxicity, skin rashes (including photosensitivity), and visual disturbances are common.# Moreover, it is advisable to monitor voriconazole levels in certain patients since:- (1) this drug is completely metabolized in the liver by CYP2C9, CYP3A4, and CYP2C19; and- (2) human genetic variability in CYP2C19 activity exists.# Dosages should be reduced accordingly in those patients with liver failure.# Dose adjustments for renal insufficiency are not necessary; however, because the IV formulation is prepared in cyclodextrin, it should not be given in severe renal insufficiency.Posaconazole# Posaconazole is approved by the FDA for prophylaxis of aspergillosis and candidiasis in patients at high risk for developing these infections because of severe immunocompromise.# This drug has also been evaluated for the Rx of zygomycosis, fusariosis, aspergillosis, and oropharyngeal candidiasis.# The relevant studies of posaconazole in zygomycosis, fusariosis, and aspergillosis have examined salvage therapy.# A study of >90 patients whose zygomycosis was refractory to other therapy yielded encouraging results.# No trials of posaconazole for the Rx of candidemia have yet been reported.# Case reports have described the drug's efficacy in coccidioidomycosis and histoplasmosis.# In addition, posaconazole has been found to be effective against fluconazole-resistant Candida species.# The results study of the use of posaconazole as salvage therapy for aspergillosis have been promising.Itraconazole# Itraconazole is available in IV and oral formulations.# Varying blood levels among patients taking oral itraconazole reflect a disadvantage compared with the other azoles.# Itraconazole is the drug of choice for -- mild to moderate histoplasmosis and blastomycosis and- has often been used for chronic mucocutaneous candidiasis.# It has been approved by the U.S. FDA for use in febrile neutropenic patients.# Itraconazole has also proven useful for the Rx of:- Chronic coccidioidomycosis,- Sporotrichosis, and- S. apiospermum infection.# The mucocutaneous and cutaneous fungal infections that have been treated successfully with itraconazole include oropharyngeal candidiasis (especially in AIDS patients), tinea versicolor, tinea capitis, and onychomycosis.# Disadvantages of itraconazole include:- its poor penetration into the CSF,- the use of cyclodextrin in both the oral suspension and the IV preparation,- Cases of severe CHF in patients taking itraconazole have been a source of concern.- Like the other azoles, itraconazole can cause hepatic toxicity.Echinocandins# The echinocandins, including the approved drugs caspofungin, anidulafungin, and micafungin, have added considerably to the antifungal armamentarium. All three of these agents inhibit -1,3-glucan synthase, which is necessary for cell wall synthesis in fungi and is not a component of human cells. None of these agents is available in an oral formulation. The echinocandins are considered fungicidal for Candida and fungistatic for Aspergillus.# Their greatest use to date is against candidal infections,# They offer two advantages:- broad-spectrum activity against all Candida species and- relatively low toxicity.# The minimum inhibitory concentrations (MICs) of all the echinocandins are highest against C. parapsilosis; it is not clear whether these higher MIC values represent less clinical effectiveness against this species. The echinocandins are among the safest antifungal agents.# In controlled trials, caspofungin has been at least as efficacious as AmB for the Rx of candidemia and invasive candidiasis and as efficacious as fluconazole for the Rx of candidal esophagitis. In addition, caspofungin has been efficacious as salvage therapy for aspergillosis. At present, it is used most extensively for the Rx of candidemic patients, especially before the infecting species is precisely identified.# Anidulafungin has been approved by the FDA as therapy for candidemia in nonneutropenic patients and for Candida esophagitis, intraabdominal infection, and peritonitis.When anidulafungin is used with cyclosporine, tacrolimus, or voriconazole, no dosage adjustment is required for either drug in the combination.# Micafungin has been approved for the Rx of esophageal candidiasis and for prophylaxis in patients receiving stem cell transplants. When micafungin is given with sirolimus, the AUC rises for sirolimus, usually necessitating a reduction in its dose. In open-label trials, favorable results have been obtained with micafungin for the Rx of deep-seated Aspergillus and Candida infections.- Posaconazole is the only azole active against mucormycosis.- Voriconazole has widest spectrum and is the drug of choice for invasive aspergillosis.Q- Caspofungin, posaconazole, and lipid-associated amphotericin B are second-line agents.- Amphotericin B is not active against A. terreus or A. niduians.Newer Topical Antifungals:# Ciclopirox olamine, haloprogin, terbinafine, and naftifine have the same clinical spectrum among the cutaneous mycoses as the imidazoles.# Tolnaftate and undecylenic acid are effective against ringworm but not candidiasis.# Keratolytic agents, such as salicylic acid, are helpful as accessory drugs for some hyperkeratotic skin lesions.