# Fungal Infections: Their Diagnosis and Treatment in  Transplant Recipients

Authors: David H. Van Thiel; Magdalena George; Christopher M. Moore
Journal: International Journal of Hepatology
 (2012)

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## Abstract

Systemic fungal infections typically occur in individuals who are seriously ill with recognized risk factors such as those frequently found in transplant recipients. Unfortunately, they are often diagnosed late, when the efficacy of the available treatments is low, often less than 50%, and the cost in terms of lives lost, hospital length of stay, and total hospital costs is substantially increased. The application of antifungal therapies associated with reported efficacy rates greater than 50% are those used prophylactically. When used prophylactically, these infections are reduced in greater than 95% of the expected cases. The choice of a prophylactic agent should be based upon its ease of administration, lack of adverse effects, reduced likelihood of potential drug interactions, and its efficacy in patients with established risk factors and comorbid disease processes that include renal, hepatic, and chronic pulmonary disease. The indications for the use of currently available antifungal agents, their adverse effects, drug interactions, ease of dosing, and applicability in patients with preexisting disease states, and especially in liver transplant recipients, are presented in this paper.


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## Body

## 1. Epidemiology

The frequency and variety of invasive fungal infections have increased greatly over the last three decades as a consequence of changes in medical and surgical care, particularly in intensive care units which utilize invasive catheters for monitoring, coupled with the use of more potent immunosuppression and antibiotic agents [1]. The current increase in invasive fungal infections is the result of changes in disease management with the use of powerful immunosuppressive agents, multiple antibiotics, the use of organ support procedures that include mechanical ventilation, hemodialysis and venovenous hemofiltration, and parental hyperalimentation. These medical and procedural advances coupled with the application of more aggressive antineoplastic therapies and transplantation of individuals with preexisting cardiopulmonary, renal, and hepatic disease processes have changed the frequency and approach to fungal infections. Specifically, as a direct result of these advances and therapeutic successes, the population at risk for fungal infections has expanded greatly [2, 3]. In the early 1980s, systemic candidiasis was recognized as an important medical problem. The mortality associated with candidiasis increased steadily until 1988, when it peaked at a rate of 0.6 per 100,000 per population [4]. As a result of recent advances in the treatment of invasive candidiasis, mortality stemming from Candidemia has decreased annually since its peak. Nonetheless, systemic candidiasis remains the fourth most common nosocomial bloodstream infection [3]. Although the number of bloodstream infections due to C. albicans has decreased, those due to other Candida species, particularly C. glabrata, C. krusei, and C. parapsilosis, have increased [1].In contrast to candidiasis, infections and death as a result of other fungal pathogens, particularlyAspergillus species, have continued to increase since the late 1980s [4–9]. The mortality of invasive aspergillosis infections remains very high, particularly in transplant recipients despite the use of new diagnostic methods and advances in therapy [10].The risk for systemic fungal infection is greatest in those with hematologic diseases requiring allogeneic hematopoietic stem cell transplantation followed by autologous grafts, other hematologic disorders associated with severe and prolonged leukopenia, those with solid organ neoplasms, and solid organ transplanted individuals [11–20]. The presence of confounding chronic pulmonary disease and heart/lung transplantation increases the risk for infections due to yeasts and molds, particularly Aspergillus.The specific fungal and yeast pathogens experienced in hematopoietic stem cell transplantation and solid organ transplantation differ dramatically. Specifically, invasiveAspergillus and other molds account for 70% of the fungal/mold infections in hematopoietic stem cell recipients, while only a minority of solid organ transplant recipients acquire these infections unless they have confounding chronic pulmonary disease or the recipient is exposed to a hospital construction site or dust containing molds [10–13, 17, 18]. Nonmold infections in hematopoietic stem cell recipients account for 30% of the total fungal/mold infections in this population. In contrast, almost all of the infections in solid organ transplant recipients are due to fungal agents with only a minority occurring as a result of Aspergillus and other molds. In this later group, invasive candidiasis accounts for 50% of the total infections followed in order by Cryptococcus (7%), endemic mycosis (6%), and finally all other fungal or mold infections combined account for 37% of the total. These differences in the pattern of invasive fungal infections between hematopoietic stem cell transplant and solid organ transplant are, at least in part, due to the routine use of azole agents for prophylaxis in the former group, but not those in the latter.


## 2. Differences due to the Type of Organ  Transplant

As expected, the overall incidence of systemic fungal infections is greatest in those receiving bone marrow transplants as compared to solid organ transplants. The incidence varies within each group as a function of the type of marrow transplanted and solid organ transplanted. In marrow recipients, the incidence is greatest in those receiving mismatched related and unrelated allogeneic stem cells (5.9%). Those receiving matched related allogeneic stem cells have a lower incidence of 3.7% and those receiving autologous stem cells have the lowest incidence (0.6%). These rates of infection reflect the major differences in chemoablative therapies used to condition the marrow, the duration of posttransplant cytopenia experienced, and the immunosuppression differences utilized between these various groups [17].Differences in the incidence and type of systemic fungal infections occurring as a consequence of the particular organ transplanted are seen in solid organ transplant recipients as well. Those receiving lung grafts have the highest incidence (7.9%) followed by heart (3.4%), then liver (3.1%), renal (1.1%), and pancreas (0.7%). Those receiving lung and heart transplants have a greater incidence ofAspergillus infections while those receiving nonthoracic solid organs experience candidiasis as their major fungal pathogen [1–4, 17–19]. The risk for candidiasis in solid organ recipients is greatest early after transplantation (first 2-3 months after transplant) and then declines as other fungal pathogens including aspergillosis, histoplasmosis, coccidioidomycosis, and blastomycosis become more prominent, with variation depending on the geographic location of the recipient [2]. The early infections due to candidiasis are a result of the use of indwelling catheters, central lines, abdominal wounds, drains, and secondary operations as well as the use of parenteral nutrition and mechanical ventilation [5]. Late infections that occur months to years after transplantation are a consequence of the life-long immunosuppressive agents that these patients take to prevent rejection and the unique local environmental exposures the recipient experiences.


## 3. Cost of Fungal Infections

The direct costs of fungal infections are substantial [19]. The global cost of candidiasis is 2.5 times that for Aspergillus infections. However, when the global costis corrected for the number of individuals infected, the individual cost is 2-3-times greater for those with an Aspergillus infection as compared to that experienced by one with candidiasis [19].


## 4. Diagnosis of Fungal Infections

Early diagnosis and treatment are critically important in terms of obtaining a better outcome defined as a reduced morbidity and mortality. The diagnosis of invasive fungal infections is difficult because of the lack of specific signs and symptoms until late in the disease process and the difficulty associated with documenting a diagnosis with current diagnostic tools, obtaining infected tissue required to establish a specific diagnosis, and in some cases defining the isolated agent’s sensitivity to the therapeutic regimen being utilized [20].


## 5. Therapeutic Definitions

The high mortality of invasive surgical infections is due in large measure to the delay in recognizing an infection in individuals at risk for severe infections and the difficulty in establishing an early diagnosis as a result of the nonspecific clinical features, low sensitivity of microscopic diagnostic methods, the difficulty in obtaining infected tissue for histologic and microbiologic diagnostic procedures, and appropriately interpreting imaging procedures [20].As a direct consequence of these factors prophylactic, empiric, and preventative therapies have been developed and utilized. The specific antifungal agent chosen for each of these therapeutic approaches varies between centers and specific types of transplantation. Factors that affect the choice of antifungal agent include characteristics of the patient, the clinical circumstances, and the presence or absence of overt sepsis and/or hemodynamic instability.Empiric therapy is defined as the initiation of antifungal treatment in an individual at high risk for an invasive fungal infection and manifesting symptoms and/or signs of an infection but without microbiological documentation of the infection. Empiric therapy utilizes a broad-spectrum antifungal agent for 3 or more days until deescalation is possible based upon the specific infection identified, its location, and the patient’s clinical status.Prophylactic therapy is defined as the use of an antifungal agent with intent to prevent the likelihood of an invasive fungal infection in an individual at high risk for such an infection. Preemptive therapy is defined as the initiation of antifungal therapy based upon the results of an early diagnostic test.


## 6. Diagnostic Tools

Currently available diagnostic tools for establishing a diagnosis of an invasive fungal infection include the following: galactomannan, (1,3)-β-glucan, and C. albicans germ tube antibody detection. Each of these procedures has its own set of problems that limit their widespread application.The galactomannan assay is an enzymatic immunoassay which has been FDA approved and is used in the United States and Europe. The assay can detect galactomannan in blood 5–8 days on mean (range 1–27 days) before the onset of clinical signs and symptoms of an invasive fungal infection. It is a nonspecific test and only suggests the presence of a fungal infection as it measures a component of fungal hyphae. When positive, the level determined varies as a function of the infectious agent burdens and can be used to monitor the response to therapy [21–24]. Unfortunately, false-positive results occur in 5.7%–14.0% of adults and as high as 83% in neonates. The cause of these positive results is not entirely clear but the use of piperacillin-tazobactam in adults and cross-reactivity with antigens expressed in Bifidobacterium species in neonates have been suggested as possible causes [25, 26].Overall, the galactomannan assay has moderate accuracy for the diagnosis of an invasive fungal infection in an immunocompromised individual and is more efficacious in those with hematologic malignancies or hematologic stem cell transplant procedures than in those undergoing solid organ transplant procedures [21–24]. Nonetheless, the presence of a positive galactomannan assay result utilizing bronchoaveolar lavage fluid in a solid organ transplant recipient with clinical signs of either a bronchial infection or pneumonia is highly diagnostic in this population [26, 27].The (1,3)-β-d-glucan assay has been approved by the FDA also and when positive in blood suggests the presence of a fungal infection. It, like the galactomannan assay, is a broad-spectrum fungal marker that requires subsequent microbiological and imaging studies to define the specific infection. Its usefulness reflects the fact that glucans are a critical compound of the cell wall of most pathologic fungi except for Cryptococcus and zygomycetes [28–33].A major problem with the (1,3)-β-d-glucan assay is its requirement for endotoxin and glucan-free glassware, and the presence of false positive result as a result of the presence of albumin, immunoglobulins, glucan-containing materials, gram-positive bacteria, and hemodialysis. As a result, its major usefulness is to exclude the possibility of a fungal infection [29–33].Antibodies toC. albicans germ tube antigens have been useful at detecting invasive candidiasis due to a broad spectrum of Candida species [34, 35]. It has been most useful in the detection of Candida infections in drug users, hematologic cancer, and transplant recipients, as well as medical patients in an ICU setting [34, 35]. Its use in solid organ transplant recipients has not been evaluated.The uses of polymerase chain reactions (PCR) to detect fungal DNAs are available in research laboratories but are not standardized or FDA approved. More bothersome is the fact that because of their sensitivity, they may be positive in samples obtained from patients with colonization rather than infection. Consequently, the diagnosis of an infection rather than colonization may in fact require the use of a less sensitive test for confirmation.Microbiological cultures of biologic fluids and tissue for the detection of an invasive fungal infection require multiple days and occasionally weeks for the identification of a specific fungal pathogen. This said, they are highly specific and can be used for antifungal resistance testing if necessary.


## 7. Available Antifungal Agents (Tables1 and 2)

Table 1
Antifungal  agents currently available, mechanism of action, principle indications, and dosing schedule.
Class
Agents
Indication
Dosing schedule
Polyenes
Polyenes bind to sterols, preferentially to the primary fungal cell membrane sterol, and ergosterol.This binding disrupts osmotic integrity of the fungal membrane
(1) Amphotericin B
Invasive fungal infections include: aspergillosis, cryptococcosis, North American blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, zygomycosis,Conidiobolus, Basidiobolus, sporotrichosis
0.3–1.5 mg/kg
(2) AmBisome
Empirical therapy in febrile  neutropenic pts.
3 mg/kg/day
Cryptococcal meningitis in HIV pts.
6 mg/kg/day
Visceral leishmaniasis
3-4 mg/kg/day
(3) Amphotericin BColloidal dispersion (ABCD)
No primary indication; only salvage therapy
3–6 mg/kg
(4) Abelcet (ABLC)
No primary indication only salvage
5 mg/kg
Azoles
Azoles inhibit cytochrome P450 14a demethylase (P45014DM) required for ergosterol synthesis
(1) Voriconazole
Invasive aspergillosis and candidemia in nonneutropenic patients
6 mg/kg IV twice a day on day 1, then 4 mg/kg twice at day or 200 mg PO twice a day
Esophageal candidiasis
200 mg PO twice a day given 1 hour before or after a meal
(2) Fluconazole
Prophylaxis in transplant pts, invasive candida infections
800 mg/day IV on day 1, then 400 mg/day
Oropharyngeal and esophageal candidiasis
200 mg/day IV or PO on day 1, then 100 mg/day
Cryptococcal meningitis
200 up to 400 mg/day IV or PO
(3) Itraconazole
Empirical therapy in febrile neutropenic patients, blastomycosis, pulmonary and extrapulmonary, histoplasmosis, chronic pulmonary and disseminated, and nonmeningeal histoplasmosis
200 mg IV twice a day or 100–400 mg po
(4) Posaconazole
Prophylaxis of invasiveAspergillus and Candida in immunocompromised patients
200 mg (5 mL) three times a day with a full meal or nutritional supplement
Oropharyngeal candidiasis
100 mg (2.5 mL) twice a day on day 1, then 100 mg (2.5 mL) once a day with a full meal or nutritional supplement
Echinocandins
The glucan synthesis inhibitors block fungal cell wall synthesis by inhibiting the enzyme 1,3-beta glucan synthase
(1) Anidulafungin
Candidemia, acute disseminated candidiasis
200 mg/day on day 1 then 100 mg/day
Esophageal candidiasis
100 mg on day 1, then 50 mg/day
(2) Caspofungin
Candidemia, acute disseminated candidiasis, empirical therapy in febrile neutropenic patients, and invasive aspergillus refractory to other therapies
70 mg/day on day 1, then 50 mg/day
Esophageal candidiasis
50 mg/day
(3) Micafungin
Candidemia, acute disseminated candidiasis
100 mg/day
Esophageal candidiasis
150 mg/day
Prophylaxis of Candida infection in pt undergoing HSCT
50 mg/dayTable 2
Pathogenic fungi and the antifungal agentsin vitro activity**.
Microorganism
Antifungal agents
Fluconazole
Voriconazole
Posaconazole
Echinocandin
Polyenes
Candida albicans
1st line
1st line
1st line
1st line
1st line
Candida glabrata
Unknown
3rd line
3rd line
1st line
2nd line
Candida tropicalis
1st line
1st line
1st line
1st line
1st line
Candida parapsilosis
1st line
1st line
1st line
2nd line
1st line
Candida krusei
No activity
2nd line
2nd line
1st line
2nd line
Candida guilliermondii
1st line
1st line
1st line
2nd line
2nd line
Candida lusitaniae
3rd line
2nd line
2nd line
2nd line
2nd line
Cryptococcus neoformans
1st line
1st line
1st line
No activity
1st line
Aspergillus fumigatus
No activity
1st line
1st line
2nd line
2nd line
Aserpgillus flavus
No activity
1st line
1st line
2nd line
2nd line
Aspergillus terreus
No activity
1st line
1st line
2nd line
No activity
Fusarium sp.
No activity
2nd line
2nd line
No activity
2nd line
Scedosporium apiospermum
No activity
1st line
1st line
Unknown
Unknown
Scedosporium prolificans
No activity
Unknown
Unknown
No activity
Unknown
Trichosporon spp.
Unknown
2nd line
2nd line
No activity
3rd line
Zygomycetes (e.g., Absidia, Mucor, and Rhizopus)
No activity
No activity
1st line
No activity
1st line
Dematiaceous molds
(e.g., Alternaria,  Bipolaris,  Curvularia,  and Exophiala)
Unknown
1st line
1st line
3rd line
3rd line
Dimorphic Fungi
Blastomyces  dermatitidis
3rd line
2nd line
2nd line
No activity
1st line
Coccidioides  immitis
1st line
2nd line
2nd line
No activity
1st line
Histoplasma  capsulatum
3rd line
2nd line
2nd line
No activity
1st line
Sporothrix  schenckii
3rd line
2nd line
2nd line
No activity
1st line
**Echinocandins, voriconazole, posaconazole, and polyenes have poor urine penetration.In general, antifungal agents target components of the fungal cell wall that result in defective cell wall homeostasis and induce an osmotic stress that leads to lysis and fungal death. The polyenes (amphotericin) bind to ergosterol, the principle sterol component of the fungal cell membrane resulting in a loss of cell wall integrity. The azoles (fluconazole, itraconazole, voriconazole, and posaconazole) inhibit enzymes involved in ergosterol synthesis. The echinocandins inhibit glucan synthesis. Glucan is a long chain polymer responsible for fungal cell wall stability. It accounts for 30–60% of the cell wall mass inCandida, Aspergillus, and Saccharomyces species. Importantly, human cells do not contain glucan, thus accounting for the low rate of human toxicity associated with this class of agents.


### 7.1. Polyenes

Amphotericin has been the principal agent for the treatment of invasive fungal infections for more than half a century. Its efficacy is based upon its ability to bind to ergosterol, the principal sterol in the fungal cell wall, inducing a loss of cell wall osmotic regulation and lysis of the infecting fungus (fungicidal). The limiting factor for its use is nephrotoxicity, particularly a progressive renal dysfunction associated with hypokalemia, renal tubular acidosis, and hypocalcemia. Lipid-based amphotericin preparations have attenuated the nephrotoxicity compared to the original agent but continue to have a similar pattern of adverse effects. Unfortunately, these lipid-based amphotericin preparations do not appear to have greater efficacy and are considerably more expensive than the original material.The use of predosing hydration regimens with normal saline and a continuous infusion of amphotericin has reduced the fever, chills, and flushing associated with its use, but can be problematic in transplant patients with preexisting renal and/or hepatic dysfunction, who often are volume overloaded complicated further by a low serum albumin level [36]. These same individuals can occasionally experience an acute pulmonary reaction similar to pulmonary edema while receiving amphotericin.Amphotericin is an accepted antifungal agent forC. albicans but has reduced activity against C. glabrata, C. krusei, C. lusitaniae, and molds. Moreover, polyenes have not been shown to be of any value in prophylaxis. The toxicity of the polyenes, especially their nephrotoxicity and their expense (lipid solubilized polyenes), make them less likely to be used than other currently available agents.


### 7.2. Azoles

This class of agents is less toxic than the polyenes and can be administered both orally and intravenously. They act by inhibiting ergosterol synthesis and through other unidentified mechanisms. Their perturbation of a large number of P450 enzyme systems limits their use in individuals, who require other agents which are metabolized by P450 enzymes which may mandate an alternative dosing regimen of these other agents (see Tables3(a) and 3(b)). The superior toxicity profile of fluconazole, its availability in an intravenous and oral formulation, and its low cost make it the agent of choice for hemodynamically stable patients with Candidemia.Table 3
Antifungal drug interactions with other drugs. Principle adverse effects of available antifungal agents.
(a)
Drug A
Drug B
Interacting drug
Echinocandins
Azoles
Polyenes
Anidulafungin
Caspofungin
Micafungin
Fluconazole
Voriconazole
Posaconazole
Amphotericin B and lipid formulations
Amitriptyline
Inc A
Aminoglycosides
Inc nephrotoxicity
Antineoplastic drugs
Inc nephrotoxicity
Astemizole
Calcium channel blockers
Inc A
Inc A
Carbamazepine
Dec B
Contraindicated Dec B
Cidofovir
Inc nephrotoxicity
Cimetidine
Dec B
Cisapride
Contraindicated
Contraindicated
Contraindicated
Cyclosporine
SlightInc B
WarningInc B
Inc A,  Inc nephrotoxicity
Inc A,  Inc nephrotoxicity
Inc A,  Inc nephrotoxicity
Inc nephrotoxicity
Dexamethasone
Dec B
Didanosine
Digitalis
Inc A
Drug interaction
Efavirenz
Dec B
Dec B, Inc A
Ergot Alkaloids
Contraindicated
Contraindicated
Flucytosine
Drug interaction
Foscarnet
Inc nephrotoxicity
Glycosides
Drug interaction
H2 blockers, antacids, and scralfate
Dec B
Halofantrine
Contraindicated
Hydantoins, (phenytoin, Dilantin)
Dec B
Inc A, Dec B
Inc A, Dec B
Inc A, Dec B
Isoniazid
Fluconazole
Drug Interaction
Itraconazole
Drug Interaction
Ketoconazole
Drug Interaction
Long acting barbitunates
Contraindicated
Lovastatin/simvastatin
Inc A
Methadone
Inc A
Midazolam/triazolam, po
Inc A
Inc A
Inc A
Nevirapine
Dec B
Nifedipine
Inc A
Oral anticoagulants
Inc A
Inc A
Oral hypoglycemics (tolbutamide, glipizide, and glyburide)
Inc A
Inc A
Pentamidine
Inc nephrotoxicity
Pimozide
Contraindicated    Inc A
ContraindicatedInc A
Protease inhibitors
Inc A
Proton pump inhibitors
Dec B,  Inc A
Quinidine
Contraindicated
Contraindicated
Ritonavir (400 mg q 12 h)
Contraindicated
Rifampin/rifabutin
Dec B
Inc A, Dec B
Contraindicated Inc A, Dec B
Inc A, Dec B
Sirolimus
Inc A
Contraindicated, Inc B
St.John's Wort
Contraindicated, Dec B
Tacrolimus
Dec A
Inc A, with toxicity
Inc A, with toxicity
Inc A, with toxicity
Terfenadine
Contraindication
Contraindicated
Theophyllines
Inc A
Thiazide diuretics
Drug interaction
Trazodone
Warfarin
Inc A
Zidovudine
Inc A
Drug interaction
(b)
Agent
Major side effects
Drug interactions
Cytochrome P450 interactions
Polyenes
The following are applicable to all polyenes
(1) Amphotericin B
Nephrotoxicity, infusion-related reaction, pain at the site of injection, phlebitis, thrombophlebitis, cardiopulmonary (cardiac arrest, hypotension, tachypnea, and arrthmia) anemia, thrombocytopenia, leukopenia, coagulation defect, anorexia, nausea, diarrhea, generalized pain, muscle, joint pain, headache, anaphylactic reaction, bronchospasm, wheezing, rash, acute liver failure, hepatitis, jaundice, convulsion, and hearing loss
Antineoplastic agents, corticosteroids and corticotropin, digitalis glycosides, flucytosine, azoles, other nephrotoxic medications, skeletal muscle relaxants, and leucocyte transfusion
No interaction in the p450 pathway
(2) AmBisome
Infusion related reaction, renal toxicity, chest pain, hypotension, tachycardia, diarrhea, nausea, vomiting, abdominal pain, bilirubinemia, liver enzymes elevation, hypokalemia, hypomagnesemia, anxiety, headache, lung disorder, pleural effusion, and rash
Same as above
No interaction in the p450 pathway
(3) Amphotericin Bcolloidal dispersion (ABCD)
Infusion-related reaction, renal toxicity, hypotension, tachycardia, abdominal pain, hypokalemia, diarrhea, nausea vomiting, rash, dyspnea, asthma, confusion, and dizziness
Antineoplastic agents, corticosteroids and corticotropin, digitalis glycosides, and azoles
No interaction in the p450 pathway
(4) Abelcet (ABLC)
Infusion-related reactions, increased serum creatinine, cardiopulmonary (hypotension, tachypnea, arrythmia, pleural effusion, anaphylactic reaction (bronchospasm, wheezing, and asthma), rash, acute liver failure, hepatitis, jaundice, nausea vomiting, abdominal pain, headache, renal toxicity dose dependent, muscle, joint pain, convulsion, and tinnitus
Same as above
No interaction in the p450 pathway
Azoles
(1) Voriconazole
Visual disturbances, hepatic toxicity, arrhythmia, QT prolongation, and infusion-related reaction
Rifampin and rifabutin, ritonavir, St.John's Wort, carbamazepine and long acting barbiturates, cimetidine, macrolide antibiotics (erythromycin), sirolimus, ergot alkaloids, cyclosporine, methadone,  tacrolimus, warfarin, oral coumarin, anticoagulants, statins, benzodiazepines, calcium channel blockers, sulfonylureas, vinca alkaloids, prednisolone, mycophenolic acid, rifabutin, efavirenz, phenytoin, omeprazole, oral contraceptives, other HIV protease inhibitors, other nonnucleoside reverse transcriptase inhibitors, and indinavir
CYP2C19, CYP2C9, and CYP3A4
(2) Fluconazole
Hepatotoxicity, anaphylactic reaction, QT prolongation, seizures, dizziness, skin disorders, leukopenia, thrombocytopenia, hypercholesterolemia, hypokalemia, vomiting, abdominal pain, nausea, and diarrhea
Oral hypoglycemics, coumarin-type anticoagulants, theophylline, rifampin, warfarin, phenytoin, cyclosporine, rifabutin, terfenadine, cisapride, tacrolimus, short acting benzodiazepines, astemizole, hydrochlorothiazide, glimepiride, losartan, methadone, losartan, and cyclophosphamide
Metabolized by cytochrome P450 systems, CYP2C19, CYP2C9, and CYP3A4
(3) Itraconazole
Hepatotoxicity, cardiac dysrhythmias, nausea, diarrhea, vomiting, hypokalemia, bilirubinemia, and rash
Digoxin, dofetilide, quinidine, disopyramide, carbamazepine, nevirapine, rifabutin, busulfan, docetaxel, vinca alkaloids, pimozide, alprazolam, diazepam, midazolam, triazolam, dihydropyridines, verapamil, cisapride, atorvastatin, cerivastatin, lovastatin, simvastatin, cyclosporin, tacrolimus, sirolimus, oral hypoglycemics, indinavir, ritonavir, saquinavir, levacetylmethadol, ergot alkaloids, halofantrine, alfentanil, buspirone, corticosteroids, budesonide, trimetrexate, cilostazol, eletriptan, warfarin, carbamazepine, phenobarbital, phenytoin, isoniazid, rifabutin, rifampine, and erythromycin,
Potent CYP3A4 isoenzyme inhibitor, CYP2C9
(4) Posaconazole
Hepatotoxicity, diarrhea, nausea, vomiting, abdominal pain, hypokalemia, thrombocytopenia, fever, rigors, headache, fatigue, hypotension, hypertension, anemia, neutropenia, and rash
Rifabutin, phenytoin, cimetidine, cyclosporin, tacrolimus, midazolam, terfenadine, astemizole, pimozide, cisapride, and quinidine
Inhibitor of CYP3A4
Echinocandins
(1) Anidulafungin
Histamine-mediated symptoms, dyspnea, and hypotension
Cyclosporin (no dose adjustment needed)
Not an inducer, inhibitor, or substrate of the P450 system
(2) Caspofungin
Histamine-mediated symptoms, anaphylactic reaction, hyperbilirubinemia, and rash
Tacrolimus, cyclosporin, rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, and carbamazeine
Is a poor substrate for cytochrome P450 enzymes
(3) Micafungin
Histamine-mediated symptoms (rash, pruritus, facial swelling, and vasodilation), diarrhea, nausea, vomiting, pyrexia, hypokalemia, thrombocytopenia, headache, hepatocellular damage, delirium, skin disorders (skin necrosis, urticaria), convulsions, and arthralgia
Sirolimus (AUC increased by 21%, no effect on micafungin), nifedipine (AUC increased by 18%, no effect on micafungin), and itraconazole (AUC increased by 22%, no effect on micafungin)
Micafungin is not an inducer or inhibitor of P-glycoprotein, but is an inducer of CYP3A4Table 4
Current contraindications and FDA warnings for each antifungal agent available.
Drug
Contraindications
Warnings
Amphotericin B deoxycholate
Hypersensitivity to amphotericin B
Anaphylaxis
Lipid formulations of AMB
Hypersensitivity to amphotericin B
Anaphylaxis
Fluconazole
Hypersensitivity to fluconazole
Hepatic injury, anaphylaxis, and dermatologic
Itraconazole
Terfenadine, astemizole, dofetilide, pimozide, quinidine, oral midazolam, triazolam, cisapride, and statins should also be discontinued during therapy
Black box for terfenadine and congestive Heart failure see contraindications
Posaconazole
Hypersensitivity to the active substance or excipients, ergot alkaloids, coadministration with 3A4 substrates (terfenadine, astemizole, cisapride, pimozide, halofantrine, and quinidine)
Hypersensitivity, hepatic toxicity, recommended monitoring of hepatic function (LFTs), cyclosporine, tacrolimus, and sirolimus
Voriconazole
Hypersensitivity to voriconazole, CYP3A4 inhibitors (terfenadine, astemizole, cisapride, pimozide, and quinidine), sirolimus, rifampin, carbamezapine, long acting barbiturates, ritonavir, efavirenz, rifabutin, and ergot alkaloids (ergotamine and dihydroergotamine)
Visual disturbances, hepatic toxicity, recommended monitoring of LFTs and bilirubin, pregnancy category D, and galactose intolerance
Anidulafungin
Hypersensitivity to anidulafungin or other echinocandins
None
Caspofungin
Hypersensitivity to caspofungin or other echinocandins
Elevated liver enzymes with cyclosporine
Micafungin
Hypersensitivity to micafungin or other echinocandins
Hypersensitivity, hematological effects (hemolysis, hemolytic anemia, and hemoglobinuria), hepatic effects (abnormal LFTs, hepatic dysfunction, hepatitis, and hepatic failure), and renal effects (elevations of BUN and creatinine, renal dysfunction, and acute renal failure)The activity of voriconazole againstCandida is superior to that achieved with fluconazole based upon MIC data, its activity against fluconazole-resistant species, and its wider spectrum make it the preferred agent for hemodynamically unstable patients or those where the infection is due to a nonalbicans Candida, Aspergillus, or any other mold [37]. It, however, has a clinically important effect on the metabolism of calcineurin inhibiting agent (immunosuppressive agents), resulting in a marked increase in their whole blood levels, which can reach toxic levels unless the dose of these immunosuppressive agents is reduced markedly. Moreover, two unique toxicities have been associated with the use of voriconazole. These are the development of a visual disturbance and cutaneous photosensitivity. The visual disturbance occurs in as many as 45% of individuals receiving the agent. Typically, it is transient and resolves with continued treatment. The cutaneous photosensitivity reaction is unusual and importantly is not prevented with sun-screen lotions. It is fully reversible with drug discontinuation. The use of voriconazole and posaconazole is contraindicated when sirolimus is being utilized as part of the immune suppressive regimen (see Table 3(a)). Itraconazole can cause a unique complex of adverse effects consisting of hypotension, hypokalemia, and edema. A negative inotropic effect causing congestive heart failure has been identified as well and limits its usefulness in individuals with preexisting heart disease [38]. Itraconazole has two other limiting issues particularly in hematopoietic stem-cell transplant patients: its potential for hepatotoxicity and its reduced absorption when used in combination with either H2 blockers or proton-pump inhibiting agents.


### 7.3. Fluorocytosine

Fluorocytosine is a pyrimidine analog that inhibits both DNA and protein synthesis. Its principal use is in combination with other agents for the treatment of cryptococcal infections [39–41].The development of rapid drug resistance and its toxicity pattern (see Table 3(b)) limits its usefulness in other fungal infections [41].


### 7.4. Echinocandins

The echinocandins are semisynthetic lipopeptides that were isolated originally from various fungal agents and subsequently modified. Specifically, they are cyclic hexapeptides with an N-linked acyl-side chain that appears to be essential for their antifungal activity. They have different molecular weights that vary around 1200 daltons. This class of agents inhibits glucan synthesis, a major component of the fungal cell wall required for stability, especially inCandida and Aspergillus species. The echinocandins have been shown to enhance phagocytic activity of macrophages, an action that may also contribute to their efficacy in eliminating fungal infections. Moreover, they also have activity against preformed Candida biofilms and thus prevent Candida species from adhering to endothelial cells.The pharmacokinetic characteristics of the echinocandins are shown in Table5. There are very minor differences between the various agents except for the precise mechanism of their metabolism. Importantly, no dose adjustments have to be made for patients with renal disease. Currently, anidulafungin is the only available echinocandin that does not require a dose adjustment in cases with moderate liver disease defined as those having Child-Pugh scores between 7 and 9.Table 5
Pharmacokinetic parameters of the major echinocandins in clinical use*.
Agent
C
max
t
1
/
2
V
d
AUC
C
t
FeU
FeS
Caspofungin
7.64
10
0.4
88–115
0.15
1.40%
35%
Micafungin
4.95
14
0.23
111
0.19
0.70%
40%
Anidulafungin
2.07–3.5
25
0.5
44–53
0.26
<1%
30%, <10% unchanged
*Dose 50 mg single dose,Cmax: maximum concentration, t1/2: elimination half-life, Vd: volume of distribution, AUC: area under the plasma concentration and time curve, Ct: total clearance, FeU: fraction excreted in urine, FeS: fraction excreted in stool.Because the echinocandins do not perpetuate cytochrome P450 enzyme systems and they do not interact with P-glycoprotein, as some azoles do, they do not affect the levels of the calcineurin-inhibiting immunosuppressive agents and the many other drugs used to manage other infections, hypertension, and cardiac arrhythmias frequently seen in transplant recipients (Tables3(a) and 3(b)). Of particular interest to the transplant population, echinocandins have limited theoretical activity against Pneumocystis carinii (P. jiroveci) infections [42, 43].They are efficacious also against the histoplasmosis species, blastomyces species, and coccidioides species—fungal agents that cause late onset infections in transplant populations.Resistance to echinocandins has been reported [44, 45]. Unfortunately, available assessments of MIC values for the echinocandins do not clearly distinguish between sensitive and resistant fungi [37, 45–48]. As a result, these assays have to be interpreted with caution and in context.The specific mechanisms responsible for resistance to the echinocandins are not clear but appear to be related to mutations in a subunit of glucan synthetase [44, 49]. Other minor mechanisms have been identified as well.Elevations of serum transaminase and alkaline phosphatase levels are among the most common laboratory changes associated with caspofungin [50, 51]. Micafungin has recently had its use in patients with liver disease restricted (as noted in its new package insert) because of reports of acute hepatitis and hepatic failure occurring with its application [51]. The use of drugs such as rifampin, phenytoin, carbamezapine, efavirenz, and nevirapine causes a reduction in caspofungin levels and necessitate a 50% increase its dosage. Caspofungin reduces the AUC for tacrolimus by 20%, while cyclosporine has been reported to cause a 35% increase in the AUC for caspofungin. Micafungin increases the AUC for sirolimus by 21% and for nifedipine by 18%. These interactions have not been reported to occur with anidulafungin (Tables 3(a) and 3(b)).It should be noted that the average wholesale cost of a 20-day course of caspofungin in the United States is approximately $7-8,000 as compared to $3-4,000 for anidulafungin and $2–5,000 for intravenous fluconazole (depending upon the dose). The average wholesale cost for micafungin for the same period would be $4-5,000.


## 7.1. Polyenes

Amphotericin has been the principal agent for the treatment of invasive fungal infections for more than half a century. Its efficacy is based upon its ability to bind to ergosterol, the principal sterol in the fungal cell wall, inducing a loss of cell wall osmotic regulation and lysis of the infecting fungus (fungicidal). The limiting factor for its use is nephrotoxicity, particularly a progressive renal dysfunction associated with hypokalemia, renal tubular acidosis, and hypocalcemia. Lipid-based amphotericin preparations have attenuated the nephrotoxicity compared to the original agent but continue to have a similar pattern of adverse effects. Unfortunately, these lipid-based amphotericin preparations do not appear to have greater efficacy and are considerably more expensive than the original material.The use of predosing hydration regimens with normal saline and a continuous infusion of amphotericin has reduced the fever, chills, and flushing associated with its use, but can be problematic in transplant patients with preexisting renal and/or hepatic dysfunction, who often are volume overloaded complicated further by a low serum albumin level [36]. These same individuals can occasionally experience an acute pulmonary reaction similar to pulmonary edema while receiving amphotericin.Amphotericin is an accepted antifungal agent forC. albicans but has reduced activity against C. glabrata, C. krusei, C. lusitaniae, and molds. Moreover, polyenes have not been shown to be of any value in prophylaxis. The toxicity of the polyenes, especially their nephrotoxicity and their expense (lipid solubilized polyenes), make them less likely to be used than other currently available agents.


## 7.2. Azoles

This class of agents is less toxic than the polyenes and can be administered both orally and intravenously. They act by inhibiting ergosterol synthesis and through other unidentified mechanisms. Their perturbation of a large number of P450 enzyme systems limits their use in individuals, who require other agents which are metabolized by P450 enzymes which may mandate an alternative dosing regimen of these other agents (see Tables3(a) and 3(b)). The superior toxicity profile of fluconazole, its availability in an intravenous and oral formulation, and its low cost make it the agent of choice for hemodynamically stable patients with Candidemia.Table 3
Antifungal drug interactions with other drugs. Principle adverse effects of available antifungal agents.
(a)
Drug A
Drug B
Interacting drug
Echinocandins
Azoles
Polyenes
Anidulafungin
Caspofungin
Micafungin
Fluconazole
Voriconazole
Posaconazole
Amphotericin B and lipid formulations
Amitriptyline
Inc A
Aminoglycosides
Inc nephrotoxicity
Antineoplastic drugs
Inc nephrotoxicity
Astemizole
Calcium channel blockers
Inc A
Inc A
Carbamazepine
Dec B
Contraindicated Dec B
Cidofovir
Inc nephrotoxicity
Cimetidine
Dec B
Cisapride
Contraindicated
Contraindicated
Contraindicated
Cyclosporine
SlightInc B
WarningInc B
Inc A,  Inc nephrotoxicity
Inc A,  Inc nephrotoxicity
Inc A,  Inc nephrotoxicity
Inc nephrotoxicity
Dexamethasone
Dec B
Didanosine
Digitalis
Inc A
Drug interaction
Efavirenz
Dec B
Dec B, Inc A
Ergot Alkaloids
Contraindicated
Contraindicated
Flucytosine
Drug interaction
Foscarnet
Inc nephrotoxicity
Glycosides
Drug interaction
H2 blockers, antacids, and scralfate
Dec B
Halofantrine
Contraindicated
Hydantoins, (phenytoin, Dilantin)
Dec B
Inc A, Dec B
Inc A, Dec B
Inc A, Dec B
Isoniazid
Fluconazole
Drug Interaction
Itraconazole
Drug Interaction
Ketoconazole
Drug Interaction
Long acting barbitunates
Contraindicated
Lovastatin/simvastatin
Inc A
Methadone
Inc A
Midazolam/triazolam, po
Inc A
Inc A
Inc A
Nevirapine
Dec B
Nifedipine
Inc A
Oral anticoagulants
Inc A
Inc A
Oral hypoglycemics (tolbutamide, glipizide, and glyburide)
Inc A
Inc A
Pentamidine
Inc nephrotoxicity
Pimozide
Contraindicated    Inc A
ContraindicatedInc A
Protease inhibitors
Inc A
Proton pump inhibitors
Dec B,  Inc A
Quinidine
Contraindicated
Contraindicated
Ritonavir (400 mg q 12 h)
Contraindicated
Rifampin/rifabutin
Dec B
Inc A, Dec B
Contraindicated Inc A, Dec B
Inc A, Dec B
Sirolimus
Inc A
Contraindicated, Inc B
St.John's Wort
Contraindicated, Dec B
Tacrolimus
Dec A
Inc A, with toxicity
Inc A, with toxicity
Inc A, with toxicity
Terfenadine
Contraindication
Contraindicated
Theophyllines
Inc A
Thiazide diuretics
Drug interaction
Trazodone
Warfarin
Inc A
Zidovudine
Inc A
Drug interaction
(b)
Agent
Major side effects
Drug interactions
Cytochrome P450 interactions
Polyenes
The following are applicable to all polyenes
(1) Amphotericin B
Nephrotoxicity, infusion-related reaction, pain at the site of injection, phlebitis, thrombophlebitis, cardiopulmonary (cardiac arrest, hypotension, tachypnea, and arrthmia) anemia, thrombocytopenia, leukopenia, coagulation defect, anorexia, nausea, diarrhea, generalized pain, muscle, joint pain, headache, anaphylactic reaction, bronchospasm, wheezing, rash, acute liver failure, hepatitis, jaundice, convulsion, and hearing loss
Antineoplastic agents, corticosteroids and corticotropin, digitalis glycosides, flucytosine, azoles, other nephrotoxic medications, skeletal muscle relaxants, and leucocyte transfusion
No interaction in the p450 pathway
(2) AmBisome
Infusion related reaction, renal toxicity, chest pain, hypotension, tachycardia, diarrhea, nausea, vomiting, abdominal pain, bilirubinemia, liver enzymes elevation, hypokalemia, hypomagnesemia, anxiety, headache, lung disorder, pleural effusion, and rash
Same as above
No interaction in the p450 pathway
(3) Amphotericin Bcolloidal dispersion (ABCD)
Infusion-related reaction, renal toxicity, hypotension, tachycardia, abdominal pain, hypokalemia, diarrhea, nausea vomiting, rash, dyspnea, asthma, confusion, and dizziness
Antineoplastic agents, corticosteroids and corticotropin, digitalis glycosides, and azoles
No interaction in the p450 pathway
(4) Abelcet (ABLC)
Infusion-related reactions, increased serum creatinine, cardiopulmonary (hypotension, tachypnea, arrythmia, pleural effusion, anaphylactic reaction (bronchospasm, wheezing, and asthma), rash, acute liver failure, hepatitis, jaundice, nausea vomiting, abdominal pain, headache, renal toxicity dose dependent, muscle, joint pain, convulsion, and tinnitus
Same as above
No interaction in the p450 pathway
Azoles
(1) Voriconazole
Visual disturbances, hepatic toxicity, arrhythmia, QT prolongation, and infusion-related reaction
Rifampin and rifabutin, ritonavir, St.John's Wort, carbamazepine and long acting barbiturates, cimetidine, macrolide antibiotics (erythromycin), sirolimus, ergot alkaloids, cyclosporine, methadone,  tacrolimus, warfarin, oral coumarin, anticoagulants, statins, benzodiazepines, calcium channel blockers, sulfonylureas, vinca alkaloids, prednisolone, mycophenolic acid, rifabutin, efavirenz, phenytoin, omeprazole, oral contraceptives, other HIV protease inhibitors, other nonnucleoside reverse transcriptase inhibitors, and indinavir
CYP2C19, CYP2C9, and CYP3A4
(2) Fluconazole
Hepatotoxicity, anaphylactic reaction, QT prolongation, seizures, dizziness, skin disorders, leukopenia, thrombocytopenia, hypercholesterolemia, hypokalemia, vomiting, abdominal pain, nausea, and diarrhea
Oral hypoglycemics, coumarin-type anticoagulants, theophylline, rifampin, warfarin, phenytoin, cyclosporine, rifabutin, terfenadine, cisapride, tacrolimus, short acting benzodiazepines, astemizole, hydrochlorothiazide, glimepiride, losartan, methadone, losartan, and cyclophosphamide
Metabolized by cytochrome P450 systems, CYP2C19, CYP2C9, and CYP3A4
(3) Itraconazole
Hepatotoxicity, cardiac dysrhythmias, nausea, diarrhea, vomiting, hypokalemia, bilirubinemia, and rash
Digoxin, dofetilide, quinidine, disopyramide, carbamazepine, nevirapine, rifabutin, busulfan, docetaxel, vinca alkaloids, pimozide, alprazolam, diazepam, midazolam, triazolam, dihydropyridines, verapamil, cisapride, atorvastatin, cerivastatin, lovastatin, simvastatin, cyclosporin, tacrolimus, sirolimus, oral hypoglycemics, indinavir, ritonavir, saquinavir, levacetylmethadol, ergot alkaloids, halofantrine, alfentanil, buspirone, corticosteroids, budesonide, trimetrexate, cilostazol, eletriptan, warfarin, carbamazepine, phenobarbital, phenytoin, isoniazid, rifabutin, rifampine, and erythromycin,
Potent CYP3A4 isoenzyme inhibitor, CYP2C9
(4) Posaconazole
Hepatotoxicity, diarrhea, nausea, vomiting, abdominal pain, hypokalemia, thrombocytopenia, fever, rigors, headache, fatigue, hypotension, hypertension, anemia, neutropenia, and rash
Rifabutin, phenytoin, cimetidine, cyclosporin, tacrolimus, midazolam, terfenadine, astemizole, pimozide, cisapride, and quinidine
Inhibitor of CYP3A4
Echinocandins
(1) Anidulafungin
Histamine-mediated symptoms, dyspnea, and hypotension
Cyclosporin (no dose adjustment needed)
Not an inducer, inhibitor, or substrate of the P450 system
(2) Caspofungin
Histamine-mediated symptoms, anaphylactic reaction, hyperbilirubinemia, and rash
Tacrolimus, cyclosporin, rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, and carbamazeine
Is a poor substrate for cytochrome P450 enzymes
(3) Micafungin
Histamine-mediated symptoms (rash, pruritus, facial swelling, and vasodilation), diarrhea, nausea, vomiting, pyrexia, hypokalemia, thrombocytopenia, headache, hepatocellular damage, delirium, skin disorders (skin necrosis, urticaria), convulsions, and arthralgia
Sirolimus (AUC increased by 21%, no effect on micafungin), nifedipine (AUC increased by 18%, no effect on micafungin), and itraconazole (AUC increased by 22%, no effect on micafungin)
Micafungin is not an inducer or inhibitor of P-glycoprotein, but is an inducer of CYP3A4Table 4
Current contraindications and FDA warnings for each antifungal agent available.
Drug
Contraindications
Warnings
Amphotericin B deoxycholate
Hypersensitivity to amphotericin B
Anaphylaxis
Lipid formulations of AMB
Hypersensitivity to amphotericin B
Anaphylaxis
Fluconazole
Hypersensitivity to fluconazole
Hepatic injury, anaphylaxis, and dermatologic
Itraconazole
Terfenadine, astemizole, dofetilide, pimozide, quinidine, oral midazolam, triazolam, cisapride, and statins should also be discontinued during therapy
Black box for terfenadine and congestive Heart failure see contraindications
Posaconazole
Hypersensitivity to the active substance or excipients, ergot alkaloids, coadministration with 3A4 substrates (terfenadine, astemizole, cisapride, pimozide, halofantrine, and quinidine)
Hypersensitivity, hepatic toxicity, recommended monitoring of hepatic function (LFTs), cyclosporine, tacrolimus, and sirolimus
Voriconazole
Hypersensitivity to voriconazole, CYP3A4 inhibitors (terfenadine, astemizole, cisapride, pimozide, and quinidine), sirolimus, rifampin, carbamezapine, long acting barbiturates, ritonavir, efavirenz, rifabutin, and ergot alkaloids (ergotamine and dihydroergotamine)
Visual disturbances, hepatic toxicity, recommended monitoring of LFTs and bilirubin, pregnancy category D, and galactose intolerance
Anidulafungin
Hypersensitivity to anidulafungin or other echinocandins
None
Caspofungin
Hypersensitivity to caspofungin or other echinocandins
Elevated liver enzymes with cyclosporine
Micafungin
Hypersensitivity to micafungin or other echinocandins
Hypersensitivity, hematological effects (hemolysis, hemolytic anemia, and hemoglobinuria), hepatic effects (abnormal LFTs, hepatic dysfunction, hepatitis, and hepatic failure), and renal effects (elevations of BUN and creatinine, renal dysfunction, and acute renal failure)The activity of voriconazole againstCandida is superior to that achieved with fluconazole based upon MIC data, its activity against fluconazole-resistant species, and its wider spectrum make it the preferred agent for hemodynamically unstable patients or those where the infection is due to a nonalbicans Candida, Aspergillus, or any other mold [37]. It, however, has a clinically important effect on the metabolism of calcineurin inhibiting agent (immunosuppressive agents), resulting in a marked increase in their whole blood levels, which can reach toxic levels unless the dose of these immunosuppressive agents is reduced markedly. Moreover, two unique toxicities have been associated with the use of voriconazole. These are the development of a visual disturbance and cutaneous photosensitivity. The visual disturbance occurs in as many as 45% of individuals receiving the agent. Typically, it is transient and resolves with continued treatment. The cutaneous photosensitivity reaction is unusual and importantly is not prevented with sun-screen lotions. It is fully reversible with drug discontinuation. The use of voriconazole and posaconazole is contraindicated when sirolimus is being utilized as part of the immune suppressive regimen (see Table 3(a)). Itraconazole can cause a unique complex of adverse effects consisting of hypotension, hypokalemia, and edema. A negative inotropic effect causing congestive heart failure has been identified as well and limits its usefulness in individuals with preexisting heart disease [38]. Itraconazole has two other limiting issues particularly in hematopoietic stem-cell transplant patients: its potential for hepatotoxicity and its reduced absorption when used in combination with either H2 blockers or proton-pump inhibiting agents.


## 7.3. Fluorocytosine

Fluorocytosine is a pyrimidine analog that inhibits both DNA and protein synthesis. Its principal use is in combination with other agents for the treatment of cryptococcal infections [39–41].The development of rapid drug resistance and its toxicity pattern (see Table 3(b)) limits its usefulness in other fungal infections [41].


## 7.4. Echinocandins

The echinocandins are semisynthetic lipopeptides that were isolated originally from various fungal agents and subsequently modified. Specifically, they are cyclic hexapeptides with an N-linked acyl-side chain that appears to be essential for their antifungal activity. They have different molecular weights that vary around 1200 daltons. This class of agents inhibits glucan synthesis, a major component of the fungal cell wall required for stability, especially inCandida and Aspergillus species. The echinocandins have been shown to enhance phagocytic activity of macrophages, an action that may also contribute to their efficacy in eliminating fungal infections. Moreover, they also have activity against preformed Candida biofilms and thus prevent Candida species from adhering to endothelial cells.The pharmacokinetic characteristics of the echinocandins are shown in Table5. There are very minor differences between the various agents except for the precise mechanism of their metabolism. Importantly, no dose adjustments have to be made for patients with renal disease. Currently, anidulafungin is the only available echinocandin that does not require a dose adjustment in cases with moderate liver disease defined as those having Child-Pugh scores between 7 and 9.Table 5
Pharmacokinetic parameters of the major echinocandins in clinical use*.
Agent
C
max
t
1
/
2
V
d
AUC
C
t
FeU
FeS
Caspofungin
7.64
10
0.4
88–115
0.15
1.40%
35%
Micafungin
4.95
14
0.23
111
0.19
0.70%
40%
Anidulafungin
2.07–3.5
25
0.5
44–53
0.26
<1%
30%, <10% unchanged
*Dose 50 mg single dose,Cmax: maximum concentration, t1/2: elimination half-life, Vd: volume of distribution, AUC: area under the plasma concentration and time curve, Ct: total clearance, FeU: fraction excreted in urine, FeS: fraction excreted in stool.Because the echinocandins do not perpetuate cytochrome P450 enzyme systems and they do not interact with P-glycoprotein, as some azoles do, they do not affect the levels of the calcineurin-inhibiting immunosuppressive agents and the many other drugs used to manage other infections, hypertension, and cardiac arrhythmias frequently seen in transplant recipients (Tables3(a) and 3(b)). Of particular interest to the transplant population, echinocandins have limited theoretical activity against Pneumocystis carinii (P. jiroveci) infections [42, 43].They are efficacious also against the histoplasmosis species, blastomyces species, and coccidioides species—fungal agents that cause late onset infections in transplant populations.Resistance to echinocandins has been reported [44, 45]. Unfortunately, available assessments of MIC values for the echinocandins do not clearly distinguish between sensitive and resistant fungi [37, 45–48]. As a result, these assays have to be interpreted with caution and in context.The specific mechanisms responsible for resistance to the echinocandins are not clear but appear to be related to mutations in a subunit of glucan synthetase [44, 49]. Other minor mechanisms have been identified as well.Elevations of serum transaminase and alkaline phosphatase levels are among the most common laboratory changes associated with caspofungin [50, 51]. Micafungin has recently had its use in patients with liver disease restricted (as noted in its new package insert) because of reports of acute hepatitis and hepatic failure occurring with its application [51]. The use of drugs such as rifampin, phenytoin, carbamezapine, efavirenz, and nevirapine causes a reduction in caspofungin levels and necessitate a 50% increase its dosage. Caspofungin reduces the AUC for tacrolimus by 20%, while cyclosporine has been reported to cause a 35% increase in the AUC for caspofungin. Micafungin increases the AUC for sirolimus by 21% and for nifedipine by 18%. These interactions have not been reported to occur with anidulafungin (Tables 3(a) and 3(b)).It should be noted that the average wholesale cost of a 20-day course of caspofungin in the United States is approximately $7-8,000 as compared to $3-4,000 for anidulafungin and $2–5,000 for intravenous fluconazole (depending upon the dose). The average wholesale cost for micafungin for the same period would be $4-5,000.


## 8. Clinical Use of the Available Antifungal  Agents

The agents available for treatment of invasive fungal infections are presented in Tables1 and 2.The mechanisms of action of each class of drugs, the specific disease indication for each drug, and the doses that are recommended for each indication are indicated in Table1.Table2 presents data relative to the choice of antifungal therapy for each fungal agent that is currently approved by the FDA. The drug choices are indicated as first line (recommended), second line (less frequently utilized but effective), and third line (potentially having efficacy) and those having unknown efficacy.Table3 presents reported efficacy data and overall mortality data achieved when treating systemic fungal infections.Voriconazole is currently the first line therapy forAspergillus infections [52, 53]. Voriconazole is also the only agent indicated for infections due to Fusarium species and Scedosporium apiospermum. Only voriconazole, fluconazole, and itraconazole are available in oral as well as the intravenous formulations. The echinocandins have replaced azole agents for the treatment of invasive candidiasis [52–54].The principal adverse effects and drug interactions of each antifungal agent are reported in Tables3(a) and 3(b).Table6 lists the contraindications and FDA warnings for the available antifungal agents.Table 6
(a)
Experience in patients with prexisting renal disease
Agent
Effects on the kidney
Dosing modifications for preexisting renal disease
(1) Amphotericin B
Nephrotoxic-elevation of BUN, creatinine
Sodium loading to ameliorate toxicity
(2) AmBisome
Nephrotoxic
Used in pt with pre-existing renal impairment
(3) ABCD
Nephrotoxic
(4) ABLC
Dose-limited renal toxicity
(5) Voriconazole
SBECD component of iv formulation
No adjustment for oral vori in pts with mild-to-severe renal impairment
associated with renal toxicity
I.V. should be avoided if creatinine clearance   <30 mL/min
(6) Fluconazole
50–400 mg creatinine clearance >50–100% creatinine clearance <50 (no dialysis)-adm.50% of dose
regular dialysis-admin 100% of dose after each dialysis
(7) Itraconazole
SBECD component of iv formulation
I.V. should not be used if creatinine clearance <30 mL/min
associated with renal toxicity
(8) Posaconazole
No dose adjustment for mild-to-moderatesevere-monitor for breakthrough IFI
(9) Anidulafungin
None
No dose adjustment, not dialyzable
(10) Caspofungin
None
No dose adjustment, not dialyzable
(11) Micafungin
None
No dose adjustment
(b)
Experience in individuals with pre-existing hepatic disease
Antifungal
Normal Patients
Mild
Moderate
Severe
Effects on the liver
(Child-Pugh 5-6)
(Child-Pugh 7–9)
(Child-Pugh >9)
Anidulafungin
200 mg loading dose on day 1 followed by 100 mg once/day
200 mg loading dose on day 1 followed by 100 mg once/day
200 mg loading dose on day 1 followed by 100 mg once/day
200 mg loading dose on day 1 followed by 100mg once/day
None
Micafungin
100 mg once/day
100 mg once/day
100 mg once/day
Not studied
None
Caspofungin
70 mg loading dose on day 1 followed by 50 mg once/day
70 mg loading dose on day 1 followed by 50 mg once/day
70 mg loading dose on day 1 followed by 35 mg once/day
Not studied
None
Fluconazole
Loading dose of 2x the daily dose, then up to 400 mg daily
No dosage adjustments initially, monitor LFTs in patients for worsening hepatic function
Hepatotoxic
Itraconazole
200 mg q12 IV 100–200 mg q12 po-solution
No studies have been conducted looking at patients with hepatic impairment, use with caution
Hepatotoxic, prolonged elimination half-life in cirrhotic patients (meds metabolized by CYP3A4)
Voriconazole
6 mg/kg IV q12h for the first 24 hours loading dose followed by 3-4 mg/kg IV q12h maintenance dose then 200 mg q12h oral
6 mg/kg IV q12h for the first 24 hours loading dose followed by 1.5–2 mg/kg IV q12h maintenance dose
6 mg/kg IV q12h for the first 24 hours loading dose followed by 1.5–2 mg/kg IV q12h maintenance dose
Not studied
Hepatotoxic
Posaconazole
Oral Suspension 200 mg (5 mL) three times a day with a full meal or liquid nutritional supplement, monitoring of LFT's is recommended
Data was not sufficient to determine dosing, should be used with caution
Mild-to-moderate elevation of liver enzymes, bilirubin-generally reversible
Amphotericin B deoxycholate
0.6 to 1 mg/kg/day
Data was not sufficient to determine dosing
Elevation of liver enzymes
Ampho B lipid complex (Abelcet)
5 mg/kg/day
Data was not sufficient to determine dosing
Elevation of liver enzymes
Ampho B colloidal  dispersion (Amphotec)
3-4 mg/kg/day can be increased up to 6 mg/kg/day
Data was not sufficient to determine dosing
Elevation of liver enzymes
Ampho B liposomal (AmBisome)
3-4 mg/kg/day can be increased up to 6 mg/kg/day
Data was not sufficient to determine dosing
Elevation of liver enzymesThe effect of preexisting renal and/or hepatic dysfunction on the dosing of these available antifungal agents is shown in Tables 6(a) and 6(b). The dose of the azole agents needs to be reduced as the creatinine clearance declines. The effect of preexisting renal disease is inconsequential for the echinocandins. As noted, little data exists for the use of antifungal agents in individuals with hepatic disease. The only agent for which no dose adjustment is required for advanced hepatic disease is anidulafungin [55].There are four emerging antifungal agents [47]. These include isavuconazole and ravuconazole both of which have a broad spectrum of activity, a large volume of distribution, and very long half-lives. Albaconazole has a broad spectrum of activity against Candida species, Aspergillus species, and Cryptococcus species as well as a long half-life. Aminocandin has a very long half-life enabling the drug to be given intravenously less often than daily.Combination antifungal therapy is occasionally used in severe and clinically drug-resistant infections in an effort to maximize efficacy and potentially minimize toxicity [56, 57]. In selecting agents to be used in combination, only those that have different mechanisms of actions should be combined. Thus, the use of an agent acting at the cytoplasmic membrane (a polyene or an azole) plus an agent acting on DNA or protein synthesis (fluorocytosine) or a cell wall active agent (echinocandins) is recommended if combination therapy is to be utilized. It should be noted, however, that there are no definitive data supporting the use of combination therapy in the treatment of fungal infections per se but such can be reasonably implied from the use of combination treatments as an accepted treatment for bacterial and viral infections. This being said, considering the low efficacy rates reported for single agent treatment of invasive fungal infections in general, combination therapy has the potential to increase the efficacy of treatment in difficult-to-treat situations. A single study consists of a triazole and an echinocandin in solid organ transplant recipients. It shows a reduction in mortality in individuals with renal failure and invasive Aspergillus [56].


## 9. Clinical and Economic Relevance of Fungal  Infections, Particularly Candidiasis

In the past, systemic fungal infections have been considered to be a problem only for neutropenic patients. However, beyond the risk factor of neutropenia, more recent data suggests that half of all hospital-acquired fungal infections have occurred in critically-ill surgical patients.Candida species account for greater than 80% of all fungal nosocomial isolates [62–64] unlike Aspergillus species and the less common Fusarium and Rhizopus species which comprise only 10% of the remaining nosocomial isolates. Invasive candidiasis is the most frequently occurring invasive fungal infection and occurs most commonly in immunocompromised solid organ transplant recipients, those receiving chemotherapy, and those having multiple, complex abdominal surgical procedures.As stated earlier,Candida species have become the fourth most common nosocomial bloodstream isolate, exceeded only by coagulase negative Staphylococcus, Staphylococcus aureus, and Enterococci. This fact is particularly important when it is recognized that less than half of these cases with invasive Candidemia documented at autopsy have had a positive premortem blood culture for Candida [59].InvasiveCandida infections have a mortality rate averaging between 25 and 38%. The specific Candida species accounting for Candidemia in high-risk populations have shifted over the last decade from C. albicans to more nonalbicans species, with approximately half the reported cases being due to the nonalbicans species [5]. More importantly these nonalbicans species (C. glabrata, C. krusei, and C. parapsilosis) have a greater mortality rate, account for the greater length of stay in ICUs, and are associated with greater rates of renal failure, thrombocytopenia, malignancy, and mechanical ventilation. The risk factors recognized for Candidemia in general include complicated abdominal operations, second operations, parenteral nutrition, the use of broad-spectrum antibiotics, the use of multiple vascular catheters, prior recognized Candida colonization, mechanical ventilation, and renal replacement therapy [58, 59].In a prospective clinical trial examining the risk factors forCandida bloodstream infections in more than 4,000 surgical patients, those identified included previous surgery (RR=7.3), acute renal failure (RR=4.2), parenteral nutrition (RR=3.6), and the presence of a triple lumen catheter (RR=5.4) [58]. Other risk factors identified in other studies included ICU hospitalization >4 days, diabetes mellitus, HIV infections, central lines, neutropenia, chemotherapy, cancer (especially hematologic cancers), use of broad-spectrum antibiotics, the use of 3 or more antibiotics, and mechanical ventilation >2 days.The initial response to a suspected Candidemia is to institute antifungal therapy with either voriconazole or an echinocandin and the removal of all vascular lines. It is important to recognize that blood cultures are positive in cases of invasive Candidemia in less than 50% of the time. InvasiveFusarium infections, similar to Candida infections, are detectable with blood culture in less than half of the cases. Worse invasive Aspergillus infections are rarely identifiable with blood cultures.First line therapy for Candidemia remains controversial as studies have reported similar efficacy rates with amphotericin, fluconazole, echinocandins, and voriconazole [65–69]. With the increasing frequency of nonalbicans species especially in critically-ill patients the use of a broad-spectrum agent such as voriconazole, an echinocandin, or amphotericin may be more appropriate at least until the specific Candida species is identified to avoid the increased mortality occurring in cases wherein an inappropriate therapeutic agent is initially started. The limitation of intravenous voriconazole is its formulation with cyclodextrin which accumulates in individuals with impaired renal function. The many adverse effects of amphotericin identified earlier limit its use. Among the echinocandins, only anidulafungin has shown superiority over fluconazole [55]. Moreover, its efficiency, safety, and lack of cytochrome P450 metabolism suggest that it should be considered as a first line option for invasive candidiasis infection. Regardless of the choice of a specific echinocandin over fluconazole, echinocandins are recommended for use in individuals who are either critically ill or hemodynamically unstable.Candidemia is associated with an increased cost of hospitalization estimated at $68,311 (95% CI $57,513–$79,108) and longer length of stay estimated at 23.1 days of hospitalization (95% CI 19.3–26.8 days) as compared to that of a DRG identified control population without Candidemia [70–72].The incidence of invasive fungal infections in solid organ transplant recipients ranges from 5–42% [73]. Depending upon the organ being transplanted, being lowest for pancreas recipients and greatest for liver graft recipients.Candida species, and to a lesser degree Aspergillus, account for the vast majority of invasive fungal agents in solid organ transplant recipients [14]. Cryptococcus and endemic mycoses occur late, typically a year or more after transplantation.Currently, most liver transplant centers use antifungal prophylaxis in the early postoperative period in individual recipients having either a complicated or repetitive posttransplant surgical procedures [74–76]. The principal problem associated with the use of azole therapy in transplant recipients is the interaction with calcineurin inhibitor agents that consequently requires a dose adjustment in one or the other agents.


## 10. Experience with Antifungal Agents in  Individuals with Liver Disease

Although considerable data exists relative to the use and precautions to be utilized with antifungal agents in individuals with advanced renal disease, little data exist for those with advanced liver disease (Tables6(a) and 6(b)).At Barnes Jewish Hospital, anidulafungin has recently been utilized instead of the hospital preferred agent caspofungin in two specific disease categories with clinical efficacy [55]. The subjects in this report consisted of those with hepatic dysfunction (71% of the group) and those with potential drug interactions with caspofungin (21% of the group). These two groups were not mutually exclusive however with 4 patients with both criteria. Together, the two groups accounted for 83% of those receiving anidulafungin in the report.The authors noted in their discussion that neither caspofungin nor micafungin have been studied in patients with severe liver disease and that anidulafungin is the only agent with suitable pharmacokinetic properties making it an acceptable agent in the liver disease population. In fact, 5 of the 35 patients (14.5%) in their study had a total bilirubin level greater than 10 mg/dL with two having a total bilirubin greater than 40 mg/dL. One of their patients had a transaminase level greater than 10 times the upper level of normal at the time when anidulafungin therapy was initiated.Fungal infections following liver transplantation although infrequently increase the mortality rate and increase the overall cost of the perioperative transplant care [70–73]. The incidence of drug-resistant C. albicans, nonalbicans Candida species, Aspergillus, and other invasive molds in transplant recipients is increasing and is associated with a reduced survival rate [77, 78]. Risk factors for fungal infections following liver transplantation are well recognized and include preoperative renal failure, fulminant hepatic failure, prolonged preoperative hospitalization particularly in an intensive care unit, an excessive intraoperative transfusion requirement, early retransplantation or complications requiring a return to the operative theater, and the number of reoperations [73, 75, 77].Despite this information, fungal prophylaxis has been a topic of considerable debate in terms of its efficacy, costs, choice of agents, the dose regimen, and the duration of therapy. Recently, failure to provide prophylaxis to a high-risk population of liver transplant recipients was associated with a 4-fold greater risk of fungal infections (P<0.05) compared to an amphotericin prophylactic risk group [79–81].Only a handful of well-designed prophylactic studies in liver transplant patients have been performed [82–88]. One study was inconclusive while two showed efficacy with fluconazoles in preventing invasive candidiasis. In particular, one study showed that fluconazole prevented infections due to C. albicans but not C. glabrata or C. krusei infections. A single report of the use of itraconazole used prophylactically posttransplant reduced the rate of fungal infections from a control value of 24% to 4% [86].A meta-analysis of the use of antifungal prophylaxis in liver transplant recipients concluded that prophylaxis reduced the total number of episodes of infections as well as the morbidity directly related to the fungal infection but did not affect overall mortality [74].No prophylactic studies in solid organ transplant recipients have demonstrated a clear beneficial effect at preventing invasiveAspergillus, but have been interpreted as suggesting such might be the case [75–77].In contrast, studies of targeted therapy after liver transplantation have demonstrated voriconazole as the initial therapy of choice for invasiveAspergillus. Continuous infusions of amphotericin have also been shown to be effective and generally safe, but the many potential effects of amphotericin make voriconazole the preferred agent for this indication [36, 52].


## 11. Summary

(1)
Fungal infections, especially candidiasis andAspergillus, are major health problems in seriously ill patients such as transplant recipients, despite the fact that the risk factors for such infections are well recognized and predictable.
(2)
Systemic fungal infections are typically diagnosed late and treatment is costly in terms of lives lost, hospital length of stay, and overall medical costs.
(3)
Despite a plethora of agents currently available for the treatment of systemic fungal infections, the efficacy of such treatments is low.
(4)
Anticipatory or prophylactic therapy of fungal infections in individual patients with 3 or more risk factors for such infections would appear to be prudent and may be the only way that these infections can be prevented. Clearly, further study is necessary to determine the best agent, optimal dosing, and duration of therapy in immunosuppressed and transplant patients.
(5)
Finally, as these agents are typically used in transplant patients with preexisting disease states, who are on a host of other therapeutic agents for comorbid disease states involving either the kidneys or the liver or both organs, the choice of the antifungal agent to be used in a particular case should be (a) the likelihood of therapeutic benefit, (b) the recognized and anticipated adverse events associated with their use, (c) the potential for drug-drug interactions, and, finally, their ease of administration with particular attention to their use in individuals with preexisting or concurrent renal and/or hepatic disease.



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