What is the impact of antifungals on the prevention and control of health care-associated infections?

Invasive fungal infections (IFI) are a common cause of health care-associated infections. Candidiasis is especially common in intensive care units (ICUs), particularly in patients with abdominal surgery, multiple trauma or severe burns, and in neonatal ICUs. In some series Candida spp ranked third in frequency as a cause of infection in critically ill patients behind Staphylococcus aureus and Pseudomonas aeruginosa. Prophylactic use of fluconazole in patients admitted to medical and surgical ICU significantly reduces the rate of invasive infection by Candida spp., and appears to reduce the mortality in these patients. Fluconazole also significantly reduce the proportion of patients with intestinal colonization by Candida spp., with no apparent fecal colonization by Candida strains resistant to fluconazole, such as C. krusei or C. glabrata. Therefore, the effectiveness of systemic antifungal prophylaxis with fluconazole in critically ill patients is beyond any doubt. However, this does not mean that fluconazole is indicated in any patient who is in critical condition, only in those with certain risk factors. In neutropenic patients, fluconazole significantly reduce the incidence of both superficial and invasive Candida infections, the related mortality, and the need to initiate empirical antifungal therapy. Some authors have reported an increase in infections caused by more resistant strains like C. krusei and C. glabrata associated with the use of fluconazole.

Besides Candida infections, patients admitted to the hospital may develop Aspergillus infections, especially neutropenic patients, patients with cancer, and patients treated with steroids or other immunosuppressive drugs. Experience with prophylaxis against Aspergillus is drawn primarily from studies in neutropenic patients and transplant recipients.

The indications for prophylaxis against Aspergillus are less well defined than for Candida. Prophylaxis of aspergillosis, both primary and secondary, can be performed with intravenous or nebulized amphotericin B, but its use may be hampered by the development of local side effects. Alternatively, itraconazole can be used in oral solution, but its erratic absorption makes it difficult to use.

The drug most effective and most used in the prophylaxis of aspergillosis in the neutropenic patient is posaconazole, but unfortunately it also has absorption problems and can only be administered by mouth and accompanied by foods rich in fat, which is poorly tolerated by these patients. Experience with voriconazole in prophylaxis is limited, but it appears to be superior to itraconazole in neutropenic patients, but liver toxicity is also high. Finally, echinochandins can also be used in the prophylaxis of IFIs. So far, there is only experience with micafungin and caspofungin. Both require intravenous administration, which limits their use to hospitalized patients. Micafungin is indicated for the prophylaxis of IFIs in patients with hematopoietic stem cell transplantation (HSCT). Caspofungin has been used for prophylaxis of IFI in liver transplant recipients because echinocandins have a lower risk of liver toxicity.

Which antifungals play a key role in the prevention and control of health care-associated infections?

The most important experience in antifungal prophylaxis is with the use of azoles such as fluconazole, itraconazole, and posaconazole. Here is briefly summarized the more important results in the prevention of IFI achieved with azoles and other agents.

Which antifungals are commonly used to prevent and control these infections, and what are key distinguishing features of each?

Antifungals are used both for primary and secondary prophylaxis of IFI. Primary prophylaxis refers to prevention of infection acquisition. Secondary prophylaxis refers to the use of antifungal prophylaxis during periods of risk following the diagnosis of IFI. We review here the main features that distinguish one from another agent used in antifungal prophylaxis.

Fluconazole is used in the prophylaxis of neutropenic patients to decrease the incidence of mucocutaneous candidiasis and it has also proved to be useful in the prevention of Candida infection in critically ill patients. The principal limitation of fluconazol is that it is not active against mycelial fungi.

The drug of choice for primary prophylaxis against Aspergillus is posaconazole. Posaconazole is available only in oral solution. The principal limitation of posaconazole is that patients with impaired oral mucositis or severe diarrhea reach frequently low levels of posaconazole in serum. Because of the absorption problems of posaconazol and the individual differences in the metabolism of this drug it is difficult to predict which are the serum levels achieved with posaconazole in a given patient, so monitoring of serum drug levels is recommended. Posaconazole prophylaxis should be avoided in patients receiving vinca alkaloids because posaconazole increases their levels and the risk of toxicity. This is especially true in adult patients receiving induction treatment of acute lymphoblastic leukemia.

The use of itraconazole can prevent the development of invasive aspergillosis in oncohematologic patients, but its use is limited by the poor drug tolerance and absorption observed in some patients. It is recommended using the oral solution better than the capsules. Itraconazole can be used intravenously. As in the case of posaconazole, serum levels of itraconazole should be measured and this drug should be avoided in patients receiving simultaneously vinca alkaloids.

With regard to voriconazole, a recent trial has shown that it is more effective than itraconazole in the prophylaxis of invasive aspergillosis in recipients of allo-HSCT. As with other azoles, serum levels of voriconazole should be measured and the drug should be avoided in patients receiving simultaneously vinca alkaloids.

There is limited experience with the use of echinochandins in prophylaxis. Micafungin shows a tendency to reduce invasive aspergillosis compared with fluconazole in allo-HSCT recipients during the neutropenic phase. Micafungin may be especially useful in patients with significant degrees of mucositis that cannot tolerate oral medication or in those with have a high risk of pharmacologic interactions with the use of azoles.

The use of low doses of liposomal amphotericin reduces the incidence of IFIs in neutropenic patients and inhaled liposomal amphotericin B reduced the incidence of invasive aspergillosis in patients with prolonged neutropenia and in lung transplant recipients.

Antifungals and their key features, efficacy and safety.

The major groups of antifungal agents used clinically are: (1) polyenes (amphotericin B and lipid formulations of amphotericin B); (2) azoles, (fluconazole, itraconazole, voriconazole, and posaconazole); (3) Echinocandins (caspofungin, micafungin, and anidulafungin); (4) fluorinated pyrimidines (flucytosine), and (5) allylamines (terbinafine). We will review each of these groups.

Amphotericin B

Amphotericin B is a macrolide used clinically in four forms: a) conventional form (amphotericin B deoxycholate); b) amphotericin B lipid complex, which is a lipidic formulation of amphotericin B; c) liposomal amphotericin B, which is composed of unilamellar liposomes; and d) amphotericin B colloidal dispersion, which is a stable complex of amphotericin B and cholesterol.

Amphotericin B remains the antifungal agent of choice for most serious IFIs and for empirical treatment of febrile neutropenia refractory to appropriate antibacterial treatment. Compared with amphotericin B deoxycholate lipid formulations produces a lower incidence of adverse effects related to the infusion (especially liposomal amphotericin B) and a marked decrease in nephrotoxicity allowing much higher doses in less time. This has led to a widespread use of liposomal amphotericin B in the critically ill with serious fungal infections and in immunocompromised patients. In these patients is often necessary to use simultaneously other drugs that could increase the toxicity of amphotericin B. Although the therapeutic index with liposomal amphotericin B is clearly better than with conventional amphotericin B, are needed well-designed comparative studies to definitively establish its superiority in terms of clinical and pharmacoeconomic efficacy.

Azoles

The azoles are a group of fungistatic drugs that are divided into two groups: imidazoles and triazoles. Imidazoles (e.g., miconazole) accounted for a major contribution to the treatment of fungal infections, but are now used less frequently because of their limited spectrum of activity, low bioavailability and the possibility of serious side effects, so we do not refer to them. The triazoles have the same mechanism of action that the imidazoles, but a higher antifungal spectrum and fewer side effects. At present, there are four triazoles available for clinical use: fluconazole, itraconazole, voriconazole and posaconazole. The antifungal spectrum of these compounds is very broad and includes filamentous fungi, yeasts and dimorphic fungi.

Fluconazole can be used either orally or intravenously. Its main indication is the treatment of oropharyngeal candidiasis, esophageal candidiasis, urinary tract infections due to Candida, and chronic invasive candidiasis (hepatosplenic candidiasis). It is as effective as amphotericin B in candidemia. It is effective in patients with Candida endocarditis, and it is also indicated for cryptococcal meningitis, alone or combined with flucytosine, Coccidioides immitis meningitis, and disseminated coccidioidomycosis.

Itraconazole may be effective against Candida species resistant to fluconazole. The oral solution is especially useful for the treatment of oral and esophageal candidiasis. The greatest usefulness of itraconazole is in the prophylaxis of the oncohematologic patient at high risk. The intravenous formulation allows its use in patients unable to tolerate the oral route.

Voriconazole is so far the drug that has proven to be more effective in the initial treatment of invasive aspergillosis, achieving a response rate of 53% compared to only 32% with conventional amphotericin B. It is also indicated for the treatment of emerging mycosis due to Fusarium and Scedosporium for which there is no other effective treatment. In contrast, voriconazole lacks activity against zygomycetes. Voriconazole is also active against Candida species resistant to other azoles. It has excellent in vitro activity against Cryptococcus but clinical experience in this infection is still limited, as with the endemic mycoses (histoplasmosis, coccidioidomycosis, etc). The FDA has not yet authorized the use of the drug in the empiric treatment of febrile neutropenic patients, although a recent study showed that it was as effective as liposomal amphotericin B in this indication.

Echinocandins

The echinocandins are a new family of antifungals. Three of them are available at this time (caspofungin, anidulafungin and micafungin). They are active in vitro and in animal models against Aspergillus spp. and against other filamentous fungi and have potent antifungal activity in vitro and in vivo against Candida spp. They are also active against some dimorphic fungi such as Histoplasma capsulatum, Coccidioides immitis and Blastomyces dermatitidis. By contrast, they have no activity in vitro against Cryptococcus neoformans, Trichosporon beigelii, and against dematiaceous fungi, Rhizopus spp. or Fusarium spp. All of them have been approved for the treatment of invasive candidiasis and candidemia and are similar in this indication to liposomal amphotericin B. Anidulafungin has shown to be superior to fluconazole in patients with candidemia. Only caspofungin has been approved for the treatment of invasive aspergillosis in patients refractory or intolerant to conventional therapy. Micafungin is the only authorized echinocandin for using in neonates. Since echinocandins act by preventing the synthesis of cell wall (external to fungal cell) may be synergistic with other fungi, such as azoles or amphotericin B, that act by preventing the synthesis of the cell membrane (internal to fungal cell). Although there is no a clear indication for the combined use of antifungal drugs, most of clinicians use echinocandins in combination with azoles or amphotericin B when treating patients with severe, CNS localized, or disseminated forms of IFI.

Flucytosine

Flucytosine (5-fluorocytosine), is an antifungal synthetic fluorinated analog of a normal body constituent, cytosine. Instead of preventing the synthesis of the cytoplasmic membrane by preventing the synthesis of ergosterol, as do the amphotericin B and azoles, flucytosine prevents the synthesis of DNA of the fungus. To perform this effect undergoes deamination and is transformed into 5-fluorouracil, a non-competitive inhibitor of thymidylate synthase which interferes with DNA synthesis. This transformation occurs preferentially within the fungus.

Flucytosine may have a beneficial effect in patients with cryptococcosis and candidiasis. It is not the drug of choice for these infections because their clinical efficacy is lower than amphotericin B and because is common the development of resistance to the drug during treatment. Leukopenia and diarrhea are frequent secondary effects during the treatment with flucytosine. These secondary effects are difficult to manage, especially in patients with AIDS, bone marrow transplantation, or hematologic malignancies. Flucytosine may be synergistic when combined with amphotericin B against yeast (Candida and Cryptococcus), reducing the doses of amphotericin B required to inhibit growth of these fungi in vitro. This combination of antifungals is frequently used for the treatment of Candida and Cryptococcus infections.

Terbinafine

Terbinafine is used in skin infections caused by dermatophytes (Epidermophyton, Microsporum, Trichophyton), and Candida. Topical application is used in the treatment of pityriasis versicolor. Occasionally terbinafine could be used in synergistic combination with azoles and polyenes against certain difficult to treat filamentous fungi as Scedosporium spp.

Summary of important PK/PD data, dosing information for prevention versus treatment, drug-drug interactions, and adverse reactions for available antifungals.

See Table I, Table II, Table III, Table IV, Table V, Table VI, and Table VII for detailed information about available antifungal agents.

Table I.

	Protein binding (%)	Cmaxmg/ml	T ½h	Biliary elimination (%)	Renal elimination (%)	Oral bioavailability
Ketoconazole	90	2-3	2-8	85-90	<1	75
Itraconazole	>99	0,19	20-30	60-70	30-40	>70
Fluconazole	11	2	24	2	>80	>80
Voriconazole	58	4-10	6	>80	<5	99
Posaconazole	98	0.5	20	77	14	44-50

Cmax = maximum drug concentration, T1/2 = half-life

Table II.

	Dose mg/Kg/día	Cmaxmg/ml	AUCmg/ml/h	Clearanceml/h/Kg	Volume of distributionL/Kg	T ½ h	Protein binding (%)
Amphotericin B deoxycholate	0,5-1	2-3,6	34	30,2	4	24-34	>90
Amphotericin B Lipid Complex	2,5-5	1,4-2,5	56	28,4	2,3	173-235	>90
Liposomal amphotericin B	3-5	15-29	423	22,2	0,56	10-23	>90

Cmax = maximum drug concentration, T1/2 = half-life

Table III.

	Dose mg/día	Cmaxmg/ml	AUCmg/ml/h	Clearance totalml/min	Volume of distributionL/Kg	T ½ h	Protein binding (%)
Caspofungin	70 initial followed by 50	9.5-12	98	10-12	0.15	9-11	97
Anidulafungin	200 initial followed by 100	7.8	110	1	0.6	40	84
Micafungin	50-75	5 (50 mg)	66 (75 mg)	12.8-14	0.2	11-15	99,8

Cmax = maximum drug concentration, T1/2 = half-life

Table IV.

Clinical situation	Treatment of choice	Alternative	Comments
The patient meets criteria for severe sepsis^#	Echinocandin (caspofungin, anidulafungin or micafungin) (grade of evidence AI)¶	Liposomal amphotericin B (3-5 mg/kg/day) (grade of evidence AI).	– Replace the venous catheter (especially if septic shock) (grade of evidence AIII) – If C. parapsilosis is isolated the echinocandin should be replaced by fluconazole (grade of evidence BIII). – Replace echinocandin by liposomal amphotericin B or an azole after clinical improvement, identification of species and result of sensitivity tests (grade of evidence AIII)
Stable patient, without evidence of severity with risks of infection by Candida species resistant to fluconazole *	Echinocandin (caspofungin, anidulafungin or micafungin) (grade of evidence AI)	Liposomal amphotericin B (3-5 mg/kg/day) (grade of evidence AI) or voriconazol (grade of evidence AII)	-If C. parapsilosis is isolated the echinocandin should be replaced by fluconazole (grade of evidence BIII). – Replace echinocandin by liposomal amphotericin B or an azole after clinical improvement, identification of species and result of sensitivity tests (grade of evidence AIII)
Stable patient, without evidence of severity and without risks of infection by Candida species resistant to fluconazole *	Fluconazole 800 mg first day, followed by 400 mg/day (grade of evidence AI)	Echinocandin (caspofungin, anidulafungin or micafungin) (grade of evidence AI), Liposomal anfotericina B (3-5 mg/kg/día) (grade of evidence AI) or voriconazole (grade of evidence AII).	– In case of infection with C. glabrata is preferable to use an echinocandin or liposomal amphotericin B until know the sensitivity of the isolated strain (grade of evidence BIII)

# Severe sepsis: hypotension (systolic pressure <90 mm Hg or decrease of <40 mm plus some data of organ dysfunction or hypoperfusion related disorders (metabolic acidosis, arterial hypoxemia (PaO2 <75 mm Hg or PaO2/FiO2 <250) , oliguria (<0.03 L / h for 3 hours or <0.7 L / h for 24 hours), coagulopathy (prothrombin time increase or decrease in platelets of 50% or <100.000/mm3) or encephalopathy (<14 in the Glasgow scale).

Grade of evidence based on recommendations following IDSA Guidelines. Clinical Infectious Diseases 2001; 32:851–4.

* Risk of infection with a Candida species resistant to fluconazole when any of these circumstances are present: 1) colonization by C. krusei or C. glabrata, 2) therapy with an azole before or during the episode of candidemia.

Table V.

Agent	Clinical Manifestation	Treatment of choice	Alternative
Aspergillus sp	Invasive	VoriconazoleAmphotericin B	Caspofungin, Posaconazole
Aspergillus sp	Aspergilloma	Voriconazole	Itraconazole
Cryptococcus neoformans	Meningitis	Amphotericin B + Flucytosin followed by Fluconazole	FluconazoleVoriconazole
Fusarium spp.	Disseminated	Voriconazole	Amphotericin B
Scedosporium spp.	Pulmonary or Disseminated	Voriconazole (± terbinafine)	Amphotericin B, Posoconazole
Zygomicetos	RhinocerebralPulmonary	Amphotericin B (± caspofungin)	Posaconazole
Histoplasma capsulatum	PulmonaryDisseminated	Amphotericin B followed by Itraconazole	Voriconazole, Posaconazole

Table VI.

	FLUCO	ITRA	VORI	POSA	Effect caused
Substrate ofCYP3A4 y CYP2C9
Ergot alkaloids	P	C	C	C	Possible toxicity (ergotism)
Anticonvulsants: Phenytoin	P	P	P	P	↑ phenytoin levels, frequent monitoring and surveillance of possible adverse effects
Antiretrovirals
PI: ritonavir	P	P	C	P	It can reduce voriconazole serum levels*. Monitoring for possible adverse effects to other PIs.
NNRTI: efavirenz	P	P	C	P	↑ efavirenz concentrations. If co-administration is needed, increase voriconazole dose and reduce efavirenz 400mg/12h 300mg/day. Monitoring for possible adverse effects to other NNRTIs.
Benzodiazepines	P	C	P	P	Monitoring potential toxicity of benzodiazepines metabolized by CYP3A4 (midazolam, triazolam, alprazolam)
Cisapride, astemizole, terfenadine, pimozide, quinidine	C	C	C	C	High potential for QT prolongation and occurrence, in rare cases, of torsade de pointes.
Statins	P	C	P	C	↑ statin levels. Monitoring adverse effects such as rhabdomyolysis. May require dose adjustment.
Oral hypoglycemic agents (sulfonylureas)	P	P	P	P	Monitoring for signs and symptoms of hypoglycemia. May require dose adjustment.
Proton pump inhibitors: Omeprazole	P	P	P	P	↑ PPI concentrations, reducing the absorption of triazoles. Reduce the dose of omeprazole to half. Do the same with the rest of PPI.
Inmunosuppressors
Cyclosporine	P	P	P	P	↑ AUC. Toxicity, renal failure. Cyclosporine dose reduction by at least 50%, monitoring levels and continuous follow-up after stopping azole.
Tacrolimus	P	P	P	P	↑ concentrations *. Toxicity, renal failure. Reduce tacrolimus dose to one third, monitoring levels and continuous follow-up after discontinuation of azole.
Sirolimus	P	P	C	P	↑ sirolimus concentrations. Not recommended, if necessary reduce doses of sirolimus.
Valdenafilo		P		P	↑ concentration, persistence, long-lasting effect
Vincristine	–	P	P	P	↑ vinca alkaloid concentrations, risk of toxicity
Warfarin	P	P	P	P	↑ prothrombin time. Monitoring and adjustment of warfarin dose.
InductorsCYP3A4 y CYP2C9
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	P	P	C	C	↓ concentrations of triazoles *
Antirretrovirals
PI: ritonavir at high doses	P	P	C	P	↓ concentrations of triazoles *
NNRTI (Efavirenz)	P	P	C	P
Anti-tuberculosis drugs: rifabutin, rifampin	P	C	C	C	↓ concentrations of triazoles *
St. John’s Wort	–	P	P	–	↓ concentrations of triazoles *

C: Contraindicated; P: Precaution. PI: protease inhiitors; NNRTI: non-nucleoside reverse transcriptase inhibitor.

PPI: Proton pump inhibitors (omeprazole, pantoprazole, etc.). Fluco: fluconazole; Itra: itraconazole; Vori: voriconazole; Posa: Posaconazole.

* C_max = maximum serum concentration; AUC = Area under a curve

Table VII.

Drug	Adverse Effects
Fluconazole	Safe and well tolerated (1-2% discontinued treatment by ARD *)Gastrointestinal discomfort (5%)HeadacheHepatotoxicity (5-20%, especially in high doses) with transient elevation of liver enzymes (exceptionally hepatitis)QT interval prolongationAlopecia (prolonged treatment and high doses)
Itraconazole	Safe (<5% drop discontinued treatment by ARD *)Skin rash (5-19%)HeadachePruritusVertigoDyscrasias (rare)
Voriconazole	Gastrointestinal disordersImpaired liver function with transient elevation of liver enzymesVisual disturbances, usually transient (20-40%)Cardiovascular effects: QT prolongation, arrhythmiasHepatotoxicity: Elevations in liver enzyme values (10-20%)Gastrointestinal upsetMiscellaneous: drug eruptions, photosensitivity, Stevens-Johnson syndrome, hair loss, peripheral edema, electrolyte abnormalities (hypokalemia), hallucinations.
Posaconazole	Gastrointestinal disordersFever (rare), with or without rashHeadache, dizziness and drowsinessAlterations of liver function with elevated liver enzymesElectrolyte imbalances (hypokalaemia)Anorexia, asthenia and fatigueArrhythmogenic cardiovascular effects: QT interval prolongationAdrenal insufficiency

*ARD: Acute reactions to drugs

Adverse reactions to other antifungals in addition to azoles

Amphotericin B

The use of amphotericin B has been associated with adverse effects related with the infusion and directly due to drug toxicity. We will review the most important adverse effects of amphotericin B deoxycholate for later compare with the new lipid formulations. It is very common the development of fever and chills during the infusion of amphotericin B, especially in the first week of treatment and usually declines thereafter. Amphotericin B may cause also hypotension, hypertension, hypothermia and bradycardia during drug infusion. Occasionally the patient may develop ventricular arrhythmias during a rapid infusion of amphotericin B. The occurrence of nausea and vomiting is common, but decreases after a few days. Anaphylactic reactions to amphotericin B are very rare but justify the conduct of the test dose.

Classically is described the development of respiratory failure and respiratory distress syndrome in adults with the appearance of interstitial infiltrates in connection with the use of transfusion of leukocytes concomitantly with amphotericin B. This has been observed in the absence of granulocyte transfusion in other situations including the use of colony stimulating factors or coinciding with the regeneration of post-chemotherapy aplasia.

The most important adverse effect of amphotericin B deoxycolate and the main limiting factor of its use is renal toxicity. Early toxicity is dose-dependent, while late toxicity is a function of cumulative dose. Usually reversible, although almost all patients receiving therapy are left with some degree of reduction of residual glomerular filtration. The risk of renal toxicity can be reduced by ensuring adequate hydration of the patient. Renal tubular acidosis occurs in patients who receive doses of 0.5-1 g, and is usually accompanied by hypokalemia and hypomagnesemia, which reverses when therapy is interrupted.

The development of renal toxicity is the main indication to switch to amphotericin B lipid formulations currently available. Renal failure caused by amphotericin B deoxycholate tends to improve or at least remain stable when replaced by lipid formulations. Amphotericin B lipid complex is better tolerated than amphotericin B deoxycholate and has a lower incidence of infusion-related effects but the use of premedication is also recommended. Cholestasis has been described that can be enhanced by cyclosporine, and presents a similar incidence of hypokalemia as amphotericin B deoxycholate but potassium levels must be regularly monitored. There are reports of respiratory distress syndrome and adult respiratory failure. With the use of liposomal amphotericin B is rare see adverse effects during infusion and it is not necessary to use premedication. It can be observed elevation of alkaline phosphatase and bilirubin less frequently and transaminases. Hypokalemia occurs in up to 30% so you have to monitor levels. Have been reported exceptional pictures of pancreatitis, ventricular fibrillation and anaphylactic reactions to the lipid component.

Echinocandins

Echinocandins are generally well tolerated. It has reported only slight reactions of intolerance during administration. These drugs are not inhibitors of cytochrome P-450, which explains the absence of interference with many drugs, however, the concomitant use of caspofungin with cyclosporine could produce elevations of transaminases in some patients. Caspofungin reduces the serum concentration of tacrolimus, it is therefore mandatory monitoring of blood concentrations of this drug. Rifampin can reduce levels of caspofungin. Concomitant use of caspofungin with other enzyme inducers such as efavirenz, nevirapine, dexamethasone, phenytoin or carbamazepine may also cause a reduction in serum levels of caspofungin. The change does not alter caspofungin levels of amphotericin B, itraconazole or voriconazole. Micafungin and anidulafungin are even safer than caspofungin. Furthermore anidulafungin has no hepatic or renal metabolism so it can be safely used in patients with impaired hepatic or renal function and it does not interfere with the simultaneous use of immunosuppressors.

Antifungal agents under development.

There are several drugs under development both in the field of azoles, polyenes, and echinocandins. Among triazoles albaconazole (UR-9825) is currently under development. The orally active agent has shown efficacy in animal models of infections caused by Aspergillus, Candida, Cryptococcus and Scedosporium spp. However, its most recent positioning in a Phase II trial in vulvovaginal candidiasis suggests it may no longer be under development for invasive fungal disease. An intravenous formulation of albaconazole does not seem to be available.

Ravuconazole (BMS-207147) is an oral broad-spectrum triazole for invasive mycoses. However, it no longer seems to be under active development and an intravenous formulation has not been developed. The ravuconazole isomer isavuconazole (BAl-4815) is undergoing development in the form of the orally active, water-soluble prodrug BAl-8557, which is amenable to intravenous formulation. Isavuconazole is currently in Phase III clinical trials. It is too early to know whether any of the triazoles mentioned will show genuine improvements over existing, licensed triazoles.

New triazoles could offer advantages by extending the spectrum of activity to include rare but difficult-to-treat invasive mycoses (infections caused by Fusarium spp., Scedosporium spp. or the Zygomycota) or by improving the drug–drug interaction profile. In addition, new triazoles might have a pharmacokinetic profile that would substantially reduce dosing frequency and/or a more favorable adverse effects profile. However, none of the triazoles in the pipeline has yet clearly shown such advantages, mainly because of the paucity of clinical data.

Among the polyenes a cochleate formulation of amphotericin B has shown efficacy in experimental models of candidiasis and aspergillosis. This formulation entraps the amphotericin B molecules in a large, stable, spirally rolled lipid bilayer. The formulation promises oral bioavailability of amphotericin B, but to date the only pharmacokinetic study involves intravenous injection in mice. A liposomal formulation of the tetraene nystatin has undergone extensive testing preclinically and in clinical trials. However, the results of Phase III clinical trials for treatment of fever in neutropenia and in cryptococcal meningitis have not been reported in detail or published in the peer-reviewed literature. The developmental status of liposomal nystatin is therefore unknown.

Several types of novel sordarin derivatives were developed preclinically in the 1990s. The compounds were found to inhibit a novel target for antifungal agents: elongation factor 2 in protein biosynthesis. A number of molecules based on the sordarin pharmacophore were shown to have therapeutic efficacy in various animal models of fungal disease but no obvious candidate for clinical development has yet emerged, and the frequency of publications on sordarins has greatly reduced since 2002.

Development of new echinocandins agents is slow, and there is only one candidate in early preclinical development: aminocandin (IP960/HMR3270). This agent has shown good in vivo and in vitro activity against Candida spp. and filamentous fungi.

Nikkomycin Z is a novel antifungal agent. The mode of action of nikkomycin Z is to competitively inhibit chitin synthases and thereby interfere with fungal cell wall construction. As mammalian hosts do not possess this target, nikkomycin Z is potentially pathogen selective. In a Phase I multi-dose safety trial, with subjects receiving 250 mg twice daily to 750 mg three times daily for 14 days, all subjects have completed drug administration, and preliminary evaluation has not identified any safety concerns. Full safety analysis and pharmacokinetics should be available in 2011.

What controversies surround key antifungals, and what are the pros and cons for each drug?

Controversies in the treatment of invasive candidiasis

Eight studies have been published in the treatment of invasive candidiasis in which was compared the clinical efficacy and tolerance of fluconazole, voriconazole, amphotericin B and echinocandins (caspofungin, micafungin, and anidulafungin). As for the azoles, the efficacy of fluconazole and voriconazole is similar to that of iv amphotericin B deoxycholate, but the toxicity and side effects of the latter are higher than for azoles. With regard to candins, caspofungin and micafungin have proved to be at least as effective as amphotericin B deoxycholate for the treatment of invasive candidiasis and have fewer side effects than this. Micafungin and caspofungin have equal activity between them. Finally, anidulafungin is the only candin that has shown to be superior to fluconazole. It should be noted that although the three candins currently available are likely to have similar efficacy between them with respect to the majority of Candida species, their effectiveness with respect to C. parapsilosis is somewhat lower.

In conclusion, in the treatment of invasive candidiasis polyenes, azoles and candins have similar efficacy. The better tolerance and lower toxicity of azoles and candins favors its use in comparison with the various formulations of amphotericin B.

Controversies in the treatment of invasive aspergillosis

Voriconazole is the drug of choice for first line treatment of invasive aspergillosis based on a randomized, multicentre open study comparing with amphotericin B deoxycholate. The lipid formulations of amphotericin B have at least one activity comparable to amphotericin B deoxycholate in the treatment of invasive aspergillosis, and lower toxicity. Liposomal amphotericin B has a lower nephrotoxicity than amphotericin B lipid complex.

Although caspofungin is used as rescue therapy in patients with invasive aspergillosis, in the first-line treatment caspofungin has not shown great effectiveness, so at this time is not considered a drug for initial treatment of patients with aspergillosis invasive. Caspofungin may be indicated along with voriconazole or liposomal amphotericin B as combination therapy in critically ill patients with disseminated disease and those with central nervous system involvement.

There is controversy about the best empirical antifungal therapy in patients with febrile neutropenia refractory to broad-spectrum antibacterial treatment. For this indication a lipid formulation of amphotericin B or caspofungin are indicated, but the broader antifungal spectrum of amphotericin B makes it preferable to caspofungin for this indication. Although it would seem reasonable to include also voriconazole for this indication, since it is the preferred treatment of invasive aspergillosis, voriconazole not met the criteria for noninferiority when it was compared with amphotericin B liposomal for this indication.

Are there specific guidelines for the use of antifungals?

There are numerous guidelines for the use of antifungal drugs published by various scientific societies. Because of its great diffusion we selected three of these guidelines: Guidelines of the Infectious Diseases Society of America (IDSA), ECIL-3 Guidelines, and Guidelines of the National Comprehensive Cancer Network (NCCN). The following tables show the most important recommendations for the treatment of invasive candidiasis and invasive aspergillosis contained in these guidelines, with the degree of scientific evidence for each of these recommendations. See Table VIII, Table IX, Table X, Table XI, Table XII, and Table XIII.

Table VIII.

Recommended drug	Clinical Situations	Evidence grade
Echinocandins (anidula, caspo or mica)	No identification of Candida species Moderate or severe clinical situation Previous treatment with azoles Infection by C. glabrata	AIAIIIAIIIBIII
Fluconazole	No identification of Candida species Stable patient or less severe clinical situation Infection by C. parapsilosis Sequential treatment when patient is stable	AIAIIIBIIIAIII
Amphotericin B	Fluconazole alternative when resources are limited	AI
Voriconazole	Isolation of C. krusei Sequential treatment when patient is stable	BIIIAIII

Table IX.

Recommended drug	Clinical Situations	Evidence grade
Echinocandins (anidula, caspo or mica)	Virtually in all clinical situations Of choice in C. glabrata infection	AIIAII
Amphotericin B	Alternative to echinocandins in virtually all clinical situations C. glabrata o C. parapsilosis	AIIBII
Fluconazole	Stable patient with less severe clinical situation without exposure to azoles C. parapsilosis	BIIIBII
Voriconazole	Stable patient with less severe clinical situation without exposure to azoles C. krusei	BIIIBII

Table X.

Drug	IDSA	ECIL
Voriconazole	AI	AI
Liposomal amphotericin B	AI	BI
Amphotericin B lipid complex		BII
Caspofungin		CII
Micafungin
Itraconazole		CIII
Posaconazole		ND
Combinated treatment*	BII	DIII

IDSA: Infectious Diseases Society of America; ECIL: European Conference on Infections in Leukemia; ND: No data or insufficient data; * To be considered in critically ill patients with disseminated disease and those with central nervous system involvement.

Table XI.

Drug	IDSA	ECIL
Liposomal amphotericin B	AII	BIII
Amphotericin B lipid complex	AII	BIII
Posaconazole	BII	BII
Voriconazole		BII
Caspofungin	BII	BII
Micafungin	BII
Itraconazole	BII	CIII
Caspofungin + Liposomal amphotericin B	BII	CII
Caspofungin + Voriconazole	BII	CII
Liposomal amphotericin B + Azoles	BII	ND

IDSA: Infectious Diseases Society of America; ECIL: European Conference on Infections in Leukemia

Table XII.

Drug	IDSA	ECIL	NCCN (5)
Posaconazole	AI	AI	AI
Voriconazole		ND	BII
Itraconazole	BI	CI
Micafungin		ND
Liposomal amphotericin B		CI	BII
Nebulized liposomal amphotericin B		BI

AML: Acute myeloid leukemia, MDS: myelodysplastic syndrome; IDSA: Infectious Diseases Society of America; ECIL: European Conference on Infections in Leukemia; NCCN: National Comprehensive Cancer Network; ND: No data or insufficient data.

Table XIII.

Drug	IDSA	ECIL	NCCN
Posaconazole	AI	AI	A1
Voriconazole		AI	BII
Itraconazole	BI	BI
Micafungin		ND	BII
Liposomal amphotericin B		CI	BII
Nebulized liposomal amphotericin B		ND

HSCT: hematopoietic progenitors Transplantation; IICH: Enfermedad GVHD; IDSA: Infectious Diseases Society of America; ECIL: European Conference on Infections in Leukemia; Comprehensive Cancer Network; ND: No data or insufficient data.

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Antifungals

What is the impact of antifungals on the prevention and control of health care-associated infections?

Which antifungals play a key role in the prevention and control of health care-associated infections?

Which antifungals are commonly used to prevent and control these infections, and what are key distinguishing features of each?

Antifungals and their key features, efficacy and safety.

Amphotericin B

Azoles

Echinocandins

Flucytosine

Terbinafine

Summary of important PK/PD data, dosing information for prevention versus treatment, drug-drug interactions, and adverse reactions for available antifungals.

Table I.

Table II.

Table III.

Table IV.

Table V.

Table VI.

Table VII.

Adverse reactions to other antifungals in addition to azoles

Amphotericin B

Echinocandins

Antifungal agents under development.

What controversies surround key antifungals, and what are the pros and cons for each drug?

Controversies in the treatment of invasive candidiasis

Controversies in the treatment of invasive aspergillosis

Are there specific guidelines for the use of antifungals?

Table VIII.

Table IX.

Table X.

Table XI.

Table XII.

Table XIII.

References

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