Amphotericin B

The prototype of the oldest antifungal class, the polyene macrolides, is amphotericin B deoxycholate. Amphotericin B was once the preferred treatment for invasive fungal infections as well as the standard of comparison for all newer antifungal agents. Amphotericin B is so named because it is amphoteric, forming soluble salts in both acidic and basic environments. However, because of its insolubility in water, amphotericin B for clinical use is actually amphotericin B mixed with the detergent deoxycholate. Amphotericin B binds to ergosterol, the major sterol found in fungal cytoplasmic membranes, and acts by creating transmembrane channels. The fungicidal activity is due to a damaged barrier and subsequent cell death through leakage of essential nutrients from the fungal cell.

Amphotericin B is released from its carrier and distributes very efficiently with lipoproteins, taken up preferentially by organs of the reticuloendothelilal system. Following an initial 24-48 hr distributional half-life there is very slow release and a subsequent terminal elimination half-life of up to 15 days. In addition to conventional amphotericin B deoxycholate, 3 fundamentally different lipid-associated formulations have been developed that offer the advantage of an increased daily dosage of the parent drug, better delivery to the primary reticuloendothelial organs (lungs, liver, spleen), and reduced toxicity. Amphotericin B lipid complex (ABLC) is a tightly packed ribbon-like structure of a bilayered membrane, amphotericin B colloidal dispersion (ABCD) is composed of disklike structures of cholesteryl sulfate complexed with amphotericin B, and liposomal amphotericin B (L-amphotericin B) consists of small uniformly sized vesicles of a lipid bilayer of amphotericin B. Lipid formulations of amphotericin B generally have a slower onset of action, presumably owing to the required disassociation of free amphotericin B from the lipid vehicle. The ability to safely administer higher daily doses of the parent drugs improves their efficacy, comparing favorably with amphotericin B deoxycholate with less toxicity. Lipid formulations have the added benefit of increased tissue concentrations compared to conventional amphotericin B, specifically in the liver, lungs, and spleen. However, it is not entirely clear if these higher concentrations in tissue are truly available to the microfoci of infection.

Tolerance to amphotericin B deoxycholate is limited by its acute and chronic toxicities. In addition to interacting with fungal ergosterol, the drug also interacts with cholesterol in human cell membranes, likely accounting for its toxicity. Up to 80% of patients receiving amphotericin B develop either infusion-related toxicity or nephrotoxicity, especially with concomitant therapy with nephrotoxic drugs such as aminoglycosides, vancomycin, cyclosporine, or tacrolimus. Renal function usually returns to normal after cessation of amphotericin B, although permanent renal impairment is common after larger doses. Amphotericin B nephrotoxicity is generally less severe in infants and children than in adults, likely due to the more rapid clearance of the drug in children. Lipid formulations appear to stabilize amphotericin B in a self-associated state so that it is not available to interact with the cholesterol of human cellular membranes.

There is no total dosage of amphotericin B recommended, and the key to success is to give high dosages in the initial phase of therapy and to reduce the dosage if toxicity develops. There are no data or consensus opinions among authorities indicating improved efficacy of any new amphotericin B lipid formulation over conventional amphotericin B deoxycholate. One exception is that L-amphotericin B has shown fewer infusion-related adverse events than the other lipid formulations or conventional amphotericin B.

5-Fluorocytosine

5-Fluorocytosine is a fluorinated analog of cytosine, and its antifungal activity results from the rapid conversion into 5-fluorouracil (5-FU) within susceptible fungal cells. Clinical and microbiologic antifungal resistance appears to develop quickly to 5-FC monotherapy, so clinicians have reserved it for combination approaches to augment other, more potent antifungals. Fungistatic 5-FC is thought to enhance the antifungal activity of amphotericin B, especially in anatomic sites where amphotericin B penetration is often suboptimal such as cerebrospinal fluid (CSF), heart valves, and the vitreal body. 5-FC penetrates well into most body sites because it is small, highly water-soluble, and not bound by serum proteins to any great extent. One explanation for the synergism detected with the combination of amphotericin B plus 5-FC is that the membrane-permeabilizing effects of low concentrations of amphotericin B facilitate penetration of 5-FC to the cell interior. 5-FC is only available as an oral formulation in the USA, and the correct dosage is 150 mg/kg/day in 4 divided doses.

5-FC can exacerbate myelosuppression in patients with neutropenia, and toxic levels can develop when used in combination with amphotericin B owing to nephrotoxicty of the amphotericin B and decreased renal clearance of 5-FC. Routine serum 5-FC level monitoring is warranted in high-risk patients, because peak serum concentrations of ≥100 µg/mL (2 hr after dose) are associated with bone marrow aplasia. Toxicities can include azotemia, renal tubular acidosis, leukopenia, thrombocytopenia, and others and appear in approximately 50% of patients in the first 2 wk of therapy.

Nearly all clinical studies involving 5-FC are combination antifungal protocols for cryptococcal meningitis, owing to the inherently rather weak antifungal activity of 5-FC monotherapy. The use of 5-FC in premature neonates is discouraged. A study evaluating risk factors and mortality rates of neonatal candidiasis among extremely premature infants showed that infants with Candida meningitis who received amphotericin B in combination with 5-FC had a prolonged time to sterilization of the CSF compared to infants receiving amphotericin B monotherapy.

Fluconazole

Fluconazole is fungistatic, and this activity is not influenced by concentration once the maximal fungistatic concentration is surpassed (concentration independent), in contrast to the concentration-dependent fungicidal activity of amphotericin B. Fluconazole is available as either an oral or intravenous form, and oral administration has a bioavailability of approximately 90% relative to intravenous administration. Fluconazole passes into tissues and fluids very rapidly, probably due to its relatively low lipophilicity and limited degree of binding to plasma proteins. Concentrations of fluconazole are 10-20 fold higher in the urine than blood, making it an ideal agent for treating fungal urinary tract infections. Concentrations in the CSF and vitreous humor of the eye are approximately 80% of those found simultaneously in blood.

It is clear that simple conversion of the corresponding adult dosage of fluconazole on a weight basis is inappropriate for pediatric patients. Fluconazole clearance is generally more rapid in children than adults, with a mean plasma half-life of approximately 20 hr in children and approximately 30 hr in adult patients. Therefore, to achieve comparable exposure in pediatric patients, the daily fluconazole dosage needs to be essentially doubled. Correct pediatric fluconazole dosages should be proportionately higher than adult dosages, generally 12 mg/kg/day. In neonates the volume of distribution is significantly greater and more variable than in infants and children, and doubling the dosage for neonatal patients is necessary to achieve comparable plasma concentrations. The increased volume of distribution is thought to be due to the larger amount of body water found in the total body volume of neonates. A pharmacokinetic study in premature infants suggests that maintenance fluconazole dosages of 12 mg/kg/day are necessary to achieve exposures similar to those in older children and adults. In addition, a loading dose of 25 mg/kg would achieve steady-state concentrations sooner than the traditional dosing scheme. Side effects of fluconazole are uncommon but generally include gastrointestinal upset (vomiting, diarrhea, nausea) and skin rash.

Fluconazole plays an important role in the treatment of invasive candidiasis. The latest guidelines suggest use of the fungistatic fluconazole in patients who have invasive candidiasis but who are not critically ill or neutropenic. Although most isolates of Candida albicans remain susceptible to fluconazole, for certain Candida species fluconazole is not an ideal agent: C. krusei is generally resistant and C. glabrata is often resistant. In treating infection caused by these Candida species, it is critical to treat with an echinocandin or amphotericin B rather than fluconazole. There is no confirmed role for combination antifungal therapy with fluconazole and another antifungal against invasive candidiasis.

Prophylaxis with fluconazole to prevent neonatal candidiasis remains a controversial topic. In a prospective, randomized double-blind trial over a 30-mo period of 100 infants with birth weights <1,000 g, infants who received fluconazole for 6 wk had a decrease in fungal colonization (22% vs 60%) and a decrease in the development of invasive fungal infection (0% vs 20%) compared to placebo. Other studies have yielded similarly encouraging results and have demonstrated that use of fluconazole prophylaxis for 4-6 wk in high-risk infants does not increase the incidence of fungal colonization and infections caused by natively fluconazole-resistant Candida species. The universal implementation of such strategy across nurseries is discouraged, because the rate of Candida infections varies greatly among centers and there are insufficient neurodevelopmental follow-up data in these infants to justify prophylaxis.

Itraconazole

Compared to fluconazole, itraconazole has the benefit of antifungal activity against Aspergillus species but comes with several practical constraints, such as erratic oral absorption in high- risk patients and significant drug interactions. These pharmacokinetic concerns have been addressed with both an intravenous formulation and a better-absorbed oral solution to replace the capsules used earlier. Itraconazole has a high volume of distribution and accumulates in tissues, and tissue-bound levels are probably more clinically relevant to infection treatment than serum levels. Dissolution and absorption of itraconazole are affected by gastric pH. Patients with achlorhydria or taking H₂-receptor antagonists might demonstrate impaired absorption, and co-administration of the capsule with acidic beverages such as colas or cranberry juice can enhance absorption. Administration with food significantly increases the absorption of the capsule formulation, but the new oral suspension with a cyclodextrin base is better absorbed on an empty stomach.

Side effects are relatively few and include nausea and vomiting (10%), elevated transaminases (5%), and peripheral edema. There have been reports in adults of development of cardiomyopathy. Itraconazole also is associated with important drug interactions, and prior or concurrent use of rifampin, phenytoin, carbamazepime, and phenobarbital should be avoided.

Itraconazole has a role in treating less-serious infections with endemic mycoses (histoplasmosis, coccidioidomycosis, and blastomycosis), as well as use in prophylaxis against invasive fungal infections in high-risk patients. The plethora of drug interactions make itraconazole a concern in complex patients receiving other medications, and itraconazole serum levels are recommended to confirm appropriate dosing. Itraconazole is no longer recommended for primary therapy of invasive aspergillosis.

Voriconazole

Voriconazole is a 2nd-generation triazole and a synthetic derivative of fluconazole. Voriconazole generally has the spectrum of activity of itraconazole and yet the bioavailability of fluconazole. Importantly, it is fungicidal against Aspergillus and fungistatic against Candida. It is extensively metabolized by the liver and has approximately 90% oral bioavailability. The cytochrome P-450 2C19 (CYP2C19) enzyme appears to play a major role in the metabolism of voriconazole, and polymorphisms in CYP2C19 are associated with slow voriconazole metabolism. As many as 20% of non-Indian Asians have low CYP2C19 activity and develop voriconazole levels as much as 4-fold higher than those in homozygous subjects, leading to potentially increased toxicity.

Voriconazole is available as an oral tablet, an oral suspension, and an intravenous solution. In adults, voriconazole exhibits nonlinear pharmacokinetics, has a variable half-life of approximately 6 hr with large interpatient variation in blood levels, and achieves good CSF penetration. In contrast to the situation in adults, elimination of voriconazole is linear in children. A multicenter safety, population pharmacokinetic study of intravenous voriconazole dosages in immunocompromised pediatric patients showed that body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics, and voriconazole needs to be dosed higher in pediatric patients than adult patients. Adult patients load with 6 mg/kg/dose and then transition to a maintenance dosage of 4 mg/kg/dose, but children should begin and continue with 7 mg/kg/dose (see Table 225-1). This need for an increased dosage in treating children is crucial to understand and is mandated by the fundamentally different pharmacokinetics of this drug in pediatric patients. Obtaining voriconazole serum levels is currently controversial, because it is unclear how to best interpret the results. Generally a trough level greater than the minimum inhibitory concentration (MIC) of the infecting organism is preferred, but much higher voriconazole levels have been associated with toxicity. The main side effects of voriconazole include reversible dosage-dependent visual disturbances (increased brightness, blurred vision) in as many as one third of treated patients, elevated hepatic transaminases with increasing dosages, and occasional skin reactions likely caused by photosensitization.

The largest prospective clinical trial of voriconazole as primary therapy for invasive aspergillosis compared initial randomized therapy with voriconazole versus amphotericin B and demonstrated improved response and survival with voriconazole over amphotericin B. Voriconazole is now guideline-recommended as the preferred primary therapy against invasive aspergillosis. Voriconazole also has a role in treating candidiasis, but its fungistatic nature makes it often less than ideal for treating critically ill or neutropenic patients where the fungicidal echinocandin antifungals are preferred.

Posaconazole

Posaconazole is a 2nd-generation triazole that is a derivative of itraconazole and is available only as an oral suspension. The antimicrobial spectrum of posaconazole is similar to that of voriconazole; however, the former is active against Zygomycetes, and voriconazole is not active against these particular mold infections. When administered with a nonfat or high-fat diet, posaconazole exposure and maximum concentration are 3 to 4 times higher than when administered in the fasting state, emphasizing the importance of diet to increase serum levels of posaconazole. Posaconazole exposure is maximized with acidic beverages, administration in divided doses, and the absence of proton pump inhibitors. Posaconazole causes transient hepatic reactions, including mild to moderate elevations in liver transaminases, alkaline phosphatase, and total bilirubin.

The correct pediatric dosage of posaconazole is not known, because initial studies are still ongoing. In adult patients, dosages >800 mg/day do not result in increased serum levels, and division of daily dosing into 3 or 4 doses/day results in greater serum levels than a once- or twice-daily dosing scheme.

In an international randomized, single-blinded study of posaconazole versus fluconazole or itraconazole in neutropenic patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes, posaconazole was superior in preventing invasive fungal infections. Fewer patients in the posaconazole group had invasive aspergillosis, and survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole. Another multisite international randomized, double-blinded study in patients with allogeneic hematopoietic stem-cell transplantation and graft vs host disease showed that posaconazole was not inferior to fluconazole in the prevention of invasive fungal infections. Posaconazole is approved for prophylaxis against invasive fungal infections but has shown great efficacy in clinical experience with recalcitrant mold infections.

In patients with chronic granulomatous disease (CGD) and proven invasive fungal infection refractory to standard therapy, posaconazole was proved to be well tolerated and quite effective. This agent might prove to be very useful in this patient population where long-term therapy with an oral agent is required.

Caspofungin

At present there is no known maximum tolerated dosage and no toxicity-determined maximum length of therapy for caspofungin. The usual course is to begin with a loading dose followed by a lesser daily maintenance dosage, which is 70 mg followed by 50 mg daily in adult patients. Much of the dosage accumulation is achieved in the 1st wk of dosing, and renal insufficiency has little effect on the pharmacokinetics of caspofungin. Caspofungin has been evaluated at double the recommended dosage (100 mg/day in adults) with no adverse effects, and it is unclear if higher dosage of this relatively safe agent results in greater clinical efficacy.

Pharmacokinetics are slightly different in children, with caspofungin levels lower in smaller children and with a reduced half-life. A study evaluated the pharmacokinetics of caspofungin in children with neutropenia and showed that in patients receiving 50 mg/m²/day (maximum, 70 mg/day), the levels were similar to those in adults receiving 50 mg/day and were consistent across age ranges. In this study, weight-based dosing (1 mg/kg/day) was suboptimal when compared to body surface area regimens, so caspofungin should be appropriately dosed in children as a loading dose of 70 mg/m²/day, followed by daily maintenance dosing of 50 mg/m²/day.

Caspofungin was approved for refractory aspergillosis or intolerance to other therapies and for candidemia and various other sites of invasive Candida infections. In the pivotal clinical study, patients with acute invasive aspergillosis underwent “salvage” therapy after failing primary therapy, and recipients had a 41% favorable response with caspofungin. In a multicenter trial of patients with invasive candidiasis, 73% of patients who received caspofungin had a favorable response at the end of therapy, compared to 62% in the amphotericin B group. Importantly, caspofungin treatment performed equally well to amphotericin B treatment for all the major Candida species, but other studies have shown that some infections with C. parapsilosis do not clear as effectively with an echinocandin. Current guideline recommendations state that infection with C. parapsilosis should be treated initially with fluconazole or amphotericin B. Caspofungin was also evaluated against L-amphotericin B in the empirical treatment of patients with persistent fever and neutropenia and was not inferior to liposomal amphotericin B in >1,000 patients.

Caspofungin in children has been reported to be safe. Caspofungin pharmacokinetics were evaluated in older infants and toddlers at 50 mg/m²/day and found to be similar to adults receiving the standard 50 mg daily dose. Caspofungin in newborns has been used off-label as single or adjuvant therapy for refractory cases of disseminated candidiasis. Neonates with invasive candidiasis are at high risk for central nervous system involvement; it is not known if the dosages of caspofungin studied provide sufficient exposure to penetrate the central nervous system at levels necessary to cure infection. Therefore, caspofungin is not recommended as monotherapy in neonatal candidiasis.

Micafungin

The pharmacokinetics of micafungin have been evaluated in children and young infants. An inverse relation between age and clearance was observed, where mean systemic clearance was significantly greater and mean half-life was significantly shorter in patients 2-8 yr of age compared to patients 9-17 yr of age. Therefore, dosing of micafungin in children is age-related and needs to be higher in children <8 yr old. To achieve micafungin exposures equivalent to exposures in adults receiving 100, 150, and 200 mg daily, as evidenced by simulation profiles, children require dosages >3 mg/kg.

Several pharmacokinetic studies of micafungin in term and preterm infants have shown that micafungin in infants has a shorter half-life and a more rapid rate of clearance compared with published data in older children and adults. These results suggest that young infants should receive 10 mg/kg daily of micafungin if used to treat invasive candidiasis.

The safety profile of micafungin is optimal when compared to other antifungal agents. Clinical trials including those of micafungin used for treatment of localized and invasive candidiasis as well as prophylaxis studies in patients following stem cell transplantation have demonstrated fewer adverse events compared to liposomal amphotericin B and fluconazole. The most common adverse events experienced by these patients are related to the gastrointestinal tract (nausea, diarrhea). Hypersensitivity reactions associated with micafungin have been reported, and liver enzymes are elevated in 5% of patients receiving this agent. Hyperbilirubinemia, renal impairment, and hemolytic anemia related to micafungin use have also been identified in postmarketing surveillance of the drug.

An open-label, noncomparative, multinational study in adult and pediatric patients with a variety of diagnoses (HSCT, hematologic malignancies) evaluated the use of micafungin monotherapy and combination therapy in 225 patients with invasive aspergillosis. Of those only treated with micafungin, favorable responses were seen in 50% of the primary and 41% of the salvage therapy group.

Micafungin at dosages of 100 and 150 mg daily was also noninferior to caspofungin in an international, randomized, double-blinded study of adults with candidemia or invasive candidiasis and was found to be superior to fluconazole in the prevention of invasive fungal infections in a randomized study of adults undergoing hematopoietic stem cell transplantation.

Of the 3 drugs within the echinocandin class, micafungin has been the one most extensively studied in children, including several pharmacokinetic studies in neonates. A pediatric substudy as part of a double-blind, randomized, multinational trial comparing micafungin (2 mg/kg/day) with liposomal amphotericin B (3 mg/kg/day) as 1st-line treatment for invasive candidiasis showed similar success for micafungin and liposomal amphotericin B. In general, micafungin was better tolerated than liposomal amphotericin B as evidenced by fewer adverse events leading to discontinuation of therapy.

Anidulafungin

Anidulafungin has the longest half-life of all the echinocandins (approximately 18 hr). In a study of 25 neutropenic children receiving anidulafungin as empirical therapy, 4 patients in the group receiving 0.75 mg/kg/day experienced adverse events such as facial erythema and rash, elevation in serum blood urea nitrogen, and fever and hypotension. The current anidulafungin formulation requires reconstitution with 20% dehydrated alcohol, and safety and pharmacokinetic profiles in infants <2 yr are being evaluated.

A randomized, double-blind study in adult patients without neutropenia with invasive candidiasis showed that anidulafungin was not inferior to fluconazole in the treatment of invasive candidiasis. In this study, the incidence and types of adverse events were similar in the 2 groups, and all-cause mortality was 31% in the fluconazole group and 23% in the anidulafungin group. No clinical studies of anidulafungin in pediatric patients are currently available.