Principles of Antifungal Therapy

Chapter 225 Principles of Antifungal Therapy



William J. Steinbach, Michael Cohen-Wolkowiez, Daniel K. Benjamin, Jr.



Due to advances in aggressive antineoplastic agents and organ transplantation, invasive fungal infections are a major cause of morbidity and mortality in children. Fortunately, the therapeutic armamentarium for invasive fungal infections has markedly increased since the turn of the century (imageSee Table 225-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com).




Table 225-1 SUGGESTED DOSING OF ANTIFUNGAL AGENTS IN CHILDREN AND NEONATES

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Polyenes



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.



Pyrimidine Analogs



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.



Azoles


The azole antifungals inhibit the fungal cytochrome P45014DM (also known as lanosterol 14α-demethylase), which catalyzes a late step in fungal cell membrane ergosterol biosynthesis. Of the older 1st-generation triazoles, itraconazole has activity against Aspergillus but fluconazole is ineffective against Aspergillus. Second-generation triazoles (voriconazole and posaconazole) are modifications of prior triazoles with an expanded antifungal spectrum of activity, including activity against moulds, and generally greater in vitro antifungal activity.



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

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Jun 18, 2016 | Posted by in PEDIATRICS | Comments Off on Principles of Antifungal Therapy

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