Amphotericin formulations

In another patient, serious adverse events (fever, severe rigors, a fall in blood pressure, worsening mental status, increasing creatinine concentration, and leukocjdosis) occurred after unrecognized substitution of one amphotericin formulation (ABLC) by another (ABCD) (132). After discovery of the switch, ABLC therapy was rein-stituted and tolerated without incident. 

A large number of clinical trials have now confirmed the effectiveness of emulsion-amphotericin formulations as a safe alternative to the conventional formulations of amphotericin B in a majority of patients with invasive or superficial fungal iiifectioiLS. Levy et al. sliowed that, inespective of the formulation used, the incorporation of amphotericin B in an emulsion formulation extended the... 

Prolonged presence of the drug at the site of injection is the aim of liposome encapsulation of drugs, which are injected in the vitreous body. Both amphotericin and gentamicin in liposome formulations were cleared from the injection site significantly more slowly than the free drug residence times depended on liposome size and, in some cases, on bilayer composition (Tremblay et al., 1985 Barza et al., 1985, 1987 Fishman et al., 1986). 

Amphotericin B-induced ARF occurs in as many as 40% to 65% of patients treated with the conventional desoxycholate formulation.30 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high doses, treatment for at least 7 days, preexisting kidney dysfunction, and concomitant use of other nephrotoxic drugs.31 Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease the incidence of ARF amphotericin B lipid complex, amphotericin colloidal dispersion, and liposomal amphotericin B. The range of... 

If a patient is non-neutropenic and has never received prior azole therapy, fluconazole 800 mg/day is an appropriate first-line therapy for invasive candidiasis until identification of the Candida isolate. Amphotericin B deoxycholate 0.7 mg/kg per day or caspofungin 70 mg on day 1, then 50 mg/day, voriconazole, or a lipid amphotericin B formulation are recommended as empiric therapy in patients with neutropenic fever. 

Amphotericin B is the mainstay of treatment of patients with severe endemic fungal infections. The conventional deoxycholate formulation of the drug can be associated with substantial infusion-related adverse effects (e.g., chills, fever, nausea, rigors, and in rare cases hypotension, flushing, respiratory difficulty, and arrhythmias). Pre-medication with low doses of hydrocortisone, acetaminophen, nonsteroidal anti-inflammatory agents, and meperidine is common to reduce acute infusion-related reactions. Venous irritation associated with the drug can also lead to thrombophlebitis, hence central venous catheters are the preferred route of administration in patients receiving more than a week of therapy. 

Fusariosis Lipid formulations of amphotericin B OR Voriconazole 6 mg/kg q12hour for 1 day, then 4 mg/kg q12hour OR Posaconazole 200 mg PO qid for 14 days, then 200 mg PO q12hour OR Combination therapy ... 

Response to antifungal therapy in invasive candidiasis is often more rapid than for endemic fungal infections. Resolution of fever and sterilization of blood cultures are indications of response to antifungal therapy. Toxicity associated with antifungal therapy is similar in these patients as described earlier with the caveat that some toxicities maybe more pronounced in crit-ically-ill patients with invasive candidiasis. Nephrotoxicity and electrolyte disturbances, with amphotericin B in particular, are problematic and may not be avoidable even with lipid amphotericin B formulations. Fluconazole and echinocandins are generally safer options, and are generally well tolerated. Decisions to use one class of agents over the other is principally driven by concerns of non-albicans species, patient tolerability, or history of prior fluconazole exposure (risk factor for non-albicans species.). 

In patients who have failed initial therapy (i.e., salvage), liposomal amphotericin products, itraconazole, or the echinocandin caspofungin can be used. Itraconazole has a response rate of approximately 40%.100 Oral itraconazole exhibits erratic absorption the IV formulation is suspended in cyclodextrin, which is eliminated renally, and thus IV itraconazole should be avoided in patients with a creatinine clearance of less than 30 mL/minute (0.29 mL/s m2).103 Itraconazole also has negative inotropic cardiac effects and increases the serum concentrations of medications (e.g., cyclophosphamide, etopo-side, calcineurin inhibitors, and sirolimus). 

For patients unable to tolerate a full course of amphotericin B, consider lipid formulations of amphotericin B or fluconazole >800 mg orally daily. 

Amphotericin B is generally preferred as initial therapy in patients with rapidly progressive disease, whereas azoles are generally preferred in patients with subacute or chronic presentations. Lipid formulations of amphotericin B have not been extensively studied for coccidioidomycosis but can offer a means of giving more drug with less toxicity. Treatments for primary respiratory disease (mainly symptomatic patients) are 3- to 6-month courses of therapy. 

CNS disease Lipid formulation of amphotericin BIV 3-6 mg/kg/day x 6-10 weeks (Note Induction therapy with azoles alone is discouraged.) Amphotericin Brf IV 0.7-1 mg/kg/day + flucytosine 100 mg/kg/ day orally x 2 wk, followed by fluconazole 400 mg orally daily for a minimum of 10 weeks (in patients intolerant to fluconazole, substitute itraconazole 200-400 mg orally daily) or Amphotericin B IV 0.7-1 mg/kg/day + 5-flucytosine 100 mg/kj day orally x 6-10 weeks or Amphotericin Brf IV 0.7-1 mg/kg/day x 10 weeks Refractory disease Intrathecal or intraventricular amphotericin B (continued)... 

In patients with significant renal disease, lipid formulations of amphotericin B can be substituted for deoxycholate amphotericin B... 

Lipid-associated formulations of amphotericin B, liposomal amphotericin B (AmBisome) and amphotericin B lipid complex (Abelcet) have been approved for use in proven cases of candidiasis however, patients with invasive candidiasis have also been treated successfully with amphotericin B colloid dispersion (Amphotec or Amphocil). The lipid-associated formulations are less toxic but as effective as amphotericin B deoxycholate. 

Lipid formulation of amphotericin B IV 3-5 m kg/day Chronic disseminated candidiasis Treatment duration Until calcification or resolution of lesions (hepatosplenic candidiasis) stable patients Fluconazole IV/po 6 mg/kg/day... 

In patients who cannot tolerate voriconazole, amphotericin B can be used. Full doses (1 to 1.5 mg/kg/day) are generally recommended, with response measured by defervescence and radiographic clearing. The lipid-based formulations may be preferred as initial therapy in patients with marginal renal function or in patients receiving other nephrotoxic drugs. The optimal duration of treatment is unknown. 

The caloric contribution from propofol infusions can require adjustment of a patient s nutrition regimen. The caloric contribution from amphotericin liposomal and lipid complex formulations is not clinically relevant. 

The optimal formulation [DMPC/DMPG/AmB in molar ratio 7/3/5, referred to as lipid complex of amphotericin B (LC-AmB)] was stable in aqueous suspension for six months after preparation when stored at +4°C, with no change in size. Other formulations increased in size a few days after the preparation with or without precipitation. 

Larabi M, et al. New lipid formulation of amphotericin B spectral and microscopic analysis. Biochim Biophys Acta 2004 1664 172. 

Loiseau PM, et al. Design and antileishmanial activity of amphotericin B-loaded stable ionic amphiphile biovector formulations. Antimicrob Agents Chemother... 

Mullen AB, Carter KC, Baillie AJ. Comparison of the efficacy of various formulations of amphotericin B against murine visceral leishmaniasis. Antimicrob Agents Chemother 1997 41 2089. 

Paul M, et al. Activity of a new liposomal formulation of amphotericin B against two strains of Leishmania infantum in a murine model. Antimicrob Agents Chemother 1997 41 1731. 

Larabi M, et al. Study of the toxicity of a new lipid complex formulation of amphotericin B. J Antimicrob Chemother 2003 53 81. 

The antimykotie amphotericine is eneapsulated in liposomes and marketed as Am-Bisome" against severe systemic mycosis. The liposomal encapsulation reduces the toxicity of amphotericine while increasing the half-life of the drug and plasma level peaks [31], For stability reasons, the parenteral formulation is a lyophilized powder whieh has to be reeonstituted by adding the solvent just before administration. 

Turtinen, L.W., Prall, D.N., Bremer, L.A., Nauss, R.E., and Hartsel, S.C., Antibody array-generated profiles of cytokine release from THP-1 leukemic monocytes exposed to different amphotericin B formulations, Antimicrob. Agents Chemother., 48, 396-403, 2004. 

Lipid-based formuiations - For use in patients refractory to conventional amphotericin B deoxycholate therapy or where renal impairment or unacceptable toxicity precludes the use of the deoxycholate formulation for the treatment of invasive fungal infections (lipid complex) for the treatment of invasive aspergillosis (cholesteryl) for the treatment of infections caused by... 

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug s functional properties relative to those of the unencapsulated or nonlipid-associated drug. Lipid-based formulations increase the circulation time and alter the biodistribution of associated amphotericin. Increasing drug levels at site of action and reducing levels in normal tissues offers 2 distinct clinical advantages An increased therapeutic index and altered toxicity profile relative to free drug. 

The following table presents pharmacokinetic parameters at steady-state for lipid-based formulations of amphotericin B the assay used to measure serum levels did not distinguish between free and complex amphotericin B. 

Lipid formulations of amphotericin B have been shown to reduce the severe kidney toxicity of amphotericin B and are indicated in patients with renal impairment or when unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses. 

Renai function impairment Use amphotericin B desoxycholate with care in patients with reduced renal function frequent monitoring is recommended (see Precautions). Lipid formulations have been reported to overcome most problems of chronic nephrotoxicity, even in patients with impaired renal function following previous treatment with amphotericin B desoxycholate. 

Invasive aspergillosis For the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (ie, amphotericin B, lipid formulations of amphotericin B, itraconazole). Caspofungin has not been studied as initial therapy for invasive aspergillosis. 

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