Lipid amphotericin

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. 

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.). 

Powers JH, Albrecht R. Lipid amphotericin B formulations as comparators in clinical trials. Clin Infect Dis 2004 38 305-6. 

Abelcet . This is a sterile aqueous suspension of a lipid-amphotericin B complex. Each 20 mL vial contains 100 mg amphotericin B, 30 mg/L a-cfimyristoylphospha-tidylglycerol, 68 mg/L a-dunyristoylphosphatidylcholine. Adult dose 5 mg/l daily. 

Cass A., Finklestein A. Krespi V. (1970) The ion permeability induced in thin lipid membranes by the polyene antibiotics nystatin and amphotericin B. J Gen Physiol, 56, 100-124. 

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... 

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 ... 

Nystatin and amphotericin B, in the presence of sterols, form temporary channels across lipid bilayers. Neutral molecules under the size of glucose can traverse the... 

ABLC = Amphotericin B Lipid Complex ABCD = Amphotericin B Colloidal Dispersion L-AMB = Liposomal Amphotericin B... 

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. 

Candida albicans, C. tropicalis, C parapsilosis and resolution of signs and symptoms of infection Remove existing central venous catheters when feasible, plus Amphotericin B IV 0.6 mg/k day or Fluconazole IV/po 6 mg/kg/day or An echinocandin or Amphotericin B IV 0.7 mg/kg/day plus fluconazole IV/po 800 mg/day Patients intolerant or refractory to other therapf Amphotericin B lipid complex IV 5 m k day Liposomal amphotericin B IV 3-5 mg/kg/day Amphotericin B colloid dispersion IV 2-6 mg/k day (continued)... 

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 mixing of nematogenic compounds with chiral solutes has been shown to lead to cholesteric phases without any chemical interactions.147 Milhaud and Michels describe the interactions of multilamellar vesicles formed from dilauryl-phosphotidylcholine (DLPC) with chiral polyene antibiotics amphotericin B (amB) and nystatin (Ny).148 Even at low concentrations of antibiotic (molar ratio of DLPC to antibiotic >130) twisted ribbons are seen to form just as the CD signals start to strengthen. The results support the concept that chiral solutes can induce chiral order in these lyotropic liquid crystalline systems and are consistent with the observations for thermotropic liquid crystal systems. Clearly the lipid membrane can be chirally influenced by the addition of appropriate solutes. 

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. 

Figure 3 Electron microscopy of lipid complex of amphotericin B. (A) Air-drying and shadowing, bar = 200 nm (B) freeze-fracture, bar = 200 nm. Source From Ref. 1.

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