Safety and efficacy of liposomal amphotericin B for the empirical therapy of invasive fungal infections in immunocompromised patients

Figures & data

Figure 1 Current strategies for the management of IFI in high-risk patients.

Notes: *High-resolution computed tomography scan of the lungs showing new ≥1 cm single or multiple nodules with or without halo sign, lobar consolidation, wedge-shaped consolidative infarct; **classic example: patients with proglonged and profound neutropenia after intense chemotherapy for hematologic malignancy.

Abbreviations: GM, serum Galactomannan; IFI, invasive fungal infection; PCR, polymerase chain reaction.

Table 1 US Food and Drug Administration-approved indication of antifungal agents for the management of IFIs

Indication	Echinocandins			Newer azoles		Polyenes
	CAS	MICA	ANID	VOR	POS	AmB-D	ABLC	ABCD	L-AmB
Empiric treatment of invasive fungal infections	YES								YES
Prophylaxis of Candida infections		YES§			YES*
Prophylaxis of invasive aspergillosis					YES*
Target therapy of invasive aspergillosis	YES			YES		YES†	YES^++	YES‡	YES○
Target therapy of mucormycosis						YES†	YES^++
Salvage treatment of IFIs				YES•			YES^++
Oropharyngeal candidiasis	YES	YES	YES	YES			YES^++		YES○
Invasive candidiasis	YES	YES	YES	YES••		YES†	YES^++		YES○

* Notes: In patients aged ≥13 years, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem-cell transplant recipients with graft versus host disease or those with hematologic malignancies with prolonged neutropenia from chemotherapy;

§ in patients undergoing allogeneic hematopoietic stem-cell transplant;

• infections with Scedosporium spp and Fusarium spp in patients refractory to or intolerant of other agents.

•• in nonneutropenic patients.

† AmB-D is approved for the treatment of potentially life-threatening fungal infections: aspergillosis; cryptococcosis (torulosis); North American blasmomycosis; systemic candidiasis; coccidioidomycosis; histoplasmosis; and zgomycosis including mucormycosis due to susceptible species of the genera Absidia, Mucor, and Rhizopus and infections due to related susceptible species of Conidiobolus and Basidiobolus, and sporotrichosis;

†† ABLC approved for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B;

‡ ABCD is approved for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of conventional amphotericin B;

○ L-AmB (AmBisome) is approved for the treatment of patients with Aspergillus spp, Candida spp, and/or infections due to Cryptococcus spp refractory to conventional AmB or in patients with marked renal impairment or when severe toxicity precludes the use of conventional AmB; also approved for the treatment of cryptococcal meningitis in human immunodeficiency virus–infected patients and visceral leishmaniasis.

Abbreviations: ABCD, amphotericin B colloidal dispersion; AmB-D, amphotericin B deoxycolate; ABLC, amphotericin B lipid complex; ANID, anidulafungin; CAS, caspofungin; IFIs, invasive fungal infections; L-AmB, liposomal amphotericin B; MICA, micafungin; POS, posaconazole; VOR, voriconazole.

Table 2 Summary of clinical trials comparing efficacy and safety of liposomal amphotericin B with other antifungal agents for empirical antifungal therapy in patients with neutropenia

Reference/type of study	Treatment regimen (dose)	Number of patients	Mean age (range)	Patient population (% of patients)	Mean duration of treatment	Renal toxicity‡ (% of patients)	Infusion related reactions† (% of patients)	Treatment success rate* (% of patients)	Comments
Walsh^Citation47 Randomized, double blind, multicenter clinical trial	L-AmB (3 mg/k/d)	343	41 (2–79)	HSCT: 45% Non-HSCT: 55%	10.8 days	19%	17%§	50.1% [95% CI: 45–56]	L-AMB was associated with significant reduction of breakthrough infections (mostly non-albicans Candida infections)
	Amb-D (0.6 mg/kg/d)	344	42 (2–80)	HSCT: 47% Non-HSCT: 53%	10.3 days	34% (P < 0.001)	44%§ (P < 0.001)	49.4% [95% CI: 44–55]
Wingard^Citation45 Randomized, double blind, multicenter clinical trial	L-AmB (3 mg/kg/d)	85	41.4 (3–74)	HSCT: 46% Non-HSCT: 54%	8 days	14.1%	51.8%1	40%	Study designed to detect differences in toxicity, not efficacy. Breakthrough infection rates were similar in three groups.
	L-AmB (5 mg/kg/d)	81	42 (2–84)	HSCT: 49% Non-HSCT: 51%	8 days	14.8%	48.1%1	42%
	ABLC (5 mg/kg/d)	78	42.8 (2–76)	BMT: 51% Non-BMT: 49%	8 days	42.3% (P ≤ 0.01)	88.5%1 (P ≤ 0.001)	33.3%
Walsh^Citation51 Randomized, open labeled, multicenter clinical trial	Voriconazole 6 mg/kg IV Q12 h on day 1, then 3 mg/kg IV Q12 h or 200 mg PO after at least 3 days of IV therapy	415	46.3 (12–82)	HSCT: 47.7%	7 days	With concomitant Nephrotoxic drugs¶: 0–1 drugs: 11.3% ≥2 drugs: 14.3% ≥3 drugs: 50%	Abnormal vision 22% Flushing 3.4% Chills 13.7%	26%	Breakthrough IFI occurred in 8 patients on voriconazole and 21 patients on L-AmB (P = 0.02). Hepatotoxicity was similar in both groups.
	L-AmB (3 mg/kg/d)	422	45 (12–80)	HSCT: 51.4%	7 days	With concomitant Nephrotoxic drugs¶: 0–1 drugs: 9.7% ≥2 drugs: 39% ≥3 drugs: 60% (P < 0.001)	Abnormal vision 0.7% Flushing 10.9% Chills 29.9% (P < 0.001)	30.6%
Walsh^Citation48 Randomized, double blind, multicenter clinical trial	Caspofungin (70 mg in day 1 and then 50 mg/d)	556	51 (17–83)	Acute leukemia: 75.8% (Allo-HSCT: 6.5%)	13 days	2.6%	47%	33.9%	Most patients included in the study had acute leukemia.
	L-AmB (3 mg/kg/d)	539	49 (16–83)	Acute leukemia: 72.2% (Allo-HSCT: 7.2%)	12.5 days	11.5% (P < 0.001)	59% (P < 0.001)	33.7%	Breakthrough infections were similar in both groups.
Maertens^Citation49 Randomized, double blind, multicenter clinical trial	Caspofungin (70 mg/m^2 on day 1, then 50 mg/m^2 daily)	56	6 (2–16)	Acute leukemia: 60.7% (Allo-HSCT: 10.7%)	11.6 days	5.5%	48.2% [95% CI: 34.7–62.0]	46.6% [95% CI: 33.5–59.6]	Study conducted exclusively in pediatric population.
	L-AmB (3 mg/kg/d)	26	5.5 (2–16)	Acute leukemia: 65.4% (Allo-HSCT: 65.4%)	11.4 days	8%	46.2% [95% CI: 26.6–66.6]	32.2% [95% CI: 13.9–50.5]	Limitation: small sample. Only 1 patient in L-AmB group had breakthrough infection.

† Notes: Infusion related reactions include fevers, chills, hypotension, chest pain, tachycardia, etc;

‡ nephrotoxic effect was defined by an elevation in the serum creatinine level to more than 1.5 times the base-line value;

* treatment success rate was determined by a composite outcome score consisting of five criteria: (1) successful treatment of any baseline fungal infection, (2) absence of any breakthrough fungal infection during therapy or within seven days after the completion of therapy, (3) survival for 7 days after the completion of therapy, (4) no premature discontinuation of study therapy because of drug related toxicity or lack of efficacy, and (5) resolution of fever during neutropenia. Treatment was considered successful if all five criteria were met.

1 Infusion-related reactions on day 1 study drug infusion;

§ fevers within 1 hour of drug infusion (increase of ≥1.0°C); overall rate of infusion-related reactions was not provided;

¶ nephrotoxic drugs were aminoglycosides, cyclosporine, and foscarnet.

Abbreviations: ABLC, amphotericin B lipid complex; AmB-D, amphotericin B deoxycolate; CI, confidence interval; L-AmB, liposomal amphotericin B; BMT, bone marrow transplant; Allo, allogeneic; HSCT, hematological stem cell transplant.

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