- Email: [email protected]
The experience is CLEAR®
International Journal of Antimicrobial Agents 27S (2006) S31–S35
The experience is CLEAR® Pranatharthi Chandrasekar ∗ Division of Infectious Diseases, Wayne State University School of Medicine, Harper Hospital, 3990 John R, 5-Hudson, Detroit, MI, USA
Abstract Conventional amphotericin B has been the ‘gold standard’ for antifungal efficacy, but nephrotoxicity problems limit its clinical utility. In the late 1990s, three lipid-based formulations of amphotericin B were introduced, all of which offered comparable efficacy and reduced renal complications. However, to date, robust safety and comparative efficacy data have been sparse. This paper briefly reviews the available clinical data on amphotericin B lipid complex (ABLC). Also, in detail, it reviews the findings of Collaborative Exchange of Antifungal Research (CLEAR® ), the most extensive dataset on systemic antifungal treatment with the lipid-based agent ABLC. © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Amphotericin B; Amphotericin B lipid complex; CLEAR® ; Aspergillosis; Fusariosis; Zygomycosis
1. Amphotericin B lipid complex—a historical perspective 1.1. Introduction Lipid formulations of amphotericin B emerged in the late 1990s, almost 40 years after the introduction of amphotericin B’s intravenous formulation (amphotericin B desoxycholate, AmBd). Today, three lipid-based compounds are commercially available: ABLC (Abelcet® ); amphotericin B colloidal dispersion (ABCD) and liposomal amphotericin B (L-AmB). Few studies are available that directly compare these lipidbased formulations with AmBd. Aggregate efficacy estimates for lipid-based compounds and conventional amphotericin B are 49% and 32%, respectively, when compared with various invasive fungal infections. It appears that the superior renal safety profile of these agents may contribute to higher response rates against aspergillosis, fusariosis, cryptococcosis, and zygomycosis [1]. All of these lipid-based formulations are pharmacologically distinct and have varying clinical indications. These approved labellings in the USA are summarized in Table 1.
∗
Tel.: +1 313 745 9649; fax: +1 313 993 0302. E-mail address: [email protected].
1.2. Pharmacokinetics In vitro data show that approximately 60–75% of the amphotericin B in ABLC is released within 3 h of administration. In comparison, 95% of L-AmB remains associated with the liposome as long as 72 h after dosing [2–6]. This may explain why, when compared with L-AmB, ABLC is more rapidly taken up by the reticuloendothelial system and therapeutic concentrations are more readily found in tissues that are common sites of fungal infection (e.g. lung, liver, spleen) [2–6]. Hence, rapid onset of action is anticipated, although such rapid release of amphotericin B from ABLC has not been shown to have superior clinical value. High levels of amphotericin B after ABLC are not found in renal tissue, a factor that may explain the low nephrotoxicity profile of ABLC [7].
1.3. Clinical outcome A historical controlled study involving 273 Aspergillusinfected patients with haematological malignancies compared the survival benefits of ABLC with those of AmBd. The researchers found that the median survival was 52 days for the ABLC group (N = 151) compared with 31 days for the AmBd group (N = 31; P = 0.023). This represents an improvement in survival of approximately 68%. Similarly, the all-cause
0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2006.03.017
S32
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
Table 1 Comparison of US-FDA approved product labelling for amphotericin B formulations Pathogen
Amphotericin B desoxycholate
Amphotericin B lipid complex
Amphotericin B colloidal dispersion
Liposomal amphotericin B
Aspergillus Blastomyces Candida albicans Non-albicans Candida Coccidioides Cryptococcus Fusarium Histoplasma Zygomycetes
• • • • • • • • •
• • • • • • • • •
•
•
mortality rates for the two groups were 56% and 71%, respectively (P = 0.017) [8]. ABLC has also been investigated in an open-label, compassionate-use study involving 556 patients. All evaluable patients (N = 291) had either experienced previous antifungal therapy failure (including AmBd) (N = 151) or had been unable to tolerate previous antifungal medication (N = 140) [9]. Of the group of patients who were intolerant of previous therapy and/or who had pre-existing renal insufficiency, 64% were successfully treated with ABLC. ABLC produced a satisfactory response in 52% of patients who had failed previous antifungal therapy [9]. Further, the overall response rates for aspergillosis, zygomycosis, and fusariosis were 42%, 71%, and 82%, respectively [9].
2. The Collaborative Exchange of Antifungal Research (CLEAR® )
• • •
(29%) or documented (70%) fungal infection (Table 3) [10]. The median daily dose of ABLC was 4.40 mg/kg (range 0.2–10 mg) and the median treatment duration was 12 days [10]. Over the trial period, patients were admitted with the following medical conditions (patients may have had more than one underlying condition): leukaemia – 38%; allogeneic bone marrow transplant – 21%; solid organ transplant – 21%; solid tumour – 10%; lymphoma – 8%; graft-versus-host disease – 5%; AIDS – 4%; autologous bone marrow transplant – 4% and peripheral stem cell transplant – 3%. Participants were further classified into five groups: patients refractory to prior antifungal therapy – 40% (N = 1411); patients intolerant of prior antifungal therapy – 16% (N = 573); patients with underlying renal disease and no prior antifungal therapy – 27% (N = 945); patients with underlying renal disease and prior antifungal therapy – 2.4% (N = 84) and patients with no underlying renal disease and no prior antifungal therapy – 12% (N = 431).
2.1. Rationale and demographics 2.2. Overall safety and tolerability The Collaborative Exchange of Antifungal Research (CLEAR® ) is a prospective, multicentre, database that was designed to allow clinicians to share and exchange pharmacoepidemiological data on the treatment of invasive fungal infections with ABLC. Between 1996 and 2000, 3514 patients from more than 160 institutions in the USA and Canada were registered to CLEAR® . Baseline demographics are shown in Table 2 [10]. All patients had received at least four doses of Abelcet® as treatment for a suspected Table 2 CLEAR® patient demographics Age Median Range Age <18 years Age >65 years
46 <1–97 454 (13%) 572 (16%)
Sex Male Female Not specified
2039 (58%) 1466 (42%) 9 (<1%)
Reprinted with permission [10]. © 2005 The University of Chicago Press.
Overall, ABLC was well tolerated by the majority of patients. Only 13% of patients experienced a doubling of baseline serum creatinine levels (median baseline level Table 3 CLEAR® patients by diagnosed fungal infection [10] Infection type
N (%)a
Suspected fungal infection Specified fungal infection Candidiasis/Candidaemia Aspergillosis Multiple pathogens Cryptococcosis Zygomycosis Blastomycosis Histoplasmosis Fusariosis Coccidioidomycosis Penicilliosis Saccharomycosis Others Not specified
1030 (29) 2469 (70) 1062 (30) 436 (12) 362 (10) 97 (3) 55 (2) 15 (<1) 24 (1) 17 (<1) 7 (<1) 3 (<1) 5 (<1) 386 (17) 15 (<1)
a
Percentage of 3514 patients.
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
S33
Table 4 Renal effects of amphotericin B lipid complex by CLEAR® patient category [10] Serum creatinine levels (mg/dL)
Refractory (N = 1411)
Intolerant (N = 573)
Underlying renal disease/no prior antifungal therapya (N = 945)
Underlying renal disease/prior antifungal therapy (N = 84)
No prior antifungal therapya /no renal disease (N = 431)
Median baseline value Median end-of-therapy value Median change
1.20 1.50 0.10
1.40 1.40 0.00
2.00 2.00 0.00
2.00 2.10 −0.10
1.00 1.20 0.20
a
First-line ABLC use.
1.4 mg/dL), whilst 3% of patients required new dialysis [10]. The change in serum creatinine values was not clinically significant in most patients. Table 4 shows the renal effects of ABLC according to the five patient sub-categories [10]. Despite an increased risk for renal impairment in allogeneic haematopoietic stem cell recipients, only 17% experienced an end-of-therapy doubling of serum creatinine levels. 2.3. Overall clinical outcome Responses were classified as successful if clinical signs and symptoms were stabilized, improved or cured. The overall success rate with ABLC was found to be 72% [10]. The CLEAR® database shows that ABLC is effective against all common invasive yeast and mould infections. The specific response rates were: candidiasis (76%, N = 857); aspergillo-
sis (65%, N = 402); cryptococcosis (85%, N = 91); zygomycosis (75%, N = 51); histoplasmosis (92%, N = 24); blastomycosis (85%, N = 13); fusariosis (59%, N = 17); coccidioidomycosis (86%, N = 7) and other mould infections (50%, N = 14). These data are further summarized in Fig. 1 and Fig. 2 [10]. Response rates by patient subclassification are provided in Fig. 3 [10]. Success rates were high in all categories [10]. No significant differences were observed in outcome among patients receiving ABLC as primary therapy or as secondary or salvage therapy. 2.4. Previous azole failure The effect of ABLC on patients who had previously experienced azole therapy failure was investigated using a sub-
Fig. 1. Clinical outcome of CLEAR® patients with yeast infections [10].
Fig. 2. Clinical outcome of CLEAR® patients with mould infections [10].
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P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
Fig. 3. Clinical outcome of CLEAR® patients by patient subcategory [10].
analysis of 778 CLEAR® patients (median age 50 years; 33% candidaemia/candidiasis). All patients received rescue doses of ABLC. Successful responses were observed in 72% of patients (15% cured; 39% improved; 18% stable) [10]. These results suggest that ABLC may be useful in azole-refractory or azole-resistant candidal and other fungal infections. 2.5. Cryptococcosis The effect of ABLC on the 107 CLEAR® patients with cryptococcal infection was investigated. Overall reported response rate was 85% (cured and improved 66%; stable 19%). Rates were also calculated according to the patient’s underlying condition: CNS infection (86%, N = 78); neutropenia (100%, N = 6); no neutropenia (84%, N = 93) and underlying HIV (87%, N = 52).
(median age 46 years). The overall response rate achieved with ABLC was 63%; 41% were cured or improved and 22% were stabilized. Response rates by patient subcategory are shown in Fig. 4. These data show that, when used as firstline therapy (no prior antifungal therapy and with or without renal disease), ABLC achieves an overall response rate of 67% (N = 210) [10]. This compares favourably with the study by Herbrecht et al. that investigated primary response rates of voriconazole (58%) and AmBd (38%) in the treatment of invasive aspergillosis [11]. Of particular note is the response rate achieved in patients refractory to prior antifungal therapy. In this difficult-to-treat group of patients, treatment with ABLC resulted in a success rate of 57% (N = 250) [10]. In the 19 cases with documented Aspergillus terreus, an infection considered to be resistant to amphotericin B, treatment with ABLC resulted in a response rate of 37% [10].
2.6. Aspergillosis
2.7. Fusariosis
The effect of ABLC on patients with aspergillosis was investigated using a subanalysis of 558 CLEAR® patients
A subanalysis was performed on 28 CLEAR® patients to investigate the effects of ABLC on invasive fusariosis. To
Fig. 4. Clinical response rates in CLEAR® patients with aspergillosis [10].
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
S35
Fig. 5. Clinical response rates in CLEAR® patients with zygomycosis [12].
date, this represents the largest evaluation of patients with this infection. Of these, 26 evaluable patients had fusariosis without other fungal pathogens. Outcome assessment was performed following course completion or hospital discharge. Overall, 46% of patients were cured or improved and 12% were stabilized. 2.8. Zygomycosis Data of 64 immunocompromised CLEAR® patients with invasive zygomycosis were analysed. Most patients received doses of 4–5 mg/kg/day of ABLC for a median duration of 16 days. Response rates with ABLC by patient subcategory are summarized in Fig. 5 [12].
3. Conclusions Since the arrival of lipid-based formulations of amphotericin B in the late 1990s, few studies have directly compared these formulations with AmBd. However, the outcomes from the CLEAR® database suggest that ABLC has a favourable safety profile and is efficacious in patients with invasive fungal infections. The CLEAR® dataset shows that ABLC results in an overall successful response rate of 72%, with only 13% of patients experiencing a doubling in serum creatinine values. Most serum creatinine elevations were of no clinical consequence. Success rates were observed in aspergillosis, fusariosis, and zygomycosis infections when ABLC was used in both the first- and second-line treatment settings. Compared with AmBd, ABLC appears to have improved efficacy and safety profiles. The overall response rate and safety profile of ABLC in patients who were largely
intolerant of, or refractory to, conventional antifungal therapy were consistent with earlier reported findings. References [1] Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: time for a new “gold standard”. Clin Infect Dis 2003;37:415–25. [2] Taraschi TF, Beggs J. A head to head comparison of the release of amphotericin B from Abelcet and AmBisome in human plasma. J Liposome Res 2000;10:96–8. [3] Legrand P, Cheron M, Leroy L, Bolard J. Release of amphotericin B from delivery systems and its action against fungal and mammalian cells. J Drug Target 1997;4:311–9. [4] Adler-Moore JP, Proffitt RT. Development, characterization, efficacy and mode of action of AmBisome, a unilamellar liposomal formulation of amphotericin B. J Liposome Res 1993;3:429–50. [5] Swenson CE, Perkins WR, Roberts P, et al. In vitro and in vivo antifungal activity of amphotericin B lipid complex: are phospholipases important? Antimicrob Agents Chemother 1998;42:767–71. [6] Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 1996;22(Suppl. 2):S133–44. [7] Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis 1998;27:603–18. [8] Enzon Pharmaceuticals Inc., data on file. [9] Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis 1998;26:1383–96. [10] Pappas PG. Amphotericin B lipid complex in the treatment of invasive fungal infections. Results of the Collaborative Exchange of Antifungal Research (CLEAR), an industry-supported patient registry. Clin Infect Dis 2005;40(Suppl. 6):S379–83. [11] Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–15. [12] Larkin JA, Monteya JA. Efficacy and safety of amphotericin B lipid complex for zygomycosis. Infect Med 2003;20:201–6.
The experience is CLEAR® Pranatharthi Chandrasekar ∗ Division of Infectious Diseases, Wayne State University School of Medicine, Harper Hospital, 3990 John R, 5-Hudson, Detroit, MI, USA
Abstract Conventional amphotericin B has been the ‘gold standard’ for antifungal efficacy, but nephrotoxicity problems limit its clinical utility. In the late 1990s, three lipid-based formulations of amphotericin B were introduced, all of which offered comparable efficacy and reduced renal complications. However, to date, robust safety and comparative efficacy data have been sparse. This paper briefly reviews the available clinical data on amphotericin B lipid complex (ABLC). Also, in detail, it reviews the findings of Collaborative Exchange of Antifungal Research (CLEAR® ), the most extensive dataset on systemic antifungal treatment with the lipid-based agent ABLC. © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Amphotericin B; Amphotericin B lipid complex; CLEAR® ; Aspergillosis; Fusariosis; Zygomycosis
1. Amphotericin B lipid complex—a historical perspective 1.1. Introduction Lipid formulations of amphotericin B emerged in the late 1990s, almost 40 years after the introduction of amphotericin B’s intravenous formulation (amphotericin B desoxycholate, AmBd). Today, three lipid-based compounds are commercially available: ABLC (Abelcet® ); amphotericin B colloidal dispersion (ABCD) and liposomal amphotericin B (L-AmB). Few studies are available that directly compare these lipidbased formulations with AmBd. Aggregate efficacy estimates for lipid-based compounds and conventional amphotericin B are 49% and 32%, respectively, when compared with various invasive fungal infections. It appears that the superior renal safety profile of these agents may contribute to higher response rates against aspergillosis, fusariosis, cryptococcosis, and zygomycosis [1]. All of these lipid-based formulations are pharmacologically distinct and have varying clinical indications. These approved labellings in the USA are summarized in Table 1.
∗
Tel.: +1 313 745 9649; fax: +1 313 993 0302. E-mail address: [email protected].
1.2. Pharmacokinetics In vitro data show that approximately 60–75% of the amphotericin B in ABLC is released within 3 h of administration. In comparison, 95% of L-AmB remains associated with the liposome as long as 72 h after dosing [2–6]. This may explain why, when compared with L-AmB, ABLC is more rapidly taken up by the reticuloendothelial system and therapeutic concentrations are more readily found in tissues that are common sites of fungal infection (e.g. lung, liver, spleen) [2–6]. Hence, rapid onset of action is anticipated, although such rapid release of amphotericin B from ABLC has not been shown to have superior clinical value. High levels of amphotericin B after ABLC are not found in renal tissue, a factor that may explain the low nephrotoxicity profile of ABLC [7].
1.3. Clinical outcome A historical controlled study involving 273 Aspergillusinfected patients with haematological malignancies compared the survival benefits of ABLC with those of AmBd. The researchers found that the median survival was 52 days for the ABLC group (N = 151) compared with 31 days for the AmBd group (N = 31; P = 0.023). This represents an improvement in survival of approximately 68%. Similarly, the all-cause
0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2006.03.017
S32
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
Table 1 Comparison of US-FDA approved product labelling for amphotericin B formulations Pathogen
Amphotericin B desoxycholate
Amphotericin B lipid complex
Amphotericin B colloidal dispersion
Liposomal amphotericin B
Aspergillus Blastomyces Candida albicans Non-albicans Candida Coccidioides Cryptococcus Fusarium Histoplasma Zygomycetes
• • • • • • • • •
• • • • • • • • •
•
•
mortality rates for the two groups were 56% and 71%, respectively (P = 0.017) [8]. ABLC has also been investigated in an open-label, compassionate-use study involving 556 patients. All evaluable patients (N = 291) had either experienced previous antifungal therapy failure (including AmBd) (N = 151) or had been unable to tolerate previous antifungal medication (N = 140) [9]. Of the group of patients who were intolerant of previous therapy and/or who had pre-existing renal insufficiency, 64% were successfully treated with ABLC. ABLC produced a satisfactory response in 52% of patients who had failed previous antifungal therapy [9]. Further, the overall response rates for aspergillosis, zygomycosis, and fusariosis were 42%, 71%, and 82%, respectively [9].
2. The Collaborative Exchange of Antifungal Research (CLEAR® )
• • •
(29%) or documented (70%) fungal infection (Table 3) [10]. The median daily dose of ABLC was 4.40 mg/kg (range 0.2–10 mg) and the median treatment duration was 12 days [10]. Over the trial period, patients were admitted with the following medical conditions (patients may have had more than one underlying condition): leukaemia – 38%; allogeneic bone marrow transplant – 21%; solid organ transplant – 21%; solid tumour – 10%; lymphoma – 8%; graft-versus-host disease – 5%; AIDS – 4%; autologous bone marrow transplant – 4% and peripheral stem cell transplant – 3%. Participants were further classified into five groups: patients refractory to prior antifungal therapy – 40% (N = 1411); patients intolerant of prior antifungal therapy – 16% (N = 573); patients with underlying renal disease and no prior antifungal therapy – 27% (N = 945); patients with underlying renal disease and prior antifungal therapy – 2.4% (N = 84) and patients with no underlying renal disease and no prior antifungal therapy – 12% (N = 431).
2.1. Rationale and demographics 2.2. Overall safety and tolerability The Collaborative Exchange of Antifungal Research (CLEAR® ) is a prospective, multicentre, database that was designed to allow clinicians to share and exchange pharmacoepidemiological data on the treatment of invasive fungal infections with ABLC. Between 1996 and 2000, 3514 patients from more than 160 institutions in the USA and Canada were registered to CLEAR® . Baseline demographics are shown in Table 2 [10]. All patients had received at least four doses of Abelcet® as treatment for a suspected Table 2 CLEAR® patient demographics Age Median Range Age <18 years Age >65 years
46 <1–97 454 (13%) 572 (16%)
Sex Male Female Not specified
2039 (58%) 1466 (42%) 9 (<1%)
Reprinted with permission [10]. © 2005 The University of Chicago Press.
Overall, ABLC was well tolerated by the majority of patients. Only 13% of patients experienced a doubling of baseline serum creatinine levels (median baseline level Table 3 CLEAR® patients by diagnosed fungal infection [10] Infection type
N (%)a
Suspected fungal infection Specified fungal infection Candidiasis/Candidaemia Aspergillosis Multiple pathogens Cryptococcosis Zygomycosis Blastomycosis Histoplasmosis Fusariosis Coccidioidomycosis Penicilliosis Saccharomycosis Others Not specified
1030 (29) 2469 (70) 1062 (30) 436 (12) 362 (10) 97 (3) 55 (2) 15 (<1) 24 (1) 17 (<1) 7 (<1) 3 (<1) 5 (<1) 386 (17) 15 (<1)
a
Percentage of 3514 patients.
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
S33
Table 4 Renal effects of amphotericin B lipid complex by CLEAR® patient category [10] Serum creatinine levels (mg/dL)
Refractory (N = 1411)
Intolerant (N = 573)
Underlying renal disease/no prior antifungal therapya (N = 945)
Underlying renal disease/prior antifungal therapy (N = 84)
No prior antifungal therapya /no renal disease (N = 431)
Median baseline value Median end-of-therapy value Median change
1.20 1.50 0.10
1.40 1.40 0.00
2.00 2.00 0.00
2.00 2.10 −0.10
1.00 1.20 0.20
a
First-line ABLC use.
1.4 mg/dL), whilst 3% of patients required new dialysis [10]. The change in serum creatinine values was not clinically significant in most patients. Table 4 shows the renal effects of ABLC according to the five patient sub-categories [10]. Despite an increased risk for renal impairment in allogeneic haematopoietic stem cell recipients, only 17% experienced an end-of-therapy doubling of serum creatinine levels. 2.3. Overall clinical outcome Responses were classified as successful if clinical signs and symptoms were stabilized, improved or cured. The overall success rate with ABLC was found to be 72% [10]. The CLEAR® database shows that ABLC is effective against all common invasive yeast and mould infections. The specific response rates were: candidiasis (76%, N = 857); aspergillo-
sis (65%, N = 402); cryptococcosis (85%, N = 91); zygomycosis (75%, N = 51); histoplasmosis (92%, N = 24); blastomycosis (85%, N = 13); fusariosis (59%, N = 17); coccidioidomycosis (86%, N = 7) and other mould infections (50%, N = 14). These data are further summarized in Fig. 1 and Fig. 2 [10]. Response rates by patient subclassification are provided in Fig. 3 [10]. Success rates were high in all categories [10]. No significant differences were observed in outcome among patients receiving ABLC as primary therapy or as secondary or salvage therapy. 2.4. Previous azole failure The effect of ABLC on patients who had previously experienced azole therapy failure was investigated using a sub-
Fig. 1. Clinical outcome of CLEAR® patients with yeast infections [10].
Fig. 2. Clinical outcome of CLEAR® patients with mould infections [10].
S34
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
Fig. 3. Clinical outcome of CLEAR® patients by patient subcategory [10].
analysis of 778 CLEAR® patients (median age 50 years; 33% candidaemia/candidiasis). All patients received rescue doses of ABLC. Successful responses were observed in 72% of patients (15% cured; 39% improved; 18% stable) [10]. These results suggest that ABLC may be useful in azole-refractory or azole-resistant candidal and other fungal infections. 2.5. Cryptococcosis The effect of ABLC on the 107 CLEAR® patients with cryptococcal infection was investigated. Overall reported response rate was 85% (cured and improved 66%; stable 19%). Rates were also calculated according to the patient’s underlying condition: CNS infection (86%, N = 78); neutropenia (100%, N = 6); no neutropenia (84%, N = 93) and underlying HIV (87%, N = 52).
(median age 46 years). The overall response rate achieved with ABLC was 63%; 41% were cured or improved and 22% were stabilized. Response rates by patient subcategory are shown in Fig. 4. These data show that, when used as firstline therapy (no prior antifungal therapy and with or without renal disease), ABLC achieves an overall response rate of 67% (N = 210) [10]. This compares favourably with the study by Herbrecht et al. that investigated primary response rates of voriconazole (58%) and AmBd (38%) in the treatment of invasive aspergillosis [11]. Of particular note is the response rate achieved in patients refractory to prior antifungal therapy. In this difficult-to-treat group of patients, treatment with ABLC resulted in a success rate of 57% (N = 250) [10]. In the 19 cases with documented Aspergillus terreus, an infection considered to be resistant to amphotericin B, treatment with ABLC resulted in a response rate of 37% [10].
2.6. Aspergillosis
2.7. Fusariosis
The effect of ABLC on patients with aspergillosis was investigated using a subanalysis of 558 CLEAR® patients
A subanalysis was performed on 28 CLEAR® patients to investigate the effects of ABLC on invasive fusariosis. To
Fig. 4. Clinical response rates in CLEAR® patients with aspergillosis [10].
P. Chandrasekar / International Journal of Antimicrobial Agents 27S (2006) S31–S35
S35
Fig. 5. Clinical response rates in CLEAR® patients with zygomycosis [12].
date, this represents the largest evaluation of patients with this infection. Of these, 26 evaluable patients had fusariosis without other fungal pathogens. Outcome assessment was performed following course completion or hospital discharge. Overall, 46% of patients were cured or improved and 12% were stabilized. 2.8. Zygomycosis Data of 64 immunocompromised CLEAR® patients with invasive zygomycosis were analysed. Most patients received doses of 4–5 mg/kg/day of ABLC for a median duration of 16 days. Response rates with ABLC by patient subcategory are summarized in Fig. 5 [12].
3. Conclusions Since the arrival of lipid-based formulations of amphotericin B in the late 1990s, few studies have directly compared these formulations with AmBd. However, the outcomes from the CLEAR® database suggest that ABLC has a favourable safety profile and is efficacious in patients with invasive fungal infections. The CLEAR® dataset shows that ABLC results in an overall successful response rate of 72%, with only 13% of patients experiencing a doubling in serum creatinine values. Most serum creatinine elevations were of no clinical consequence. Success rates were observed in aspergillosis, fusariosis, and zygomycosis infections when ABLC was used in both the first- and second-line treatment settings. Compared with AmBd, ABLC appears to have improved efficacy and safety profiles. The overall response rate and safety profile of ABLC in patients who were largely
intolerant of, or refractory to, conventional antifungal therapy were consistent with earlier reported findings. References [1] Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: time for a new “gold standard”. Clin Infect Dis 2003;37:415–25. [2] Taraschi TF, Beggs J. A head to head comparison of the release of amphotericin B from Abelcet and AmBisome in human plasma. J Liposome Res 2000;10:96–8. [3] Legrand P, Cheron M, Leroy L, Bolard J. Release of amphotericin B from delivery systems and its action against fungal and mammalian cells. J Drug Target 1997;4:311–9. [4] Adler-Moore JP, Proffitt RT. Development, characterization, efficacy and mode of action of AmBisome, a unilamellar liposomal formulation of amphotericin B. J Liposome Res 1993;3:429–50. [5] Swenson CE, Perkins WR, Roberts P, et al. In vitro and in vivo antifungal activity of amphotericin B lipid complex: are phospholipases important? Antimicrob Agents Chemother 1998;42:767–71. [6] Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 1996;22(Suppl. 2):S133–44. [7] Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis 1998;27:603–18. [8] Enzon Pharmaceuticals Inc., data on file. [9] Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis 1998;26:1383–96. [10] Pappas PG. Amphotericin B lipid complex in the treatment of invasive fungal infections. Results of the Collaborative Exchange of Antifungal Research (CLEAR), an industry-supported patient registry. Clin Infect Dis 2005;40(Suppl. 6):S379–83. [11] Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–15. [12] Larkin JA, Monteya JA. Efficacy and safety of amphotericin B lipid complex for zygomycosis. Infect Med 2003;20:201–6.