Caspofungin plus posaconazole as salvage therapy of invasive fungal infections in immunocompromised patients

Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients. Substantial improvements of treatment have been achieved by the introduction of new antifungal agents including azoles (e.g. posaconazole) and echinocandins (e.g. caspofungin). However, mortality associated with treatment-refractory aspergillosis remains high. Preliminary data suggest that the combination of azoles and echinocandins may increase activity against refractory IA. The objective of the present study was to evaluate efficiency and safety of caspofungin plus posaconazole for salvage therapy in immunocompromised patients. In this monocentric, retrospective study, 31 hospitalised haematopoietic stem cell transplant recipients with IA refractory to primary treatment were treated with a combination therapy of caspofungin 50 mg a day and posaconazole 200 mg four times per day. Efficacy was assessed by signs, symptoms and the degree of pulmonary infiltrate regression. A favourable response was seen in the majority of patients (77%). In two patients (6%), clinical improvement, but no decline in pulmonary infiltrates, was observed. Five patients (16%) did not respond to combination therapy with a fatal outcome in four of them. Combination therapy was well tolerated. No patient discontinued treatment due to toxicity. This study indicates that the combination of caspofungin and posaconazole may provide an effective and tolerable therapy of IA in immunocompromised patients refractory to primary treatment.     

Retrospective evaluation of caspofungin therapy in invasive aspergillosis (RECAM‐IA)

To evaluate caspofungin in high‐risk invasive aspergillosis (IA) patient, a retrospective review of patient characteristics, antifungal therapies and clinical outcomes on hospitalised patients at sites in Russia, Canada, Germany, and Thailand was performed. Fifty‐five patients were included, six with proven and 49 with probable aspergillosis; 76.4% had haematological diseases, 80% were on immunosuppressive drugs, 32.7% were neutropenic at caspofungin initiation. Median duration of prior antifungal therapy was 9 days (range 1–232). Reasons for initiating caspofungin included: disease refractory to first‐line antifungal (49.1%) and toxicities with prior antifungals (18.2%). Median caspofungin therapy duration was 14 days (range 2–62), with a median of 13 days (range 1–62) as monotherapy. Favourable responses were observed in 45.5% of the patients, complete responses in 40% and partial responses in 5.5%; 74.5% survived 7 days after completion of caspofungin therapy with 69.1% having been successfully discharged from the hospital. Few patients (14.6%) on caspofungin switched because of suspected resistance, lack of response or adverse events. There were no increases in hospital stay as a result of adverse events or drug–drug interactions related to caspofungin; 7.3% of patients had a mean value of 13 (±14.11) days of increased stay attributable to treatment failure. Caspofungin was well‐tolerated. It exhibited effectiveness and high survival in treating severe IA patients.     

Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies

BACKGROUND: Caspofungin (CAS) as salvage therapy for refractory invasive aspergillosis (IA) had a response rate of 45% among a heterogeneous group of patients. The use of CAS with other agents is appealing given its unique mechanism of action. Therefore, the authors retrospectively evaluated the efficacy and toxicity of CAS plus liposomal amphotericin B (LipoAMB) in patients with documented (definite or probable) or possible IA. METHODS: Patients were evaluable for outcome if they received CAS/LipoAMB for at least 7 days. Patients who received CAS and LipoAMB sequentially were excluded. All patients were evaluable for toxicity. Outcome was assessed weekly and at the end of therapy. Stable disease and progression were considered treatment failures. RESULTS: Forty-eight patients with documented (n=23) or possible (n=25) IA were identified between March 2001 and December 2001. The majority of the patients (65%) received CAS/LipoAMB as salvage therapy for progressive IA despite 7 or more days of previous LipoAMB monotherapy. The overall response rate was 42%. No significant toxic effects were seen. Factors associated with failure at the end of therapy were documented IA (P=0.03), significant steroid use before the study (P=0.02), and duration of combination therapy for less than 14 days (P=0.01). The response rate in patients with progressive documented IA was low (18%). CONCLUSIONS: The CAS/LipoAMB combination is a promising preemptive therapy for IA and was generally well tolerated. This combination might have limited benefit as salvage therapy for documented IA.     

Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal, caspofungin

Caspofungin, a semisynthetic derivative of the pneumocandin B(0), is the first licensed compound of a new class of antifungal agents, the echinocandins. It attacks the fungal cell by selective inhibition of the beta-(1,3)-d-glucan synthase, which is not present in mammalian cells. In vitro studies have indicated a potent fungicidal effect on Candida species, and in vivo studies in immunocompromised animals with invasive candidiasis demonstrated a favourable outcome. In randomized clinical trials in patients with oropharyngeal/oesophageal and invasive candidiasis, caspofungin was at least as effective as amphotericin B deoxycholate, yet showed a significantly superior safety profile. Of patients with invasive aspergillosis refractory to or intolerant of other antifungal agents, 45% showed a partial or complete response to caspofungin given as a salvage treatment. Also, it demonstrated comparable clinical efficacy but superior tolerability in the empirical antifungal therapy in neutropenic patients compared with liposomal amphothericin B. Caspofungin has an excellent tolerability and a low potential for drug interactions. Thus, caspofungin represents an interesting and clinically valuable new antifungal drug that broadens the available therapeutic armamentarium for the treatment of invasive fungal infections.     

Clinical efficacy and tolerability of caspofungin in a renal transplant patient with Aspergillus flavus lung infection: case report

Organ transplant recipients are at increased risk for severe invasive aspergillosis, and amphotericin deoxycholate has been the standard treatment for many years. Currently, however, lipid formulations are preferred due to their few side effects. Also, a number of new antifungal drugs have been developed including new azoles and echinocandins. Caspofungin is the first of the echinocandin derivatives patented to treat patients with invasive aspergillosis who are refractory or intolerant to other therapies. A renal transplant patient on immunosuppressive treatment with chronic hepatitis B virus infection was admitted with fever, hemophthisis and lung consolidation, diagnosed to be probably caused by Aspergillus flavus. The patient developed cholestatic hepatitis most likely related to itraconazole. Clinical failure and in vitro itraconazole resistance of the isolate was also documented while the patient was receiving itraconazole at a reduced dosage. Caspofungin was administered once a day as ambulatory treatment and was well tolerated. Clinical improvement was observed after 6 weeks of treatment and no hepatic toxicity was documented. Caspofungin seems to be a potentially useful antifungal agent in renal transplant patients with invasive aspergillosis. Further evaluation of the efficacy of caspofungin is needed.     

Update on antifungal treatment of invasive Candida and Aspergillus infections

Invasive Candida and Aspergillus infections are among the most common serious complications occurring in chronically immunosuppressed patients, in particular those with hematological malignancies and transplant recipients. A rational, early systemic antifungal treatment can be based upon imaging diagnostic techniques as well as upon conventional mycological and non-culture-based procedures. The availability of well tolerable and highly efficacious systemic antifungals has improved the spectrum of therapeutic options and the success rates of antifungal treatment. However, with respect to high treatment costs associated with these new agents, it is mandatory to specify indications and limitations for the use of these substances. Voriconazole may well become the new standard primary treatment of invasive aspergillosis. The role of the new echinocandins such as caspofungin, which has recently been approved for salvage treatment of resistant and refractory Aspergillus infections, in primary or combination treatment of invasive aspergillosis must be further studied. Caspofungin is at least as effective as, yet significantly better tolerated than amphotericin B for primary treatment of invasive candidosis in non-neutropenic patients, and has been approved for this indication. The selection of systemic antifungals in patients with invasive Candida infection critically depends upon the identification of Candida species involved, because some non-albicans Candida spp. are resistant to azole antifungals.     

Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin

BACKGROUND: Pulmonary aspergillosis and other invasive fungal infections (IFIs) commonly complicate the management of patients with acute leukemia. Standard amphotericin-based therapies may be ineffective for many patients and the available salvage agents (itraconazole and caspofungin) are reported to possess only moderate activity against resistant infections. Laboratory evidence suggests a synergistic interaction between amphotericin and caspofungin. The authors treated a group of patients with amphotericin-refractory IFIs with the combination of caspofungin and amphotericin (or liposomal amphotericin). METHODS: A retrospective evaluation of patients with amphotericin-resistant IFIs was conducted. Diagnosis was based on clinical, radiographic, and when available, microbiologic data. Response to combination antifungal therapy was graded as either favorable or unfavorable. Favorable responses included improvement of both clinical and radiographic signs of fungal pneumonia. All other responses were graded as unfavorable. RESULTS: Thirty patients were included in this analysis. Twenty-six patients had acute leukemia. Based on recently published criteria, the IFIs were classified as proven in 6 patients, probable in 4 patients, and possible in 20 patients. The median duration and dose of amphotericin monotherapy were 12 days (range, 4-65 days) and 7.8 mg/kg (range, 4.2-66.1 mg/kg), respectively. The median duration of combination therapy was 24 days (range, 3-74 days). Eighteen patients (60%) experienced a favorable antifungal response. Twenty patients with acute leukemia received combination therapy for fungal pneumonias arising during intensive chemotherapy treatments. Favorable responses were observed in 15 of these patients (75%), and antifungal response did not depend on the response of the underlying leukemia. Survival to hospital discharge was significantly better (P < 0.001) in patients having a favorable response. Mild to moderate nephrotoxicity was noted in 50% of patients, necessitating the substitution of liposomal amphotericin. Mild elevation of alkaline phosphatase levels occurred in 30% of patients. Caspofungin was temporarily withheld from one patient who developed moderate but reversible biochemical hepatotoxicity. CONCLUSIONS: The antifungal combination of caspofungin and amphotericin can be administered safely to high-risk patients with hematologic malignancies. Although an absolute assessment of efficacy is limited by the design of this study, encouraging outcomes were noted for many patients. The authors plan to evaluate this regimen further in a randomized clinical trial.     

The first echinocandin: caspofungin

The antifungal agent caspofungin is the first echinocandin that has been approved in the US and in Europe for treatment of invasive aspergillosis in adult patients who are refractory to or intolerant of conventional amphotericin B, its lipid-based formulations, and/or itraconazole. It is given as a 70 mg loading dose and a 50 mg daily maintainance dose as a one hour infusion. Due to low intestinal absorption an oral formulation has not been developed. Caspofungin is active against Candida spp. and Aspergillus spp. by inhibition the synthesis of beta-(1,3)-D-glucan, a cell wall component. The drug is inactive against Cryptococcus spp., Fusarium spp., Trichosporon spp., Rhizopus spp., and Pseudoallescheria spp. In invasive aspergillosis caspofungin resulted in higher response rates compared to a historic control under standard therapy. Efficacy data on persistently febrile neutropenic patients are pending. In several multicenter randomised double blind trials on candida infections caspofungin proved to be at least non-inferior to standard therapies. Reports of combination therapy or highly effective antifungal treatment (HEAT) in limited patient numbers are promising. New trials of combination therapy are warranted.     

Clinical Efficacy and Tolerability of Caspofungin in a Renal Transplant Patient with Aspergillus flavus Lung Infection: Case Report

Abstract

Organ transplant recipients are at increased risk for severe invasive aspergillosis, and amphotericin deoxycholate has been the standard treatment for many years. Currently, however, lipid formulations are preferred due to their few side effects. Also, a number of new antifungal drugs have been developed including new azoles and echinocandins. Caspofungin is the first of the echinocandin derivatives patented to treat patients with invasive aspergillosis who are refractory or intolerant to other therapies.

A renal transplant patient on immunosuppressive treatment with chronic hepatitis B virus infection was admitted with fever, hemophthisis and lung consolidation, diagnosed to be probably caused by Aspergillus flavus. The patient developed cholestatic hepatitis most likely related to itraconazole. Clinical failure and in vitro itraconazole resistance of the isolate was also documented while the patient was receiving itraconazole at a reduced dosage. Caspofungin was administered once a day as ambulatory treatment and was well tolerated. Clinical improvement was observed after 6 weeks of treatment and no hepatic toxicity was documented.

Caspofungin seems to be a potentially useful antifungal agent in renal transplant patients with invasive aspergillosis. Further evaluation of the efficacy of caspofungin is needed.     

Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients

BACKGROUND: Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). METHODS: The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm(3) at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. RESULTS: Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). CONCLUSIONS: A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA.     

Clinical evidence for caspofungin monotherapy in the first‐line and salvage therapy of invasive Aspergillus infections

In 2001, caspofungin received market authorisation by the FDA and EMA and is globally licensed for several indications, including candidiasis, empirical antifungal therapy in patients with neutropenic fever of unknown origin and treatment of invasive aspergillosis in patients refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B or itraconazole. Despite the lack of phase III data in first‐line treatment of invasive aspergillosis, increasing evidence supports the use of first‐line therapy. Here, we analyse the evidence of therapeutic activity, represented by favourable response rates, of caspofungin for invasive aspergillosis. A systematic literature search was conducted to identify international presentations and papers reporting monotherapy with caspofungin. Efficacy data are summarised separately for first‐line and salvage therapy. Thirty‐one papers and published abstracts reported caspofungin therapy for aspergillosis. Fifteen full papers and two abstracts fulfilled the criteria of reporting significant outcome data for caspofungin monotherapy for invasive aspergillosis. Consistent with other analyses and the known safety profile, few adverse events and associated terminations of caspofungin medication have been reported. Although a randomised, comparative, prospective study using caspofungin in this indication is still lacking, growing evidence supports the efficacy of this echinocandin not only for salvage but also for first‐line therapy.     

Amphotericin B lipid complex versus liposomal amphotericin B monotherapy for invasive aspergillosis in patients with hematologic malignancy

BACKGROUND: Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients with hematologic malignancy (HM). There are 2 lipid formulations of amphotericin B (AMB) currently in widespread use: AMB lipid complex (ABLC) and liposomal AMB (L-AMB). There are limited data comparing the efficacy and safety of these 2 agents in the treatment of IA in patients with cancer. METHODS: The authors retrospectively studied 381 consecutive patients with HM who had proven or probable IA (according to European Organization for Research and Treatment of Cancer/Mycosis Study Group of the National Institute of Allergy and Infectious Diseases criteria) between June 1993 and December 2005. Of these patients, 158 received primary antifungal therapy with either L-AMB (n=106) or ABLC (n=52). The number of salvage antifungal regimens given were 51 L-AMB regimens and 30 ABLC regimens. It should be noted that the population described in this report was not typical of the hematologic cancer population with IA because of the advanced stage and the severity of the underlying diseases. RESULTS: Risk factors for IA, such as underlying malignancy, neutropenia, steroid use, admission to an intensive care unit, and the presence of graft-versus-host disease, were comparable among the study drug group in the primary or salvage setting. Likewise, comparable distribution of types of Aspergillus species and the presence of disseminated IA were observed. Response to primary or salvage therapy was equally poor in both drug study groups regardless of treatment modality (range, 7.7-15.8% response). In the primary therapy group, ABLC was associated with significantly higher nephrotoxicity than L-AMB (P<.001). CONCLUSIONS: Among patients with HM, primary therapy and salvage therapy for IA with either ABLC or L-AMB as single agent were associated equally with poor outcome. L-AMB appeared to be less nephrotoxic in the primary therapy setting.     

Does combination of lipid formulation of amphotericin B and echinocandins improve outcome of invasive aspergillosis in hematological malignancy patients?

BACKGROUND:

In vitro and in vivo studies suggested that combination of lipid formulation of amphotericin B (L‐AMB) and echinocandins may have a synergistic or additive effect against Aspergillus. Furthermore, clinical studies suggested that this combination may improve response of invasive aspergillosis (IA).

METHODS:

Between August 1993 and June 2008, the authors identified a total of 159 patients with hematological malignancies who received salvage therapy for IA, with L‐AMB alone, echinocandins alone, or a combination of L‐AMB and echinocandins. Clinical characteristics, response to salvage therapy, and death up to 12 weeks after initiation of salvage therapy were retrospectively determined for all patients.

RESULTS:

Seventy patients received salvage therapy with L‐AMB, 18 patients received echinocandins alone (89% of whom received caspofungin), and 71 patients received the combination therapy of amphotericin B and echinocandins (90% of who received caspofungin). The 3 salvage treatment groups were comparable in regard to clinical characteristics; graft versus host disease was more frequently encountered in the echinocandin group, whereas more patients in the L‐AMB and combination groups had neutropenia and received immunotherapy. The response to salvage therapy was better in the echinocandin group (9% L‐AMB, 28% echinocandins, and 21% for combination therapy). The 3 groups had a comparable rate of Aspergillus‐related death (58%‐64%) and overall mortality (61%‐67%).

CONCLUSIONS:

The combination of L‐AMB and echinocandins offered no advantage in terms of improving response or reducing mortality over either drug alone. Hence, this combination will only add to the cost of therapy without any improvement in outcome in patients with hematological malignancies. Cancer 2010. © 2010 American Cancer Society.     

Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis

BACKGROUND: Invasive aspergillosis (IA) is associated with poor outcome in patients with hematologic malignancy treated with amphotericin B (AMB)-based therapy. Itraconazole (ITC), a triazole with activity against Aspergillus, has been used in combination with AMB or lipid formulations of AMB (LipoAMB) in the treatment of IA, although the efficacy of this strategy is uncertain. METHODS: To determine whether the addition of ITC to LipoAMB improves outcome of IA, the authors retrospectively studied 179 consecutive patients with hematologic malignancies and definite or probable IA who received primary antifungal therapy with either LipoAMB (n = 146), or lipoAMB plus ITC (n = 33) between June 1993 and June 2003. In view of the erratic absorption of ITC tablets, only patients who received either intravenous or liquid ITC were analyzed. Patients who received < 1 week of treatment were excluded. RESULTS: Evaluable patients in both groups (LipoAMB: n =101; ITC and LipoAMB: n = 11) had comparable distribution of risk factors of poor outcome such as neutropenia at onset of IA, persistent neutropenia, systemic steroids, previous antifungal prophylaxis, admission to the intensive care unit, disseminated IA, previous bone marrow transplant, and IA due to infection by a non-fumigatus Aspergillus species. Response to primary antifungal therapy was equally poor in both groups (LipoAMB group: 10%; ITC and LipoAMB group: 0%; P = not significant). CONCLUSIONS: In the authors' 10-year study of patients with hematologic malignancy and IA, the response rate to LipoAMB given as primary therapy was very poor. In a comparable group of patients, the addition of ITC did not result in a therapeutic benefit.     

Pharmacoeconomic assessment of therapy for invasive aspergillosis

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised hosts. Economic expenditures prompted by this invasive fungal infection (IFI) are significant. Although, the duration and associated costs of hospitalization comprise the largest proportion of costs in large surveillance studies, the newer oral antifungal agents may impact significantly on these costs. A review of the pharmacoeconomic (PE) studies is provided focussing on primary therapy, salvage therapy, empiric therapy and prophylaxis for IA. PE evaluations have demonstrated the cost effectiveness and dominance of voriconazole for targeted primary treatment of IA compared with other available agents. Differences in the drug choice and analytic methodology of the PE analyses of empiric antifungal strategy hamper definitive conclusions about the agents employed as empiric antifungal that may be directed at suspected IA although both caspofungin and voriconazole appear to be cost effective and dominant over liposomal amphotericin B (LAmB), whereas LAmB is more costly than conventional amphotericin B. Posaconazole is the most cost‐effective agent for antifungal prophylaxis against IFI and IA.     

Aspergillus terreus: an emerging amphotericin B-resistant opportunistic mold in patients with hematologic malignancies

BACKGROUND: Invasive aspergillosis (IA) has emerged as a common cause of morbidity and mortality among immunocompromised patients. At The University of Texas M. D. Anderson Cancer Center (Houston, TX), Aspergillus terreus is second to A. fumigatus as the most common cause of IA. In the current study, the authors compared the risk factors and outcomes associated with IA caused by A. terreus and IA caused by A. fumigatus. METHODS: The authors retrospectively reviewed the medical records of 300 patients who received care at our institution between 1995 and 2001 and who had cultures that were positive for Aspergillus infection, including 90 patients whose cultures were positive for A. fumigatus and 70 patients whose cultures were positive for A. terreus. RESULTS: Thirty-two patients with IA caused by A. terreus and 33 patients with IA caused by A. fumigatus were evaluated. The two groups were comparable in terms of age, gender, and underlying disease. Leukemia was the most common underlying malignancy (84%). More than 40% of patients in each group had undergone bone marrow transplantation. There was a trend toward a higher frequency of neutropenia among patients with IA caused by A. terreus (P = 0.12). IA caused by A. terreus was considered to be nosocomial in origin significantly more frequently compared with IA caused by A. fumigatus (P = 0.03). In vitro, A. terreus was found to be more resistant to amphotericin B (minimal inhibitory concentration [MIC90], 4.0 microg/mL) than to antifungal therapy (MIC90, 1.0 Hg/mL) in the isolates that were tested (< 50% of all isolates). The overall rate of response to antifungal therapy was 39% for patients with A. fumigatus infection, compared with 28% for patients with A. terreus infection (P = 0.43). CONCLUSIONS: Despite the decreased in vitro susceptibility of A. terreus (relative to A. fumigatus) to amphotericin B, the two groups within the current patient population had comparably poor responses to amphotericin B preparation and somewhat improved responses to posaconazole.     

Aspergillus galactomannan testing in patients with long-term neutropenia: implications for clinical management.

We carried out a prospective study on galactomannan enzyme immuno assay (GEI) (Platelia Aspergillus EIA, Bio-Rad) testing for diagnosis of invasive aspergillosis (IA) in serum and broncho-alveolar lavage (BAL) in 200 patients with hematological malignancies and profound neutropenia. The incidence of proven and probable IA was 6% and 5.5%, respectively. In patients with fever or pneumonia, a single-positive GEI test result (galactomannan index >or= 0.5) had excellent specificity (100%). Sensitivity was relatively low (40%) at onset of fever, but increased to 94.7% after 6 days of fever. In patients with infiltrates in chest X-ray or computed tomography scan (n = 48), GEI testing in BAL had a favorable diagnostic accuracy as compared with GEI testing in serum (sensitivity 100% versus 71%). Our findings indicate that antifungal therapy should be started immediately at onset of fever in neutropenic patients with positive GEI tests. In patients with fever refractory to broad-spectrum antibiotics (>or=6 days of fever), the high diagnostic accuracy makes GEI testing a valuable diagnostic tool and questions the common strategy to carry out antifungal treatment irrespective of diagnostic testing in this situation. Our data also show that GEI testing in BAL can be useful for early diagnosis of IA in patients with hematological malignancies and pulmonary infiltrates.     

Randomised,multicentre trial of micafungin vs. an institutional standard regimen for salvage treatment of invasive aspergillosis

Invasive aspergillosis remains associated with significant morbidity and mortality, necessitating new options for salvage therapy. The objective of this study was to evaluate the efficacy and safety of micafungin as salvage monotherapy in patients with invasive aspergillosis. Patients with proven or probable invasive aspergillosis, who were refractory or intolerant to previous systemic antifungal therapy, were randomised 2 : 1 to receive 300 mg day^?1 intravenous micafungin monotherapy or an intravenous control monotherapy [lipid amphotericin B (5 mg kg^?1 day^?1), voriconazole (8 mg kg^?1 day^?1) or caspofungin (50 mg day^?1)] for 3–12 weeks. Patients underwent final assessment 12 weeks after treatment start. Seventeen patients with invasive aspergillosis (proven, n = 2; probable, n = 14; not recorded, n = 1) participated in the study (micafungin arm, n = 12; control arm, n = 5). Three patients each in the micafungin (25.0%; 95% CI: 5.5–57.2) and control arm (60.0%; 95% CI: 14.7–94.7) had successful therapy at end of treatment as assessed by an Independent Data Review Board. Eleven patients died; six due to invasive aspergillosis. No deaths were considered related to study treatment. During this study it became increasingly common to use combination treatment for salvage therapy. Consequently, enrolment was low and the study was discontinued early. No clear trends in efficacy and safety can be concluded.     

Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial)

BACKGROUND: Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds. METHODS: Patients with proven or probable IA were randomized in a prospective, open pilot study to receive either a combination of liposomal amphotericin B (AmB) at the standard dose (3 mg/kg daily) and caspofungin at the standard dose or monotherapy with a high-dose AmB regimen (10 mg/kg daily). RESULTS: Thirty patients (21 men and 9 women) with hematologic malignancies were analyzed, and there were 15 patients in each arm. The median duration of treatment was 18 days for the combination group and 17 days for the high-dose monotherapy group. At the end of treatment, there were significantly more favorable overall responses (partial or complete responses; P = .028) in the combination group (10 of 15 patients; 67%) compared with the high-dose monotherapy group (4 of 15 patients; 27%). Survival rates at 12 weeks after inclusion were 100% and 80%, respectively. Infusion-related reactions occurred in 3 patients in the high-dose monotherapy group. A 2-fold increase in serum creatinine occurred in 4 of 17 patients (23%) who received high-dose monotherapy and 1 of 15 patient (7%) who received combination therapy; hypokalemia <3 mmol/L occurred in 3 patients and 2 patients, respectively. CONCLUSIONS: The combination of liposomal AmB and caspofungin was promising as therapy for IA compared with monotherapy. A trial that includes more patients will be required next to confirm the results of this pilot study.     

A rescue therapy with a combination of caspofungin and liposomal amphotericin B or voriconazole in children with haematological malignancy and refractory invasive fungal infections

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5–17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3–69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3–14) days and 91 patient days for LAmB + caspofungin combination and 49 (7–126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve‐week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies.