Case reports. Secondary prophylaxis with liposomal amphotericin B after invasive aspergillosis following treatment for haematological malignancy

We report our recent experience with two cases of invasive pulmonary aspergillosis in patients who were both undergoing chemotherapy, one for acute myeloid leukaemia and the other for primary amyloidosis. Both patients had bad prognostic factors and were in very poor clinical condition, but both recovered from infection after a prolonged therapy with liposomal amphotericin B (AmBisome) without signs of toxicity.     

Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials

Background:

Objectives were to compare systemic mould-active vs fluconazole prophylaxis in cancer patients receiving chemotherapy or haematopoietic stem cell transplantation (HSCT).

Methods:

We searched OVID MEDLINE and the Cochrane Central Register of Controlled Trials (1948-August 2011) and EMBASE (1980-August 2011). Randomised controlled trials of mould-active vs fluconazole prophylaxis in cancer or HSCT patients were included. Primary outcome was proven/probable invasive fungal infections (IFI). Analysis was completed by computing relative risks (RRs) using a random-effects model and Mantel–Haenszel method.

Results:

From 984 reviewed articles, 20 were included in this review. Mould-active compared with fluconazole prophylaxis significantly reduced the number of proven/probable IFI (RR 0.71, 95% CI 0.52 to 0.98; P=0.03). Mould-active prophylaxis also decreased the risk of invasive aspergillosis (IA; RR 0.53, 95% confidence interval (CI) 0.37–0.75; P=0.0004) and IFI-related mortality (RR 0.67, 95% CI 0.47–0.96; P=0.03) but is also associated with an increased risk of adverse events (AEs) leading to antifungal discontinuation (RR 1.95, 95% CI 1.24–3.07; P=0.004). There was no decrease in overall mortality (RR 1.0; 95% CI 0.88–1.13; P=0.96).

Conclusion:

Mould-active compared with fluconazole prophylaxis significantly reduces proven/probable IFI, IA, and IFI-related mortality in cancer patients receiving chemotherapy or HSCT, but increases AE and does not affect overall mortality.(PROSPERO Registration: CRD420111174)     

Current scenario of cryptococcosis and antifungal susceptibility pattern in India: a cause for reappraisal

This study analysed the spectrum, antifungal susceptibility pattern, clinical course and molecular epidemiology of cryptococcosis. Four hundred and thirty-nine samples obtained from 378 meningitis patients were processed by standard procedures. Minimum inhibitory concentration (MIC) of fluconazole and amphotericin B for the isolates was tested by broth micro dilution and by E-strip method. Molecular analysis by random amplified polymorphic DNA-PCR of eight isolates was performed using M13 primer. Cryptococcosis was diagnosed in 35 patients [HIV-1 seropositive (19) and apparently immunocompetent (16)]. Cryptococcus neoformans var. neoformans (serotype A and D) was the predominant isolate on phenotypic identification. Three C. neoformans var. gattii were isolated from HIV-1 seropositive (2) and apparently immunocompetent (1) patients. MIC 90 for amphotericin B and fluconazole were 1 and 8 μg ml⁻¹ respectively. On RAPD-PCR, less diversity was seen among Indian isolates. AIDS remains the single most important risk factor for cryptococcosis. Rising MIC of the available induction and maintenance drugs is of grave concern. The DNA typing technique showed less diversity among Indian strains. Routine surveillance and application of molecular typing methods are crucial to know the baseline and existing pattern of cryptococcosis.     

Epidemiology of invasive fungal infections and rationale for antifungal therapy in patients with haematological malignancies

Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7‐month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty‐four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes. Fifty‐two of 117 patients (44%) received antifungal prophylaxis, 81 of 117 (69%) received empirical (31/117; 26%) or pre‐emptive (50/117; 43%) antifungal therapy and four of 117 patients (3.4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre‐emptively. Twenty‐nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections were rare.     

Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine

We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occurred in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.     

Cost‐effectiveness of amphotericin B formulations in the treatment of systemic fungal infections

Amphotericin formulations, indicated for invasive fungal infections (IFIs), vary in effectiveness, safety and costs. In Brazil, only the conventional formulation is provided by the Public Health System. The aim of this study was to perform a cost‐effectiveness analysis comparing conventional amphotericin B (CAB), liposomal amphotericin B (LAB) and amphotericin B lipid complex (ABLC). Therefore, a decision tree was developed. The model began with high‐risking patients on suspicion or confirmation of IFI. The analysis was conducted under the perspective of the Brazilian Public Health System. Model health states were defined according to medication use and clinical evolution. Clinical efficacy (cure) and transition probabilities were derived from the literature. Resource use was estimated from Brazilian data. Time horizon followed the maximum treatment time determined in the patient information leaflets (3 or 6 weeks). One‐way and probabilistic‐sensitivity analyses were conducted. The conventional formulation was the most cost‐effective. No dominance was observed; however, high incremental cost‐effectiveness ratios were obtained for LAB (USD 313 130) and ABLC (USD 1 711 280). Sensitivity analyses demonstrated the robustness of the results. CAB is the most cost‐effective treatment, followed by LAB and ABLC. Although CAB presents critical safety aspects, the high acquisition costs of the other formulations prevent their large‐scale use in Brazil.     

Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment

The treatment of colorectal cancer is rapidly becoming a significant financial burden to health-care systems within economically developed nations. A current challenge for oncologists and health-care payers is to integrate new, often high-cost, biologic therapies into clinical practice. Inherent to this process is the consideration of cost-effectiveness. The aim of this study was to compare the cost-effectiveness of cetuximab plus irinotecan with an appropriate comparator from a National Health Service (NHS) perspective. This economic evaluation is a trial-based study of cetuximab vs active/best supportive care. Effectiveness estimates for the treatment groups were modelled from key clinical trials. Cunningham et al (2004) compared cetuximab/irinotecan with cetuximab monotherapy; Cunningham et al (1998) compared irinotecan monotherapy in a second-line setting with supportive care. Modelling was necessary owing to an absence of head-to-head clinical trial data of cetuximab/irinotecan vs current standard care. Costs were calculated for the study drugs received, associated administration, palliative chemotherapy for patients in the standard care arm and other nonchemotherapy resources. The discounted life-expectancy of patients treated with cetuximab/irinotecan was 0.91 life-years, and 0.47 discounted life-years for patients receiving active/best supportive care. Patients treated with cetuximab/irinotecan accumulated mean additional costs of 18 901 pounds per patient relative to the comparator arm, with 11 802 pounds attributable to cetuximab. The incremental cost per life-year gained with cetuximab/irinotecan therapy compared with active/best supportive care was 42 975 pounds . The incremental cost per quality adjusted life-year gained was 57 608 pounds . The incremental cost per life-year gained for cetuximab/irinotecan is relatively high compared with other health-care interventions. However, this result should be considered in the context of a number of factors specific to the treated patient population.     

Posaconazole prophylaxis – impact on incidence of invasive fungal disease and antifungal treatment in haematological patients

Since two large‐scale, randomised studies on posaconazole prophylaxis have demonstrated a clear benefit for patients at high risk for contracting invasive fungal disease (IFD), posaconazole prophylaxis has been adopted as standard of care for this patient collective. Several years on from implementation at our institution, we wanted to evaluate its impact on the incidence and use of empirical antifungal therapy in a real‐life setting. We analysed retrospectively incidence and severity of IFD in high‐risk patients with prophylaxis, using a historical cohort as comparator. A total of 200 patients had either received the extended spectrum triazole posaconazole in prophylactic dosage of 200 mg tid or empirical antifungal therapy. Disease events were analysed by application of the revised EORTC/MSG definitions for IFD. Before posaconazole prophylaxis, we recorded 57/100 cases of IFD which was reduced to 28/100 with prophylaxis. The empirical use of antifungal drugs was reduced to 41% from 91% in the non‐prophylaxis cohort. Furthermore, we observed a shift in the categorisation of IFD according to EORTC/MSG criteria. Our data suggest that posaconazole was effective in reducing the rate and probability of invasive fungal disease in high‐risk patients.     

Posaconazole for primary antifungal prophylaxis in patients with acute myeloid leukaemia or myelodysplastic syndrome during remission induction chemotherapy: a single‐centre retrospective study in Korea and clinical considerations

Posaconazole was introduced as the primary antifungal prophylaxis (PAP) in acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) patients during remission induction chemotherapy. Data on breakthrough invasive fungal infections (IFIs) from various centres are essential, as there are several considerations in treating IFIs in the posaconazole era. The aim of this study was to evaluate the effectiveness of posaconazole PAP and identify characteristics of IFIs at a single centre in Korea. We retrospectively reviewed consecutive patients with AML/MDS undergoing remission induction chemotherapy between December 2010 and November 2013. Of the 424 patients, 140 received posaconazole and 284 received fluconazole prophylaxis. The incidence of breakthrough proven/probable IFIs (15.5% vs. 2.9%, P < 0.001) and empirical antifungal treatment (EAFT) (45.8% vs. 12.9%, P < 0.001) decreased in the posaconazole group compared to the fluconazole group. In the posaconazole PAP group, two cases of breakthrough mucormycosis were noted among 13 proven/probable/possible IFI cases (15.4%). Overall and IFI‐related mortality was 12.1% and 1.9% respectively. Fungus‐free survival was significantly higher in the posaconazole group (74.7% vs. 87.1%, P = 0.028). Breakthrough IFIs and EAFT decreased significantly after posaconazole PAP. The benefit in fungus‐free survival was noted with posaconazole PAP. Clinicians should be vigilant to identify non‐Aspergillus IFIs with active diagnostic effort.     

Port-a-cath-related Fusarium oxysporum infection in an HIV-infected patient: treatment with liposomal amphotericin B

Summary. The first case of Port-a-cath-related disseminated fusariosis in an HIV-infected patient is presented. Antifungal treatment with liposomal amphotericin B (AmBisome) in a dose of 2 mg kg^-1 day^-1 for 14 days was successful.
Zusammenfassung. Wir berichten über den ersten Fall einer Port-a-cath assoziierten disseminierten Fusariose bei einem HIV-infizierten Patienten. Die systemische antimykotische Therapie mit liposomal verkapseltem Amphotericin B (2 mg kg^-1 d^-1über 14 Tage) war erfolgreich.     

Cost-effectiveness of systemic therapies for metastatic pancreatic cancer

PurposeGemcitabine and capecitabine (gem-cap), gemcitabine and erlotinib (gem-e), and folfirinox (5-fluorouracil–leucovorin–irinotecan–oxaliplatin) are new treatment options for metastatic pancreatic cancer, but they are also more expensive and potentially more toxic than gemcitabine alone (gem). We conducted a cost-effectiveness analysis of these treatment options compared with gem.MethodsA Markov model was constructed to examine costs and outcomes of gem-cap, gem-e, folfirinox, and gem in patients with metastatic pancreatic cancer from the perspective of a government health care plan. Ontario health economic and costing data (2010 Canadian dollars) were used. Efficacy data for the treatments were obtained from the published literature. Resource utilization data were derived from a chart review of consecutive metastatic patients treated for pancreatic cancer at Princess Margaret Hospital, Toronto, Ontario, 2008–2009, and supplemented with data from the literature. Utilities were obtained by surveying medical oncologists across Canada using the EQ-5D. Incremental cost-effectiveness ratios (icers) were calculated.ResultsThe icers for gem-cap, gem-e, and folfirinox compared with gem were, respectively, CA$84,299, CA$153,631, and CA$133,184 per quality-adjusted life year (qaly). The model was driven mostly by drug acquisition costs. Given a willingness-to-pay (wtp) threshold greater than CA$130,000/qaly, folfirinox was most cost-effective treatment. When the wtp threshold was less than CA$80,000/qaly, gem alone was most cost-effective. The gem-e option was dominated by the other treatments.ConclusionsThe most cost-effective treatment for metastatic pancreatic cancer depends on the societal wtp threshold. If the societal wtp threshold were to be relatively high or if drug costs were to be substantially reduced, folfirinox might be cost-effective.     

Susceptibility of clinical isolates of Fusarium to antifungal drugs

Summary. The inhibitory activities of amphotericin B, fluconazole, itraconazole, miconazole, ketoconazole and terbinafine against nine isolates from clinically apparent infections of Fusarium solani , four isolates of Fusarium moniliforme and 10 isolates of Fusarium oxysporum were determined with an agar diffusion method (Neo-sensitabs) and an agar dilution method. The inhibition zones obtained with antifungal Neo-sensitabs need very careful interpretation. We did not find a good correlation between the agar diffusion method using Neo-sensitabs preloaded with azoles and amphotericin B and the agar dilution method. Amphotericin B (12/23) and terbinafine (18/23) showed good activity. Miconazole (7/23) and ketoconazole (3/23) had poor inhibitory activity. Fluconazole and itraconazole (0/23) had no in vitro activity against any of the isolates tested.
Zusammenfassung. Die inhibitorische Aktivität von Amphotericin B, Fluconazol, Itraconazol, Miconazol, Ketoconazol und Terbinafin gegen 9 klinische Isolate von Fusarium solani , 4 von Fusarium moniliforme und 10 von Fusarium oxysporum wurde mit einer Agar-Diffusionstechnik (Neo-sensitabs) und einer Agar-Dilutionsmethode untersucht. Die Hemmhöfe mit Neo-sensitabs müssen mit Vorsicht interpretiert werden. Es wurde keine gute Korrelation zwischen der Agar-Diffusionstechnik mit Neo-sensitabs, beladen mit Azolen und Amphotericin B, und der Agar-Dilutionstechnik gefunden. Amphotericin B (12/23) und Terbinafin (18/23) zeigen eine gute Aktivität. Miconazol (7/23) und Ketoconazol (3/23) haben nur schwache inhibitorische Aktivität. Fluconazol und Itraconazol (0/23) zeigen in vitro keine Aktivität gegen die untersuchten Fusarium -Stämme.     

In vitro antifungal activity of Indian liposomal amphotericin B against clinical isolates of emerging species of yeast and moulds,and its comparison with amphotericin B deoxycholate,voriconazole, itraconazole and fluconazole

Fungisome^TM is a liposomal preparation of amphotericin B (AMB), already marketed in India. However, its antifungal activity has not been evaluated against a wide range of fungal pathogens. The study was planned to elucidate the in vitro antifungal activity of Fungisome^TM against wide range of fungi and compare it with AMB deoxycholate (AMB‐d), voriconazole (VOR), itraconazole (ITR) and fluconazole (FLU). Minimum inhibitory concentrations (MICs) of the drugs were determined for 262 clinical fungal isolates, including yeast, dimorphic and filamentous fungi, by broth microdilution method approved by Clinical and Laboratory Standards Institute, USA (yeast, M27‐A3; filamentous fungi, M38‐A2). The MIC_90s of Fungisome^TM were 0.125, 0.5 and 0.25 mg l^?1 against yeast, filamentous and dimorphic fungi respectively. In comparison, MIC_90s of AMB‐d, FLU, ITR and VOR were 1, 1 and 1 mg l^?1 (AMB‐d), 4, 64 and 64 mg l^?1 (FLU), 1, 16 and 16 mg l^?1 (ITR) and 0.5, 4 and 16 mg l^?1 (VOR) against yeast, filamentous and dimorphic fungi respectively. The MIC of Fungisome^TM was two to 16‐fold lower than AMB‐d. These results reveal an efficient in vitro activity of Fungisome^TM.     

Fluconazole vs. amphotericin B for the management of candidaemia in adults: a meta-analysis

The incidence of bloodstream infections caused by Candida species is rising. Few published studies have compared the efficacy of fluconazole with that of amphotericin B. We performed a meta-analysis of the prospective studies that compared fluconazole and amphotericin B for the treatment of candidaemia in adults. Data on total mortality, candidaemia-attributable mortality, efficacy, microbiological failure, and toxicity were extracted from eligible studies. All studies appeared homogeneous with respect to the outcome measures. Most patients were at relatively low risk for death as evidenced by the low average physiologic score and the lack of intense immunosuppression. The odds ratios (OR) of treatment with amphotericin B versus fluconazole and 95% confidence intervals (CI) were as follows: total mortality (OR, 1.06; CI, 0.89-1.25), candidaemia-attributable mortality (OR, 1.0; CI, 0.70-1.45), clinical response (OR, 1.14; CI, 0.93-1.39) and microbiological failure according to all Candida species (OR, 0.99; CI, 0.78-1.26). A trend favouring amphotericin B was seen in mycological eradication of non-albicans Candida species (OR, 0.70; CI, 0.47-1.06). Finally, amphotericin B was more toxic than fluconazole (OR, 2.94; CI, 2.14-4.4). In conclusion, fluconazole is as efficacious and less toxic than amphotericin B in stable, not severely immunosuppressed candidaemic patients at low risk for death. However, fluconazole may be less effective than amphotericin B in candidaemias caused by some non-albicans Candida species.     

Chronic rhinocerebral mucormycosis: a rare case report and review of the literature

Rhinocerebral mucormycosis is an invasive infection caused by filamentous fungi of the Mucoraceae family. The rhinocerebral form of the disease represents the most common form and has two distinct clinical entities. The common presentation consists of a rapidly progressive infection with high mortality rate, while the other presentation is that of a chronic infection with lower mortality. In the present paper we report a rare case of chronic rhinocerebral mucormycosis. An 85‐year‐old male with a 6‐month history of purulent and odorous nasal discharge, and sporadic episodes of epistaxis and anosmia, presented to the outpatient department of our clinic. Initial cultures were positive only for Pseudomonas aeruginosa. The patient was unresponsive to ciprofloxacin treatment, developing necrotic areas of the nasal septum suspicious for rhinocerebral mucormycosis. Admission to the ENT clinic followed, with histopathologic evaluation of the vomer bone confirming the diagnosis. The patient was treated with amphotericin B and was discharged 3 weeks later on oral posaconazole therapy. Chronic rhinocerebral mucormycosis may present with atypical symptoms or coinfection with another agent. A high degree of clinical suspicion is required for correct diagnosis and prompt initiation of appropriate treatment.     

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.     

Addition of DNase improves the in vitro activity of antifungal drugs against Candida albicans biofilms

Cells within Candida albicans biofilms display decreased susceptibility to most clinically used antifungal agents. We recently demonstrated that extracellular DNA (eDNA) plays an important role in biofilm integrity, as a component of the biofilm matrix. This study aimed at gaining insights into the contributions of eDNA to C. albicans biofilms antifungal susceptibility by the investigation of the impact of the combined use of deoxyribonuclease I (DNase) and antifungals to treat biofilms. Candida albicans biofilms were formed using a simple and reproducible 96-well plate-based method. The activity of the combined use of 0.13 mg l(-1) DNase and antifungals was estimated using the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay and total viable counts. Herein, we report the improved efficacy of amphotericin B when in combination with DNase against C. albicans biofilms, as assessed using XTT readings and viable counts. Furthermore, although DNase increased the efficacy of caspofungin in the reduction of mitochondrial activity, no changes were observed in terms of culturable cells. Deoxyribonuclease I did not affect biofilm cells susceptibility to fluconazole. This work suggests that agents that target processes affecting the biofilm structural integrity may have potential use as adjuvants of a catheter-lock therapy.     

In vitro antifungal activity of amphotericin B and 11 comparators against Aspergillus terreus species complex

Aspergillus terreus infections are difficult to treat because of the intrinsic resistance to amphotericin B, and higher mortality compared to infections caused by other Aspergillus species. The aim of the present study was to determine the in vitro antifungal activity of amphotericin B and 11 comparators against clinical (n = 36) and environmental (n = 45) A. terreus isolates. In vitro antifungal susceptibility was performed using the CLSI M38‐A2 procedure. Amphotericin B exhibited the highest MICs (MIC range, 0.125‐4 μg/mL; MIC₉₀, 2 μg/mL), followed by terbinafine (MIC range, 0.002‐1 μg/mL; MIC₉₀, 1 μg/mL). Only one isolate (1/81) showed amphotericin B MIC above the epidemiologic cut‐off value (ECV; 4 μg/mL). None of the isolates had a MIC of ≥ ECV for voriconazole, itraconazole and posaconazole. The reasons for the difference in amphotericin B susceptibility patterns between studies remain unknown. The genetic and species diversity, clinical, environmental and ecological factors in Terrei section on various amphotericin B susceptibility profiles in different countries should be considered more as the main reasons associated with these differences.