Antifungal Prophylaxis In High-risk Patients Research Articles

New Developments in Pediatric Antifungal Pharmacology.

New Developments in Pediatric Antifungal Pharmacology.

Health-care utilization and outcomes of patients at high risk of invasive fungal infection.

PurposeThe objectives of this study were to present trends in posaconazole use over time and describe selected outcomes among patients at high risk of invasive fungal infections (IFIs) by use and type of antifungal medicine.MethodsA retrospective observational study using data from the Premier Healthcare Database between January 2007 and March 2016 was conducted. Inpatient use of posaconazole by formulation and year is described. Separately, four cohorts of patients at high risk of IFI – those with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), hematopoietic stem-cell transplantation (HSCT), and graft-vs-host disease (GVHD) – but without a diagnosis code for IFI during the index encounter were identified as potential candidates for antifungal prophylaxis. Use of antifungal medication(s) in these patients was categorized. Index length of stay (LOS), index hospital costs, and subsequent inpatient and outpatient encounters with IFI at 30, 60, and 90 days post-index encounter are presented by antifungal group for each cohort. The percentage of patients with inpatient and outpatient encounters with IFI at 90 days post-index encounter was determined for each cohort by year.ResultsUse of posaconazole oral suspension increased through 2012, then declined as the tablet formulation became available in 2013. A total of 19,872 AML patients, 12,125 MDS patients, 14,220 HSCT patients, and 5,431 GVHD patients were considered potential candidates for antifungal prophylaxis; however, a large proportion of patients within each cohort (33%–94%) did not receive any antifungal drug during the index hospitalization. Index LOS, hospital costs, and subsequent encounters for IFI varied among cohorts and by antifungal group. Within each cohort, subsequent encounters for IFI at 90 days post-index encounter fluctuated but remained rare across different years.ConclusionOver time and as new posaconazole formulations became available, the frequency of use of each formulation changed. In addition, this study suggested a low rate of potential antifungal prophylaxis in high-risk patients. This is one of the first reports attempting to describe antifungal prophylaxis in a contemporary, large, all-payer, geographically representative hospital database.

Cost–benefit Analysis of Posaconazole Versus Fluconazole or Itraconazole as a Primary Antifungal Prophylaxis in High-risk Hematologic Patients: A Propensity Score-matched Analysis

PurposePosaconazole is effective for the prophylaxis of invasive fungal infections (IFIs) in patients with acute myeloid leukemia or myelodysplastic syndrome during remission induction chemotherapy. However, a cost–benefit analysis of posaconazole versus fluconazole or itraconazole has not been conducted in Korea. MethodsWe retrospectively reviewed data for all consecutive patients who received primary antifungal prophylaxis during remission induction chemotherapy in our acute myeloid leukemia/myelodysplastic syndrome cohort from December 2010 to November 2013. Patient characteristics and factors known as a risk of IFI were matched with propensity score analysis. We evaluated the medical cost according to the prophylactic antifungal agents (posaconazole vs fluconazole/itraconazole), the development of breakthrough IFIs, and survival status after propensity score matching in a 1:1 ratio. FindingsOf the 419 baseline patients, 100 patients in each group were analyzed after matching. A significant decrease was found in the development of breakthrough proven or probable IFIs (3.0% vs 14.0%; P = 0.009) and the rate of empirical antifungal therapy (EAFT) (12.0% vs 46.0%; P < 0.001) in the posaconazole group. Total in-hospital medical costs per patient were not statistically different between posaconazole and fluconazole/itraconazole prophylaxis. However, the daily medical cost was lower for posaconazole prophylaxis, resulting in a total daily cost savings of $72 (₩79,458) per patient (P = 0.002). In the cases of breakthrough proven/probable IFIs, EAFT, and in-hospital deaths, the total medical costs per patient were significantly higher than in nonproven/probable IFIs, non-EAFT, and in-hospital survivors, as much as $7,916 (₩8,700,758), $4605 (₩5,062,529), and $11,134 (₩12,238,422), respectively. Costs for the antifungal agent used in targeted or empirical therapy were lower in the posaconazole group, resulting in a savings of $697 (₩766,347) per patient (P < 0.001). ImplicationsPosaconazole appears to be cost beneficial for primary antifungal prophylaxis in high-risk patients with hematologic malignancy, at a single center, in Korea. Cost–benefit is closely related with clinical outcomes, including breakthrough IFI development, EAFT, and survival status.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.

Intestinal Mucormycosis With Rhizopus microsporus After Liver Transplantation—Successful Treatment of a Rare but Life-Threatening Complication

Intestinal Mucormycosis With Rhizopus microsporus After Liver Transplantation—Successful Treatment of a Rare but Life-Threatening Complication

Voriconazole-Induced Photosensitivity in Children: A Case Report and Literature Review.

Voriconazole is a broad-spectrum triazole antifungal with a reliable oral bioavailability introduced in 2002. It is indicated for treatment of pulmonary aspergillosis, primary treatment of amphotericin B and fluconazole-resistant fungal infections such as Fusarium spp and Scedosporium apiospermum (asexual form of Pseudoallescheria boydii).1,2 Voriconazole is also used for empirical antifungal therapy of neutropenic fever in patients receiving nephrotoxins (cyclosporine, tacrolimus) and antifungal prophylaxis in high-risk patients undergoing bone marrow transplantation and patients with severe graft-versus-host disease.1,2 Common side effects include abnormal vision, elevation of liver enzymes, as well as skin rashes including allergic reactions and Stevens–Johnson syndrome.1 Metabolic side effects include hypokalemia and hypomagnesemia. Photosensitivity is a rare complication of voriconazole therapy3; a limited number of cases have been reported in the pediatric population.4-12 We report a teenager with common variable immunodeficiency who developed voriconazole-induced severe photosensitivity reaction mimicking Stevens–Johnson syndrome requiring treatment in the burn unit with frequent dressing changes for 2 days.

Papel de la anidulafungina en el paciente con trasplante de órgano sólido

The incidence of invasive fungal infections in solid organ transplant recipients varies according to the type of transplant. Most of these infections are due to Candida spp. and less frequently to Aspergillus spp. or other fungi such as Cryptococcus spp. Currently, overall mortality due to invasive fungal infections in solid organ transplant recipients ranges between 25% and 80% and half of these deaths are directly related to the fungal infection. A number of well-defined risk factors favor the development of invasive fungal infections in these patients and allow antifungal prophylaxis in high-risk patients. The candins are a new class of antifungal agent with potential use both in the treatment and in the prophylaxis of invasive fungal infections in solid organ transplant recipients. Anidulafungin has a wider spectrum of action and lower toxicity than caspofungin. Anidulafungin has good in vitro antifungal activity against Candida and Aspergillus spp. One of the most interesting features of anidulafungin in solid organ transplant recipients is that this drug is not metabolized by or eliminated through the kidney so that dosage adjustments are not required in these patients, who frequently show renal function alterations. Moreover, anidulafungin is not metabolized in the liver and is consequently free of interactions with other drugs metabolized in this organ. Equally, dosage adjustments are not required in patients with severe liver disease or in those administered immunosuppressive agents such as prednisone, cyclosporin A, tacrolimus, mofetil mycophenolate or sirolimus. Although experience is still limited, these data suggest that anidulafungin will be highly useful in the clinical management of solid organ transplant recipients.

Treatment of invasive fungal infections in immunocompromised and transplant patients: AmBiLoad Trial and other new data

Opportunistic invasive fungal infections (IFIs) have changed. Moreover, a significantly greater therapeutic armamentarium is now available, with liposomal amphotericin B (L-AmB) administered in new ways, for example in higher doses, in combination with other compounds or inhaled. The objective of this study was to review these three aspects. The AmBiLoad study was designed to clarify whether higher doses of L-AmB could be more efficacious than the licensed dose of 3–5 mg/kg. It was a multicentric study where patients were randomised to receive a 14-day course of 3 mg/kg/day or 10 mg/kg/day L-AmB. A total of 339 patients were enrolled during the study period (April 2003 to October 2004). Discontinuation of treatment, mainly due to adverse events, was frequent (13% in the standard dose group vs. 24% in the high dose group), and only 66% and 50%, respectively, completed 14 days of randomised treatment. There was no statistically significant difference with regard to favourable overall responses between the treatment groups (50% in the standard dose group vs. 46% in the high dose group; P = 0.65). In addition, there was no significant difference according to type of IFI (invasive aspergillosis, 50% vs. 46% in the standard and high dose groups, respectively). The obvious conclusion of this study was that administration of 10 mg/kg/day L-AmB to patients with IFI does not improve efficacy but increases toxicity and price. In vitro and experimental data suggest that the combination of AmB with other antifungal agents may be more effective than monotherapy; however, data regarding the clinical efficacy of L-AmB in combination with other agents are scarce. The use of inhaled L-AmB has shown promising results for use as antifungal prophylaxis in high-risk patients.

Echinocandins: a wealth of choice – how clinically different are they?

The recent decade has been a 'golden age' for antifungal therapy. The introduction of a novel class of antifungals, the echinocandins, has revolutionized the therapy for invasive candidiasis, provided increasing options for antifungal prophylaxis in high-risk patients and energized the debate regarding combination antifungal therapy for invasive mycoses. Randomized, controlled data exist for each echinocandin in the treatment of invasive candidiasis, and experts largely believe the agents to be equivalent in this setting. Future trials of combined echinocandin-triazole therapy for invasive aspergillosis are desired. Additionally, maximal dosing limitations are being pursued. The echinocandins as a class offer an advance in the treatment of invasive candidiasis, an additional option for prophylaxis and an attractive choice for the study of combination antifungal therapy. Particularly for the major indication (treatment of invasive candidiasis), major clinical differences between agents have not been noted.

Posaconazole for paediatric patients: status of development and future perspectives

Posaconazole is a novel oral antifungal triazole with potent and broad-spectrum antifungal activity, favourable pharmacokinetic properties and a limited spectrum of adverse events. The compound has documented clinical efficacy in the settings of oropharyngeal candidiasis, refractory aspergillosis, fusariosis, zygomycosis, and as antifungal prophylaxis in high-risk patients with acute myeloblastic leukaemia or graft-vs.-host disease. Whereas, posaconazole is approved for use in adults, however, the appropriate dosage and the safety of the compound have not been systematically investigated in paediatric age groups. This paper reviews the relevant pharmacological characteristics of posaconazole, the published data on its use in paediatric patients without therapeutic alternative and perspectives for the clinical development in paediatric patients at risk for invasive fungal infections.

Antifungal efficacy and pharmacodynamics of posaconazole in experimental models of invasive fungal infections

Posaconazole is a novel lipophilic antifungal triazole with potent and broad-spectrum activity against opportunistic, endemic and dermatophytic fungi. This activity extends to organisms that are often refractory to existing triazoles, amphotericin B or echinocandins such as Candida glabrata, Candida krusei, Aspergillus terreus, Fusarium spp. and the Zygomycetes. A large number of experimental animal models of invasive fungal infections has demonstrated the potent and broad-spectrum efficacy of posaconazole in vivo, both in normal and in immunocompromised animals. Consistent with these preclinical data, posaconazole showed strong a antifungal efficacy in phase II and phase III clinical trials in immunocompromised patients with oropharyngeal and oesophageal candidiasis and as salvage therapy in patients with invasive fungal infections, and was effective as antifungal prophylaxis in high-risk patients. This paper reviews the preclinical disposition, antifungal efficacy and pharmacodynamics of posaconazole in and its implications for treatment and prevention of invasive fungal infections.

Antifungal prophylaxis with azoles in high-risk, surgical intensive care unit patients: A meta-analysis of randomized, placebo-controlled trials*

The use of antifungal prophylaxis remains controversial in most populations including surgical intensive care unit patients. A meta-analysis of randomized controlled trials was performed to evaluate the safety and effectiveness of azoles as antifungal prophylaxis in high-risk patients receiving treatment in the surgical intensive care unit. Data were obtained from PubMed, Current Contents, Cochrane central register of controlled trials, and references from relevant articles. Randomized controlled trials using azoles as antifungal prophylaxis vs. placebo were included in the study. Two independent reviewers extracted data concerning the development of fungal infections (superficial or invasive), adverse effects, and mortality. Six randomized controlled trials were included in the main analysis. Publication bias and statistically significant heterogeneity were not observed among the analyzed studies. Patients receiving antifungal prophylaxis developed fewer episodes of candidemia (odds ratio [OR] = 0.28, 95% confidence interval [CI] 0.09-0.86), nonbloodstream invasive fungal infections (OR = 0.26, 95% CI 0.12-0.53), and noninvasive (superficial) fungal infections (OR = 0.22, 95% CI 0.11-0.43), respectively. No reduction in mortality was observed among patients who received azole prophylaxis (OR = 0.74, 95% CI 0.52-1.05). There was no significant difference in reported adverse effects (OR = 1.28, 95% CI 0.82-1.98). Despite its limitations, our meta-analysis suggests that the prophylactic use of azoles in high-risk surgical intensive care unit patients is associated with a reduction of fungal infections but not in all-cause mortality. However, although not noted in the analyzed randomized controlled trials, there is concern about the use of azoles due to possible shift toward non-albicans species and development of resistance to azoles.