Economic evaluation of isavuconazole for suspected invasive pulmonary aspergillosis in Canada.

BACKGROUND: Invasive mold infections (IMI) directly impact life expectancy, especially with delayed therapy. Among IMI, aspergillosis (IA) is more common than mucormycosis (IM), resulting in IA-targeted empirical treatment with voriconazole for suspected invasive pulmonary aspergillosis (IPA), despite IM ineffectiveness. Recently, isavuconazole was approved in Canada for IA and IM. The primary objective was to assess the cost-effectiveness of isavuconazole compared to voriconazole for suspected IPA in Canada. A secondary objective was to assess the impact of varying time horizons to address the wide spectrum of life expectancies, according to patients underlying diseases. RESEARCH DESIGN AND METHODS: A 5-year decision-tree was developed from the Canadian Ministry of Health (MoH) and societal perspectives. Efficacy parameters were extracted from SECURE/VITAL trials. Costs included treatment acquisition, hospitalization, adverse events and productivity loss. 3- and 10-year time horizon alternative scenarios and extensive sensitivity analyses were also conducted. RESULTS: From a MoH perspective, isavuconazole compared to voriconazole resulted in an incremental cost-utility ratio (ICUR) of $C30,160/QALY. 3- and10-year ICURs were also cost-effective, relative to a willingness-to-pay threshold of $C50,000/QALY. CONCLUSIONS: This study demonstrates that, in comparison to voriconazole, isavuconazole is a cost-effective strategy for the treatment of patients with suspected IPA, regardless of their life expectancy.

Evaluation of a routine screening program with tuberculin skin testing on rates of detection of latent tuberculosis infection and prevention of active tuberculosis in patients with multiple myeloma at a Canadian cancer centre.

Background: Chemotherapy-induced T cell dysfunction, resulting from treatment of multiple myeloma (mm), enhances the risk for reactivation of latent tuberculous infection (ltbi). However, routine screening for ltbi has its limitations. The objective of the present study was to assess the number of patients treated for ltbi both before and after the introduction of a consistent tuberculin skin test (tst) screening program for patients with mm at our cancer centre. Methods: This retrospective observational study analyzed adult patients with mm treated with autologous hematopoietic stem-cell transplantation from 1 January 2013 to 31 December 2014, for whom tst was consistently performed at our cancer facility. Baseline demographic characteristics of patients who received tst testing and ltbi therapy were compared with those of a pre-intervention cohort of patients (1 January 2008 to 31 December 2009) who were not tested. Results: During the post-intervention period, 170 patients with mm had a tst. In 14 patients (8.2%) results were positive, and 11 of the 14 received ltbi therapy. Of another 12 patients with radiographic imaging changes consistent with prior granulomatous disease and negative tst results, 2 were treated. No cases of tuberculosis (tb) reactivation were noted in individuals who completed ltbi therapy. One case of active tb was diagnosed in a patient with a negative tst. In contrast, in the pre-intervention matched cohort of 170 patients, no tsts were performed, and no cases of active tb were documented. Conclusions: Patients with mm could benefit from a consistent tst testing policy coupled with subsequent ltbi therapy. However, universal testing might not be required. A targeted program combining evaluation of host risk factors, imaging findings, and screening tests might optimize ltbi diagnosis and management, and thus be effective in preventing the development of active tb in at-risk patients with mm.

Aspergillus galactomannan detection in exhaled breath condensate compared to bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in immunocompromised patients.

OBJECTIVES: Exhaled breath condensate (EBC) is a noninvasive means of sampling the airways that has shown significant promise in the diagnosis of many disorders. There have been no reports of its usefulness in the detection of galactomannan (GM), a component of the cell wall of Aspergillus. The suitability of EBC for the detection of GM for the diagnosis of invasive aspergillosis (IA) using the Platelia Aspergillus enzyme-linked immunosorbent assay was investigated. METHODS: Prospective, cross-sectional study of lung transplant recipient and haemotologic malignancy patients at a university centre. EBC samples were compared to concomitant bronchoalveolar lavage (BAL) samples among lung transplant recipients and healthy controls. EBC was collected over 10 minutes using a refrigerated condenser according to the European Respiratory Society/American Thoracic Society recommendations, with the BAL performed immediately thereafter. RESULTS: A total of 476 EBC specimens with 444 matched BAL specimens collected from lung transplant recipients (n = 197) or haemotologic malignancy patients (n = 133) were examined. Both diluted and untreated EBC optical density (OD) values (0.0830, interquartile range (IQR) 0.0680-0.1040; and 0.1130, IQR 0.0940-0.1383), respectively, from all patients regardless of clinical syndrome were significantly higher than OD values in healthy control EBCs (0.0508, IQR 0.0597-0.0652; p < 0.0001). However, the OD index values did not correlate with the diagnosis of IA (44 samples were associated with IA). Furthermore, no significant correlation was found between EBC GM and the matched BAL specimen. CONCLUSIONS: GM is detectable in EBC; however, no correlation between OD index values and IA was noted in lung transplant recipients.

Successful treatment of gastrointestinal mucormycosis in an adult with acute leukemia: case report and literature review.

Mucormycosis has emerged as an important cause of invasive fungal infection in patients with hematologic malignancies. Gastrointestinal mucormycosis is an unusual presentation of this invasive fungal infection, and it causes considerable morbidity and mortality. Such outcomes are due in part to a nonspecific presentation that results in delays in diagnosis and treatment. Successful treatment of gastrointestinal mucormycosis involves surgical debridement and appropriate antifungal therapy.

The Role of Antiviral Prophylaxis for the Prevention of Epstein-Barr Virus-Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review.

The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein-Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta-analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV-associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58-1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high-risk EBV-naive patients has no effect on the incidence of PTLD in SOT recipients.

Rate of cyp51A mutation in Aspergillus fumigatus among lung transplant recipients with targeted prophylaxis.

OBJECTIVES: The most common mechanism of azole (itraconazole and voriconazole) resistance in Aspergillus fumigatus is a mutation at the cyp51A locus. The aim of our study was to determine the rate of cyp51A mutations in lung transplant recipients (LTR) undergoing targeted antifungal prophylaxis with 12 weeks of voriconazole. METHODS: We conducted a prospective study that included 22 LTR with A. fumigatus between October 2008 and November 2011. Of those, 10 LTR were colonized with A. fumigatus and 12 had invasive pulmonary aspergillosis. RESULTS: Four patients were found to have A. fumigatus isolates with a cyp51A mutation, two had colonization and two had invasive pulmonary aspergillosis. The remaining 18 LTR had WT cyp51A A. fumigatus isolates. All A. fumigatus isolates (except one due to mixed growth) were tested for antifungal susceptibility. A total of nine LTR were exposed to azoles prior to A. fumigatus isolation for a median duration of 249 (IQR 99-524) days. Azole exposure preceded the isolation of two mutant isolates and seven WT isolates. None of the cyp51A mutant isolates conferred phenotypic resistance to azoles. CONCLUSIONS: Targeted antifungal prophylaxis in LTR did not lead to cyp51A resistance mutations in this cohort. Data on larger cohorts who receive universal antifungal prophylaxis are needed.

A comparative study of the use of selective digestive decontamination prophylaxis in living-donor liver transplant recipients.

INTRODUCTION: Bacterial infections are major causes of early morbidity and mortality after liver transplantation. Selective digestive decontamination (SDD) can be used pre-operatively for living-donor liver transplant (LD-LT), but its role in this setting remains controversial. METHODS: To evaluate this strategy, we retrospectively analyzed a cohort of consecutive LD-LTs performed in our center from March 2007 to February 2011 and compared the incidence and nature of early infectious complications, length of intensive care unit stay and hospitalization, antibiotic use, and emergence of resistant bacteria in patients with or without SDD prophylaxis. RESULTS: Of 148 LD-LTs in the study period, 111 received SDD prophylaxis while 37 did not. In a multivariate model, the independent factors associated with an increased risk of early post-transplant infections were length of postoperative mechanical ventilation (for every additional day odds ratio [OR] = 2.37, 95% confidence interval [CI] 1.4-4.0; P = 0.002), and choledochojejunostomy (OR = 4.5, 95% CI 1.95-10.5; P < 0.001). Use of SDD did not affect the rate or distribution of infectious complications, duration of hospitalization, antibiotic use, or acquisition of resistant bacteria (OR = 3.52, 95% CI 0.43-15.17; P = 0.376). CONCLUSION: In conclusion, the use of SDD prophylaxis in LD-LT was not beneficial and should be avoided, as it offers no advantage and could potentiate the emergence of multidrug-resistant organisms.

Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.

Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis in lung transplant recipients. However, the use of voriconazole may at times be limited by the development of hepatotoxicity. Our goal is to determine predictors of voriconazole-associated hepatotoxicity in lung transplant recipients. We conducted a single center retrospective cohort study of lung transplant recipients from 2006 to 2010 who received voriconazole therapy. We compared characteristics of patients who developed hepatotoxicity and those who did not. One hundred five lung transplant recipients received voriconazole. Hepatotoxicity occurred in 51% (54/105) of patients and lead to discontinuation in 34% (36/105). In univariate analysis, age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity. In multivariable logistic regression analysis, perioperative initiation of voriconazole (within 30 days of transplantation) was independently associated with hepatotoxicity (OR 4.37, 95% CI: 1.53-12.43, p = 0.006). The five risk factors identified in the univariate analysis were used to build a K-nearest neighbor algorithm predictive model for hepatotoxicity. This model predicted hepatotoxicity with an accuracy of 70%. Voriconazole therapy initiated within the first 30 days of transplantation is associated with a greater risk of developing hepatotoxicity.

Post renal transplantation Kaposi's sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy.

BACKGROUND: Kaposi's sarcoma (KS) is a vascular malignancy primarily involving the skin. This neoplasm occurs commonly in acquired immunodeficiency syndrome (AIDS) and post solid organ transplantation. Human herpesvirus type 8 (HHV-8) has been shown to play a causative role in AIDS-associated KS and in post renal transplantation KS. METHODS: Based on a MEDLINE search, we present a review of the current information on the epidemiology, pathogenesis, diagnosis and treatment of post-transplantation KS (PT-KS) with an emphasis on renal transplantation. RESULT: The different frequencies of PT-KS in different parts of the world seem to be related to seroprevalence of HHV-8 infection. Following renal transplantation and the administration of immunosuppressive therapy, HHV-8 may reactivate. The renal tubular epithelium is a site for HHV-8 latency. Rates of PT-KS in seropositive recipients and anti-HHV-8 mismatched recipients (donor+/recipient-) are approximately 13% and 4.6%, respectively. Additional risk factors for the development of PT-KS include skin color, country of birth, age at the time of transplantation, and different induction regimens including anti-thymocyte globulin, steroid, or anti-interleukin 2-receptor antagonists. Skin is the major site of involvement. Surprisingly, involvement of the transplanted organ has been reported to be extremely rare. Reduction in immunosuppressive therapy and switching to mammalian targets of rapamycin inhibitors, such as sirolimus, are effective treatments for PT-KS. In patients with no response to reduction in immunosuppressive therapy, systemic chemotherapy with different regimens has been reported to be successful. CONCLUSION: PT-KS in renal transplant patients is an important problem specifically in southern Europe and the Middle East. In the majority of patients, the diagnosis based on clinical suspicion is always essential. Clinicians should bear in mind that PT-KS may threaten graft function and hence result in rejection complications. Appropriate management increases patient survival.

Hepatitis C core Ag and its clinical applicability: potential advantages and disadvantages for diagnosis and follow-up?

Chronic hepatitis C virus (HCV) infection which is often a silent disease has resulted in a global epidemic. The diagnosis of hepatitis C virus often requires confirmation with molecular techniques such as the polymerase chain reaction for detection of HCV RNA. Following laboratory confirmation of the diagnosis, molecular techniques are routinely used to monitor HCV RNA levels, particularly in those undergoing treatment. Unfortunately, molecular tests are relatively expensive and their cost may be prohibitive in the developing world. Several studies have investigated the applicability of the hepatitis C core Ag (HCVcAg), as a substitute for measuring HCV RNA levels. In this review, we provide an overview of the major findings of these studies focused on the utility of measuring HCVcAg antigen levels in the clinical setting. Overall, measuring HCVcAg levels is associated with several advantages and disadvantages. It may be useful in different clinical settings for monitoring HCV patients after obtaining an initial baseline HCV RNA result.

Pediatric antifungal therapy. Part II: neonatal infections.

The management of neonatal fungal infections poses several challenges, including the fact that the choices of available agents are limited, given the paucity of data relating to the use of newer antifungal agents in the group of infants. The information summarized herein represents in part the consensus of a group of clinicians involved in the care of neonates at risk of and with fungal infections. The document addresses the prophylaxis and treatment of fungal infections in neonates. It highlights the role of current and emerging antifungal agents, including the lipid amphotericin B products, echinocandins and triazoles.

Pediatric antifungal therapy. Part I: focus on febrile neutropenia, invasive aspergillosis, combination antifungal therapy and invasive candidiasis in immunocompromised pediatric patients.

The number of available antifungal agents has significantly increased in recent years. These agents are starting to take over niches that were previously occupied by conventional amphotericin B. For many of these agents, pediatric data from randomized trials are generally lacking and clinicians are faced with extrapolating from data generated in adult patients. This notwithstanding, this report summarizes recommendations that define the roles of newer antifungal agents in the treatment of selected scenarios among immunocompromised pediatric patients. The report includes the outcome of a Canadian conference on the use of antifungal agents in children, supplemented by literature reviews and incorporating information from existing national or international guidelines, where appropriate. The focus of the report is on febrile neutropenia, invasive aspergillosis, combination antifungal therapy and selected aspects of the management of invasive candidiasis.

A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

BACKGROUND: The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime. METHODS: We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety. RESULTS: For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P< or = .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated. CONCLUSIONS: This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.

Economic evaluation of voriconazole compared with conventional amphotericin B for the primary treatment of aspergillosis in immunocompromised patients.

OBJECTIVE: The objective of this study was to conduct an economic evaluation of voriconazole compared with conventional amphotericin B deoxycholate (CAB) using data from a recently reported randomized comparative trial in patients with various underlying immunosuppressive conditions. This trial demonstrated the superiority of voriconazole in terms of clinical response, survival and safety when used as primary therapy for invasive aspergillosis. METHODS: A decision analytic model was designed using an expert panel and populated primarily with efficacy and resource utilization data collected prospectively during the clinical trial. The analysis was carried out from the perspective of the health care system and all costs are reported in 2002 US dollars. RESULTS: Average total treatment costs per patient were 10% lower in the voriconazole arm ($30 664) than in the CAB arm ($34 144), resulting from reduced consumption of hospital resources and fewer changes in antifungal therapy. In the base case analysis, voriconazole provided an average saving of $3481 per treated patient, resulted in a lower cost per survivor ($43 310 versus $58 971) and a lower cost per successfully treated patient ($58 100 versus $108 124) compared with CAB. Sensitivity analyses demonstrated that the cost savings observed were maintained over a wide range of alternative values for both unit costs and resource utilization, including length of hospital stay, time spent in intensive care units, bed day costs and the cost of lipid formulations of amphotericin B. CONCLUSION: Incremental cost-effectiveness analysis indicated the dominance of voriconazole because of both lower costs and greater efficacy.

Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. The Canadian Fluconazole Study.

Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P<0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P< or =0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index < or =0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.

Comparative in vitro activities of ciprofloxacin, gemifloxacin, grepafloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, and other antimicrobial agents against bloodstream isolates of gram-positive cocci.

The in vitro activity of gemifloxacin against 316 bloodstream isolates of staphylococci, pneumococci, and enterococci was compared with the activities of six fluoroquinolones and three other antimicrobial agents. Of the antimicrobial agents tested, gemifloxacin was the most potent against penicillin-intermediate and -resistant pneumococci, methicillin-susceptible and -resistant Staphylococcus epidermidis isolates, and coagulase-negative staphylococci.

Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a fourth-generation cephalosporin.

In a prospective, multicentre double-blind trial, 151 patients over the age of 65 years were randomly assigned to receive either cefepime 2 g every 12 h for a minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum of 3 days and up to 14 days. Antibiotics were maintained until 48 h after fever had resolved; no other antibiotics were permitted. The average age in each group exceeded 77 years and significant co-morbidity was found in the majority of patients. The mean total duration of therapy was 5.8+/-2.4 days for the cefepime group and 6.7+/-2.7 days for the ceftriaxone group (P = 0.06). The clinical success rate at the end of therapy was 79.1% with cefepime and 75.4% with ceftriaxone (P = 0.62). At the end of follow-up, 91.7% of the cefepime-treated patients and 86.5% of the ceftriaxone patients had a satisfactory clinical response (P = 0.38). In 35 bacteriological evaluable patients, potential pathogens were eradicated in all but one patient receiving cefepime. Seven patients in each group died during the study period but in each case the death was unrelated to study drug. The commonest side-effect was diarrhoea (cefepime, five patients; ceftriaxone, two patients). The clinical and microbiological efficacy of cefepime is similar to that of ceftriaxone in elderly patients with community-acquired pneumonia requiring hospitalization. Cefepime is an appropriate choice for the treatment of community-acquired respiratory tract infections in the elderly.

Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group.

A randomized, double-blind trial comparing oral fluconazole (400 mg daily) with placebo as prophylaxis for adult patients receiving intensive cytotoxic therapy for acute leukemia or autologous bone marrow transplantation was conducted in 14 Canadian university-affiliated hospitals. Although fluconazole prophylaxis did not obviate the need for parenteral antifungal therapy compared with placebo (81 [57%] of 141 vs. 67 [50%] of 133, respectively), its use resulted in fewer superficial fungal infections (10 [7%] of 141 vs. 23 [18%] of 131, respectively; P = .02) and fewer definite and probable invasive fungal infections (9 vs. 32, respectively; P = .0001). Fluconazole recipients had fewer deaths attributable to definite invasive fungal infection (1 of 15 vs. 6 of 15, respectively; P = .04) and achieved more frequent success without fungal colonization (52 [37%] of 141 vs. 27 [20%] of 133, respectively; P = .004; relative risk reduction, 85%) than did placebo recipients. Patients benefiting the most from fluconazole prophylaxis included those with acute myeloid leukemia who were undergoing induction therapy with cytarabine plus anthracycline-based regimens and those receiving marrow autografts not supported with hematopoietic growth factors. Fluconazole prophylaxis reduces the incidence of superficial fungal infection and invasive fungal infection and fungal infection-related mortality among patients who are receiving intensive cytotoxic chemotherapy for remission induction.