Association between drug tolerability and medical resource use in prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplant.

OBJECTIVES: To conduct a retrospective analysis of the association between drug tolerability and potential economic impact measured by medical resource utilization (MRU) for prophylaxis of invasive antifungal infections (IFI) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS: An open-label, multi-center study (IMPROVIT) included patients (≥12-years old) who were randomized to receive oral voriconazole (VOR) or oral itraconazole (ITR) from the alloHCT day for at least 100 days and up to 180 days. Trial data on discontinuation and MRU for the first 100 days were analyzed. RESULTS: Two hundred and twenty-four patients were in VOR and 241 in ITR, with similar demographic distributions (average age of 43 years, 58% male, 92% Caucasian). All-cause and study drug intolerance discontinuations were less frequent with VOR than ITR (50% vs 63%, p = 0.0137; 7% vs 22%, p < 0.0001). VOR patients had longer study drug exposure (median = 96 vs 68 days, p < 0.0001; mean = 68 vs 60 days, p = 0.0044). ITR patients were 2-times more likely (p = 0.0110) to use other antifungals vs VOR patients. Controlling for treatment and key baseline variables, longer IFI prophylaxis was associated with fewer hospital days (p < 0.0001) and less other antifungal use (p < 0.0001). Patients who discontinued prophylaxis during the first 100 days incurred 10 more hospital days (p < 0.0001) and 17 more other antifungal days (p < 0.0001) compared to their counterparts. Eight more prophylaxis days were associated with ∼1 less hospital day and 3.6 less other antifungal days (p < 0.0001). Key limitation: MRU data collection was limited to the first 100 days post-transplant, which may not fully capture the real-world utilization and outcomes. CONCLUSIONS: Patients' ability to tolerate and continue their antifungal prophylaxis after alloHCT is associated with less use of MRU such as other antifungals and hospital days. In the current resource-constrained healthcare environment, it is important to consider the potential economic impact of the tolerability of antifungal prophylaxis.

Risk-adjusted relationship between voriconazole utilization and non-melanoma skin cancer among lung and heart/lung transplant patients.

BACKGROUND: We examined the relationship between voriconazole utilization and non-melanoma skin cancer (NMSC) development among adult lung and heart/lung transplant patients who were continuously enrolled in a large U.S. commercial health plan. METHODS: Cox proportional hazards regression models were constructed to assess both the crude and adjusted effect of voriconazole usage on NMSC development. Overall, 467 adult lung (98%) and heart/lung (2%) transplant patients (60% male) with median age of 58 years were analyzed. RESULTS: Fifty-seven (12%) patients developed NMSC over a median follow-up time of 610 days. At the crude level, patients with any (vs. none) claim for voriconazole were more likely to develop NMSC (19% vs. 12%, hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.02, 2.96, P = 0.04). However, after statistical adjustment for demographic and clinical factors, the effect was largely diminished and no longer statistically significant (HR: 1.23, 95% CI: 0.71, 2.14, P = 0.45). Results were similar when modeling average and total dose of voriconazole. Risk factors significantly related to NMSC development were being male, older age, sun exposure, history of chronic obstructive pulmonary disorder, and history of immune disorder. CONCLUSION: Results suggest that the relationship between voriconazole utilization and NMSC among lung transplant patients may be a result of confounding by indication, and that controlling for underlying patient characteristics is paramount.

Safety and tolerability of voriconazole in patients with baseline renal insufficiency and candidemia.

Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.

Echinocandins: are they all the same?

The discovery of echinocandins, and their development and approval, was hailed as a significant addition to our antifungal armamentarium, previously predominated by polyenes and azoles. To date, three echinocandins (anidulafungin, caspofungin, and micafungin) have been approved by the U.S. Food and Drug Administration for the treatment of fungal infections. Since all three echinocandins target the fungal cell wall and share a similar structural chemical backbone, they are perceived to be identical. However, a scientific literature review shows distinct differences among the echinocandins in terms of in vitro activity, fungicidal activity, post-antifungal effect, paradoxical effect, and activity on biofilms. More investigation is warranted to determine if the observed differences among the echinocandins can translate to clinical advantages.

Resource use and cost of treatment with voriconazole or conventional amphotericin B for invasive aspergillosis.

BACKGROUND: Voriconazole, a broad-spectrum triazole, has demonstrated significantly improved survival compared with conventional amphotericin B (CAB) as initial therapy for invasive aspergillosis (IA). OBJECTIVE: To compare health care resource use and cost at 12 weeks following first-line treatment with voriconazole compared with CAB for IA using resource use data collected during a clinical trial. METHODS: Days of hospitalization, intensive care, antifungal drug use, and outpatient care were collected during a large randomized, controlled trial of patients with IA receiving initial treatment with voriconazole or CAB. Unit costs based on published data sources were applied to healthcare use to estimate 12-week costs following initiation of therapy. Resource use and costs were compared for each treatment arm overall and by survival. The sensitivity of total costs to changes in healthcare use and unit costs was examined. RESULTS: Total hospital days and intensive care unit (ICU) days were similar for voriconazole and CAB (total: 27.8 vs. 27.7, P=0.97 and ICU: 5.6 vs. 8.1, P=0.11). Among survivors, voriconazole was associated with similar numbers of total hospital days (29.8 vs. 32.0 days, P=0.54) to CAB, but fewer ICU days (3.9 vs. 8.2, P=0.03). For non-survivors, those treated with voriconazole had a similar number of total hospital days (23.0 vs. 21.8, P=0.73) and ICU days (9.8 vs. 7.9, P=0.44). Patients treated with voriconazole had significantly more days alive and out of the hospital than with CAB at 12 weeks (40.3 vs. 28.4 days, P<0.001). Total costs were similar with voriconazole compared with CAB ($78,860 vs. $83,857, P=0.51). Differences in cost were not sensitive to changes in the input parameter values. CONCLUSIONS: Using voriconazole first-line for treatment of IA resulted in significantly fewer deaths and similar treatment costs. Hospital-free survival was significantly greater for patients initially treated with voriconazole.

Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial.

BACKGROUND: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients. METHODS: Non-neutropenic patients with a positive blood culture for a species of candida and clinical evidence of infection were enrolled. Patients were randomly assigned, in a 2:1 ratio, either voriconazole (n=283) or amphotericin B followed by fluconazole (n=139). The primary efficacy analysis was based on clinical and mycological response 12 weeks after the end of treatment, assessed by an independent data-review committee unaware of treatment assignment. FINDINGS: Of 422 patients randomised, 370 were included in the modified intention-to-treat population. Voriconazole was non-inferior to amphotericin B/fluconazole in the primary efficacy analysis, with successful outcomes in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). At the last evaluable assessment, outcome was successful in 162 (65%) patients assigned voriconazole and 87 (71%) assigned amphotericin B/fluconazole (p=0.25). Voriconazole cleared blood cultures as quickly as amphotericin B/fluconazole (median time to negative blood culture, 2.0 days). Treatment discontinuations due to all-cause adverse events were more frequent in the voriconazole group, although most discontinuations were due to non-drug-related events and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/fluconazole group. INTERPRETATION: Voriconazole was as effective as the regimen of amphotericin B followed by fluconazole in the treatment of candidaemia in non-neutropenic patients, and with fewer toxic effects. RELEVANCE TO PRACTICE: There are several options for treatment of candidaemia in non-neutropenic patients, including amphotericin B, fluconazole, voriconazole, and echinocandins. Voriconazole can be given both as initial intravenous treatment and as an oral stepdown agent.

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.

Haemophilus influenzae pneumonia in young adults with AIDS, ARC, or risk of AIDS.

PURPOSE: Since the acquired immunodeficiency syndrome (AIDS) was first described in 1981, we have observed an increasing number of cases of Haemophilus influenzae pneumonia, particularly in young adult patients. To confirm this observation, we systematically identified and reviewed all cases of H. influenzae pneumonia that occurred in adult patients recently hospitalized at our institution. PATIENTS AND METHODS: Using a strict case definition, we identified all cases of adult H. influenzae pneumonia that were observed during a recent 32-month period at our institution, a large teaching hospital in New York City. We further reviewed each case record for evidence of AIDS, AIDS-related complex (ARC), or risk of AIDS. RESULTS: H. influenzae pneumonia was diagnosed in 51 adults. Thirty-four cases occurred in young adults (mean age = 33.9 years) with AIDS risk factors, including 23 (67 percent) intravenous drug abusers, six (18 percent) homosexual men, and five (15 percent) with both risks. Nine patients (26 percent) had a previous or concurrent diagnosis of AIDS, four (12 percent) developed AIDS later, and 13 (38 percent) others had ARC. The common presenting symptoms in young adult patients with H. influenzae pneumonia were fever (100 percent), productive cough (100 percent), chest pain (53 percent), and dyspnea (47 percent). Lung consolidation was detected on physical examination in 20 (59 percent), and chest radiograph demonstrated unilateral infiltrates in 18 (53 percent) and bilateral infiltrates in 16 (47 percent), with pleural effusions in three (nine percent). Most patients had an elevated white blood cell count (mean = 9.6 X 10(9)/liter) with a left shift in 22 (65 percent), and hypoxia on room air (mean partial pressure of oxygen = 69 mm Hg). Four patients with H. influenzae pneumonia and coexisting Pneumocystis carinii pneumonia had diffuse, bilateral infiltrates on chest radiograph, with significantly more dyspnea and a higher serum lactate dehydrogenase level than the others. All but one patient showed improvement with appropriate therapy. CONCLUSION: We conclude that potentially serious pneumonia caused by H. influenzae occurs in young adult patients with AIDS, ARC, or AIDS risk.

Treatment of cytomegalovirus retinitis with ganciclovir (9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (BW B759U).

Six patients (11 eyes) with virologically confirmed cytomegalovirus (CMV) retinitis involving the posterior pole of the eye were treated with a new drug, ganciclovir. Treatment with intravenous ganciclovir consistently halted progression of retinitis and produced improvement in measures of visual function. However, within three weeks after cessation of therapy renewed CMV activity and worsening of visual function were observed in most cases. Maintenance therapy with ganciclovir extended the period of remission from CMV retinitis.

Clinical effectiveness of a pancreatic enzyme supplement.

In 23 adult patients with pancreatic insufficiency, we evaluated the efficacy of a pancreatic enzyme delivered as pH-sensitive enteric-coated pancreatic lipase microspheres, and compared it with placebo and other available enzyme supplements. In a short-term study, fecal fat was 23.5 +/- 7 g/day with the microspheres, compared with 29.9 +/- 8 with other supplements, providing fat utilization of 76 +/- 7% versus 63 +/- 10% (p less than 0.05). Microspheres reduced daily stool frequency to 1.9 movements from 4.3 on other enzymes (p less than 0.01). These results were obtained with an average intake of 10 microsphere capsules/day. In a year-long study of 22 patients, an average weight gain of 4.0 +/- 1.1 kg was observed associated with return of near-normal social and work life-style in previously housebound patients.

Nutritional assessment and treatment of hospital malnutrition.

A thorough awareness of the nutritional and metabolic status of the hospitalized patient is crucial for all persons directly involved in patient care. The catabolic nature of the body's response to illness or injury induces a serious drain on vital organs and tissues. Therefore, a complete assessment of the body's various compartments must be carefully taken, and any nutritional depletion must be quickly alleviated. Due to the alarming incidence of often undetected severe malnutrition in hospitalized patients, if becomes imperative that attention be paid to nutritional status, to decrease unnecessary morbidity and mortality.