Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non-fumigatus): A multicentre, non-interventional registry study.

BACKGROUND: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad-spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively. OBJECTIVES: The objective of this study is to determine all-cause mortality and safety outcomes among adults with IM and/or IA non-fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT). PATIENTS AND METHODS: This multicentre, non-interventional registry enrolled patients aged ≥18 years with IM or IA-nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non-primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all-cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF. RESULTS: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non-primary ISAVUSULF, and 100 other AFT. All-cause mortality through Day 42 was numerically lower in the non-primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA-nf (0% vs. 14.8% and 17.8%, respectively). All-cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug-related deaths. CONCLUSIONS: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy.

Safety and Efficacy of Fidaxomicin and Vancomycin in Children and Adolescents with Clostridioides (Clostridium) difficile Infection: A Phase 3, Multicenter, Randomized, Single-blind Clinical Trial (SUNSHINE).

BACKGROUND: Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children. METHODS: Patients aged <18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily). Safety assessments included treatment-emergent adverse events. The primary efficacy end point was confirmed clinical response (CCR), 2 days after the end of treatment (EOT). Secondary end points included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured. RESULTS: Of 148 patients randomized, 142 were treated (30 <2 years old). The proportion of participants with treatment-emergent adverse events was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of 3 deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76 of 98 patients) with fidaxomicin and 70.5% (31 of 44) with vancomycin, whereas the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% vs 50.0%; adjusted treatment difference, 18.8%; 95% confidence interval, 1.5%-35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal, and stool concentrations were high. CONCLUSIONS: Compared with vancomycin, fidaxomicin was well tolerated and demonstrated significantly higher rates of GC in children and adolescents with CDI. CLINICAL TRIALS REGISTRATION: NCT02218372.

Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial.

BACKGROUND: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. METHODS: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. RESULTS: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. CONCLUSIONS: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. CLINICAL TRIALS REGISTRATION: NCT00413218.

Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial.

Background: Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA. Methods: A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count <0.5 × 109/L for >10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed. Results: One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P < 0.001; EOT, P < 0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P = 0.002) and numerically higher at day 7 and EOT (P > 0.05 for both). Conclusions: Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes.

Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial.

Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species.

The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species.

Isavuconazole for treatment of rare invasive fungal diseases.

Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs.

Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study.

BACKGROUND: Catheter-related bloodstream infection (CRBSI) causes substantial morbidity and mortality, but few randomized, controlled studies have been conducted to guide therapeutic interventions. METHODS: To determine whether linezolid would be noninferior to vancomycin in patients with CRBSI, we conducted an open-label, multicenter, comparative study. Patients with suspected CRBSI were randomized to receive linezolid or vancomycin (control group). The primary end point was microbiologic outcome at test of cure 1-2 weeks after treatment, as assessed by step-down procedure. The first analysis population was complicated skin and skin structure infection (cSSSI) in patients with suspected CRBSI; patients with CRBSI were analyzed if noninferiority criteria (lower bound of the 95% confidence interval [CI] not outside -15%) were met. RESULTS: Noninferiority criteria were met for cSSSI (microbiologic success rate for linezolid recipients, 89.6% [146 for 163 patients]; for the control group, 89.9% [134 of 149]; 95% CI, -7.1 to 6.4) and CRBSI (for linezolid recipients, 86.3% [82 of 95]; for the control group, 90.5% [67 of 74]; 95% CI, -13.8 to 5.4). The frequency and severity of adverse events were similar between groups. Mortality rates were 10.4% for linezolid recipients (28 of 269 patients) and 10.1% for control subjects (26 of 257) in the modified intent-to-treat population (i.e., all patients with gram-positive baseline culture) through test of cure, and they were 21.5% for linezolid recipients (78 of 363) and 16.0% for the control group (58 of 363; 95% CI, -0.2 to 11.2) for all treated patients through poststudy treatment day 84. CONCLUSIONS: Linezolid demonstrated microbiologic success rates noninferior to those for vancomycin in patients with cSSSIs and CRBSIs caused by gram-positive organisms. Patients with catheter-related infections must be carefully investigated for the heterogeneous underlying causes of high morbidity and mortality, particularly for infections with gram-negative organisms.

Linezolid for the treatment of infections caused by Gram-positive pathogens in China.

In this randomised, double-blind, comparator-controlled, multicentre study conducted in China, 142 hospitalised patients aged 18-75 years with pneumonia (n=80) or complicated skin and soft-tissue infection (cSSTI) (n=62) due to suspected or known Gram-positive pathogens were randomised (1:1) to receive either linezolid 600mg (n=71) or vancomycin 1g in patients aged < or =60 years or 0.75g in patients aged >60 years (n=71) intravenously every 12h. The duration of treatment was 10-21 days for patients with pneumonia and 7-21 days for patients with cSSTI. Clinical outcomes were assessed at end-of-treatment (EOT) visit and follow-up (FU) visit 7-28 days post therapy. Staphylococcus aureus was the most common pathogen at baseline and most of these isolates were resistant to meticillin. All isolates were susceptible to linezolid and vancomycin. For the evaluable patients, the effective treatment rate for linezolid was higher than that for vancomycin at EOT (86.9% (53/61) vs. 61.7% (37/60)) and at FU (83.1% (49/59) vs. 64.9% (37/57)). Pathogen eradication rates for the microbiologically evaluable patients at FU were 79.2% (42/53) for linezolid and 61.5% (32/52) for vancomycin. The incidence of drug-related adverse events (AEs) was 25.4% (18/71) for linezolid and 16.9% (12/71) for vancomycin. Four (5.6%) linezolid-treated and eight (11.3%) vancomycin-treated patients discontinued the study drug because of an AE. Linezolid was well tolerated and effective for the treatment of infections caused by Gram-positive pathogens, including meticillin-resistant S. aureus.

Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia.

OBJECTIVE: To assess the effect of baseline variables, including treatment, on outcome in patients with nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: Retrospective analysis of data from two prospective, randomized, double-blind studies. SETTING: Multinational study with 134 sites. PATIENTS: A total of 1,019 patients with suspected Gram-positive nosocomial pneumonia, including 339 patients with documented S aureus pneumonia (S aureus subset) and 160 patients with documented MRSA pneumonia (MRSA subset). INTERVENTIONS: Linezolid, 600 mg, or vancomycin, 1 g, q12h for 7 to 21 days, each with aztreonam. MEASUREMENTS AND RESULTS: Outcome was measured by survival and clinical cure rates (assessed 12 to 28 days after the end of therapy). Logistic regression analysis was used to determine the effect of treatment and other baseline variables on outcome. Kaplan-Meier survival rates for linezolid vs vancomycin were 80.0% (60 of 75 patients) vs 63.5% (54 of 85 patients) for the MRSA subset (p = 0.03). Logistic regression analysis confirmed that the survival difference favoring linezolid remained significant after adjusting for baseline variables (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0 to 4.8; p = 0.05). Other baseline variables associated with significantly higher survival rates in MRSA pneumonia were serum creatinine levels less than or equal to two times the upper limit of normal and absence of cardiac comorbidities. Clinical cure rates for linezolid vs vancomycin (excluding indeterminate or missing outcomes) were 59.0% (36 of 61 patients) vs 35.5% (22 of 62 patients) for the MRSA subset (p < 0.01). Logistic regression analysis confirmed that the difference favoring linezolid remained significant after adjusting for baseline variables (OR, 3.3; 95% CI, 1.3 to 8.3; p = 0.01). Other baseline variables associated with significantly higher clinical cure rates in MRSA pneumonia were single-lobe pneumonia, absence of ventilator-associated pneumonia, and absence of oncologic and renal comorbidities. CONCLUSIONS: In this retrospective analysis, initial therapy with linezolid was associated with significantly better survival and clinical cure rates than was vancomycin in patients with nosocomial pneumonia due to MRSA.

Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin.

OBJECTIVE: To assess the effect of baseline variables, including treatment, on clinical cure and survival rates in patients with Gram-positive, ventilator-associated pneumonia (VAP). DESIGN: Retrospective analysis of two randomized, double-blind studies. SETTING: Multinational study with 134 sites. PATIENTS: 544 patients with suspected Gram-positive VAP, including 264 with documented Gram-positive VAP and 91 with methicillin-resistant S. aureus (MRSA) VAP. INTERVENTIONS: Linezolid 600 mg or vancomycin 1 g every 12 h for 7-21 days, each with aztreonam. MEASUREMENTS AND RESULTS: Clinical cure rates assessed 12-28 days after the end of therapy and excluding indeterminate or missing outcomes significantly favored linezolid in the Gram-positive and MRSA subsets. Logistic regression showed that linezolid was an independent predictor of clinical cure with odds ratios of 1.8 for all patients, 2.4 for Gram-positive VAP, and 20.0 for MRSA VAP. Kaplan-Meier survival rates favored linezolid in the MRSA subset. Logistic regression showed that linezolid was an independent predictor of survival with odds ratios of 1.6 for all patients, 2.6 for Gram-positive VAP, and 4.6 for MRSA VAP. CONCLUSIONS: Initial linezolid therapy was associated with significantly better clinical cure and survival rates than was initial vancomycin therapy in patients with MRSA VAP.