Post-hoc analysis of the safety and efficacy of isavuconazole in older patients with invasive fungal disease from the VITAL and SECURE studies.

Isavuconazole is a triazole with broad-spectrum antifungal activity. In this post-hoc analysis of two prospective clinical trials (VITAL and SECURE), the safety and efficacy of isavuconazole in patients aged ≥ 65 years with invasive fungal diseases were evaluated. Patients were divided into two subgroups (≥ 65 and < 65 years). Adverse events (AEs); all-cause mortality; and overall, clinical, mycological, and radiological response were assessed. A total of 155 patients ≥ 65 years were enrolled in both trials. Most patients reported AEs. In the isavuconazole arm of both studies, serious AEs (SAEs) were greater in patients ≥ 65 versus < 65 years: 76.7% versus 56.9% (VITAL); 61.9% versus 49.0% (SECURE). In SECURE, SAE rates were similar in the ≥ 65 years subgroup of both treatment arms (61.9% vs 58.1%), while in the < 65 years subgroup the SAE rate was lower in the isavuconazole arm (49.0% vs 57.4%). In VITAL, all-cause mortality through day 42 (30.0% vs 13.8%) was higher, and overall response at end of treatment (27.6% vs 46.8%) was lower in patients ≥ 65 years versus < 65 years. In SECURE, all-cause mortality was similar between both subgroups, and isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms. The overall response was lower in the ≥ 65 years than the < 65 years subgroup in the isavuconazole (23.7% vs 39.0%) and voriconazole (32.0% vs 37.5%) arms. The safety and efficacy of isavuconazole were better in patients < 65 versus ≥ 65 years, and the safety profile was more favorable than that of voriconazole in both subgroups.Clinicaltrials.gov identifier NCT00634049 and NCT00412893.

A phase 2 pharmacodynamic dose-finding, safety, and efficacy study of dalteparin for pediatric venous thromboembolism treatment in children with and without cancer.

Data from registrational trials of pediatric venous thromboembolism (VTE) treatment are sparse, especially among cancer patients. We conducted a prospective, multicenter, open-label trial (NCT00952380) on dose-finding, safety, and efficacy (measured by 90-day risks of clinically relevant bleeding [CRB] and symptomatic recurrent VTE [srVTE]) of twice-daily subcutaneous dalteparin for acute VTE treatment in patients ≤18 years old. Among 38 patients (cancer, n = 26; noncancer, n = 12), median dalteparin dose requirements per kilogram varied with age but not cancer status. Risks of CRB and srVTE were <4% in cancer and noncancer subgroups. Dalteparin is an important FDA-approved treatment for pediatric VTE, particularly with cancer.

Efficacy and Safety of Ceftaroline Fosamil in Hospitalized Patients with Community-Acquired Pneumonia in China: Subset Analysis of an International Phase 3 Randomized Controlled Trial.

BACKGROUND: Ceftaroline fosamil has demonstrated superior clinical efficacy versus ceftriaxone for hospitalized adults with moderate-to-severe community-acquired pneumonia (CAP) in a Phase 3 trial in Asia and in a meta-analysis of three trials in Asia, North America, and Europe. Efficacy and safety outcomes for the subset of patients in China in the ASIA CAP trial were analyzed to determine if the same conclusions hold in the China subpopulation. METHODS: Hospitalized adults with Pneumonia Outcomes Research Team risk class III-IV CAP were randomized (1:1) to receive either intravenous ceftaroline fosamil 600 mg every 12 h or ceftriaxone 2 g every 24 h for 5-7 days. The primary efficacy variable was clinical response at test-of-cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included microbiological responses and safety. RESULTS: Of 302 patients randomized in China, 205 were included in the CE population. Clinical cure rates at TOC were 80/105 (76.2%) for ceftaroline fosamil and 61/100 (61.0%) for ceftriaxone (difference 15.2%, 95% CI 2.5, 27.6), thereby meeting predefined non-inferiority and superiority criteria for the overall study. Subgroup analyses of the primary endpoint demonstrated consistency of favourable efficacy of ceftaroline fosamil across age groups, Pneumonia Outcomes Research Team risk classes and CURB-65 scores. Microbiological responses were presumed from clinical outcomes. Adverse events were consistent with the study treatments' known safety profiles. CONCLUSION: The China subset results are consistent with the overall study population, despite the smaller sample size. Ceftaroline fosamil was both non-inferior and superior to ceftriaxone for empiric treatment of Chinese patients with moderate-to-severe CAP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01371838.

Impact of Underlying Comorbidities on Outcomes of Patients Treated with Ceftaroline Fosamil for Complicated Skin and Soft Tissue Infections: Pooled Results from Three Phase III Randomized Clinical Trials.

INTRODUCTION: In three phase III randomized controlled trials, ceftaroline fosamil was shown to be non-inferior to vancomycin plus aztreonam for the treatment of complicated skin and soft tissue infections (cSSTIs). This exploratory analysis evaluated the impact of underlying comorbidities on clinical outcomes in patients with cSSTI pooled from these three studies. METHODS: CANVAS 1 and 2 and COVERS evaluated ceftaroline fosamil (600 mg every 12 h [q12h]; 600 mg every 8 h [q8h; COVERS]) versus vancomycin plus aztreonam (1 g q12h each [CANVAS 1 and 2]; vancomycin 15 mg/kg q12h and aztreonam 1 g q8h [COVERS]) in hospitalized adults with cSSTI. The primary efficacy variable in each trial was clinical response at the test-of-cure (TOC) visit. Subgroup analyses were performed on the pooled clinically evaluable (CE) population, exploring the impact of age and various baseline comorbidities. RESULTS: Overall, 1808 patients were included in the CE population (1005 ceftaroline fosamil; 803 vancomycin plus aztreonam). Clinical cure rates at TOC were 89.7% (ceftaroline fosamil) and 90.8% (vancomycin plus aztreonam) (difference [95% confidence interval] - 1.13 [- 3.87, 1.67]). Clinical response rates were similar between treatment groups, regardless of age (≤ 65 years or > 65 years), and in subgroups of patients with and without diabetes mellitus, peripheral vascular disease, cancer/malignancy, renal impairment, and obesity; within these subgroups, efficacy and safety results were generally consistent with those of the overall cSSTI population. CONCLUSIONS: This analysis provides supportive evidence of the efficacy of ceftaroline fosamil in patients with cSSTI and underlying comorbidities. TRIAL REGISTRATION: CANVAS 1, NCT00424190 and CANVAS 2, NCT00423657 (both trials first posted on ClinicalTrials.gov 18/01/2007); COVERS, NCT01499277 (first posted on ClinicalTrials.gov 26/12/2011).

Treatment outcomes of secondary bacteraemia in patients treated with ceftaroline fosamil: pooled results from six phase III clinical trials.

OBJECTIVES: This exploratory pooled analysis assessed the efficacy and safety of ceftaroline fosamil and comparators across six phase III clinical trials in adults with community-acquired pneumonia (CAP) or complicated skin and soft-tissue infection (cSSTI) and secondary bacteraemia. METHODS: In each trial, FOCUS 1 and 2 (CAP), Asia CAP trial, CANVAS 1 and 2 (cSSTI) and COVERS (cSSTI), patients were randomised to ceftaroline fosamil [600 mg q12h by 1-h i.v. infusion, except in COVERS (600 mg q8h by 2-h i.v. infusion), adjusted for renal function] or comparator. Efficacy assessments included clinical and microbiological responses at test-of-cure visit [microbiological modified intent-to-treat (mMITT) population]. Safety outcomes were assessed. RESULTS: The pooled mMITT population comprised 1976 patients, of whom 138 had baseline bacteraemia (ceftaroline fosamil, n = 72; comparator, n = 66). Predominant baseline blood pathogens were Staphylococcus aureus (n = 29), Streptococcus pneumoniae (n = 19) and other streptococci (n = 12). Clinical cure rates in bacteraemic patients were 55/72 (76.4%) and 51/66 (77.3%) for ceftaroline fosamil and comparators, respectively, and in non-bacteraemic patients were 822/966 (85.1%) and 717/872 (82.2%). Favourable microbiological response rates in bacteraemic patients were 56/72 (77.8%) for ceftaroline fosamil and 54/66 (81.8%) for comparators, and in non-bacteraemic patients were 825/966 (85.4%) and 719/872 (82.5%). Adverse events in bacteraemic patients were consistent with the known ceftaroline fosamil safety profile or the underlying indications. CONCLUSION: These pooled clinical and microbiological efficacy data demonstrate generally favourable outcomes for ceftaroline fosamil in patients with CAP or cSSTI and secondary bacteraemia. [Trial Registration: NCT00621504, NCT00509106; NCT01371838; NCT00424190, NCT00423657; NCT01499277].

Invasive Candidiasis in Patients with Solid Tumors Treated with Anidulafungin: A Post Hoc Analysis of Efficacy and Safety of Six Pooled Studies.

BACKGROUND: Solid tumors are a common predisposing factor for invasive candidiasis (IC) or candidemia due to IC. OBJECTIVES: Post hoc analysis of patient-level efficacy and safety data from six studies of anidulafungin (with similar protocols/endpoints) in adults with IC/candidemia summarized by past or recent diagnosis of solid tumors. PATIENTS/METHODS: Patients received a single intravenous (IV) dose of anidulafungin 200 mg, followed by 100 mg once daily. After ≥ 5 to ≥ 10 days of IV treatment, switch to oral voriconazole/fluconazole was permitted in all but one study. Time of solid tumor diagnosis was defined as past, ≥ 6; and recent, < 6 months prior to study entry. Primary endpoint: global response of success (GRS) rate at the end of IV therapy (EOIVT). Secondary endpoints included the GRS rate at the end of all therapy (EOT), all-cause mortality, and safety. RESULTS: The GRS rate in the overall population was 73.4% at EOIVT and 65.5% at EOT. Past or recent solid tumor diagnosis did not affect GRS at EOIVT or EOT (past: 75.5% and 71.4%; recent: 72.2% and 62.2%, respectively). All-cause mortality was 14.4% on day 14 and 20.1% at day 28. Most treatment-emergent adverse events were mild/moderate in severity (81.6%). CONCLUSIONS: Treatment of IC was effective regardless of the time of solid tumor diagnosis. TRIAL REGISTRATION: Data were pooled from six studies: NCT00496197 (first posted on ClinicalTrials.gov on July 4, 2007); NCT00548262 (first posted on ClinicalTrials.gov on October 23, 2007); NCT00537329 (first posted on ClinicalTrials.gov on October 1, 2007); NCT00689338 (first posted on ClinicalTrials.gov on June 3, 2008); NCT00806351 (first posted on ClinicalTrials.gov on December 10, 2008); NCT00805740 (first posted on ClinicalTrials.gov on December 10, 2008).

Patients with solid tumor cancers (cancer of internal organs) have increased risk of fungal infections that can spread in the body through the blood. Infection with Candida species, known as invasive candidiasis (IC) (Candida invades the body in places normally free from germs) or candidemia (Candida infection in the blood), can cause severe illness and/or death. Anidulafungin is an antifungal drug recommended to treat IC/candidemia. This post hoc analysis looked at how effective and safe anidulafungin was in adult patients with IC/candidemia with 'recent' or 'past' history of solid tumors. The analysis included patients diagnosed with cancer less than 6 months before (recent history) or more than 6 months before (past history) they first received anidulafungin. Patients received anidulafungin by injection (intravenously [IV]) into the veins and, for continued treatment, were able to take a different antifungal drug orally. Of 539 patients from six studies, 139 had confirmed IC/candidemia and a history of solid tumors. Approximately 7 out of 10 (72%) patients were cured or no longer had signs of Candida infection at the end of IV anidulafungin treatment. Results were similar in patients with past or recent diagnosis of solid tumors. Treatment side effects reported in approximately 8 out of 10 (82%) patients were mild-to-moderate in severity. This analysis suggests anidulafungin was well tolerated and effective at treating IC/candidemia in patients with solid tumors, whether diagnosed recently or in the past.

Baseline Characteristics and Outcomes Among Patients with Complicated Skin and Soft Tissue Infections Admitted to the Intensive Care Unit: Analysis of the Phase 3 COVERS Randomized Trial of Ceftaroline Fosamil Versus Vancomycin Plus Aztreonam.

AIM: Exploratory analyses evaluated patient characteristics and outcomes among patients with complicated skin and soft tissue infection (cSSTI) in the phase 3 COVERS study who were admitted to an intensive care unit (ICU). METHODS: Adults with cSSTI (surface area ≥ 75 cm2) and evidence of systemic inflammation and/or underlying comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h [q8h]) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g q8h) for 5-14 days. Clinical response and ICU length of stay (LOS) within first hospitalization were evaluated in the modified intent-to-treat (MITT) and clinically evaluable (CE) populations; a Cox proportional hazards model identified factors associated with increased hospital LOS. RESULTS: Overall, 42 of 761 randomized patients were admitted to the ICU (ceftaroline fosamil, n = 32; vancomycin plus aztreonam, n = 10) prior to, or at start of, study treatment. Baseline differences between the ICU and non-ICU populations were indicative of more severe disease in ICU patients; within this subset, there were also some notable imbalances between treatment groups. Clinical cure rates at test-of-cure (ceftaroline fosamil vs. vancomycin plus aztreonam) were generally similar in the non-ICU and ICU subsets (MITT population 79% vs. 79% and 69% vs. 90.0%, respectively; CE population 87% vs. 85% and 80% vs. 89%, respectively). Median ICU LOS was 8 vs. 13 days, respectively. ICU admission was a risk factor predicting increased hospital LOS (P < 0.001). CONCLUSIONS: Clinical outcomes for patients admitted to the ICU were generally similar to non-ICU patients, despite more severe baseline disease, with shorter median treatment duration in the ceftaroline fosamil group. ICU admission was associated with longer hospital LOS. Given the small sample size and unbalanced patient and disease characteristics within the ICU subgroup, differences between treatment groups should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01499277.

Safety, Efficacy and Pharmacokinetics of Anidulafungin in Patients 1 Month to <2 Years of Age With Invasive Candidiasis, Including Candidemia.

Nineteen patients 1 month to <2 years of age with (n = 16) or at high risk of (n = 3) invasive candidiasis received anidulafungin for 5-35 days (3 mg/kg day 1, 1.5 mg/kg daily thereafter) followed by optional fluconazole (NCT00761267). Most treatment-emergent adverse events were mild/moderate, and no treatment-related deaths occurred. End of intravenous therapy global response success rate was 68.8%. Pharmacokinetics were similar to adult patients.

Phase 2 Study of the Safety, Pharmacokinetics and Efficacy of Ceftaroline Fosamil in Neonates and Very Young Infants With Late-onset Sepsis.

BACKGROUND: With increasing antimicrobial resistance, antibiotic treatment options for neonatal late-onset sepsis (LOS) are becoming limited. Primary objective of this study was assessment of the safety of ceftaroline fosamil in LOS. METHODS: Eligible neonates and very young infants 7 to <60 days of age with LOS were enrolled in this phase 2, open-label, multicenter study (NCT02424734) and received ceftaroline fosamil 4 or 6 mg/kg every 8 hours by 1-hour intravenous infusion plus intravenous ampicillin and optional aminoglycoside for 48 hours-14 days. Safety was assessed through the final study visit (21-35 days after the last study therapy dose). Efficacy, assessed as clinical and microbiologic response, was evaluated at end-of-treatment and test-of-cure. Pharmacokinetic samples were collected via sparse-sampling protocol. RESULTS: Eleven patients [54.5% male, median (range) age 24 (12-53) days] were enrolled and received ceftaroline fosamil for a median (range) duration of 8 (3-15) days. Ten adverse events (AEs) occurred in 5 (45.5%) patients (safety population); most frequent AE was diarrhea (n = 2). All except 1 AE (diarrhea) were nontreatment-related. Predominant baseline pathogen was Escherichia coli. No patients were clinical failures at end-of-treatment/test-of-cure. Observed sparse steady-state pharmacokinetics data (19 samples) were comparable to previous pediatric data and generally within 90% model prediction intervals; neonatal probability of target attainment was >95% based on established pharmacokinetic/pharmacodynamic targets. CONCLUSIONS: Safety in neonates and very young infants was consistent with the known ceftaroline fosamil safety profile. These results support the use of ceftaroline fosamil (6 mg/kg every 8 hours) as a potential treatment option for LOS.

Efficacy and safety of combination antifungal therapy in Korean haematological patients with invasive aspergillosis.

This randomised, double-blind, placebo-controlled trial assessed the efficacy, safety and tolerability of voriconazole+anidulafungin (combination) or voriconazole+placebo (monotherapy) for invasive aspergillosis (IA; NCT00531479). We present a post hoc analysis of Korean and non-Korean patients with IA (including baseline positive serum galactomannan [GM]). Immunocompromised patients ≥ 16 years with IA were randomised 1:1, combination or monotherapy, for ≥ 2 weeks' treatment. The primary endpoint was 6- and 12-week all-cause mortality (Korean modified intent-to-treat [mITT] population). Overall, 454 patients enrolled (Koreans: 56 [combination: 28, monotherapy: 28], non-Koreans: 398 [combination: 200, monotherapy: 198]). The mITT population comprised 40 Koreans (combination: 23; monotherapy: 17) and 237 non-Koreans (combination: 112; monotherapy: 125). Week 6 treatment difference in mortality rate between combination and monotherapy was -6.4% in non-Koreans. This reduction was more marked in Koreans (-22.4%). Week 12 difference in all-cause mortality between combination and monotherapy was -17.7% (Koreans) and -20.2% at Week 6 (Koreans; positive baseline GM). Week 6 mortality (Koreans [mITT]; baseline GM >0.5-2.0) was 0/13 (combination) and 2/6 (monotherapy). Serious adverse events were numerically higher for combination than monotherapy (Koreans: 57.1%, 46.4%; non-Koreans: 49.5%, 46.0%). In Koreans, combination therapy was associated with marginally better outcomes than monotherapy and more so than in non-Koreans.

Evaluation of anidulafungin in the treatment of intra-abdominal candidiasis: a pooled analysis of patient-level data from 5 prospective studies.

The incidence of nosocomial invasive fungal infections involving Candida spp. has increased markedly in recent years in patients undergoing abdominal surgery. This post hoc analysis aimed to determine the efficacy and safety of anidulafungin treatment in patients with intra-abdominal candidiasis (IAC) from five prospective studies (one comparative and four open-label) of adult surgical patients with microbiologically confirmed Candida intra-abdominal infection. Patients received an intravenous (IV) loading dose of anidulafungin 200 mg, followed by a daily 100-mg maintenance dose. Per study protocols, some patients could be switched to an oral azole after ≥ 5 or ≥ 10 days of IV treatment. Antifungal treatment was maintained for ≥ 14 days after the last positive Candida culture and resolution of symptoms. The global response rate (GRR) at the end of IV treatment (EOIVT) was the primary endpoint. GRR at the end of therapy (EOT), all-cause mortality at days 14 and 28, and safety was also evaluated. Seventy-nine patients had IAC from peritoneal fluid or hepatobiliary tract. C. albicans (72.2%) and C. glabrata (32.9%) were the most common pathogens. Overall GRR was 73.4% and 67.1% at EOIVT and EOT, respectively. All-cause mortality was 17.7% at day 14 and 24.1% at day 28 in the modified intent-to-treat population. Anidulafungin was well tolerated in this population, with most adverse events mild or moderate in severity. In these patients with IAC, anidulafungin showed a GRR at EOIVT similar to the anidulafungin registrational trial, and the results of our analysis confirmed the known safety profile of anidulafungin. ClinicalTrials.gov registration number NCT00496197, registered July 3, 2007, https://clinicaltrials.gov/ct2/show/study/NCT00496197 ; ClinicalTrials.gov registration number NCT00548262, registered October 19, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00548262 ; ClinicalTrials.gov registration number NCT00537329, registered September 25, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00537329 ; ClinicalTrials.gov registration number NCT00689338, registered May 29, 2008, https://clinicaltrials.gov/ct2/show/study/NCT00689338 ; ClinicalTrials.gov registration number NCT00805740, registered November 26, 2008, https://clinicaltrials.gov/ct2/show/NCT00805740.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data.

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

Summary of the safety and tolerability of two treatment regimens of ceftaroline fosamil: 600 mg every 8 h versus 600 mg every 12 h.

BACKGROUND: The recommended adult dose of ceftaroline fosamil is 600 mg q12h by 1 h intravenous (iv) infusion for 5-14 days in complicated skin and soft tissue infection (cSSTI) and 5-7 days in community-acquired pneumonia (CAP). A dosage of 600 mg q8h by 2 h iv infusion is approved in some regions for cSSTI patients with Staphylococcus aureus infection where the ceftaroline MIC is 2 or 4 mg/L. This analysis compares the safety profiles of the q8h and q12h regimens. METHODS: Safety data from six Phase III, randomized, double-blind clinical trials were collated into the q8h cSSTI pool (ceftaroline fosamil n = 506; NCT01499277) and the q12h pool {ceftaroline fosamil n = 1686; comprising five studies [two cSSTI (NCT00424190 and NCT00423657) and three CAP (NCT01371838, NCT00621504 and NCT00509106)]}. RESULTS: The pattern and incidence of adverse events were similar between the q8h and q12h ceftaroline fosamil pools. Most were gastrointestinal and of mild or moderate intensity. Overall, rash intensity was similar between the q8h pool and the q12h pool. For the q8h regimen, there was a higher frequency of rash in some Asian study sites, associated with longer duration of therapy (≥7 days); most cases were mild and resolved following treatment discontinuation. No dose-related vital sign or ECG abnormalities were detected with either regimen. CONCLUSIONS: The q8h regimen in cSSTI was generally well tolerated; the observed safety profile was consistent with the known safety profile of ceftaroline fosamil, reflective of the cephalosporin class and qualitatively consistent with the q12h regimen.

Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.

Objectives: To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L). Methods: A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study. Results: The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L. Conclusions: The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

A Prospective, Open-label Study to Assess the Safety, Tolerability and Efficacy of Anidulafungin in the Treatment of Invasive Candidiasis in Children 2 to <18 Years of Age.

BACKGROUND: Treatment with an echinocandin is recommended as first-line therapy for patients with invasive candidiasis (ICC) including candidemia. Little is known about the efficacy and safety of anidulafungin in children with ICC. METHODS: Eligible patients with ICC 2 to <18 years old were enrolled into this prospective, open-label, noncomparative, international study (NCT00761267) and received anidulafungin for 10-35 days (3 mg/kg on day 1, 1.5 mg/kg daily thereafter). Safety was assessed through week 6 follow-up. Efficacy, measured by global response (based on clinical and microbiologic responses), was assessed at end of intravenous treatment (EOIVT), end of treatment, weeks 2 and 6 follow-up. RESULTS: Forty-nine patients (n = 19, 2 to <5 years; n = 30, 5 to <18 years) received ≥1 dose of anidulafungin (median 11 days; range 1-35 days) and were assessed for safety. Among 48 patients with a Candida species isolated, C. albicans (37.5%), C. parapsilosis (25.0%), C. tropicalis (14.6%) and C. lusitaniae (10.4%) were the most frequent Candida spp. All patients reported ≥1 treatment-emergent adverse event, with diarrhea (22.4%), vomiting (24.5%) and pyrexia (18.4%) being most frequent. Five patients discontinued treatment because of adverse events, of which 4 discontinuations were considered related to anidulafungin. All-cause mortality was 8.2% (4/49) by EOIVT and 14.3% (7/49) by week 6 follow-up. None of 7 deaths during the study period were considered treatment related. Global response success rate was 70.8% at EOIVT. CONCLUSIONS: These data support the use of anidulafungin as a treatment option for ICC in children 2 to <18 years old at the studied dose.

Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies.

Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after ≥5 or ≥10 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC ≥8 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740).

Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials.

Objectives: To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non- albicans Candida species. Methods: Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; ClinicalTrials.gov). In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5-10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population. Results: In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%-80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin. Conclusions: These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population.

Safety, Efficacy, and Exposure-Response of Voriconazole in Pediatric Patients With Invasive Aspergillosis, Invasive Candidiasis or Esophageal Candidiasis.

BACKGROUND: Data on safety and efficacy of voriconazole for invasive aspergillosis (IA) and invasive candidiasis/esophageal candidiasis (IC/EC) in pediatric patients are limited. METHODS: Patients aged 2-<18 years with IA and IC/EC were enrolled in 2 prospective open-label, non-comparative studies of voriconazole. Patients followed dosing regimens based on age, weight and indication, with adjustments permitted. Treatment duration was 6-12 weeks for IA patients, ≥14 days after last positive Candida culture for IC patients and ≥7 days after signs/symptoms resolution for EC patients. Primary analysis for both the studies was safety and tolerability of voriconazole. Secondary end points included global response success at week 6 and end of treatment (EOT), all-causality mortality and time to death. Voriconazole exposure-response relationship was explored. RESULTS: Of 53 voriconazole-treated pediatric patients (31 IA; 22 IC/EC), 14 had proven/probable IA, 7 had confirmed IC and 10 had confirmed EC. Treatment-related hepatic and visual adverse events, respectively, were reported in 22.6% and 16.1% of IA patients, and 22.7% and 27.3% of IC/EC patients. All-causality mortality in IA patients was 14.3% at week 6; no deaths were attributed to voriconazole. No deaths were reported for IC/EC patients. Global response success rate was 64.3% (week 6 and EOT) in IA patients and 76.5% (EOT) in IC/EC patients. There was no association between voriconazole exposure and efficacy; however, a slight positive association between voriconazole exposure and hepatic adverse events was established. CONCLUSIONS: Safety and efficacy outcomes in pediatric patients with IA and IC/EC were consistent with previous findings in adult patients.

Clinical response and mortality in tigecycline complicated intra-abdominal infection and complicated skin and soft-tissue infection trials.

An imbalance in all-cause mortality was noted in tigecycline phase 3 and 4 comparative clinical trials across all studied indications. We investigated clinical failure and mortality in phase 3 and 4 complicated skin and soft-tissue infection (cSSTI) and complicated intra-abdominal infection (cIAI) tigecycline trials using descriptive analyses of a blinded adjudication of mortality and multivariate regression analyses. Attributable mortality analyses of cSSTI revealed death due to infection in 0.1% of each treatment group (P=1.000). In cIAI, there were no significant differences between tigecycline (1.2%) and comparator (0.7%) subjects who died due to infection (P=0.243). For cIAI clinical failure, treatment interaction with organ dysfunction was observed with no difference observed between clinical cure for tigecycline (85.4%) and comparator (76.7%) treatment groups (odds ratio=0.58, 95% confidence interval 0.28-1.19). Tigecycline-treated subjects had more adverse events of secondary pneumonias (2.1% vs. 1.2%) and more adverse events of secondary pneumonias with an outcome of death (0.5% vs. 0.1%). These analyses do not suggest that tigecycline is a factor either for failure (cSSTI and cIAI studies) or for death (cIAI studies).

Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis.

A phase 3, randomized, double-blind trial was conducted in subjects with diabetic foot infections without osteomyelitis (primary study) or with osteomyelitis (substudy) to determine the efficacy and safety of parenteral (intravenous [iv]) tigecycline (150 mg once-daily) versus 1 g once-daily iv ertapenem ± vancomycin. Among 944 subjects in the primary study who received ≥1 dose of study drug, >85% had type 2 diabetes; ~90% had Perfusion, Extent, Depth/tissue loss, Infection, and Sensation infection grade 2 or 3; and ~20% reported prior antibiotic failure. For the clinically evaluable population at test-of-cure, 77.5% of tigecycline- and 82.5% of ertapenem ± vancomycin-treated subjects were cured. Corresponding rates for the clinical modified intent-to-treat population were 71.4% and 77.9%, respectively. Clinical cure rates in the substudy were low (<36%) for a subset of tigecycline-treated subjects with osteomyelitis. Nausea and vomiting occurred significantly more often after tigecycline treatment (P = 0.003 and P < 0.001, respectively), resulting in significantly higher discontinuation rates in the primary study (nausea P = 0.007, vomiting P < 0.001). In the primary study, tigecycline did not meet criteria for noninferiority compared with ertapenem ± vancomycin in the treatment of subjects with diabetic foot infections.