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Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (−1·5% [95% CI −10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI −0·3 to 20·4]). Safety profiles were similar across groups. Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. Melinta Therapeutics and Cidara Therapeutics.

Background.Artemisinin-based combination therapies are now widely recommended as first-line treatment for uncomplicated malaria. However, which therapies are optimal is a matter of debate. We aimed to compare the short- and longer-term efficacy of 2 leading therapies in a cohort of young Ugandan children. Methods.A total of 351 children aged 6 weeks to 12 months were enrolled and followed up for up to 1 year. Children who were at least 4 months of age, weighted at least 5 kg, and had been diagnosed as having their first episode of uncomplicated malaria were randomized to receive artemether-lumefantrine or dihydroartemisinin-piperaquine. The same treatment was given for all subsequent episodes of uncomplicated malaria. Recrudescent and new infections were distinguished by polymerase chain reaction genotyping. Outcomes included the risk of recurrent malaria after individual treatments and the incidence of malaria treatments for individual children after randomization. Results.A total of 113 children were randomized to artemether-lumefantrine and 119 to dihydroartemisinin-piperaquine, resulting in 320 and 351 treatments for uncomplicated falciparum malaria, respectively. Artemether-lumefantrine was associated with a higher risk of recurrent malaria after 28 days (35% vs 11%; P<.001). When the duration of follow-up was extended, differences in the risk of recurrent malaria decreased such that the overall incidence of malaria treatments was similar for children randomized to artemether-lumefantrine, compared with those randomized to dihydroartemisinin-piperaquine (4.82 vs 4.61 treatments per person-year; P=.63). The risk of recurrent malaria due to recrudescent parasites was similarly low in both treatment arms. Conclusions.Artemether-lumefantrine and dihydroartemisinin-piperaquine were both efficacious and had similar long-term effects on the risk of recurrent malaria. Clinical trials registration. NCT00527800.

Background Rezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation. Methods STRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics. Results Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6–43.0) versus 38 (interquartile range, 15.9–211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117). Conclusions Rezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population.

Background Invasive candidiasis/candidemia (IC/C) is associated with a substantial health economic burden driven primarily by prolonged hospital stay. The once-weekly IV echinocandin, rezafungin acetate, has demonstrated non-inferiority to caspofungin in the treatment of IC/C. This paper reports a post hoc pooled exploratory analysis of length of stay (LoS) for hospital and intensive care unit (ICU) stays in two previously published clinical trials (ReSTORE [NCT03667690] and STRIVE [NCT02734862], that compared rezafungin with daily IV caspofungin (stable patients in the caspofungin group who met relevant criteria could step down to fluconazole after 3 days or more). Methods LoS outcomes were analysed descriptively in the pooled modified intention to treat (mITT) population (all patients who had a documented Candida infection in line with trial requirements and received at least one dose of study drug). In addition, to adjust for an imbalance between treatment groups in the proportion receiving mechanical ventilation at baseline, a generalised linear model with mechanical ventilation as a binary covariate was applied. Responses to an exploratory question in the phase 3 trial on possible earlier discharge with weekly rezafungin are also reported. Results 294 patients were included (rezafungin 139, caspofungin 155), of whom 126 (43%) had ICU admission. Patients treated with rezafungin had a numerically shorter LoS than with caspofungin in all analyses. Mean total LoS was 25.2 days, vs 28.3 days with caspofungin, and mean ICU LoS was 16.1 vs 21.6 days for rezafungin and caspofungin, respectively. After adjustment for mechanical ventilation status the difference in ICU LoS was 4.1 days, a relative difference of 24% (95% CI -11%, 72%). Physicians would have considered earlier discharge for 16% of patients (30/187) with weekly rezafungin, an average of 5–6 days earlier. Conclusions Rezafungin may enable shorter hospital and ICU LoS in IC/C compared with daily IV caspofungin, with accompanying savings in resource use. Further research is needed to confirm this in the real-world setting. Trial registration. NCT03667690 (ReSTORE; September 12, 2018); NCT02734862 (STRIVE; April 12, 2016).

Abstract Background Rezafungin (RZF) once weekly (QWk) is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in BMT. Objectives The Phase 3 ReSTORE treatment trial (NCT03667690) demonstrated RZF QWk noninferiority to caspofungin (CAS) QD. This sub-analysis evaluated efficacy and safety outcomes in patients identified as immunocompromised (immuno-c) during the trial. Methods As previously described, adults with confirmed candidaemia and/or IC were randomized to RZF QWk (400 mg Wk1 then 200 mg QWk) or CAS QD for ≥14 days (≤4 weeks) with optional oral fluconazole stepdown for CAS. In this sub-analysis, immuno-c patients were those with prior and/or concomitant use of immunosuppressants (e.g. calcineurin inhibitors and corticosteroids) and/or medical history ongoing at screening of neutropenia, BMT, SOT, lymphoma or leukaemia. Results Of 187 patients (mITT population), 90 were immuno-c as defined. Results are for those with data available for analyses: Day 14 global cure—Immuno-c: RZF, 51.1% (23/45); CAS, 55.6% (25/45); –No immuno-c: RZF, 66.7% (32/48); CAS 65.3% (32/49). Day 5 mycological eradication—Immuno-c: RZF, 64.4% (29/45); CAS, 51.1% (23/45); no immuno-c: RZF, 72.9% (35/48); CAS, 71.4% (35/49). Among immuno-c, more had ≥1 AE (96.9%) and ≥1 SAE (64.6%) versus no immuno-c (79.0% and 45.0% respectively). Conclusions In this sub-analysis of ReSTORE, immune-c status reduced efficacy rates overall but did not change efficacy rate differences between RZF and CAS.

Abstract Background Rezafungin (RZF) once weekly (QWk) is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in BMT. RZF QWk was compared with caspofungin (CAS) QD in two double-blind, randomized, controlled trials of treatment of candidaemia and/or IC: STRIVE (Phase 2, NCT02734862) and ReSTORE (NCT03667690). Objectives Trial data (Phase 2 + Phase 3) were analysed to evaluate outcomes stratified by renal function at baseline: CrCl ≥ 60 mL/min (normal/mild impairment [Norm/Mild]) and <60 mL/min (moderate/severe impairment [Mod/Sev]). Methods Outcomes were evaluated for differences between CrCl categories and between treatment groups: RZF QWk 400 mg on Wk 1 then 200 mg versus CAS QD 70 mg on Day (D)1 then 50 mg, for ≥14 days (≤4 Wks) w/optional oral fluconazole stepdown for CAS. Results D30 all-cause mortality (ACM)—Mod/Sev: RZF, 13% (7/54); CAS, 30.5% (18/59); Norm/Mild: RZF, 22.7% (17/75); CAS, 10.8% (9/83). Mycological eradication (ME) at D5—Mod/Sev: RZF, 75.9% (41/54); CAS, 61.0% (36/59); Norm/Mild: RZF, 74.7% (56/75); CAS, 66.3% (55/83). ME at D14—Mod/Sev: RZF, 75.9% (41/54); CAS, 57.6% (34/59); Norm/Mild: RZF, 69.3% (52/75); CAS, 74.7% (62/83). ≥1 treatment-emergent AE—Mod/Sev: RZF, 93.2% (55/59); CAS, 88.9% (56/63); Norm/Mild: RZF, 88.9% (72/81); CAS, 76.7% (69/90). Conclusions RZF efficacy was comparable across CrCl categories, with higher ME and lower D30 ACM in the Mod/Sev group. Further analyses are needed to evaluate the observed differences between treatment groups.

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited). Unsolicited AEs were generally mild to moderate and not rezafungin‐related. Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (Cmax) was 105.0 ng/ml and the median time to Cmax was 144 h. The GM area under the concentration‐time curve was 32,770 ng*h/ml. The median estimated terminal half‐life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re‐evaluation of the rezafungin s.c. formulation could be considered in the future.

Background In sub-Saharan Africa, malnutrition and malaria remain major causes of morbidity and mortality in young children. There are conflicting data as to whether malnutrition is associated with an increased or decreased risk of malaria. In addition, data are limited on the potential interaction between HIV infection and the association between malnutrition and the risk of malaria. Methods A cohort of 100 HIV-unexposed, 203 HIV-exposed (HIV negative children born to HIV-infected mothers) and 48 HIV-infected children aged 6 weeks to 1 year were recruited from an area of high malaria transmission intensity in rural Uganda and followed until the age of 2.5 years. All children were provided with insecticide-treated bed nets at enrolment and daily trimethoprim-sulphamethoxazole prophylaxis (TS) was prescribed for HIV-exposed breastfeeding and HIV-infected children. Monthly routine assessments, including measurement of height and weight, were conducted at the study clinic. Nutritional outcomes including stunting (low height-for-age) and underweight (low weight-for-age), classified as mild (mean z-scores between -1 and -2 during follow-up) and moderate-severe (mean z-scores < -2 during follow-up) were considered. Malaria was diagnosed when a child presented with fever and a positive blood smear. The incidence of malaria was compared using negative binomial regression controlling for potential confounders with measures of association expressed as an incidence rate ratio (IRR). Results The overall incidence of malaria was 3.64 cases per person year. Mild stunting (IRR = 1.24, 95% CI 1.06-1.46, p = 0.008) and moderate-severe stunting (IRR = 1.24, 95% CI 1.03-1.48, p = 0.02) were associated with a similarly increased incidence of malaria compared to non-stunted children. Being mildly underweight (IRR = 1.09, 95% CI 0.95-1.25, p = 0.24) and moderate-severe underweight (IRR = 1.12, 95% CI 0.86-1.46, p = 0.39) were not associated with a significant difference in the incidence of malaria compared to children who were not underweight. There were no significant interactions between HIV-infected, HIV-exposed children taking TS and the associations between malnutrition and the incidence of malaria. Conclusions Stunting, indicative of chronic malnutrition, was associated with an increased incidence of malaria among a cohort of HIV-infected and -uninfected young children living in an area of high malaria transmission intensity. However, caution should be made when making causal inferences given the observational study design and inability to disentangle the temporal relationship between malnutrition and the incidence of malaria. Trial Registration ClinicalTrials.gov: NCT00527800 .

Abstract Background Factors including frailty and multimorbidity can affect candidaemia and/or invasive candidiasis (C/IC) treatment in older people.1 The current analysis explored data from C/IC patients aged ≥65 years who were treated with rezafungin or caspofungin in the STRIVE (Phase 2: NCT02734862) and ReSTORE (Phase 3: NCT03667690) clinical trials.2,3 Methods STRIVE and ReSTORE were double-blind, randomized studies. Adults with C/IC, diagnosed by systemic signs and mycological confirmation, received rezafungin once-weekly (Week 1: 400 mg; Weeks 2–4: 200 mg) or once-daily caspofungin (Day 1: 70 mg; Days 2–28: 50 mg) by IV injection for ≥14 days (≤4 weeks). Post hoc analysis examined pooled STRIVE/ReSTORE data for subjects aged ≥65 years. Safety outcomes included treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) in subjects who received ≥1 dose of study drug (safety population). Day 30 all-cause mortality (ACM) and mycological response at Days 5 and 14 were examined for the modified intention-to-treat (mITT) population (subjects with mycological C/IC diagnosis within 96 h of randomization who received ≥1 study drug dose). Results The safety population included 132 subjects (rezafungin arm: 64; caspofungin arm: 68). The mITT population included 120 subjects (rezafungin arm: 57; caspofungin arm: 63). The most common TEAEs with rezafungin were hypokalaemia, diarrhoea, vomiting and anaemia (Table 1). Eight subjects reported rezafungin-related TEAEs and seven had caspofungin-related TEAEs. SAEs comprised one case each of first degree atrioventricular block (rezafungin arm) and acute liver injury (caspofungin arm). Day 30 ACM rate was 14.0% (rezafungin arm) and 31.7% (caspofungin arm). The between-group difference (95% CI) was -17.6 (−32.5, −2.8). Day 5 mycological response was 78.9% (rezafungin arm) and 58.7% (caspofungin arm; difference [95% CI]: 19.3 [3.3, 35.2]; Figure 1). Conclusions Integrated analysis of pooled STRIVE/ReSTORE study data revealed similar incidence of drug-related TEAEs and SAEs in patients aged ≥65 years treated with rezafungin or caspofungin. Further analyses are required to understand underlying factors influencing between-group differences regarding treatment outcomes. Table 1. Safety data for candidaemia/invasive candidiasis patients aged ≥65 years treated with rezafungin (400 mg/200 mg) or caspofungin (70 mg/50 mg) (safety population) Rezafungin (400/200 mg) (N=64), n (%) Caspofungin (70/50 mg) (N=68), n (%) Subjects with at least 1 TEAE 59 (92.2) 62 (91.2) Subjects with TEAEs leading to study discontinuation 7 (10.9) 19 (27.9) Subjects with at least 1 drug-related TEAE 8 (12.5) 7 (10.3) Subjects with at least 1 SAE 37 (57.8) 38 (55.9) Subjects with at least 1 drug-related SAE 1 (1.6) 1 (1.6) TEAEs affecting at least 10% of safety population  Hypokalaemia 11 (17.2) 7 (10.3)  Diarrhoea 10 (15.6) 9 (13.2)  Vomiting 8 (12.5) 2 (2.9)  Anaemia 7 (10.9) 5 (7.4)  Septic shock 6 (9.4) 8 (11.8)  Acute kidney injury 4 (6.3) 8 (11.8)  Urinary tract infection 1 (1.6) 7 (10.3) The safety population included all subjects who had received ≥1 dose of study drug. Figure 1. Analysis regarding mycological response at Days 5 and 14 in candidaemia/invasive candidiasis patients aged ≥65 years included in the STRIVE (Phase 2) and ReSTORE(Phase 3)clinical trials and integrated analysis of STRIVE/ReSTORE data (mITT population). All analyses were conducted using the mITT population, which included all subjects with a mycological diagnosis of candidaemia and/or invasive candidiasis within 96 h of randomization who received ≥1 dose of study drug.

Background. Although dihydroartemisinin-piperaquine (DP) is used primarily in children, pharmacokinetic/pharmacodynamic (PK/PD) data on DP use in young children are lacking. Methods. We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63. Results. The median capillary piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria. Conclusions. These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMP-SMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of piperaquine.