Randomized Multicenter Study Comparing Safety and Efficacy of Daptomycin Versus Standard-of-care in Pediatric Patients With Staphylococcal Bacteremia.

BACKGROUND: Staphylococcus aureus, including community-associated methicillin-resistant S. aureus, is an important cause of pediatric bacteremia. Daptomycin is a well-established treatment option for Gram-positive bacteremia in adults, but its safety and efficacy in children require confirmation. METHODS: This was a randomized (2:1), evaluator-blinded, multicenter, phase 4 clinical trial comparing intravenous daptomycin with standard-of-care (SOC) for treatment of S. aureus bacteremia in 1- to 17-year-old patients (Clinicaltrials.gov: NCT01728376). Total treatment duration (intravenous followed by oral step-down therapy) was 5-42 days. Daptomycin was dosed once daily by patient age: 12-17 years, 7 mg/kg; 7-11 years, 9 mg/kg and 1-6 years, 12 mg/kg. The primary objective was to evaluate daptomycin safety in children who received ≥1 dose; secondary objectives included comparing daptomycin efficacy with SOC (the trial was not designed to confirm noninferiority) and pharmacokinetic analysis. RESULTS: Fifty-five children were randomized to daptomycin and 27 to SOC (primarily vancomycin or cefazolin); 90% had S. aureus. In both groups, 15% of patients had drug-related adverse events, primarily diarrhea (4% daptomycin, 8% SOC) and increased creatine phosphokinase (4% daptomycin, 0% SOC). Clinical success (blinded evaluator-assessed complete/partial resolution of bacteremia signs and symptoms 7-14 days after end-of-treatment) rates were similar for daptomycin (88%) and SOC (77%; 95% confidence interval for difference: -9% to 31%). Daptomycin plasma levels across age groups were comparable with those in adults receiving daptomycin at 6 mg/kg. CONCLUSIONS: Once-daily, age-appropriate daptomycin was well tolerated in children with staphylococcal bacteremia; efficacy was comparable with SOC. Daptomycin in age-adjusted doses is a safe treatment alternative in this setting.

Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers.

BACKGROUND: Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models. METHODS: Safety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies. RESULTS: Participants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [Cmax]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6-12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (Cmax: 25.5, 37.6, and 93.5 ng/mL) than on day 1 (Cmax: 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 µg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate. CONCLUSION: Both SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea. TRIAL REGISTRATION: NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.

Daptomycin for Complicated Skin Infections: A Randomized Trial.

BACKGROUND: Complicated skin and skin structure infections (cSSSI) are common in children. Due to safety and resistance issues with recommended agents, new treatment options would be advantageous. METHODS: Multicenter, evaluator-blinded clinical trial. Patients 1 to 17 years old with cSSSI caused by Gram-positive pathogens were randomized 2:1 to intravenous daptomycin or standard-of-care (SOC) treatment for ≤14 days. Daptomycin was administered once daily with dosing by patient age: 12 to 17 years, 5 mg/kg; 7 to 11 years, 7 mg/kg; 2 to 6 years, 9 mg/kg; 12 to 23 months, 10 mg/kg. The primary objective was to evaluate daptomycin safety. The secondary objective was to assess the efficacy of daptomycin compared with SOC. The intent-to-treat (ITT) population consisted of all randomized patients with any dose of study drug. RESULTS: The ITT population comprised 257 daptomycin and 132 SOC patients (primarily clindamycin or vancomycin); 35% had confirmed methicillin-resistant Staphylococcus aureus. The most common adverse events were diarrhea (7% daptomycin, 5% SOC) and increased creatine phosphokinase (6% daptomycin, 5% SOC). The proportions of safety population patients with treatment-related adverse events were similar between the daptomycin (14%) and SOC (17%) groups. Clinical success rates (blinded evaluator-assessed complete/partial resolution of cSSSI signs and symptoms 7-14 days after end-of-treatment) in the ITT population were also similar for the daptomycin (91%) and SOC groups. CONCLUSIONS: Once-daily daptomycin was well tolerated, with safety and efficacy comparable to SOC in children/adolescents with cSSSI caused by Gram-positive pathogens, including community-acquired methicillin-resistant S aureus.

Surotomycin versus vancomycin for Clostridium difficile infection: Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial.

OBJECTIVES: Clostridium difficile infection (CDI) is a major public health concern. Treatment with commonly prescribed antibiotics is associated with high rates of recurrence after initial cure. Here, we present the efficacy and safety of surotomycin, an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide, compared with vancomycin, in patients with CDI. METHODS: In this Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial, participants received surotomycin 125 mg twice daily, surotomycin 250 mg twice daily or vancomycin 125 mg four times daily for 10 days. The primary efficacy outcome was clinical response at end of treatment. The registration number of the study on clinicaltrials.gov is NCT01085591. RESULTS: Clinical cure rates were similar among treatment groups (92.4% for surotomycin 125 mg twice daily, 86.6% for surotomycin 250 mg twice daily and 89.4% for vancomycin). Recurrence rates were 27.9% for surotomycin 125 mg twice daily, 17.2% for surotomycin 250 mg twice daily and 35.6% for vancomycin. The lower recurrence rate with surotomycin 250 mg twice daily versus vancomycin was statistically significant (P = 0.035). Recurrence rates were statistically similar between the surotomycin dose groups (P = 0.193). Rates of sustained clinical response at end of study were 66.7% for surotomycin 125 mg twice daily, 70.1% for surotomycin 250 mg twice daily and 56.1% for vancomycin. Incidence of adverse events was similar among treatment arms. CONCLUSIONS: Recurrence rates of CDI were lower with surotomycin with higher sustained clinical response rates compared with vancomycin, both of which may offer potential clinical benefits.

Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease.

This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n = 10) were compared with those of a placebo (n = 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n = 21) and 300 mg q.d. (n = 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {Cavgs}], of ≥ 500 to ≤ 2,500 ng/ml in ≥ 90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state Cavg, ∼ 1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.).

Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species.

Two large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in Saccharomyces yeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicans cultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glabrata cultures increased by two- and fourfold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive C. krusei cultures increased twofold. C. glabrata was the species that most frequently exhibited decreases in susceptibility, and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects from whom colonizing C. glabrata isolates were recovered at the baseline and the end of treatment, approximately 40% of the isolates exhibited more than fourfold increases in MICs during therapy. Molecular typing of the C. albicans and C. glabrata isolates confirmed that the majority of the baseline and end-of-treatment isolates were closely related, suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by Candida species were very rare (approximately 1%), and C. glabrata was the colonizing species that was the most frequently associated with breakthrough infections.

Posaconazole as salvage therapy in patients with invasive fungal infections after solid organ transplant.

BACKGROUND: The incidence of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients has increased during the past 20 years and is associated with significant morbidity and mortality. In this post hoc analysis of a large, open-label, multicenter study, we evaluated efficacy and safety of posaconazole, a new extended-spectrum triazole, as salvage therapy for IFIs in SOT recipients. METHODS: Twenty-three SOT recipients with proven or probable IFI and evidence of disease refractory to, or intolerant of, standard antifungal therapies received posaconazole oral suspension (40 mg/mL) 800 mg daily in divided doses. An independent, blinded data-review committee assessed patient diagnosis and outcome. RESULTS: Complete or partial response was documented in 13 of 23 (57%) SOT recipients with proven or probable IFIs, including 1 of 2 (50%) refractory patients, 5 of 8 (63%) intolerant to prior therapy, and 7 of 13 (54%) who were both. Successes by type of IFI included 7 of 12 with invasive aspergillosis, 2 of 2 with invasive fusariosis, 1 of 1 with cryptococcosis, and 1 of 2 with zygomycosis. Treatment-related adverse events (TRAEs) were reported in 12 of 23 patients. Severe TRAEs occurred in 4 of 23 patients including increased levels of cyclosporine or tacrolimus requiring immunosuppressive dose adjustments in three patients and in one, termination of posaconazole. Severe TRAEs associated with renal and liver toxicities were uncommon. CONCLUSION: Posaconazole was well tolerated and effective against IFIs including invasive aspergillosis, zygomycosis, fusariosis, and cryptococcosis in SOT recipients intolerant of or failing other antifungal therapies. Calcineurin inhibitor levels should be closely monitored in patients treated concomitantly with posaconazole to avoid toxicity from drug interaction.

Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease.

STUDY OBJECTIVE: To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft-versus-host disease (GVHD). DESIGN: Pharmacokinetic analysis in a subset of posaconazole-treated patients from a large, multicenter, phase III, randomized, double-blind, double-dummy, parallel-group trial that compared posaconazole with fluconazole. SETTING: Ninety international medical centers. PATIENTS: The subset of patients comprised 246 HSCT recipients for whom pharmacokinetic data were available. INTERVENTION: All patients received posaconazole 200 mg oral suspension 3 times/day for a maximum of 16 weeks. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected after dosing on day 2; at weeks 2, 4, 8, and 12; and on the last day of oral treatment. After patients had received posaconazole for at least 7 days (i.e., after achieving steady state), both maximum observed posaconazole concentration (C(max)) and average posaconazole concentration (C(av)) were determined. Five patients developed invasive fungal infections while receiving treatment. Median C(av) and C(max) were 611 and 635 ng/ml, respectively, in these five patients and were 922 and 1360 ng/ml, respectively, in the 241 patients without invasive fungal infection. In patients without invasive fungal infection, posaconazole concentrations were not clinically affected by race, body weight, or age. Median plasma posaconazole concentrations were higher in patients with chronic GVHD than in those with acute GVHD. In 18 patients without invasive fungal infection who experienced diarrhea on the day of sampling, posaconazole concentrations were lower than the concentrations in patients without diarrhea. No relationship was observed between alanine aminotransferase, aspartate aminotransferase, or bilirubin levels and posaconazole concentrations. CONCLUSION: Posaconazole 200 mg 3 times/day resulted in median plasma drug concentrations sufficiently high to prevent invasive fungal infections in HSCT recipients with GVHD, without compromising patient safety. Plasma posaconazole concentrations are generally unaffected by demographic variables, including race, sex, body weight, and age.

Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease.

BACKGROUND: Invasive fungal infections are an important cause of morbidity and mortality after allogeneic hematopoietic stem-cell transplantation. METHODS: In an international, randomized, double-blind trial, we compared oral posaconazole with oral fluconazole for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The primary end point was the incidence of proven or probable invasive fungal infections from randomization to day 112 of the fixed treatment period of the study. RESULTS: Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole. At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence, 5.3% and 9.0%, respectively; odds ratio, 0.56; 95 percent confidence interval [CI], 0.30 to 1.07; P=0.07) and was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13 to 0.75; P=0.006). While patients were receiving study medications (exposure period), in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough invasive fungal infections (2.4% vs. 7.6%, P=0.004), particularly invasive aspergillosis (1.0% vs. 5.9%, P=0.001). Overall mortality was similar in the two groups, but the number of deaths from invasive fungal infections was lower in the posaconazole group (1%, vs. 4% in the fluconazole group; P=0.046). The incidence of treatment-related adverse events was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group), and the rates of treatment-related serious adverse events were 13% and 10%, respectively. CONCLUSIONS: Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections. (ClinicalTrials.gov number, NCT00034645 [ClinicalTrials.gov].).

Posaconazole treatment of refractory eumycetoma and chromoblastomycosis

Eumicetoma e cromoblastomicose são infecções fúngicas crônicas do tecido subcutâneo que evoluem com aspecto desfigurado, raramente involuindo espontaneamente. A maioria dos pacientes não apresenta melhora sustentada por longo tempo com os tratamentos disponíveis, sendo de grande importância as novas opções terapêuticas. A eficácia do posaconazol, um novo agente antifúngico de amplo espectro do grupo dos triazóis, foi estudada em 12 pacientes com eumicetoma ou cromoblastomicose refratária às terapêuticas antifúngicas disponíveis. Os pacientes receberam por no máximo 34 meses, doses divididas de 800 mg/dia de posaconazol. Resposta clínica parcial ou completa foi considerada como sucesso; doença estável ou falha terapêutica foi considerada como insucesso. Todos os 12 pacientes tinham infecções comprovadas ou prováveis, refratárias à terapêutica padrão preconizada. Sucesso clínico foi registrado em cinco de seis pacientes com eumicetoma e cinco de seis pacientes com cromoblastomicose. Em dois pacientes observou-se doença estável. Como parte do protocolo de extensão do tratamento, dois pacientes com eumicetoma que inicialmente tinham tido sucesso terapêutico e que após um intervalo maior de 10 meses apresentaram recidiva da micose, foram retratados com sucesso com posaconazol. Posaconazol foi bem tolerado durante o longo período de administração (até 1015 dias). A terapêutica com posaconazol foi seguida de sucesso na maioria dos pacientes com eumicetoma ou cromoblastomicose refratária à terapêutica padrão, sugerindo que tal droga possa ser uma importante opção no tratamento de tais doenças.

Posaconazole treatment of refractory eumycetoma and chromoblastomycosis.

Eumycetoma and chromoblastomycosis are chronic, disfiguring fungal infections of the subcutaneous tissue that rarely resolve spontaneously. Most patients do not achieve sustained long-term benefits from available treatments; therefore, new therapeutic options are needed. We evaluated the efficacy of posaconazole, a new extended-spectrum triazole antifungal agent, in 12 patients with eumycetoma or chromoblastomycosis refractory to existing antifungal therapies. Posaconazole 800 mg/d was given in divided doses for a maximum of 34 months. Complete or partial clinical response was considered a success; stable disease or failure was considered a nonsuccess. All 12 patients had proven infections refractory to standard therapy. Clinical success was reported for five of six patients with eumycetoma and five of six patients with chromoblastomycosis. Two patients were reported to have stable disease. As part of a treatment-use extension protocol, two patients with eumycetoma who initially had successful outcome were successfully retreated with posaconazole after a treatment hiatus of > 10 months. Posaconazole was well tolerated during long-term administration (up to 1015 d). Posaconazole therapy resulted in successful outcome in most patients with eumycetoma or chromoblastomycosis refractory to standard therapies, suggesting that posaconazole may be an important treatment option for these diseases.