ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis.

BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.

Pseudomonas aeruginosa Susceptibility Patterns and Associated Clinical Outcomes in People with Cystic Fibrosis following Approval of Aztreonam Lysine for Inhalation.

The approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect the susceptibility profiles of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic P. aeruginosa infection. Sputum cultures were collected annually (2011 to 2016). The primary study endpoint was the proportion of subjects whose least susceptible P. aeruginosa isolate had an aztreonam MIC that was >8 µg/ml (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and percent of predicted forced expiratory volume in 1 s (FEV1% predicted) were obtained from the CF Foundation Patient Registry and compared between subjects meeting and those not meeting the primary endpoint. A total of 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13 to 22%) met the primary endpoint each year, and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual declines in lung function were comparable for subjects meeting and those not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it. The aztreonam susceptibility of P. aeruginosa remained consistent during the 5-year study. The relationship between P. aeruginosa isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with an accelerated decline in lung function but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01375036.).

Randomized comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia.

Objectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL). Patients and methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB. Results: Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB ( n = 237) or placebo ( n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group ( P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group ( P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo ( P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB. Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL.

Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are standard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients, initially approved for intermittent administration. However, use of continuous inhaled antibiotic regimens of differing combinations is growing. METHODS: This double-blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS). RESULTS: 90 subjects were randomized over 18months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p=0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p=0.14). AZLI/TIS CAT therapy was well tolerated. CONCLUSIONS: This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone. Clinicaltrials.gov: NCT01641822.

Inhaled aztreonam for chronic Burkholderia infection in cystic fibrosis: a placebo-controlled trial.

BACKGROUND: Individuals with Burkholderia spp. infection have historically been excluded from efficacy trials of inhaled antibiotics, including aztreonam for inhalation solution (AZLI). METHODS: A double-blind, placebo-controlled, 24-week trial of continuous AZLI/placebo treatment was undertaken in individuals with cystic fibrosis (CF) and chronic Burkholderia spp. infection. All subjects also received usual medical care (determined by their physicians). Additional antibiotic use was not restricted. RESULTS: Baseline FEV1% predicted values ranged from 15.8% to 114.6%. No significant treatment differences (AZLI vs. placebo) were observed at week 24 for any endpoints, including FEV1% predicted, number of respiratory exacerbations requiring systemic/inhaled antibiotics, or hospitalizations. Continuous AZLI administration was well tolerated. Burkholderia spp. susceptibility to antibiotics commonly used in CF therapy showed little change. CONCLUSIONS: 24-weeks of continuous AZLI treatment did not significantly improve lung function in CF subjects with chronic Burkholderia spp. infection. Non-study antibiotic use may have confounded any potential AZLI effects.

Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial.

BACKGROUND: Open-label, parallel-group, international trial comparing aztreonam for inhalation solution (AZLI) and tobramycin nebulizer solution (TNS) for cystic fibrosis patients with airway Pseudomonas aeruginosa. METHODS: 273 patients (≥ 6 years); randomized to three 28-day courses (AZLI 75 mg [three-times/day] or TNS 300 mg [twice/day]); 28 off-days separated each course. RESULTS: 268 patients were treated (AZLI/TNS: 136/132). Mean baseline FEV1 was 52% predicted. Mean relative changes after 1 course (AZLI: 8.35%; TNS: 0.55%; p<0.001) and mean actual changes across 3 courses (AZLI: 2.05%; TNS: -0.66%; p=0.002) indicated AZLI statistical superiority vs. TNS. AZLI-treated patients had fewer respiratory hospitalizations (p=0.044) and respiratory events requiring additional antipseudomonal antibiotics (p=0.004); both treatments were well tolerated. 133 patients received 1 to 3 courses of AZLI treatment in the open-label extension-period (28-day courses separated by 28 days off-treatment); lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period. CONCLUSIONS: AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

Efficacy outcomes in a randomised trial of liposomal amphotericin B based on revised EORTC/MSG 2008 definitions of invasive mould disease.

In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) published revised definitions for diagnosing invasive fungal disease. A previous prospective trial of liposomal amphotericin B for invasive mould disease (AmBiLoad) used modified EORTC/MSG 2002 criteria. We wished to re-evaluate the response and survival based on the revised definitions to compare the outcomes of early vs. late treatment. Patients who had received an allogeneic haematopoietic stem cell transplant or who were neutropaenic (absolute neutrophil count <500 µl(-1) within 14 days of study entry) had been recruited on the basis of a halo or air crescent sign on chest computerised tomography. Originally classified as probable invasive mould disease, they were categorised as possible invasive mould disease using 2008 criteria. Patients had received liposomal amphotericin B at either 3 or 10 mg kg(-1) QD for 14 days, followed by 3 mg kg(-1) QD. Response at end of treatment and the 12-week survival were re-calculated according to 2008 definitions. Six-week survival was estimated by Kaplan-Meier analysis. Of 201 patients with invasive mould disease, 118 (59%) had a diagnosis based on halo signs (possible cases). Mycological evidence was present in 83 (41%) cases (probable/proven cases). Survival rates at 12 weeks for possible vs. probable/proven cases in the 3 mg kg(-1) QD group were 82% vs. 58% (P = 0.006), and 65% vs. 50% (P = 0.15) in the 10 mg kg(-1) QD group. At 6 weeks, rates were 87% vs. 69% in the 3 mg kg(-1) QD group (P = 0.009), and 75% vs. 61% in the 10 mg kg(-1) QD group (P = 0.01). Patients with possible invasive mould disease based on EORTC/MSG 2008 criteria had improved survival rates compared with those treated for probable/proven invasive mould disease. As possible invasive mould disease probably reflects an early-stage of disease, a better outcome might be expected when treatment with liposomal amphotericin B is started preemptively.

A safety and feasibility study comparing an intermittent high dose with a daily standard dose of liposomal amphotericin B for persistent neutropenic fever.

A high intermittent dose regimen (group A: 10 mg kg(-1) on day 1, 5 mg kg(-1) on days 3 and 6) was compared with standard dosing (group B: 3 mg kg(-1) per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (P=0.002), which extended the mean infusion time by 20 min (P=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUC(CREATININE)) for days 2-7 was 1.09 (P=0.27) and for days 2-14 was 1.05 (P=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), P=0.21], a higher AUC(POTASSIUM) (A : B ratio of 1.06, P=0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, P=0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), P<0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). Beta-D-Glucan levels were similar in both groups for patients without an IFI [AUC(GLUCAN) of 362 and 683 (P=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (P=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg(-1) on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg(-1) per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial).

BACKGROUND: Treatment of invasive mold infection in immunocompromised patients remains challenging. Voriconazole has been shown to have efficacy and survival benefits over amphotericin B deoxycholate, but its utility is limited by drug interactions. Liposomal amphotericin B achieves maximum plasma levels at a dosage of 10 mg/kg per day, but clinical efficacy data for higher doses are lacking. METHODS: In a double-blind trial, patients with proven or probable invasive mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for 14 days, followed by 3 mg/kg per day. The primary end point was favorable (i.e., complete or partial) response at the end of study drug treatment. Survival and safety outcomes were also evaluated. RESULTS: Of 201 patients with confirmed invasive mold infection, 107 received the 3-mg/kg daily dose, and 94 received the 10-mg/kg daily dose. Invasive aspergillosis accounted for 97% of cases. Hematological malignancies were present in 93% of patients, and 73% of patients were neutropenic at baseline. A favorable response was achieved in 50% and 46% of patients in the 3- and 10-mg/kg groups, respectively (difference, 4%; 95% confidence interval, -10% to 18%; P>.05); the respective survival rates at 12 weeks were 72% and 59% (difference, 13%; 95% confidence interval, -0.2% to 26%; P>.05). Significantly higher rates of nephrotoxicity and hypokalemia were seen in the high-dose group. CONCLUSIONS: In highly immunocompromised patients, the effectiveness of 3 mg/kg of liposomal amphotericin B per day as first-line therapy for invasive aspergillosis is demonstrated, with a response rate of 50% and a 12-week survival rate of 72%. The regimen of 10 mg/kg per day demonstrated no additional benefit and higher rates of nephrotoxicity.