Absence of Clinically Meaningful Drug-Drug Interactions with Rezafungin: Outcome of Investigations.

Rezafungin is a novel once-weekly echinocandin for intravenous injection currently in development for the treatment of Candida infections and the prevention of Candida, Aspergillus, and Pneumocystis infections in allogeneic blood and marrow transplant recipients. While in vitro data indicated that rezafungin exposure was unlikely to be affected by commonly prescribed medicines, interactions resulting in the altered systemic exposure of some drugs coadministered with rezafungin could not be excluded. Two phase 1 open label crossover studies, conducted in healthy subjects, examined drug interactions between rezafungin and multiple drug probe cytochrome P450 (CYP) substrates and/or transporter proteins, immunosuppressants, and cancer therapies. Statistical analysis compared the outcomes for drugs coadministered with rezafungin to those for the drugs administered alone. The geometric mean ratio was reported, and a default 90% confidence interval (CI) no-effect equivalence range of 80 to 125% was used for the maximal plasma concentration (Cmax), the area under the curve from time zero to the final sampling time point (AUC0-t), and the AUC from time zero to infinity (AUC0-∞). Most probes and concomitant drugs were within the equivalence range. For tacrolimus, ibrutinib, mycophenolic acid, and venetoclax, the AUC or Cmax was reduced (10 to 19%), with lower bounds of the 90% CI values falling outside the no-effect range. The rosuvastatin AUC and Cmax and the repaglinide AUC0-∞ were increased (12 to 16%), with the 90% CI being marginally above the upper bound. Overall, the in vitro and in vivo data demonstrated a low drug interaction potential with rezafungin via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration was unlikely to result in clinically significant effects. Treatment-emergent adverse events were typically mild, and rezafungin was generally well tolerated. IMPORTANCE Antifungal agents used to treat life-threatening infections are often associated with severe drug-drug interactions (DDIs) that may limit their usefulness. Rezafungin, a newly approved once-weekly echinocandin, has been shown to be free of DDIs based on extensive nonclinical and clinical testing described in this study.

Pharmacokinetic predictors for recurrent malaria after dihydroartemisinin-piperaquine treatment of uncomplicated malaria in Ugandan infants.

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.

Effect of nutritional status on response to treatment with artemisinin-based combination therapy in young Ugandan children with malaria.

The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <-1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <-1 and ≥-2 = 2.89 [P = 0.039]; HR for height-for-age z score of <-2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention.

Using computerized clinical decision support for latent tuberculosis infection screening.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) has published guidelines recommending screening high-risk groups for latent tuberculosis infection (LTBI). The goal of this study was to determine the impact of computerized clinical decision support and guided web-based documentation on screening rates for LTBI. DESIGN: Nonrandomized, prospective, intervention study. SETTING AND PARTICIPANTS: Participants were 8463 patients seen at two primary care, outpatient, public community health center clinics in late 2002 and early 2003. INTERVENTION: The CDC's LTBI guidelines were encoded into a computerized clinical decision support system that provided an alert recommending further assessment of LTBI risk if certain guideline criteria were met (birth in a high-risk TB country and aged <40). A guided web-based documentation tool was provided to facilitate appropriate adherence to the LTBI screening guideline and to promote accurate documentation and evaluation. Baseline data were collected for 15 weeks and study-phase data were collected for 12 weeks. MAIN OUTCOME MEASURES: Appropriate LTBI screening according to CDC guidelines based on chart review. RESULTS: Among 4135 patients registering during the post-intervention phase, 73% had at least one CDC-defined risk factor, and 610 met the alert criteria (birth in a high-risk TB country and aged <40 years) for potential screening for LTBI. Adherence with the LTBI screening guideline improved significantly from 8.9% at baseline to 25.2% during the study phase (183% increase, p < 0.001). CONCLUSIONS: This study demonstrated that computerized, clinical decision support using alerts and guided web-based documentation increased screening of high-risk patients for LTBI. This type of technology could lead to an improvement in LTBI screening in the United States and also holds promise for improved care for other preventive and chronic conditions.