Teicoplanin as Infection Prophylaxis in Pediatric Acute Myeloid Leukemia

Due to intensified treatment, pediatric patients with acute myeloid leukemia (AML) are at high risk of developing severe infections. In this population, Viridans Group Streptococci (VGS) are a prevalent cause of Gram-positive bloodstream infections (BSIs), which occur in about 30% of the patients. These VGS BSIs infections are associated with severe complications and may result in VGS shock syndromes, which are associated with intensive care admission rates up to 60% in some series, and mortality rates up to 20%. Nonetheless, no antibiotic VGS prophylaxis is recommended by (inter)national guidelines because of the lack of supporting evidence.

Our aims are to assess the safety of i.v. teicoplanin prophylaxis three times per week with a two to three days interval during a safety run-in, and to prospectively evaluate whether this schedule decreases the occurrence of culture-proven VGS BSIs during initial pediatric AML treatment. Additionally, a population pharmacokinetic (PK) model of teicoplanin will be constructed using this schedule.

The study is set up as a prospective, international, multicenter, open-label, randomized clinical trial, preceded by a safety run-in. Pediatric patients (0-19 years) with newly-diagnosed AML treated according to the international NOPHO-DBH AML 2012, or a consecutive protocol, are eligible. Patients will be randomized to receive either teicoplanin or no teicoplanin prophylaxis.

The primary endpoint of the safety run-in is the number of dose-limiting toxicities (DLTs) observed. The primary endpoint of the randomized phase is the (first) occurrence of a culture-proven BSI with VGS during initial AML treatment.

PK samples will be drawn from the central venous line (CVL) on different time points to determine teicoplanin serum levels.

A sample size of 122 patients (n=61 in each arm) will achieve 80% power to detect an absolute reduction of 20% VGS BSIs (that is, from a conservative estimate of 25% in the control group to 5% in the intervention group) at a significance level of 0.05 using a two-sided test for proportions. An interim analysis is considered at 75% (n=92) of evaluable patients.
The results will help to develop international evidence-based guidelines concerning infection prophylaxis during pediatric AML treatment. If the number of VGS BSIs can be reduced, this will contribute to a reduction of infection-related morbidity and ultimately mortality.

Intravenous teicoplanin prophylaxis dosed 20 mg/kg/once daily three times per week with a two to three days interval is safe and effective in decreasing the occurrence of culture-proven VGS BSIs in pediatric patients with newly-diagnosed AML during initial treatment.

1. End of safety run-in: number of DLTs --> completed. The data safety monitoring board did not observe any safety issue at the end of the safety run-in and recommended to continue with the trial with i.v. teicoplanin 20 mg/kg/once daily three times per week with a two to three days interval.
2. Interim analysis at 75% of enrolled patients (n=92)
3. End of RCT

i.v. teicoplanin prophylaxis 20 mg/kg/once daily three times per week.