Clinical Significance of Arbekacin Sulfate for High-Risk Infections Among Patients with Hematological Malignancies

Introduction

Patients with hematological malignancies are at high-risk for severe infections with drug-resistant gram-positive bacteria, as typified by methicillin-resistant staphylococcus aureus (MRSA). Vancomycin (VCM) is widely used as empirical therapy for these high-risk infections, but the global decline in their susceptibilities to VCM is at issue. Arbekacin sulfate (ABK), a unique aminoglycoside with anti-MRSA activity, has not yet been evaluated in this setting.

Patients and methods

This is a phase 4 study to evaluate the efficacy and safety of ABK for adult patients with hematological malignancies complicated with infections including febrile neutropenia, who are at high-risk for MRSA. All participant provided written informed consent and this study was approved by the institutional review board of the hospital. ABK was administered intravenously at a dose of 100–400mg every 24–48 hours based on the patients’ body weight and the renal function. Therapeutic drug monitoring (TDM) using Habekacin TDM software (Meiji Seika Pharma, Tokyo, Japan) was performed 48–96 hours after the initiation of ABK. The clinical response was rated as “effective” if the symptoms of infection disappeared or significantly improved, taking into account the vital signs, the serum C-reactive protein (CRP) concentration, and other clinical parameters at baseline and after completion/discontinuation of the treatment.

Results

From December 2010 to June 2012, 35 eligible patients were treated with ABK up to 4 times with intervals of at least 2 weeks. Consequently, a total of 54 febrile or infectious episodes were registered. The median age, serum creatinine concentration, absolute neutrophil count, axillary temperature, and serum CRP concentration for all cases at baseline were 59 (range 34–77) years, 0.64 (range 0.34–1.31) mg/dl, 0.2 X 10⁹/L (range 0–15.1), 38.4°C (range 37.2–40.5), and 8.2 mg/dl (range 0.7–40.6), respectively. Primary diseases consisted of 34 cases of acute myeloid leukemia, 12 cases of relapsed/advanced non-Hodgkin lymphoma, 3 cases of acute lymphoblastic lymphoma/leukemia, 3 cases of myelodysplastic syndrome/aplastic anemia, and 2 cases of multiple myeloma. Diagnosis of infections consisted of 26 cases of febrile neutropenia, 18 cases of septicemia (methicillin-resistant coagulase negative staphylococci in most cases), 7 cases of pneumonia (MRSA pneumonia in one case), 2 cases of cellulitis, and 1 case of neutropenic colitis. Fifty-two cases (96%) had already received oral prophylaxis using fluoroquinolones and/or intravenous therapy with broad-spectrum antibacterials, and 47 (87%) had received cytotoxic chemotherapies. ABK was initiated with a median of 2 days (range 0–14) after the onset of fever/infection, concomitantly with a variety of broad-spectrum beta-lactams. Overall, 43 cases (80%) attained afebrile states with the absence of symptoms and rated as “effective” at the end of treatment with a median of 10 days (range 4–35). All grade renal toxicity was observed in 6 cases (11%), but they were generally mild and reversible. There were 3 deaths within 30 days of the treatment, but all of them were associated with the progression of the primary disease.

Conclusion

This study demonstrated for the first time the high efficacy of ABK for persistent or high-risk infections in patients with hematological malignancies. Further evaluations­—e.g. randomized controlled trials comparing ABK with VCM for these populations—are therefore warranted.