1418. Pharmacokinetics (PK) and Toxicity of Intravenous Amikacin (AMK) Dosed Three Times a Week (TIW) for Treatment of Disseminated Mycobacterium abscessus Infection in Children

Abstract

BackgroundAMK exhibits concentration-dependent bactericidal activity where larger intermittent doses with higher peaks (Cmax) may be less toxic than more frequent dosing while achieving similar efficacy. An AMK containing regimen was used for treatment of M. abscessus odontogenic outbreak infections in children. Additionally, synergy has been observed between AMK and clofazimine (CFZ). Previous reports of daily AMK for M. abscessus infection in children resulted in high rates of toxicity. This is the first report of PK and safety of AMK dosed TIW for disseminated M. abscessus infections in children.MethodsTreatment regimen initially included high dose AMK TIW with azithromycin (AZM) and a β-lactam followed by lower dose AMK with CFZ and AZM. Data collected included demographics, weekly laboratories, treatment details and adverse effects. AMK levels were drawn at 2- and 6-hour postdose for PK determination and to attain a Cmax of 8 × minimum inhibitory concentration. Audiograms were obtained every 2 weeks.ResultsOf 27 children who received treatment, 13 were male, mean age was 5.8 years (3.0–9.4 years) and mean weight was 21.4 kg (14–37 kg). Dissemination (lung nodules (16 [59.3%]) and granulomatous cervical lymphadenitis (10 [37%]) was common. All patients underwent oral surgical debridement. Mean total treatment duration was 135 ± 19 days (mean ± SD). Initial AMK dose was 23.7 ± 5 mg/kg to achieve a Cmax 58.7 ± 6.3 mg/L. Dosage was reduced to 12.6 ± 2.2 mg/kg after addition of CFZ at 65 ± 14 days to target Cmax 25 ± 5 mg/L. No nephrotoxicity was noted, however a transient increase in serum creatinine of 50% from baseline was seen in seven (25%) patients. Two children experienced mild–moderate hearing loss during treatment which normalized by final audiogram. All children showed evidence of jaw healing with resolved or improving lung nodules at 12-months follow-up.ConclusionTIW AMK containing regimen is well tolerated and potentially less toxic than daily dosing for treatment of M. abscessus infection in children.AMK PK Parameters (Mean ± SD) k e (hour−1) t 1/2 (hour) V d (L/kg) C max (mg/L)CL (mL/minute)AUC (mg hour/L)0.46 ± 0.071.5 ± 0.250.38 ± 0.1158.7 ± 6.359.3 ± 17.7145.6 ± 24.6Disclosures A. Arrieta, Melinta Therapeutics: Investigator, Research support.