CASE REPORT
A 4-year old female with t (8,21) AML and central nervous system involvement was treated with NOPHO-AML 2012 protocol. She developed neutropenic fever 4 days after completed course 2 induction chemotherapy, which persisted for 1 week despite multiple antimicrobials and antifungals. She then complained of fluctuating right knee, hip and ankle pain over 4 weeks (Fig. 1) . Clinical microbiologists and orthopedic surgeons were consulted. Subsequent magnetic resonance imaging (MRI) of right lower limb revealed multiple abscesses over right groin and popliteal region with calcaneal osteomyelitis and subcutaneous edema (Figs. 2A and 2B) . Ultrasound-guided aspiration and biopsy yielded granulomas with surrounding suppurative inflammation(Fig. 2C) . Smear of joint fluid was positive for acid-fast bacilli (AFB), while polymerase chain reaction (PCR) forMycobacterium tuberculosis (M. TB ) was negative. Child was covered with intravenous (IV) daptomycin, meropenem, levofloxacin and amikacin while awaiting identity and sensitivity testing of mycobacteria. Calcaneal bone excision and debridement of right ankle with incision and drainage (I&D) were then performed followed by anti-mycobacterial chemotherapy with IV amikacin, oral clarithromycin, oral levofloxacin, and oral ethambutol (stopped after 1 week after revealing identity of NTM). Histology of excised os calcis bone confirmed osteomyelitis, and culture of bone and pus grew M. abscessus . Susceptibility testing of the M. abscessus isolate was determined by broth microdilution method and results were interpreted according to the Clinical and Laboratory Standards Institute. The isolate was susceptible to amikacin and trimethoprim-sulfamethoxazole, intermediate to cefoxitin, imipenem, linezolid, and resistant to ciprofloxacin, doxycycline and moxifloxacin. Antimicrobials were thus switched to oral trimethoprim-sulfamethoxazole (with trimethoprim dosage 10mg/kg/day), oral clarithromycin, IV imipenem-cilastatin (later switched to IV cefoxitin), IV amikacin and thrice weekly interferon-gamma (IFN-γ). In retrospect, the child might have sustained external injury to foot due to tight shoe according to mother.
Initial clinical response was noted but patient developed another abscess at right posterior thigh 12 days after the first operation as confirmed with PET-CT (Fig. 2D) . Second operation was performed 3 weeks from first operation with I&D of right groin and popliteal abscesses along with debridement of right ankle soft tissue achieved. Pus from posterior thigh grew M. abscessus . Low dose chemotherapy with oral thioguinine (6-TG) and IV with intrathecal cytarabine were resumed when fever subsided for 48 hours, and was given for 4 weeks, which led to worsening of infection necessitating third operation 4 weeks from second operation, involving sequestrectomy of right calcaneus and insertion of antibiotic-infused cement (vancomycin, amikacin and gentamycin). Child then developed drug-related rash and hepatitis with highest alanine aminotransferase and aspartate aminotransferase above 1500IU/L. Rash subsided and liver function improved after stopping all antimicrobials. Bedaquiline (100mg 3 days per week) and clofazimine (50mg 2 days per week) were introduced as salvage therapy for NTM infection 18 days from third operation. Antibiotic-infused cement was kept 7 months before removal and bone graft insertion. Peri-operatively patient was covered with 1-week course of IV amikacin and imipenem-cilastatin. Intra-operative cultures did not yield any aerobic, anaerobic bacteria, fungi or AFB. Histology showed granulomatous inflammation with no evidence of AFB or fungi. Bone graft donor site and right calcaneal wounds healed well with stitches removed on post-operative day 11 and non-weight bearing for 6 weeks post-operatively. Bedaquiline and clofazimine were continued for 4 more weeks post-operatively then stopped. Total duration of usage was 8 months. Apart from mild prolongation of QTc from 450ms to 470ms during initiation of medication, she did not suffer from any adverse effects. Serial electrocardiograms and echocardiograms showed normal cardiac anatomy and function. Serial audiograms also reported normal hearing despite courses of prolonged amikacin. She was now 18 months from last operation. Limb function was preserved with no problem in walking and daily activities. For disease control, she had been followed up for 24 months since last chemotherapy given and remained in clinical and hematological remission with regular monitoring by 4-weekly quantitative PCR (qPCR) and 8-weekly marrow exam. Minimal residual disease (MRD) was persistently negative <0.1%. No relapse so far for 2 years now.