Rolfe, Nancy E. ACNP, MS*; Toney, John F. MD†; Green, Myke R. PharmD, BCOP‡; Sandin, Ramon L. MD, MS, FACP§; Greene, John N. MD, FACP∥
*Department of Infectious Diseases, H. Lee Moffitt Cancer Center and Research Institute, †James A. Haley VA Hospital, Division of Infectious Disease & International Medicine, ‡Department of Interdisciplinary Oncology, §Department of Pathology and Cell Biology, ∥Division of Infectious Diseases and Tropical Medicine, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL.
Address correspondence and reprint requests to Nancy E. Rolfe, ACNP, MS, H. Lee Moffitt Cancer Center and Research Institute University of South Florida College of Medicine. E-mail: firstname.lastname@example.org.
Nontuberculous mycobacteria are widely distributed in the environment and have the potential to cause serious infections, particularly in immunocompromised patients. Allogeneic bone marrow transplant recipients have severely impaired cell-mediated immunity as a result of chemotherapy, radiation therapy, underlying disease, and graft-versus-host disease; thus, they are susceptible to infections by multiple organisms. Successful treatment of mycobacterial infections in bone marrow transplant patients can be difficult, requiring aggressive and rapid intervention. Novel antimicrobial combinations are necessary to overcome microbial resistance factors. We present a case of refractory Mycobacterium fortuitum osteomyelitis after allogeneic bone marrow transplantation that was treated successfully with tigecycline and moxifloxacin.
A 40-year-old woman was referred to the infectious diseases service for management of osteomyelitis. The patient had a history of chronic myelogenous leukemia, in remission after an allogeneic bone marrow transplant 3 years before. The posttransplant course was complicated by cytomegalovirus antigenemia and bacteremias caused by Rhodococcus species and Mycobacterium fortuitum, requiring catheter removal and treatment with clarithromycin. She developed graft-versus-host disease of the skin, gastrointestinal tract, and liver and was treated with prednisone 35 mg twice daily and mycophenolate mofetil 500 mg twice daily. Two years after bone marrow transplant, she developed right anterior calf pain. Magnetic resonance imaging of the affected extremity showed diffuse heterogeneous signal of the distal tibia. A biopsy of the lesion revealed no evidence of malignancy; however, tissue cultures were positive for M. fortuitum. She received a 6-week course of intravenous meropenem 1500 mg twice daily along with a 6-month course of oral doxycycline 100 mg twice daily, azithromycin 250 mg once daily, and levofloxacin 500 mg once daily. Amikacin was avoided because of potential additive nephrotoxicity.
Despite prolonged treatment with antibiotics, the patient developed increasing pain and wound drainage. Repeat culture and sensitivities were obtained and showed persistent growth of M. fortuitum with increasing resistance to minocycline and clarithromycin. The patient underwent surgical debridement, followed by a second 8-week course of intravenous meropenem 1500 mg twice daily while receiving a concomitant 6-month course of oral linezolid 600 mg twice daily, clarithromycin 500 mg twice daily, and sulfamethoxazole/trimethoprim, 1 double-strength tablet twice daily. She also continued on her immunosuppressive therapy for treatment of chronic graft-versus-host disease with prednisone 40 mg once daily and mycophenolate mofetil 1000 mg twice daily.
During the next 4 months, she experienced persistent intermittent drainage of the leg wound with associated development of nodular lesions and increasing difficulty with ambulation. Because of concurrent immunosuppressive therapy, amputation was considered; however, she refused, and she was restarted on a third course of intravenous meropenem. She was admitted to the hospital 4 weeks later with increased tibial drainage and fevers felt to be secondary to progressive osteomyelitis. Because of given refusal of amputation and the perception of incurability, intravenous tigecycline 50 mg twice daily (after a loading dose of 100 mg) and oral moxifloxacin 400 mg daily were started as a salvage regimen. Moxifloxacin was chosen because it has the most bactericidal activity against atypical mycobacteria.1 She defervesced on this treatment. The only side effect noted was mild nausea while receiving tigecycline, and this was alleviated with antiemetics. She had complete resolution of right tibial pain and drainage and improved ambulation within 6 weeks of starting treatment.
After completion of tigecycline and during the seventh week of moxifloxacin therapy, Clostridium difficile colitis developed, and moxifloxacin was discontinued. After 7 months without antibiotics, the patient remained without tibial pain or evidence of infection despite continued immunosuppression. A radiograph showed increased callous formation at the site of prior osteomyelitis, consistent with healing of infection.
Rapidly growing mycobacteria are saprophytes found in the air, water, dust, and soil. They differ from other nontuberculous organisms in that they form mature colonies on Lowenstein-Jensen agar within 7 days. They can cause a wide spectrum of infections including pneumonia and soft tissue and bone infections and may disseminate. There have been multiple reports of atypical mycobacterial infections in patients after the treatment of hematologic malignancies and after hematopoietic stem cell transplants and solid organ transplantation.2-6 Although M. fortuitum has been demonstrated to be susceptible to a variety of antibiotics, resistance may develop when these agents are used for long periods. Treatment of bone infections presents a difficult challenge in the immunocompromised patient. Despite prolonged courses of antibiotics and surgical debridement, clinical success still may not be achieved. The choice of drugs may be limited because of poor bone penetration, intolerance of treatment, hepatic or renal toxicity, and drug interactions with the plethora of medications used by transplant patients.
Tigecycline, a new glycylcycline with bacteriostatic activity, has demonstrated excellent activity against many organisms including rapidly growing mycobacteria.7 It is indicated for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections. Tigecycline is well tolerated, with nausea and vomiting being the most common adverse effect, occurring in 20% to 30% of patients.8 In addition, tigecycline does not interfere with P450 enzyme systems, making drug interactions less problematic.
Although there were no data available regarding the efficacy of tigecycline in human osteomyelitis, a rabbit model had shown extensive distribution in bone, with increased concentration of tigecycline when infection was present. Yin et al9 studied the efficacy of tigecycline as compared with vancomycin, with and without rifampicin, for the treatment of rabbit tibial methicillin-resistant Staphylococcus aureus osteomyelitis. Rabbits that received tigecycline and oral rifampicin showed 100% clearance of infection and 90% clearance with tigecycline alone. Rabbits treated with vancomycin and oral rifampicin also showed 90% clearance of bacteria, and those treated with vancomycin alone showed only 81.8% clearance. In addition, the bone concentration of tigecycline in infected bone was significantly higher than that in noninfected bone, a finding that requires further study.
Despite being a bacteriostatic agent, tigecycline, in combination with a fluoroquinolone, seems to have efficacy for the treatment of severe and refractory orthopedic infections caused by M. fortuitum even in immunocompromised patients. Further clinical studies are warranted to further validate the clinical efficacy and safety of prolonged tigecycline for the treatment of osteomyelitis.
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