Safety and tolerability of clofazimine as salvage therapy for atypical mycobacterial infection in solid organ transplant recipients

Cariello, Paloma F.; Kwak, Eun Jeong; Abdel-Massih, Rima; Silveira, F.

doi:10.1111/tid.12340

Cited by 35 publications

(15 citation statements)

References 11 publications

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“…This antimicrobial was recently introduced for the treatment of multidrug-resistant or extensively drug-resistant tuberculosis (14)(15)(16)(17). Several reports have also reported the clinical efficacy of CFZ in the treatment of Mycobacterium avium complex lung disease (18)(19)(20)(21)(22); however, the results are inconsistent. Regarding M. abscessus infection, in vitro DST studies demonstrated a low MIC of CFZ and in vitro synergy between CFZ and other antibiotics, such as clarithromycin (CLR), AMK, or tigecycline (23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 77%

“…Notably, a recent experimental study reported that CFZ prevented the regrowth of the M. abscessus type strain exposed to AMK and CLR (28). Although the experimental studies cited above suggest a potential role for CFZ in the treatment of NTM lung disease, several clinical studies evaluating the efficacy of CFZ for the treatment of M. avium complex lung disease reported inconsistent response rates (18)(19)(20)(21)(22), and clinical data on the outcomes of patients with M. abscessus lung disease treated with CFZ are extremely limited (31).…”

Section: Discussionmentioning

confidence: 99%

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Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Yang

Jhun

Moon

et al. 2017

Antimicrob Agents Chemother

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Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P ϭ 0.018) and salvage (P ϭ 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted.

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confidence: 77%

Section: Discussionmentioning

confidence: 99%

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Yang

Jhun

Moon

et al. 2017

Antimicrob Agents Chemother

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“…It is well known that soluble CFZ is toxic in vitro, with a 50% inhibitory concentration of approximately 5 M, whereas the insoluble crystalline form of CFZ that bioaccumulates in macrophages leads to very few signs of toxicity even at 100 M (23). Indeed, in spite of its massive accumulation in the liver, the hepatotoxicity of CFZ in mice and human patients has not been a significant concern (45)(46)(47). Like humans, mice treated with therapeutic CFZ doses (10 mg/kg/day) did not show signs of deteriorated health.…”

Section: Figmentioning

confidence: 99%

Clofazimine Biocrystal Accumulation in Macrophages Upregulates Interleukin 1 Receptor Antagonist Production To Induce a Systemic Anti-Inflammatory State

Yoon

Keswani

Sud

et al. 2016

Antimicrob Agents Chemother

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Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Therefore, to specifically elucidate the off-target consequences of drug bioaccumulation in macrophages, we compared the level of inflammasome activation in CFZ-accumulating organs (spleen, liver and lung) in mice after 2 and 8 weeks of CFZ treatment when the drug exists in soluble and insoluble (biocrystalline) forms, respectively. Surprisingly, the results showed a drastic reduction in caspase 1 and interleukin-1␤ (IL-1␤) cleavage in the livers of mice treated with CFZ for 8 weeks (8-week-CFZ-treated mice) compared to 2-week-CFZ-treated and control mice, which was accompanied by a 3-fold increase in hepatic IL-1 receptor antagonist (IL-1RA) production and a 21-fold increase in serum IL-1RA levels. In the lung and spleen, IL-1␤ cleavage and tumor necrosis factor alpha expression were unaffected by soluble or biocrystal CFZ forms. Functionally, there was a drastic reduction of carrageenan-and lipopolysaccharide-induced inflammation in the footpads and lungs, respectively, of 8-week-CFZ-treated mice. This immunomodulatory activity of CFZ biocrystal accumulation was attributable to the upregulation of IL-1RA, since CFZ accumulation had minimal effect in IL-1RA knockout mice or 2-week-CFZ-treated mice. In conclusion, CFZ accumulation and biocrystal formation in resident tissue macrophages profoundly altered the host's immune system and prompted an IL-1RA-dependent, systemic anti-inflammatory response.

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“…The use of clofazimine in combination therapy has been associated with sputum conversion and favorable treatment outcomes for MAC pulmonary disease. [66][67][68] Clofazimine also has a synergistic effect with amikacin, macrolides, and other antimicrobials for M abscessus complex, and it is often used for this difficultto-treat disease, but effectiveness data are limited. [69][70][71] Clofazimine is usually well tolerated.…”

Section: Clofaziminementioning

confidence: 99%

Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections

Shulha

Escalante

Wilson

2019

Mayo Clinic Proceedings

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Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring. Antimicrobial susceptibility testing and patient monitoring on therapy were also examined. We used PubMed to review the published literature on the management of select NTM pathogens, the common syndromes encountered since 2000, and select pharmacokinetic principles of select antimicrobial agents used since 1990. We included select clinical trials, systematic reviews, published guidelines, and observational studies when applicable. The prolonged duration and the necessity for combination therapy for most forms of NTM disease can be problematic for many patients. A multidisciplinary care team that includes pharmacy engagement may help increase rates of optimal patient tolerability and successful treatment completion.

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Safety and tolerability of clofazimine as salvage therapy for atypical mycobacterial infection in solid organ transplant recipients

Abstract: Clofazimine appears safe and may be considered as a salvage therapeutic option in SOT recipients with MAC infection who are intolerant or unresponsive to standard therapy. The small sample size does not allow conclusions regarding efficacy.

Cited by 35 publications

References 11 publications

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Clofazimine Biocrystal Accumulation in Macrophages Upregulates Interleukin 1 Receptor Antagonist Production To Induce a Systemic Anti-Inflammatory State

Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections

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