Abstract
Although sitafloxacin (STFX) is known to have a favorable minimum inhibitory concentration for Mycobacterium avium, few studies have evaluated the clinical efficacy of an STFX-containing regimen for pulmonary M avium complex (MAC) disease. To evaluate the clinical efficacy of STFX-containing regimens for relapsed or refractory pulmonary MAC disease, we retrospectively reviewed 18 patients with pulmonary MAC disease who received STFX for at least 4 weeks for pulmonary MAC disease between January 2008 and February 2016. Of 18 patients, 10 (55.6%) showed improved radiological characteristics and 8 (44.4%) showed negative sputum cultures at 6 months. Regarding the clinical symptoms, improvements were observed in decreasing order in sputum production (77.8%), cough (72.2%), and malaise (55.6%). Common adverse events included nausea or vomiting (38.9%), followed by loose stool or diarrhea (27.8%) and sleepiness (11.1%). Although this study contained a small number of subjects, we describe a STFX-containing regimen that was effective in achieving sputum culture negative conversions and had an acceptable adverse events profile.
Keywords: fluoroquinolone, Mycobacterium avium complex, nontuberculous mycobacteria, salvage therapy, sitafloxacin
Pulmonary Mycobacterium avium complex (MAC) disease is becoming more prevalent worldwide [1]. This disease causes progressive deterioration of lung function and possible chronic respiratory failure. Although physicians have wrestled with this disease for a long time, pulmonary MAC disease is refractory in nature and often difficult to control under clinical conditions. According to the 2007 American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guideline, the standard treatment regimen for pulmonary MAC disease contains a combination of rifampicin (RFP), ethambutol (EB), and macrolides (clarithromycin [CAM] or azithromycin) [2]. Macrolides are the key drug for treatment of MAC disease, and macrolide-containing therapy can eradicate MAC strains in 50%–60% of cases as an initial therapy [2]. However, it is known that microbiological recurrence is relatively common after successful treatment [3, 4]. Because many of these cases are refractory to standard therapy, current treatment regimens for pulmonary MAC disease remain unsatisfactory in these cases. In recent studies, certain fluoroquinolones have been receiving attention as alternative drugs for the therapy of pulmonary MAC disease. Koh et al [5] reported the advantages of moxifloxacin (MFLX)-containing treatments in refractory pulmonary MAC disease. Fujita et al [6] conducted a randomized control trial comparing gatifloxacin (GFLX)-containing regimens and CAM-containing regimens, and showed the noninferiority of GFLX. Sitafloxacin ([STFX] Gracevit) is a fluoroquinolone oral antibiotic that inhibits deoxyribonucleic acid replication in bacteria. It was released in June 2008 and is currently marketed in Japan and Thailand. Sitafloxacin is known to have similar minimum inhibitory concentration in vitro and in vivo for M avium when compared with other commercially available quinolones that show the clinical efficacy for pulmonary MAC disease [7]. However, there is limited experience regarding the use of STFX in the treatment of pulmonary MAC disease [8]. Therefore, we conducted a retrospective study to analyze the clinical efficacy of STFX-containing regimens among several teaching hospitals in Japan.
PATIENTS AND METHODS
Study Design and Participants
This was a multicenter retrospective study conducted among 3 teaching hospitals in Japan: National Hospital Organization Kyoto Medical Center (600 beds, Kyoto), Kyoto University Hospital (1121 beds, Kyoto), and Fukuoka University Hospital (915 beds, Fukuoka). To evaluate the clinical efficacy and side effects of STFX-containing regimens, we retrospectively reviewed 18 patients with pulmonary MAC disease who received STFX for at least 4 weeks for pulmonary MAC disease between January 2008 and February 2016. All patients met the 2007 ATS/IDSA diagnostic criteria and tested negative for human immunodeficiency virus infection. Patients were either refractory for a standard therapy or relapse after a standard therapy. We considered standard therapy as receiving a combination of macrolide and RFP- or EB-containing regimen. We defined refractory status as presenting continuous positive sputum culture after at least 1 year of standard therapy. The local institutional review boards approved this retrospective study.
Clinical Evaluation
We evaluated treatment response by the negative conversion of sputum culture, radiographic changes of computed tomography (CT) scan data, and clinical symptoms. The negative conversion of expectorated sputum culture was defined as 3 consecutive negative sputum cultures. If sputum was not expectorated, the sputum was considered to have converted to negative [6]. Radiographic changes of CT scan data and clinical symptoms were evaluated as improved, unchanged, or worse at 3 months and 6 months after STFX-containing treatment was started [6, 9]. All radiographic reports were reviewed by 1 and more board certified radiologists. In accordance with previous reports, we defined radiological classification as 3 forms; nodular bronchiectatic (NB) form, fibrocavitary (FC) form, and NB + FC form [10, 11]. Although we did not evaluate dose ranges, we gave STFX between 50 mg and 100 mg ranges according to previous report [12]. Type, frequency, and severity of adverse events were also recorded during the course of treatment with STFX. Severity of adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. We extracted all data from the electronic medical records in participants' institutions.
RESULTS
We reviewed 18 patients from participating hospitals. Characteristics of participants are shown in Table 1. Participants were aged 66.6 ± 7.5 years and predominantly infected with Mycobacterium intracellulare. Two patients had coinfection with Pseudomonas aeruginosa. Sitafloxacin was used because of relapse in 4 patients and refractory state in 14 patients. All patients had received prior treatment for pulmonary MAC disease; 13 (72.2%) and 5 (27.8%) had received 1 and 2 or more regimens, respectively, before starting the STFX-containing regimen. Clarithromycin, RFP, and EB were frequently used as companion drugs with STFX. Two patients also received streptomycin twice a week. The median duration of STFX administration was 12.1 ± 7.3 months. The starting dose of STFX was 100 mg/day for 17 patients and 50 mg/day for 1 patient. Of the 17 patients receiving 100 mg/day STFX, 2 required reduction to 50 mg/day in the course of therapy. Radiological findings were classified into 3 forms; there were 8 patients with the NB form, 4 with the FC form, and 6 with the NB + FC form.
Table 1.
Characteristic of Participants With Relapsed or Refractory Pulmonary Mycobacterium avium Complex Diseasea
| Characteristics | n = 18 |
|---|---|
| Age, years | 66.6 ± 7.5 |
| Gender (female) | 15 (83.3) |
| Body mass index, kg/m2 | 18.7 ± 2.8 |
| Infected MAC strain (Mycobacterium intracellulare) | 11 (61.1) |
| Coinfected microorganism | |
| Pseudomonas aeruginosa | 2 (11.1) |
| Duration of MAC disease, years | 6.0 ± 5.3 |
| Underlying condition | |
| COPD | 4 (22.2) |
| Asthma | 1 (5.6) |
| Autoimmune disease | 3 (16.3) |
| Use of corticosteroids | 1 (5.6) |
| Radiographic pattern | |
| Nodular bronchiectatic form | 8 (44.4) |
| Fibrocavitary form | 4 (22.2) |
| NB + FC form | 6 (33.3) |
| History of previous treatment | |
| One regimen | 13 (72.2) |
| Two or more regimens | 5 (27.8) |
| Companion drugs with STFX | |
| Clarithromycin | 17 (94.4) |
| Ethambutol | 8 (44.4) |
| Rifampicin | 12 (66.7) |
| Streptomycin | 2 (11.1) |
| Prior drugs used in treatment | |
| Clarithromycin | 18 (100) |
| Ethambutol | 13 (72.2) |
| Rifampicin | 16 (88.9) |
| Streptomycin | 3 (16.7) |
| Fluoroquinolone (other than STFX) | 3 (16.7) |
Abbreviations: COPD, chronic obstructive pulmonary disease; FC, fibrocavitary; MAC, Mycobacterium avium complex; NB, nodular bronchiectatic; SD, standard deviation; STFX, sitafloxacin.
a Data show either number (%) of patients or mean ± SD.
Treatment responses are shown in Table 2. Of 18 patients, 6 (33.3%) and 8 (44.4%) improved their sputum culture status at 3 months and 6 months after therapy, respectively. Eight patients (44.4%) achieved negative conversion of their sputum culture at 6 months. Regarding the clinical symptoms, improvements were seen in sputum production (77.8%), followed by cough (72.2%) and malaise (55.6%), at 6 months. No clinical symptoms changed to worse during STFX treatment.
Table 2.
Response to Treatment With Sitafloxacin-Containing Regimena
| Parameters | 3 Months After Therapy |
6 Months After Therapy |
||||
|---|---|---|---|---|---|---|
| Worse | Unchanged | Improved | Worse | Unchanged | Improved | |
| Clinical symptoms (n = 18) | ||||||
| Cough | 0 | 8 (44.4) | 10 (55.6) | 0 | 5 (27.8) | 13 (72.2) |
| Sputum | 1 (5.6) | 5 (27.8) | 12 (66.7) | 0 | 4 (22.2) | 14 (77.8) |
| Hemosputum | 0 | 13 (72.2) | 5 (27.8) | 0 | 12 (66.7) | 6 (33.3) |
| Fever | 0 | 15 (83.3) | 3 (16.7) | 0 | 15 (83.3) | 3 (16.7) |
| Malaise | 0 | 13 (72.2) | 5 (27.8) | 0 | 8 (44.4) | 10 (55.6) |
| Sputum culture status (n = 18) | 1 (5.6) | 11 (61.1) | 6 (33.3) | 0 | 10 (55.6) | 8 (44.4) |
| Radiological findings (n = 18) | ||||||
| Nodular bronchiectatic form (n = 8) | 0 | 4 (50.0) | 4 (50.0) | 0 | 2 (25.0) | 6 (75.0) |
| Fibrocavitary form (n = 4) | 0 | 2 (50.0) | 2 (50.0) | 1 (25.0) | 2 (50.0) | 1 (25.0) |
| NB + FC form (n = 6) | 0 | 4 (66.7) | 2 (33.3) | 0 | 3 (50.0) | 3 (50.0) |
Abbreviations: FC, fibrocavitary; NB, nodular bronchiectatic.
a Data show number (%) of patients.
Regarding the radiological findings, 6 of 8 patients (75.0%) with the NB form showed improvements in the abnormal shadows. By contrast, only 1 of 4 patients (25.0%) with the FC form improved.
Type, frequency, and severity of adverse events observed in this study are shown in Table 3. Gastrointestinal symptoms were most commonly observed as adverse events; of these, nausea was the most frequent. Two patients required dose reduction of STFX because of nausea and diarrhea, and 2 patients finally discontinued the STFX-containing regimen because of diarrhea and bitterness of the drug. Serious adverse events with grade 3 or more were not observed during STFX administration.
Table 3.
Type, Frequency, and Severity of Adverse Events Observed During Sitafloxacin Administrationa
| Type of Adverse Event | Total Number | Grade 1 | Grade 2 | Grade 3 or More |
|---|---|---|---|---|
| Nausea | 6 | 5 (83.3) | 1 (16.7) | 0 |
| Loose stool | 3 | 3 (100) | 0 | 0 |
| Diarrhea | 2 | 1 (50.0) | 1 (50.0) | 0 |
| Sleepiness | 2 | 1 (50.0) | 1 (50.0) | 0 |
| Vomiting | 1 | 1 (100) | 0 | 0 |
| Bitterness of drug | 1 | 1 (100) | 0 | 0 |
| ECG changesb | 1 | 1 (100) | 0 | 0 |
| Elevation of liver enzymes | 1 | 0 | 1 (100) | 0 |
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; ECG, electrocardiogram.
a Data show number (%) of patients. Grade of adverse event was evaluated according to CTCAE, version 4.0.
b ECG change of transient QT prolongation was detected in a patient.
DISCUSSION
Controversy remains regarding the clinical benefits of fluoroquinolone-containing regimens in the treatment of pulmonary MAC disease. Although ciprofloxacin-containing regimens failed to show any advantages [13], MFLX-containing regimens showed a certain level of efficacy in the treatment of refractory pulmonary MAC disease [5]. Both STFX and MFLX displayed favorable in vitro and in vivo activities against M avium strains [7]; however, STFX exhibited slightly greater therapeutic efficacy than MFLX based on intrapulmonary bacterial elimination [7]. Although the present preliminary study included only a small number of subjects, the results revealed that use of STFX-containing regimens in the treatment of pulmonary MAC disease was clinically effective and acceptable to patients. Eight of 18 patients (44.4%) in our preliminary study achieved negative conversion of sputum culture at 6 months. This therapeutic efficacy compared favorably with MFLX-containing regimens. Radiological findings were improved in 10 of 18 patients (55.6%) at 6 months; however, response to STFX-containing regimens tended to be smaller in patients with the FC than NB form. This observation might be related to the fact that FC disease is known as a factor causing refractory disease with poor prognosis [10, 14]. Fluoroquinolones may cause many adverse events, and long-term use is potentially of concern. Previous studies found that adverse events manifesting as gastrointestinal symptoms were more frequently observed with STFX-containing regimens than MFLX- or GFLX-containing regimens [5, 6]. Our study findings agreed with those results in that gastrointestinal symptoms were the main adverse events that might have hindered prolonged use of fluoroquinolones. However, all but 1 patient could tolerate the gastrointestinal symptoms, and we did not experience serious adverse events such as severe arrhythmia or seizures during STFX administration.
This study has several limitations. First, the study had a retrospective design and included only a small number of patients. Although our multicenter study could reduce the recruitment bias, the results should not be overemphasized. Second, because we did not examine the drug susceptibility of STFX or CAM in this study, we could not discuss the relationship between clinical efficacy and drug susceptibility. Furthermore, the assessment tools of clinical efficacy of STFX were not objective. Third, concerns relating to drug resistance with combination therapy are not addressed in this study. Griffith et al [15] warned that combination therapy with CAM and levofloxacin could induce CAM-resistant MAC. Furthermore, because pulmonary MAC patients are known to have possible coinfection with other microorganisms, especially P aeruginosa [16], long-term use of fluoroquinolones may induce drug resistance in microorganisms other than MAC. Finally, the follow-up periods of STFX administration in this study were less than those of conventional standard therapy. These shorter follow-up periods might have led to overestimation of the effectiveness of STFX because instances of later recurrence and adverse events of STFX treatment might have been missed. To overcome and clarify these limitations, prospective study is warranted.
CONCLUSIONS
In conclusion, STFX may be effective and acceptable as a salvage therapy for relapsed or refractory pulmonary MAC disease.
Acknowledgments
Author contributions. K. F. and M. F. designed this study. K. F., M. F., Y. I., T. H., and T. M. recruited and cared the patients. K. F. drafted and revised the manuscript. M. F. and Y. I. revised the manuscript. T. H., T. M., K. W., and M. M. supervised this study and revised the manuscript.
Financial support. This study was partly funded by a grant from the National Hospital Organization Annual fiduciary funds.
Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
References
- 1.Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin Chest Med 2015; 36:13–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367–416. [DOI] [PubMed] [Google Scholar]
- 3.Wallace RJ Jr, Brown-Elliott BA, McNulty S et al. Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease. Chest 2014; 146:276–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lee BY, Kim S, Hong Y et al. Risk factors for recurrence after successful treatment of Mycobacterium avium complex lung disease. Antimicrob Agents Chemother 2015; 59:2972–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Koh WJ, Hong G, Kim SY et al. Treatment of refractory Mycobacterium avium complex lung disease with a moxifloxacin-containing regimen. Antimicrob Agents Chemother 2013; 57:2281–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Fujita M, Kajiki A, Tao Y et al. The clinical efficacy and safety of a fluoroquinolone-containing regimen for pulmonary MAC disease. J Infect Chemother 2012; 18:146–51. [DOI] [PubMed] [Google Scholar]
- 7.Sano C, Tatano Y, Shimizu T et al. Comparative in vitro and in vivo antimicrobial activities of sitafloxacin, gatifloxacin and moxifloxacin against Mycobacterium avium. Int J Antimicrob Agents 2011; 37:296–301. [DOI] [PubMed] [Google Scholar]
- 8.Fujita M, Matsumoto T, Hirano R et al. Measurement of sitafloxacin MIC for Mycobacterium avium complex and application for treatment of pulmonary nontuberculous mycobacteriosis. Jpn J Antibiot 2014; 67:395–400. [PubMed] [Google Scholar]
- 9.Philley JV, Wallace RJ Jr, Benwill JL et al. Preliminary results of bedaquiline as salvage therapy for patients with nontuberculous mycobacterial lung disease. Chest 2015; 148:499–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hayashi M, Takayanagi N, Kanauchi T et al. Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2012; 185:575–83. [DOI] [PubMed] [Google Scholar]
- 11.Wallace RJ Jr, Zhang Y, Brown BA et al. Polyclonal Mycobacterium avium complex infections in patients with nodular bronchiectasis. Am J Respir Crit Care Med 1998; 158:1235–44. [DOI] [PubMed] [Google Scholar]
- 12.Nakashima M, Uematsu T, Kosuge K et al. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers. Antimicrob Agents Chemother 1995; 39:170–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Jenkins PA, Campbell IA, Banks J et al. Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy. Thorax 2008; 63:627–34. [DOI] [PubMed] [Google Scholar]
- 14.Ito Y, Hirai T, Maekawa K et al. Predictors of 5-year mortality in pulmonary Mycobacterium avium-intracellulare complex disease. Int J Tuberc Lung Dis 2012; 16:408–14. [DOI] [PubMed] [Google Scholar]
- 15.Griffith DE, Brown-Elliott BA, Langsjoen B et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006; 174:928–34. [DOI] [PubMed] [Google Scholar]
- 16.Fujita K, Ito Y, Hirai T et al. Prevalence and risk factors for chronic co-infection in pulmonary Mycobacterium avium complex disease. BMJ Open Respir Res 2014; 1:e000050. [DOI] [PMC free article] [PubMed] [Google Scholar]