Failure among Patients with Non-Tuberculous Mycobacterial Infections in Skin,Soft Tissue,and Musculoskeletal System in Southern Taiwan,2012

Abstract

Background:

The incidence of non-tuberculous mycobacterial (NTM) infections of the skin, soft tissue, and musculoskeletal system (SSTI) has increased over the past two decades, however, relatively few studies have documented the reasons for the reported increase. Specifically, no standardized treatment protocols have been adopted, therefore, clinical prognosis of the patients with NTM SSTI has thus far remained uncertain. In our study, we sought to identify risk factors for treatment failure in southern Taiwan.

Methods:

Patients with NTM SSTI, who received treatment between 2012 and 2015 were included in this retrospective study; detailed medical records, images, tissue specimens for culture, and pathology reports were collected for further analysis. Risk factors for treatment failure were determined using multivariable logistic regression.

Results:

Forty-two patients (16 females, 26 males; aged 58 ± 14 years) with NTM SSTI were included in the study. Isolated mycobacterial species included Mycobacterium abscessus complex, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium avium-intracellulare complex (MAC), Mycobacterium fortuitum, Mycobacterium gordonae, Mycobacterium haemophilum, Mycobacterium peregrinum, and Mycobacterium chelonae. The incidence of NTM SSTI was 23.6 per 100,000 inpatients. The sites of infection included the hand/wrist areas, spine, feet, lower legs, femur, knees, shoulders, and elbows, in 15, 6, 5, 5, 4, 3, 2, and 1 patients, respectively. The time interval between culturing the specimens and diagnosis averaged 21.2 ± 11.4 days. The main risk factors for treatment failure included treatment delays exceeding two months and infection with Mycobacterium abscessus complex.

Conclusions:

Improved clinical outcome of NTM with STI may be achieved by identifying the causative NTM species, and by initializing appropriate pharmacotherapy and surgical intervention. Non-tuberculous mycobacterial infection should be included in the differential diagnosis of SSTI and it is recommended that patients with an increased risk of treatment failure should receive prolonged antibiotic treatment and prompt surgical intervention upon diagnosis or indication of NTM infections.

Non-tuberculous mycobacteria (NTM) are a diverse group of ubiquitous, environmental, acid-fast organisms that can trigger a wide range of diseases, including infections of the skin and soft tissues. More than 170 species of NTM have been identified, most of which may cause skin and soft tissue infections [1]. Traditionally, NTM have been classified as members of Runyon groups defined by colony morphology, growth rate, and pigmentation [2]. In recent years, the practical use of this classification system has declined and been replaced by new identification methods based on rapid molecular diagnostic systems [3]. Thus, NTM can be categorized into rapidly growing mycobacteria (RGM) and slowly growing mycobacteria (SGM) [4].

In approximately 90% of the NTM cases, infection of the lungs is present. However, over the past two decades, the incidence of NTM infections of the skin, soft tissue, and musculoskeletal system (SSTI) has increased [5 –7]. Non-tuberculous mycobacteria infections are easily misdiagnosed because of difficulties in diagnosis, which often lead to delays in diagnosis and treatment [8]. Whereas NTM SSTI are often difficult to treat, key risk factors in treatment failure have not been identified in previous studies.

In Taiwan, the proportion of NTM among mycobacterial isolations increased considerably from 32.3% to 49.8% of cases between 2000 and 2008. The incidence of diseases related to NTM also increased dramatically, from 2.7 to 10.2 cases per 100,000 inpatients and outpatients [9]. Among NTM infections, 13.8% was related to SSTI [10]. In a Taiwanese study of 58 patients with clinically noteworthy NTM skin and soft tissue infections who were treated between 1999 and 2009, the most commonly isolated NTMs were RGM (n = 30), Mycobacterium marinum (n = 17), and Mycobacterium avium-intracellulare complex (MAC; n = 4) [11]. However, this was a single-center study conducted in a tertiary-care medical center in northern Taiwan, which may not be representative of the epidemiology in Taiwan because geographic variations often exist.

To identify risk factors for treatment failure, we conducted a retrospective chart review of 42 patients diagnosed with NTM SSTI who were treated between 2012 and 2015 in a single medical center in southern Taiwan. Multiple parameters were analyzed to determine these risk factors, using a logistic regression approach.

Patients and Methods

Study population, inclusion, and exclusion criteria

Between 2012 and 2015, 222 cases were identified by positive NTM cultures from the microbiology laboratory and electronic records identified through International Classification of Diseases, Ninth Revision (ICD-9) codes in Kaohsiung Veterans General Hospital, southern Taiwan. The exclusion criteria included duplicate data, cases with unevaluable outcome, and NTM infections of the lung, parotid, eyes, or those causing lymphadenitis, otitis media, and initial disseminated infections (Fig. 1). Only 42 NTM infections involving the skin, soft tissue, and musculoskeletal system were enrolled into the study. The following information was extracted from the medical records: a detailed medical history, physical examination, results of diagnostic imaging, including radiography, bone scans, and/or magnetic resonance imaging (MRI). Additionally, the results of bacterial and mycobacterial cultures of tissue specimens and pathologic analysis were collected.

FIG. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram (Adapted from Moher et al. 2010 [29]).

Definitions of treatment outcome

Treatment was considered to be successful when symptoms were resolved and discontinuation of treatment was possible; clinical cure was defined as the absence of signs of infection, such as localized heat or tenderness, and normalization of the erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels after discontinuation of antimycobacterial therapy. Finally, treatment failure was defined as local recurrence of infection or secondary disseminated disease.

Laboratory tests

Patient data on ESR, CRP, total leucocyte, and differential counts were collected, as well as medical images, such as radiographs, bone scans, and/or MRIs. Specimens obtained from the infected sites during surgery under sterile conditions were examined for histopathology. Multiple intra-operative cultures were tested for the presence of aerobic/anaerobic organisms and fungal elements and stained for acid-fast bacilli (AFB).

Culturing of mycobacteria was performed by inoculating the digested-decontaminated specimens onto Lowenstein-Jensen slants with MGIT broth. The MGIT broths were deposited in an MGIT 960 system (Becton, Dickinson and Company, Franklin Lakes, NJ), incubated at 37°C and monitored automatically. Non-tuberculous mycobacteria were identified to the species level using DR. Chip Microorganism IVD kit (Dr Chip Biotech Inc., Chu-Nan, Miao-Li, Taiwan), a microchip array for Mycobacterium [12].

Statistical analysis

Univariable and multivariable logistic regression analyses were conducted to identify risk factors for treatment failure. Gender, age, laboratory parameters, and history of other medical diseases were included as independent variables that might correlate with treatment failure in patients with NTM infection. Stata 9.1 software (StataCorp, Inc., College Station, TX) was used for modeling and statistical analyses. The analyzed data types included numbers, percentages, odds ratios, and 95% confidence intervals. For normally distributed data, continuous variables were compared using Student t-tests. Logistic regression modeling was performed to quantify the contribution of different variables to the risk of treatment failure. Tests yielding two-sided p values of <0.05 as statistically significant.

Results

The incidence of NTM infection was 40.4 per 100,000 inpatients during the period 2012–2015, whereas the incidence of SSTI due to NTM was 23.6 per 100,000 inpatients.

General patient characteristics

The study cohort comprised 42 patients, whose main characteristics are summarized in Table 1. Sixty-two percent (26 patients) of the patients were male and 38% were female. The median age of patients was 58 years (range, 33–77). Almost one-third of the patients had a history of trauma (30.9%) or surgery in the previous 12 months (33%). Treatment delays exceeding two months were observed in 33% of the patients. Underlying comorbid diseases included diabetes mellitus in 10 patients (24%), rheumatologic disease in 10 patients (23.8%), liver cirrhosis in 7 patients (16.7%), and malignancy in two (4.8%). Six patients were exposed to anti-tumor necrosis factor/CD20/interleukin-1 antagonist for treatment of systemic lupus erythematosus (SLE) or rheumatoid arthritis. None of the patients in the SSTI groups had human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS). C-reactive protein was available in 26 patients (61.9%), ESR in 25 patients (40.5%), and both ESR and CRP were available in 20 patients (47.6%) at initial presentation. Erythrocyte sedimentation rate was elevated >20 mm/h in 20 (80%) and markedly elevated >100 mm/h in four (16%) patients. C-reactive protein was abnormal (>0.6 mg/dL) in 23 (88.5%), and markedly elevated >10 mg/dL in nine (34.6%).

Table 1.

Clinical Manifestations and Outcome of the Forty-Two Patients with Non-Tuberculous Mycobacterial Infection of the Skin, Soft Tissue, and Musculoskeletal System

Variable	No.	%
Gender
Male	26	62
Female	16	38
Age, y
0–30	4	9.5
30–60	14	33.3
61–75	13	31
>75	11	26.2
Location
Hand and wrist	15	35.7
Spine	6	14.3
Foot	5	11.9
Lower limb	5	11.9
Femur	4	9.5
Knee	3	7.1
Shoulder	2	4.8
Elbow	2	4.8
Mycobacteria species isolated
Mycobacterium abscessus complex	17	40.4
M. marinum	6	14.3
M. kansasii	5	11.9
M. avium-intracellulare complex	4	9.5
M. fortuitum	3	7.1
M. gordonae	2	4.8
M. haemophilum	2	4.8
M. peregrinum	1	2.4
M. chelonae	1	2.4
Non-classified	1	2.4
Stain for acid-fast bacilli
Positive	11	26
Trauma history
Positive	13	31
Previous operation history in 1 y
Positive	14	33
Immune condition
Underlying comorbid diseases	29	60
Combined bacterial infection
Positive	8	19
Treatment
Antibiotic alone	9	22
Surgical debridement performed	33	78
Outcome
Clinical cure	27	64.3
Failure	15	35.7

Affected body regions and results from cultures

The most frequently affected sites were in the hand and wrist region (15 patients, 35.7%), and the most commonly isolated mycobacteria species was Mycobacterium abscessus complex (17 patients, 40.4%). The AFB stains were positive in 26% of cases (Table 1). None of the patients had concurrent infection with two NTM species, and none had recurrent infection. The overall mean time interval between culturing and diagnosis was 21.2 days (range, 10–60). The time interval for RGM was 17.2 ± 5.4 days (range, 10–30), whereas for SGM it was 25 ± 14 days (range, 10–60).

Treatment

Single-antibiotic treatment was administered to nine patients (22%). In general, multi-drug therapy is required for patients with atypical mycobacterial infections. Combined treatment with minocycline, clarithromycin, ciprofloxacin, and ethambutol or rifampin was most often administered, given empirically based on the mycobacterial species isolated (Table 2). Surgical debridement was performed in 33 patients (78%), with an average number of surgical debridement sites of 1.8 (range, 1–4). In cases in which bacterial infections developed simultaneously, antibiotic therapy was also initialized in accordance with the laboratory results. Initial intravenous regimens were applied for at least two weeks, followed by a switch to oral therapy after symptoms had improved. The median duration of anti-mycobacterial chemotherapy was 15 months (range, 2–24). Treatment failure occurred in 15 patients (36%).

Table 2.

Recommendations for Empiric Treatment of Non-Tuberculous Mycobacterial Infections Based on Isolated Mycobacterial Species

Mycobacterial species	Recommended agents	Alternative agents
RGM
Mycobacterium abscessus-chelonae complex	Cefoxitin (3 g IV every 8 h) or imipenem-cilastatin (500 IV every 6 h) + amikacin (15 mg/kg IV) ± tygecycline (50 mg IV every 12 h) for 2–4 wks, followed by Clarithromycin (500 mg orally twice daily) or Azithromycin (500 mg orally daily) + ethambutol (15 mg/kg orally daily) ± rifabutin (150–300 mg orally daily) or rifampin (600 mg orally daily)	Ciprofloxacin (750 mg orally twice daily) Moxifloxacin (400 mg orally daily) Isoniazid (300 mg orally daily)
M. fortuitum M. peregrinum M. mageritense	Ciprofloxacin (750 mg orally twice daily) + minocycline (100 mg orally twice daily) or clarithromycin (500 mg orally twice daily) or TMP/SMX (160/800 mg orally twice daily)	Amikacin (7.5–10 mg/kg IM/IV daily), cefoxitin (200 mg/kg IV) imipenem-cilastatin (500 mg IV daily),
SGM
M. avium-intracellulare complex (MAC)	Clarithromycin (500 mg orally twice daily) + ethambutol (15 mg/kg orally daily) ± rifabutin (300 mg orally daily)	Azithromycin (500 mg orally daily)Moxifloxacin (400 mg orally daily)
M. scrofulaceum	Clarithromycin (500 mg orally twice daily) + rifampin (600 mg orally daily) + ethambutol (15 m/kg orally daily)	Isoniazid (300 mg orally daily)Streptomycin (15 m/kg IV/IM daily)
M. haemophilum	Rifampin (600 mg orally daily) or rifabutin (300 mg orally daily) + clarithromycin (500 mg orally twice daily) or ciprofloxacin (500 mg orally twice daily)	TMP/SMX (160/800 mg orally twice daily), Doxycycline (100 mg orally twice daily), Amikacin (15 mg/kg daily)
M. kansasii	Isoniazid (300 mg orally daily) + rifampin (600 mg orally daily) or rifabutin (300 mg orally daily) + ethambutol (15 mg/kg orally daily)	Clarithromycin (500 mg orally twice daily) or Azithromycin (500 mg daily)Moxifloxacin (400 mg orally daily)
M. marinum	Rifampin (600 mg orally daily) or rifabutin (300mg orally daily) + ethambutol (15 mg/kg orally daily) or TMP/SMX (160/800mg orally twice daily) or clarithromycin (500 mg orally twice daily)	Doxycycline (100 mg orally twice daily) or minocycline(100 mg orally twice daily) or fluoroquinolones
M. gordonae	Consider clarithromycin (500 mg orally twice daily) or azithromycin + ciprofloxacin (750 mg orally twice daily) or levofloxacin (500 mg orally daily) or moxifloxacin (400 mg orally daily) + ethambutol(15 mg/kg orally daily)	Rifabutin (300 mg orally daily)TMP/SMX (160/800 mg orally twice daily)

RGM = rapid-growing mycobacterium; SGM = slow-growing mycobacterium; IV = intravenous; IM = intramuscular; TMP/SMX = trimethoprim-sulfamethoxazole

Risk factors for treatment failure

Univariable logistic regression analysis showed an association of NTM infection treatment failure with several factors, including misdiagnosis, absence of trauma history, combined bacterial infection, treatment delays of over two months, isolation of the Mycobacterium abscessus complex species, and having undergone more than two debridement interventions (Table 3). In multivariable logistic regression analysis, independent variables that were associated with treatment failure were delays of treatment exceeding two months and isolation of the Mycobacterium abscessus complex species (Table 3). Variables such as gender, age, combined morbidity, prior surgical history, and laboratory parameters did not predict risk of treatment failure of NTM infections.

Table 3.

Predictors of Treatment Failure for Skin, Soft Tissue, and Musculoskeletal Infections by Non-Tuberculous Mycobacteria by Logistic Regression Analysis

Characteristic	Crude OR	95% CI	p	Adjusted OR	95% CI	p
Clinical characteristics
Age	2.93	0.71–12.10	0.13
Gender	0.57	1.35–47.16	0.39
Misdiagnosis	5.33	1.09–25.9	0.02^*	11.37	0.36–351.1	0.16
Absence of trauma history	6.4	1.44–28.44	0.02^*	2.55	0.15–42.2	0.51
Combined bacterial infection	8	1.35–47.16	0.02^*	15.78	0.15–159.7	0.24
Previous operation history in one year	2.5	0.66–9.45	0.17
Local steroid injection	4	0.33–48.29	0.27
Immune-compromised	2.55	0.64–10.05	0.18
DM	2.2	0.51–9.35	0.28
Liver disease	0.67	0.11–4.00	0.66
Malignancy	1.85	0.10–32.00	0.67
Rheumatologic disease	1.05	0.22–5.42	0.95
Area of involvement
Hand and wrist	0.45	0.11–1.79	0.26
Spine	2	0.34–11.43	0.43
Lower limb	0.96	0.26–3.51	0.96
Pathogen
Acid fast stain test positive	0.28	0.05–1.58	0.15
Rapid grower mycobacteria	3.75	0.93–14.96	0.06
M. marinum	—	—	—
M. kansasii	4	0.33–48.2	0.27
M.avium-intracellulare complex	1.92	0.24–15.2	0.53
M. abscessus complex	9.16	2.21–39.61	0.003^**	26.60	1.73–579.6	0.02^*
Treatment
Antibiotics treatment alone	0.43	0.07–2.45	0.34
Antibiotics treatment >1 year	2.1	0.56–7.81	0.26
Delayed Treatment ^a	28.87	4.55–183.16	0.001^**	25.78	1.43–492.6	0.04^*
Debridement >2 times	5	1.26–19.83	0.02^*	1.03	0.04–21.98	0.98

p < 0.05; ^**p < 0.005, statistically significant.

Delayed treatment: Defined as duration from onset of symptoms to treatment of longer than 2 mo.

OR = odds ratio; CI = confidence interval.

Discussion

Thus far, available studies showed an increasing incidence of NTM infection in Taiwan, and a widening distribution of species among the various infection sites [9 –11,13 –15]. However, none of these studies analyzed risk factors for treatment failure in patients with NTM SSTI. The current retrospective study identified two risk factors associated with failed treatment: delays of diagnosis longer than two months and infection with Mycobacterium abscessus complex. The outcome of this study underscores the importance of increasing awareness among clinical physicians of risk factors for treatment failure in NTM SSTI patients. In practice, increased attention for adequate microbiologic testing as well as reduced delays in diagnostics and treatment could be expected to improve the treatment success of cases with NTM infections.

Increased incidence of NTM infections

Non-tuberculous mycobacteria are ubiquitous in our environment and are often isolated from skin and wound specimens [5,13,16]. The numbers, as well as the variety of species of NTM isolated from clinical specimens, are increasing [9,17]. According to Lai et al. [9], the NTM isolation rate increased substantially, accounting for 39.2% of positive mycobacterial cultures, an increase over previous studies [10,11,18]. In our study, the incidence of NTM SSTI, observed between 2012 and 2015 reached 40.4 per 100,000 inpatients overall and 23.6 per 100,000 inpatients with NTM SSTI, representing a considerable increase compared with previously reported incidence of 10.2 per 100,000 inpatients and outpatients between 2000 and 2008 [9]. This increase could be explained by increased awareness among physicians of NTM infections and advances in laboratory methods [17]. The apparent increase in NTM-related diseases might also be attributed to the increased number of immunocompromised hosts resulting from recent medical advances (e.g., the advent of novel therapeutics, including tumor necrosis factor inhibitors, human interleukin-1 receptor antagonists, and anti-CD20 antibodies [14]. The prevalence of mycobacteria species responsible for different diseases is known to vary markedly by geographic region. In the United States and Japan, MAC and Mycobacterium kansasii are the most common species [4], whereas in England and Scotland, Mycobacterium kansasii and Mycobacterium malmoense, respectively, are the most common pathogens (19). In a Taiwanese study of 58 patients with clinically significant NTM infection treated between 1999 and 2009, the most commonly isolated NTM were RGM (n = 30) [11]. In other reports, MAC was found to be the most common NTM species in Taiwan, followed by Mycobacterium abscessus complex. In localized pulmonary infection and disseminated infection, the most common organism was MAC, whereas Mycobacterium abscessus predominated in skin and soft tissue infections and lymphadenitis [9,10]. In our study, Mycobacterium abscessus was also the most common isolate in SSTI (40.5%), consistent with previous studies [10], followed by Mycobacterium marinum (14.3%) and Mycobacterium kansasii (11.9%).

Treatment failure

Delays in diagnosis exceeding two months were associated with increased treatment failure. In our study, a low rate of AFB positivity (11 patients; 26%) was observed. Appropriate treatment should be based on identification of the specific causative NTM; and empiric anti-mycobacterial agents were prescribed based on published susceptibility data [20]. However, overall the time between the culture and diagnosis was 21.2 days (range, 10–60). Thus, 74% of the patients were exposed to delayed treatment with appropriate anti-NTM medication, and at risk of receiving unnecessary antibiotics treatment for more than three weeks. Even when they test positive for AFB, patients are often treated for Mycobacterium tuberculosis complex infection initially, because the incidence of tuberculosis in Taiwan remains high (43 per 100,000 in 2016). Delayed diagnosis and ineffective initial treatment of NTM may eventually result in treatment failure.

Another risk factor for treatment failure in patients was the presence of Mycobacterium abscessus complex. Mycobacterium abscessus complex comprises a group of rapidly growing, multidrug-resistant, NTM that are responsible for a wide spectrum of infections, including skin and soft tissue diseases, central nervous system infections, bacteremia, ocular, and other infections. Mycobacterium abscessus complex is divided into three subspecies: Mycobacterium abscessus subsp. abscessus, Mycobacterium abscessus subsp. massiliense, and Mycobacterium abscessus subsp. bolletii. The two major subspecies, Mycobacterium abscessus subsp. abscessus and massiliense, have different erm(41) gene patterns. This gene provides intrinsic resistance to macrolides, standard anti-tuberculosis agents and most antimicrobial agents [13,21]. The mechanism conferring macrolide resistance involves methylation of 23S ribosomal RNA [22]. Several recent major studies from Asia showed susceptibility and resistance rates of Mycobacterium abscessus complex against antimicrobial agents [15,23 –25].) This may explain the higher treatment failure rates among patients with Mycobacterium abscessus complex infection.

Mycobacterium abscessus complex infection can be acquired in the community or in hospital settings. In community settings, water supply systems have been postulated to be a source of human infections [26]. In-hospital settings, disinfectant failure, contamination of medical devices and water, and indirect transmission between patients are considered to be sources of infections [27]. In Korea, Mycobacterium abscessus outbreaks occurred in association with acupuncture or other medical procedures [28].

Limitations

This study identified essential characteristics of NTM SSTI disease in southern Taiwan and elucidated the risk factors responsible for treatment failure. However, several limitations of our study should be noted. First, the incidence of NTM SSTI may have been underestimated in this retrospective study. However, because of modern laboratory techniques and increased tendency of physicians to order mycobacterial culture testing, we may have detected a spuriously increased incidence of NTM compared to previous reports. Second, no phylogenetic analysis was performed to determine the genomic relatedness between the NTM strains. Future studies should elucidate this further. Third, routine antimicrobial susceptibilities were not performed, and therefore, the empirical treatment is dependent on previous susceptibility studies in Taiwan, which may result in treatment failure due to resistance. However, only a limited choice of anti-NTM drugs is available, and most patients used multiple drugs in combination. Treatment failure associated with Mycobacterium abscessus may be explained by its high rate of resistance to available drugs.

Conclusions

Treatment delays exceeding two months and Mycobacterium abscessus complex infection are associated with increased rates of treatment failure among patients with NTM infections of skin, soft tissue, or musculoskeletal system. The introduction of new, immunosuppressive agents in various patient groups facilitated the increased occurrence of NTM infections. This increase may become more evident with the increased demand for cosmetic surgery. Further research should focus on the improvement of NTM-susceptibility testing and on the validation of single- and multiple-drug treatment regimens using defined clinical end points. In addition, prospective trials comparing different regimens of antimicrobial agents are needed to optimize treatment. We suggest that patients at high risk for NTM infections factors should be eligible to receive appropriate antibiotic treatment and prompt surgical intervention, whenever necessary.

Footnotes

Author Disclosure Statement

None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article.

References

Falkinham

3rd . Surrounded by mycobacteria: Nontuberculous mycobacteria in the human environment. J Appl Microbiol, 2009; 107:356–367.

Runyon

. Anonymous mycobacteria in pulmonary disease. Med Clin North Am, 1959; 43:273–290.

Bicmen

, Gunduz

, Coskun

, et al. Molecular detection and identification of mycobacterium tuberculosis complex and four clinically important nontuberculous mycobacterial species in smear-negative clinical samples by the genotype mycobacteria direct test. J Clin Microbiol, 2011; 49:2874–2878.

Griffith

, Aksamit

, Brown-Elliott

, 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.

Falkinham

3rd . Epidemiology of infection by nontuberculous mycobacteria. Clin Microbiol Rev, 1996; 9:177–215.

Zenone

, Boibieux

, Tigaud

, et al. Non-tuberculous mycobacterial tenosynovitis: a review. Scand J Infect Dis, 1999; 31:221–228.

Wentworth

, Drage

, Wengenack

, et al. Increased incidence of cutaneous nontuberculous mycobacterial infection, 1980 to 2009: A population-based study. Mayo Clin Proc, 2013; 88:38–45.

Piersimoni

, Scarparo

. Extrapulmonary infections associated with nontuberculous mycobacteria in immunocompetent persons. Emerg Infect Dis, 2009; 15:1351–1358.

Lai

, Tan

, Chou

, et al. Increasing incidence of nontuberculous mycobacteria, Taiwan, 2000–2008. Emerg Infect Dis, 2010; 16:294–296.

10.

Ding

, Lai

, Lee

, et al. Disease caused by non-tuberculous mycobacteria in a university hospital in Taiwan, 1997–2003. Epidemiol Infect, 2006; 134:1060–1067.

11.

Hsiao

, Tsai

, Hsueh

. Characteristics of skin and soft tissue infection caused by non-tuberculous mycobacteria in Taiwan. Int J Tuberc Lung Dis, 2011; 15:811–817.

12.

Lee

, Cheng

, Huang

, et al. Performance assessment of the DR. TBDR/NTM IVD kit for direct detection of Mycobacterium tuberculosis isolates, including rifampin-resistant isolates, and nontuberculous Mycobacteria. J Clin Microbiol, 2012; 50:3398–3401.

13.

Lee

, Sheng

, Hung

, et al. Mycobacterium abscessus Complex Infections in Humans. Emerg Infect Dise, 2015; 21:1638–1646.

14.

Hsueh

, Liu

, So

, et al. Mycobacterium tuberculosis in Taiwan. J Infect, 2006; 52:77–85.

15.

Huang

, Liu

, Shen

, et al. Clinical outcome of Mycobacterium abscessus infection and antimicrobial susceptibility testing. J Microbiol Immunol Infect, 2010; 43:401–406.

16.

Wallace

, Dykewicz

, Bernstein

, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol, 2008; 122:S1–84.

17.

Marras

, Mendelson

, Marchand-Austin

, et al. Pulmonary nontuberculous mycobacterial disease, Ontario, Canada, 1998–2010. Emerg Infect Dis, 2013; 19:1889–1891.

18.

Liao

, Lai

, Ding

, et al. Skin and soft tissue infection caused by non-tuberculous mycobacteria. Int J Tuberc Lung Dis, 2007; 11:96–102.

19.

Management of opportunist mycobacterial infections: Joint Tuberculosis Committee Guidelines 1999. Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Thorax. 2000; 55:210–218.

20.

Huang

, Lee

, Hsueh

, et al. Antimicrobial resistance of rapidly growing mycobacteria in western Taiwan: SMART program 2002. J Formos Med Assoc, 2008; 107:281–287.

21.

Nessar

, Cambau

, Reyrat

, et al. Mycobacterium abscessus: A new antibiotic nightmare. J Antimicrob Chemother, 2012; 67:810–818.

22.

Nash

, Brown-Elliott

, Wallace

Jr . A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother, 2009; 53:1367–1376.

23.

Lee

, Yoo

, Kim

, et al. The drug resistance profile of Mycobacterium abscessus group strains from Korea. Ann Lab Med, 2014; 34:31–37.

24.

Brown-Elliott

, Mann

, Hail

, et al. Antimicrobial susceptibility of nontuberculous mycobacteria from eye infections. Cornea, 2012; 31:900–906.

25.

Broda

, Jebbari

, Beaton

, et al. Comparative drug resistance of Mycobacterium abscessus and M. chelonae isolates from patients with and without cystic fibrosis in the United Kingdom. J Clin Microbiol, 2013; 51:217–223.

26.

Thomson

, Tolson

, Sidjabat

, et al. Mycobacterium abscessus isolated from municipal water—A potential source of human infection. BMC Infect Dis, 2013; 13:241.

27.

Bryant

, Grogono

, Greaves

, et al. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: A retrospective cohort study. Lancet, 2013; 381:1551–1560.

28.

Koh

, Song

, Kang

, et al. An outbreak of skin and soft tissue infection caused by Mycobacterium abscessus following acupuncture. Clin Microbiol Infect, 2010; 16:895–901.

29.

Mohrer

, Liberati

, Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analysis: the PRISMA statement. Int J Surg, 2010; 8:336–341.

Failure among Patients with Non-Tuberculous Mycobacterial Infections in Skin,Soft Tissue,and Musculoskeletal System in Southern Taiwan,2012–2015

Abstract

Abstract

Background:

Methods:

Results:

Conclusions:

Patients and Methods

Study population, inclusion, and exclusion criteria

Definitions of treatment outcome

Laboratory tests

Statistical analysis

Results

General patient characteristics

Affected body regions and results from cultures

Treatment

Risk factors for treatment failure

Discussion

Increased incidence of NTM infections

Treatment failure

Limitations

Conclusions

Footnotes

Author Disclosure Statement

References