Nontuberculous mycobacterial infections in cancer patients in a medical center in Taiwan, 2005-2008

Data on the nontuberculous mycobacterial (NTM) species that cause infection and the characteristics of disease caused by these pathogens in cancer patients are limited, so we perform this study to investigate the species distribution of NTM isolates from various clinical specimens and to elucidate the epidemiologic trends in NTM isolates and diseases among cancer patients. From 2005 through 2008, cancer patients with NTM infections as defined by the American Thoracic Society/Infectious Diseases Society of America criteria were identified at the National Taiwan University Hospital. The medical records of all patients were reviewed. During the study period, a total of 219 cancer patients with NTM infections were identified. Among them, 133 (60.7%) patients were older than 65 years, most of whom were men. Lung cancer was the most common type of cancer, followed by hematologic cancer and gastrointestinal tract cancer. Pulmonary NTM infection was the most common type of infection in 205 (93.6%) patients, followed by skin and soft tissue infections (n = 7, 3.2%), disseminated infections (n = 4, 1.8%), and genitourinary tract infection (n = 3, 1.4%). Disseminated infections occurred exclusively in patients with hematologic cancer. Mycobacterium avium complex (MAC) caused the majority of pulmonary NTM infections in cancer patients; in contrast, M. abscessus was the most common causative pathogen of extrapulmonary NTM diseases, followed by MAC. In conclusion, physicians need to be aware of the possibility of co-existing pulmonary NTM infection in patients with lung cancer. In addition, disseminated NTM infection should be considered in patients with hematologic cancer.     

Clinical characteristics of extrapulmonary nontuberculous mycobacteria infections in comparison with pulmonary infections: A single-center,retrospective study in Japan

IntroductionThe prevalence of nontuberculous mycobacteria (NTM) infections is increasing worldwide. Although NTM can affect extrapulmonary organs, studies on the clinical characteristics of extrapulmonary NTM are rare.MethodsWe retrospectively analyzed patients who were newly diagnosed with NTM infections at Hiroshima University Hospital between 2001 and 2021 to investigate species distribution, infected sites, and risk factors of extrapulmonary NTM compared to pulmonary NTM.ResultsOf the 261 NTM infections, 9.6% and 90.4% had extrapulmonary and pulmonary NTM, respectively. The mean ages of patients with extrapulmonary and pulmonary NTM were 53.4 and 69.3 years, 64.0% and 42.8% were male, 36.0% and 9.3% received corticosteroids, 20.0% and 0% had acquired immune deficiency syndrome (AIDS), and 56.0% and 16.1% had any immunosuppressive conditions, respectively. Younger age, corticosteroid use, and AIDS were associated with extrapulmonary NTM. In pulmonary NTM, Mycobacterium avium complex (MAC) accounted for 86.4% of NTM species, followed by M. abscessus complex (4.2%), whereas in extrapulmonary NTM, M. abscessus complex, MAC, M. chelonae, and M. fortuitum accounted for 36.0%, 28.0%, 12.0%, and 8.0%, respectively. Compared to pulmonary NTM, extrapulmonary NTM were significantly more likely to be rapid-growing mycobacteria (RGM) (56.0% vs. 5.5%). The most common sites of infection were the skin and soft tissues (44.0%), followed by the blood (20.0%), tenosynovium, and lymph nodes (12.0%).ConclusionYounger age and immunosuppressive conditions are associated with extrapulmonary NTM, with a higher prevalence of RGM in extrapulmonary NTM than in pulmonary NTM. These results provide a better understanding of extrapulmonary NTM.     

Increased Incidence of Cutaneous Nontuberculous Mycobacterial Infection, 1980 to 2009: A Population-Based Study

ObjectivesTo determine the incidence and clinical characteristics of cutaneous nontuberculous mycobacterial (NTM) infection during the past 30 years and whether the predominant species have changed.Patients and MethodsUsing Rochester Epidemiology Project data, we identified Olmsted County, Minnesota, residents with cutaneous NTM infections between January 1, 1980, and December 31, 2009, examining the incidence of infection, patient demographic and clinical features, the mycobacterium species, and therapy.ResultsForty patients (median age, 47 years; 58% female [23 of 40]) had positive NTM cultures plus 1 or more clinical signs. The overall age- and sex-adjusted incidence of cutaneous NTM infection was 1.3 per 100,000 person-years (95% CI, 0.9-1.7 per 100,000 person-years). The incidence increased with age at diagnosis (P=.003) and was higher in 2000 to 2009 (2.0 per 100,000 person-years; 95% CI, 1.3-2.8 per 100,000 person-years) than in 1980 to 1999 (0.7 per 100,000 person-years; 95% CI, 0.3-1.1 per 100,000 person-years) (P=.002). The distal extremities were the most common sites of infection (27 of 39 patients [69%]). No patient had human immunodeficiency virus infection, but 23% (9 of 39) were immunosuppressed. Of the identifiable causes, traumatic injuries were the most frequent (22 of 29 patients [76%]). The most common species were Mycobacterium marinum (17 of 38 patients [45%]) and Mycobacterium chelonae/Mycobacterium abscessus (12 of 38 patients [32%]). In the past decade (2000-2009), 15 of 24 species (63%) were rapidly growing mycobacteria compared with only 4 of 14 species (29%) earlier (1980-1999) (P=.04).ConclusionThe incidence of cutaneous NTM infection increased nearly 3-fold during the study period. Rapidly growing mycobacteria were predominant during the past decade.     

Mycobacterium abscessus and massiliense lung infection during macrolide treatment for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT), post-transplant lung infection is critical for their prognosis. Mycobacterium abscessus complex is not fully recognized as a nontuberculous mycobacteria (NTM) pathogen of post-SCT lung infection. Here, we present three post-allogeneic SCT patients who developed pulmonary infection caused by M. abscessus complex including M. abscessus and M. massiliense. In all three cases, macrolide antibiotics had been administered for bronchiolitis obliterans syndrome (BOS) before the confirmation of their infection, and macrolide resistance was noted in the M. abscessus isolates, one of which resulted in an unfavorable treatment outcome. It is important to consider M. abscessus lung infection as well as other NTM in patients receiving allo-SCT, particularly those receiving macrolide therapy for BOS.     

Comparison of real-time polymerase chain reaction and conventional biochemical methods for identification of Mycobacterium chelonae–Mycobacterium abscessus group to the species level

The Mycobacterium chelonae–Mycobacterium abscessus group (MCAG) is the most common cause of infections because of rapidly growing mycobacteria. Rapid identification of MCAG to the species level is essential for choosing empiric antibiotic treatment and for public health measures. In this study, we compared the performance of a single-tube multiplex, real-time polymerase chain reaction (PCR) assay to 3 biochemical tests for species-level identification of 46 MCAG isolates. We show that real-time PCR provides the most accurate results for rapid species-level identification of MCAG.     

Differentiating rapid- and slow-growing mycobacteria by difference in time to growth detection in liquid media

Nontuberculous mycobacteria (NTM) are classified into 2 categories: slow-growing mycobacteria (SGM) and rapid-growing mycobacteria (RGM), based on interval to colony formation by subculture on solid media. However, little is known about the growth rate of NTM in liquid broth media. We evaluated the differences in time to growth detection (TGD) of RGM and SGM in liquid broth media according to acid-fast stain. Among the 696 NTM isolates, 201 were RGM and 495 were SGM. In acid-fast bacilli (AFB)–negative specimens, the mean TGD was 133 h for RGM and 269 h for SGM (P < 0.001). In AFB-positive specimens, the mean TGD was 112 ± 37 h for RGM and 155 ± 125 h for SGM (P = 0.063). In the AFB-negative group, a cut-off value of 6 days was most effective for distinguishing SGM from RGM; however, in the AFB-positive group, an appropriate cut-off value was hard to define with TGD only.     

Inactivation of nontuberculous mycobacteria by gaseous ozone treatment

Nontuberculous mycobacteria (NTM) are environmental bacteria resistant to many common disinfectants and ultraviolet radiation. Inhalation of aerosols generated from NTM-containing water and soil causes NTM lung disease, especially in people with underlying lung diseases and decreased immunity. To prevent healthcare-acquired NTM infections, it is important to eradicate NTM living in hospital environments. Therefore, we evaluated the efficacy of gaseous ozone for the inactivation of NTM, namely Mycobacterium (M.) avium, M. intracellulare, M. kansasii, M. abscessus subsp. abscessus and M. abscessus subsp. massiliense. Gaseous ozone treatment at 1 ppm for 3 h reduced the bacterial number of all strains by more than 97%. Gaseous ozone treatment could be a practical, effective and convenient disinfection method for NTM living in hospital environments.     

Clinicopathologic characteristics of nontuberculous mycobacterial lung disease in Taiwan

Taiwan is an endemic area for tuberculosis (TB), and the incidence of pulmonary infection caused by nontuberculous mycobacteria (NTMs) is also increasing. This study aims to investigate the clinicopathologic characteristics of patients with NTM lung disease during 1998 to 2007 at a medical center in Taiwan. The medical records of patients with confirmed NTM pulmonary infections who underwent open lung surgery in a medical center were reviewed. Twenty-four patients with confirmed NTM pulmonary infections were identified. These patients were histologically classified into 4 types: fibrocavitary/tuberculoid (n = 10), nodular bronchiectatic (n = 4), sarcoidal (n = 6), and other (n = 4). The fibrocavitary/tuberculoid type usually (90%) develops in the upper lobes of old patients with preexisting lung disease. Pulmonary TB (n = 7, 70%) was the major underlying disease before 2003. Nodular bronchiectatic type occurred mainly in the middle lobe of middle-aged women without preexisting lung disease. Sarcoidal type was usually associated with Mycobacterium avium complex infection and develops in middle-aged women. Immunoreactive bacilli were detected in 21 patients (87 %) by immunohistochemical staining using a polyclonal antibody against Mycobacterium tuberculosis and other mycobacterial species (M. avium-intracellulare, Mycobacterium phlei, and Mycobacterium parafortuitum), whereas conventional acid-fast staining was positive in only 21% of patients. In conclusion, TB was the major underlying disease in patients with NTM lung disease in Taiwan. The different histologic types of pulmonary NTM infection suggest each had a distinct pathogenesis.     

Nontuberculous mycobacteria pulmonary infection in medical intensive care unit: the incidence,patient characteristics,and clinical significance

Background  The clinical significance of nontuberculous mycobacteria (NTM) pulmonary infection in medical intensive care unit (ICU) is still unclear. Materials and methods  We conducted a retrospective study in the medical ICUs of a medical center in Taiwan from January 1999 to June 2007. Patients with NTM isolated from respiratory specimens within 1 month before or during the ICU course were identified. Those who fulfilled the diagnostic criteria of NTM pulmonary infection were identified and compared with patients with NTM colonization and control subjects who were culture-negative for mycobacteria. Results  Among the 5,378 patients admitted to medical ICUs, 2,866 (53.3%) had received mycobacterial culture for respiratory specimens. NTM were isolated from 169 (5.8%) patients. Of them, 47 (27.8%) were considered NTM pulmonary infection. M. avium complex and M. abscessus were the most common pathogens. Within 100 days after ICU admission, significantly more patients with NTM infection died than those with NTM colonization and control subjects (47 vs. 8 vs. 14%, P < 0.001). Twenty-one (49%) patients with NTM pulmonary infection received anti-NTM treatment, with four experiencing adverse effects. Although statistically insignificant, anti-NTM treatment was associated with prolonged survival for those who died in the ICU and shorter ICU stay for those who survived the ICU course. Conclusion  Our findings suggest that NTM pulmonary infection seems to associate with higher mortality in medical ICUs. Anti-NTM treatment is probably associated with a better outcome. Therefore, keeping a high suspicion when NTM is isolated and using careful consideration when starting anti-NTM treatment should be emphasized. Taiwan Anti-Mycobacteria Investigation (TAMI) group: J.-Y. Wang, L.-N. Lee, C.-J. Yu, P.-C. Yang, W.-J. Su, C.-C. Shu, H.-C. Lai, C.-H. Lee and M.-C. Yu.     

Rapid identification of strains belonging to the Mycobacterium abscessus group through erm(41) gene pyrosequencing

Mycobacterium abscessus and Mycobacterium massiliense lung infections have different clarithromycin susceptibilities, making proper identification important; however, standard multi-gene sequencing in clinical laboratories is laborious and time consuming. We developed a pyrosequencing-based method for rapid identification of strains belonging to the M. abscessus group by targeting erm(41). We examined 55 isolates from new pulmonary M. abscessus infections and identified 28 M. abscessus, 25 M. massiliense, and 2 Mycobacterium bolletii isolates. Multi-gene sequencing of 16S rRNA, hsp65, rpoB, and the 16S–23S ITS region was concordant with the results of erm(41) pyrosequencing; thus, the M. abscessus group can be identified by single-nucleotide polymorphisms in erm(41). The method also enables rapid identification of polymorphic, inducible clarithromycin-resistant sequevars (T28 or C28). Pyrosequencing of erm(41) is a rapid, reliable, high-throughput alternative method for identifying and characterizing M. abscessus species. Further testing of a diverse collection of isolates is necessary to demonstrate the discriminatory power of erm(41) sequencing to differentiating species with this highly divergent group.     

Standardization of multilocus sequence typing scheme for Mycobacterium abscessus and Mycobacterium massiliense

This study aims to develop a multilocus sequence typing (MLST) scheme for Mycobacterium abscessus complex for the typing of stains within each species. A total of 89 clinical isolates of M. abscessus complex from 71 patients of 2 tertiary care hospitals in South Korea were included. Forty-two isolates were identified as M. abscessus, and 29, as Mycobacterium massiliense through sequencing of 8 housekeeping genes and rpoB. The MLST scheme identified 26 different sequence types(STs) and 13 different clonal complexes (CCs) in M. abscessus and 12 different STs and 6 different CCs in M. massiliense. The MLST data showed high concordance with the XbaI-macrorestriction patterns of pulsed-field gel electrophoresis in the duplicated isolates. Our MLST schemes could identify different strains of M. abscessus and M. massiliense, and the schemes also showed a reliable reproducibility. Therefore, our MLST schemes may be useful in studying the epidemiology of M. abscessus and M. massiliense infections.     

Mycobacterium simiae pulmonary infection unmasked during immune reconstitution in an HIV patient

Highly active antiretroviral therapy in human immunodeficiency virus (HIV) patients may trigger the onset of immune reconstitution inflammatory syndrome (IRIS). Among HIV patients with IRIS, infections are commonly due to Mycobacterium tuberculosis and nontuberculous mycobacteria. We report the first case in Spain and the second in Europe of Mycobacterium simiae pulmonary infection unmasked during immune reconstitution in an HIV patient.     

Mycobacterium malmoense: an underestimated nontuberculous mycobacterium

We present a case report of Mycobacterium malmoense in a 53-year-old white man. The incidence of M. malmoense infections is a rare event compared with other nontuberculous mycobacteria, but it has increased since 1980, especially in northern Europe. Many patients have disposing underlying diseases. In most cases, it is a pulmonary infection. The most frequent used antibiotics are rifampicin (or rifabutin), ethambutol, and clarithromycin.     

In vitro susceptibility patterns for rapidly growing nontuberculous mycobacteria in the United States

Antimicrobial susceptibility testing for rapidly growing mycobacteria (RGM) is uncommon or only performed in large reference laboratories. Here we developed a cumulative antibiogram for 14 RGM using the largest sample size to date (N = 3860). All RGM showed 82% to 100% susceptibility to amikacin. Mycobacterium abscessus showed low percentages of susceptibility to most antimicrobials; of antimicrobials without interpretations, the minimum inhibitory concentration-90 for clofazimine was low (≤0.5mg/L). All three subspecies had ≤2.6% rrl resistance mutations, however intact erm(41) was detected in 70% to100% of M. abscessus abscessus and bolletii. Mycobacterium chelonae had a similar susceptibility pattern to M. abscessus subsp. massiliense and Mycobacterium immunogenum except that it was susceptible to tobramycin (87%). Mycobacterium fortuitum complex and similar organisms showed higher frequency of susceptibility to fluoroquinolones, beta-lactams, linezolid, and trimethoprim/sulfamethoxazole. Although relatively small published RGM antibiograms showed substantial variance, a comprehensive antibiogram can help influence treatment and monitoring patterns of resistance.     

Microbial substitution of <Emphasis Type="Italic">Mycobacterium avium-intracellulare</Emphasis> to <Emphasis Type="Italic">Mycobacterium abscessus</Emphasis> during clinical course

Mycobacterium avium-intracellulare (MAI) is, among acid-fast bacilli, the most common cause of nontuberculous pulmonary diseases, and MAI infections are often treated according to the guidelines of the American Thoracic Society. However, despite the use of multiple drugs, patients sometimes do not recover with the initial round of treatment. Other kinds of nontuberculous mycobacteria are sometimes found in patients' respiratory samples, even during such treatment for MAI pulmonary disease. We experienced three patients with pulmonary disease due to Mycobacterium abscessus (MA) in whom the disease was difficult to treat because of resistance to all the antituberculous agents used. MA infection had occurred in these patients after long-term treatment with multiple drugs for previous MAI pulmonary disease. We considered that the MA infection in these patients appeared to be the result of insufficient efficacy of the drugs used for MAI and insufficiently aggressive use of antituberculous agents. It thus appeared that MA infection was the result of microbial substitution, and that, if this is the case, the guidelines for the treatment of MAI may need to be modified to eliminate microbial substitution.     

Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

Over the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden.     

Direct identification of mycobacteria from culture media using a multiplex real-time PCR assay: report on its application in a clinical laboratory in a region of high tuberculosis endemicity

There are few commercial assays that easily and correctly identify the mycobacteria from culture in a clinical laboratory with a high workload. Thus, we developed and evaluated a scheme for the identification of mycobacteria using a multiplex real-time PCR assay and report on its application in our laboratory. The scheme consisted of 3 stepwise PCRs. Mycobacterium tuberculosis complex (MTC) and nontuberculous mycobacteria (NTM) were differentially detected in the step 1 PCR, and the NTM species were identified in the step 2 and 3 PCRs. Over the 1.5-year study period, 1136 isolates of MTC and 618 isolates of NTM were detected, and the species of 608 (98.4%) of the 618 NTM isolates were identified. We conclude that the established scheme is a very useful diagnostic approach for the rapid and accurate identification of MTC and clinically relevant NTM in a clinical laboratory in a region where tuberculosis is endemic.     

Vertebral osteomyelitis caused by Mycobacteroides abscessus subsp. abscessus resulting in spinal cord injury due to vertebral body fractures

Nontuberculous mycobacteria (NTM) rarely cause vertebral osteomyelitis; however, the clinical characteristics of vertebral osteomyelitis caused by NTM are poorly understood due to its rarity. A 74-year-old man with lung cancer was treated with prednisolone for immune checkpoint inhibitor-associated immune-related adverse events. He had been experiencing mild back pain without febrile episodes for five months, and was admitted to the hospital for worsening back pain and progressive paraplegia. Magnetic resonance imaging showed spinal cord compression at T4-5 due to fractures of the T5 and T7 vertebral bodies. The culture of a sample of pus from the T7 vertebral body obtained at the time of spinal fusion surgery yielded the Mycobacteroides abscessus (M. abscessus) complex. The patient was diagnosed with vertebral osteomyelitis caused by M. abscessus complex and treated with clarithromycin, amikacin, and imipenem; clarithromycin was later replaced by sitafloxacin because of inducible macrolide resistance. However, his neurologic deficits were irreversible, and he died due to a deteriorating general condition. The strain was identified up to subspecies level as M. abscessus subsp. abscessus by hsp65 and rpoB sequencing and nucleic acid chromatography. Although vertebral osteomyelitis due to NTM is rare, delayed diagnosis can lead to serious complications or poor outcomes. A prolonged clinical course, less frequent fever, vertebral destruction or spinal deformity, neurological deficits, or immunosuppressed conditions might be suggestive of NTM vertebral osteomyelitis.     

Antimicrobial susceptibility testing of Mycobacteroides (Mycobacterium) abscessus complex,Mycolicibacterium (Mycobacterium) fortuitum,and Mycobacteroides (Mycobacterium) chelonae

The drug susceptibility of rapidly growing mycobacteria (RGM) varies among isolates. Treatment strategies similarly differ depending on the isolate, and for some, no clear strategy has been identified. This complicates clinical management of RGM. Following Clinical and Laboratory Standards Institute standard M24-A2, we assessed the susceptibility of 140 RGM isolates to 14 different antimicrobial drugs by measuring their minimal inhibitory concentrations (MICs). We also investigated the correlation of clarithromycin (CAM) MICs with the erm(41) and rrl gene mutations in the Mycobacteroides (Mycobacterium) abscessus complex, the rrl mutation in Mycobacteroides (Mycobacterium) chelonae, and the erm(39) mutation in Mycolicibacterium (Mycobacterium) fortuitum to determine the contribution of these mutations to CAM susceptibility. The five species and subspecies examined included 48 M. abscessus subsp. abscessus isolates (34.3%), 35 (25.0%) being M. abscessus subsp. massiliense, and two (1.4%) being M. abscessus subsp. bolletii. The M. abscessus complex accounted for 85 isolates (60.7%) in total, whereas 43 isolates (30.7%) were M. fortuitum, and 12 (8.6%) were M. chelonae. Our results demonstrated species-specific susceptibility to antimicrobials. In most cases, susceptibility to CAM could be predicted based on genetic pattern, but since one isolate did not fit that pattern, MIC values needed to be measured. Some isolates also exhibited rates of resistance to other drugs that differed from those previously reported in other locations, indicating that accurate identification of the bacterial isolate and use of the correct method for determining MIC are both important for the diagnosis of RGM.