A case of severe Mycobacterium thermoresistibile pneumonia

Abstract

Mycobacterium thermoresistibile is a thermotolerant nontuberculous mycobacterium which can rarely result in human infection. Although immunosuppression has been identified as a risk factor for infection, it is possible that mycobacterial laboratories may have previously under‐recognized M. thermoresistibile as standard mycobacterial incubation temperatures are suboptimal for culture of this organism. Here, we present a case of severe M. thermoresistibile pneumonia associated with achalasia requiring life support in the intensive care unit. We speculated that the interplay between specific host and environmental risk factors contributed to acquisition of infection. Infection with this fastidious organism required prolonged treatment with multiple antimicrobials and adjunctive therapeutic drug monitoring which led to clinical cure despite residual lung injury. We also reviewed literature documenting cases of human infection with M. thermoresistibile. The diagnosis of M. thermoresistibile requires a high degree of clinical suspicion considering its association with immunosuppressive conditions, postulated environmental inoculation and eponymous culture growth characteristics.

We present a case of severe pneumonia associated with achalasia requiring intensive care unit treatment caused by Mycobacterium thermoresistibile. We hypothesized the correlation between host and environmental factors leading to infection, citing its unique eponymous characteristics. We also reviewed published literature documenting cases of previous human infection with this organism.

INTRODUCTION

Mycobacterium thermoresistibile, a scotochromogenic thermotolerant nontuberculous mycobacterium causing human infection, is rarely reported in published literature. Inadequate laboratory culture temperature conditions may have led to its under‐recognition. Here, we present a case of M. thermoresistibile pneumonia and include a literature review.

CASE REPORT

A previously healthy 51‐year‐old man presented to hospital with 4 weeks of progressive dyspnoea, fever, fatigue, and myalgia.

He worked as a manual labourer in waste removal and was a coach for a community football team. He had no prescribed or illicit drug use. Twelve months prior to this admission, he was referred by his local doctor for a CT chest after developing a ‘flu‐like illness’ from which he spontaneously recovered. It demonstrated bilateral pulmonary infiltrates with severe oesophageal dilatation (Figure 1A). He was referred for upper gastrointestinal endoscopy, but this did not occur.

FIGURE 1.

Clinical course and radiological findings. (A) Computed tomography of the chest 12 months prior to presentation demonstrating right lower lobe consolidation and ground glass infiltrate with mediastinal setting image highlighting achalasia associated oesophageal dilatation. (B) Chest x‐ray at presentation demonstrating dense right lung consolidation. (C) Computed tomography of the chest at presentation confirming severe right lung consolidation and less severe left lung disease. (D) Computed tomography at the end of treatment demonstrating bronchiectasis and peri‐bronchial fibrosis.

On presentation to hospital, the patient was febrile (38.2°C), tachycardic (132 beats/min) and tachypneic (18 breaths/min). The initial laboratory tests revealed leucocytosis of 23.07 × 10⁹/L, platelet count of 662 × 10⁹/L and C‐reactive protein of 142.8 mg/L. He was HIV negative. A chest x‐ray demonstrated bilateral infiltrates, with dense multi‐lobar consolidation in the right lung and less severe disease in the left lung (Figure 1B,C). He was treated for community acquired pneumonia in accordance with local guidelines (ceftriaxone and azithromycin) and was escalated to piperacillin‐tazobactam after 2 weeks due to clinical deterioration. Serial chest x‐ray demonstrated progressively worsening bilateral multifocal consolidation. After 3 weeks, he was admitted to the Intensive Care Unit (ICU) with severe hypoxic respiratory failure requiring initial high flow oxygen therapy with subsequent invasive mechanical ventilation.

In the ICU, three expectorated sputum samples and bronchoscopy directed bronchoalveolar lavage (BAL) specimens revealed the presence of acid‐fast bacilli on auramine stained fluorescence microscopy. Nucleic acid amplification for Mycobacterium Tuberculosis Complex was performed (GeneXpert MTB/RIF, Cepheid, Sunnyvale, CA) and was negative. Nucleic acid amplification for Influenza A on the BAL specimen was positive, and the patient was treated with a course of oseltamivir.

Due to diagnostic uncertainty with regards to the relative contribution of the presumed non‐tuberculous mycobacterial infection to the progressive respiratory failure, a CT guided lung biopsy was performed. Histology demonstrated dense inflammatory cell infiltrate in the parenchyma comprising histiocytes, multinucleate giant cells and neutrophils with possible granuloma formation (Figure 2A). Numerous acid‐fast bacilli were visualized on Ziehl‐Neelsen stain (Figure 2B).

FIGURE 2.

Histopathological findings. (A) Haematoxylin & eosin, 400× magnification. The image, taken from the edge of the core biopsy, shows a centrally necrotic granuloma comprised of aggregated epithelioid and multinucleated histiocytes associated with lymphocytes and small numbers of neutrophils. (B) Ziehl‐Neelsen stain, 400× magnification. The image highlights a magenta‐staining microorganism centrally within the granuloma, consistent with an acid‐fast bacillus.

A broad‐spectrum anti‐mycobacterial antibiotic regimen comprising meropenem 1000 mg 8 hourly, azithromycin 500 mg daily, rifampicin 600 mg daily and ethambutol 1200 mg daily was commenced while awaiting microbiological specification.

Airway specimens were culture positive after 2 weeks incubation at 37°C on the Bactec Mycobacteria Growth Indicator Tube (MGIT) 960 automated broth‐based system (Becton Dickinson, Cockeysville, Maryland, USA) and grew on Lowenstein‐Jensen media incubated at 37°C. M. thermoresistible identification was confirmed using Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI‐TOF MS) and 16S RNA gene sequencing. Colony morphology and scotochromogenic properties supported the molecular identification.

Due to the lack of data correlating in vitro antimycobacterial susceptibility for M. thermoresistibile, empirical intravenous amikacin (targeting a peak serum concentration of 40 mg per ml with trough concentrations of <0.5 mg per ml) and moxifloxacin 400 mg daily were added while meropenem was ceased.

After initial improvement, the patient was liberated from mechanical ventilation. However, he subsequently deteriorated with severe hypoxic respiratory failure requiring reintubation and mechanical ventilation. Drug sensitivity testing was performed given the patient's critical illness and uncertainty regarding the optimal drug regimen. Broth Microdilution sensitivity testing was conducted using Thermofisher Scientific TM Sensititre Slow Growing Mycobacteria (SLOWMYCOI) Plate. This has not been fully validated to National Pathology Accreditation Advisory Council standards. The Clinical and Laboratory Standards Institute Susceptibility Testing document (M62) was used to interpret MIC data. ¹ The isolate tested resistant to rifamycins and susceptible to clarithromycin, moxifloxacin, sulfamethoxazole, amikacin, linezolid, and doxycycline (Table 1).

TABLE 1.

Anti‐microbial MIC values.

Agent	MIC (μg/mL)	Interpretation (breakpoint)	Agent	MIC (μg/mL)	Interpretation (breakpoint)
Clarithromycin	<0.06	Sensitive (≤8)	Amikacin	<1	Sensitive (≤16)
Rifabutin	4	Resistant (≥4)	Linezolid	<1	Sensitive (≤8)
Ethambutol	16	‐	Ciprofloxacin	<0.12	Sensitive (≤1)
Isoniazid	>8	‐	Streptomycin	1	‐
Moxifloxacin	<0.12	Sensitive (≤1)	Doxycycline	1	Sensitive (≤1)
Rifampin	>8	Resistant (≥2)	Ethambutol	>20	‐
Trimethoprim	<0.12/2.38	Sensitive (≤2/38)

Abbreviations: MIC, minimal inhibitory concentration; S, susceptible; R, resistant.

Accordingly, an all‐oral anti‐mycobacterial regimen comprising linezolid 600 mg daily, moxifloxacin 400 mg daily, doxycycline 100 mg twice daily, sulfamethoxazole/trimethoprim 800/160 mg twice daily and azithromycin 500 mg daily was formulated. The dose of linezolid was increased to 600 mg twice daily, and moxifloxacin to 800 mg daily based on therapeutic drug monitoring, performed immediately prior to and 2 h after dosing. Target trough levels for linezolid were between 2 and 8 mmol/L and for moxifloxacin a peak serum concentration of between 3 and 5 mg/L. Therapeutic drug monitoring was repeated after 3 months to guide dosing.

Progressive clinical improvement was noted on this regimen. Weekly sputum sampling was undertaken throughout the course of treatment. Durable smear conversion was achieved within 7 days while durable culture conversion was achieved 3 months after commencing treatment.

Once stabilized, upper gastrointestinal endoscopy was performed, and achalasia confirmed via oesophageal manometry. Subsequently endoscopic balloon dilatation of a lower oesophageal stricture was undertaken, which was followed by Peroral Endoscopic Myotomy for persistent achalasia.

After completion of treatment at 15 months, radiological evidence of bilateral parenchymal scarring and post infective bronchiectasis was noted (Figure 1D) along with severe sensorineural deafness likely due to amikacin. Surveillance sputum testing upon follow up in chest clinic 2 years later confirmed culture negative for M. thermoresistibile. Pulmonary function tests at that time depicted restrictive ventilatory abnormality with Forced Expiratory Volume in 1 s of 1.36 L (32% predicted), Forced Vital Capacity of 2.52 L (47% predicted) and impaired gas transfer (49% predicted). Despite sustaining long‐term lung injury, the patient returned to independent living and re‐joined the workforce.

DISCUSSION

Mycobacterium thermoresistibile is a nontuberculous mycobacterium (NTM), which is a genus of more than 150 species of free‐living bacteria with a wax and lipid rich outer membrane which confers them the resilience to survive in a myriad of natural and engineered environments incorporating water or soil. ² Initially discovered by Tsukamura from soil samples in Japan in 1966—published evidence of M. thermoresistibile's pathogenicity in humans was first described in 1981, where the organism was cultured from a sputum sample obtained from a patient with pneumonia. This organism was noted to be thermoresistant up to 60°C—contrasting that of other NTM controls which did not share this property, ³ hence granting its nomenclature. This property, and the presence of scotochromogenicity (strains form yellow‐orange‐red pigmented colonies in the dark) can provide clues in the mycobacterial reference laboratory to the presence of this this organism.

A total of nine cases of human infection caused by M. thermoresistibile have been published thus far, including four cases of pulmonary infection (Table 2). Immunosuppression appears to be an important risk factor for disease associated with M. thermoresistibile—including solid organ transplant, diabetes mellitus, long‐term treatment with systemic glucocorticoids, haematological disease and hypogammaglobulinemia as reported within this case series.

TABLE 2.

Summary of Mycobacterium thermoresistibile human infections in the literature.

Year/reference	Location	Age (years) /gender	Co‐morbidities	Infection site	Diagnostic technique	Antibiotherapy	Duration	Outcome
1981/ 3	NY, USA	50/F	‐	Lung	Culture in Middlebrook 7H11 medium at 25, 37 and 45°C in 5% CO2; biochemical tests	Rifampicin + Ethambutol + Streptomycin	Not stated	Afebrile after 7 days
1984/ 13	Utah, USA	64/M	Hypogammaglobinaemia	Lung/Sinus	Culture in Middlebrook 7H11 medium and in LJM at 25, 35, 45 and 52°C in 7% CO2; biochemical tests	Rifampicin 600 mg/day + Ethambutol 15 mg/kg/day + Streptomycin 1 g twice weekly then Rifampicin + Ethambutol	Not stated	Recovery
1989/ 14	California, USA	41/M	Cardiac transplant, Diabetes Mellitus	Skin	Culture at 42 and 50°C; biochemical tests; HPLC	Rifampicin 600 mg/day + Ethambutol 1.2 g/day	12 months	Recovery
1992/ 15	California, USA	41/F	None	Mammoplasty implant	Culture in LJM at 37°C and in Middlebrook 7H10 medium at 42 and 52°C, biochemical tests, HPLC	Rifampicin 600 mg/day + Ethambutol 1.6 g/day then 1 g/day	Not stated	Recovery 16 months after beginning therapy
2000/ 16	Texas, USA	Unspecified/F	None	Skin	Culture in LJM at 37°C; biochemical tests, HPLC, co‐infection with M.fortuitum	Levofloxacin 2 g/day + Doxycycline 200 mg/day	12 weeks (non‐compliant)	Recovery at 1 year follow up
2005/ 17	Unspecified	72/F	Diabetes Mellitus	Knee prosthesis related osteomyelitis	Culture in LJM at 35°C and in VersaTREK liquid medium; biochemical tests and HPLC	Moxifloxacin + Linezolid for 6 weeks, then Linezolid replaced with doxycycline	40 weeks	Recovery 7 months after beginning therapy
2006/ 18	Iran	5/M	Langerhans Cell Histiocytosis on steroid therapy	Abdomen, Lungs, Lymph Nodes	PCR, Gastric lavage	Isoniazid + Rifampicin + Ethambutol + Pyrazinamide	Not stated	Afebrile after 1 month, Acid Fast Bacilli negative after 4 months
2009/ 5	Greece	67/M	Chronic Obstructive Pulmonary Disease, Diabetes Mellitus	Lungs	Culture in LJM at 37°C, 45°C; biochemical tests, 16S rRNA and hsp65 PCR sequencing	Ciprofloxacin + cefuroxime	Not stated (treated as colonization)	Recovery
2013/ 19	France	43/M	Intellectual impairment	Tibial nail related osteomyelitis	Culture in blood agar, MALDI‐TOF MS; 16S rRNA and hsp65 sequencing	Levofloxacin 1 g/day + Clarithromycin 1 g/day + trimethoprim‐sulfamethoxazole 3200 mg/800 mg/day for 2 weeks then Levofloxacin + Clarithromycin	24 weeks	Recovery 6 months after beginning therapy
2019	Adelaide, Australia	51/M	Achalasia	Lungs	Culture on MGIT, LJM & blood agar, MALDI‐TOF MS	Rifampicin 600 mg/day + Ethambutol 15/mg/day + Azithromycin 500 mg/day + Intravenous Amikacin 15 mg/kg thrice weekly	18 months	Recovery after 18 months

Abbreviations: HPLC, High Performance Liquid Chromatography; LJM, Löwenstein–Jensen Medium; MALDI‐TOF MS, Matrix‐Assisted Laser Desorption Ionization‐Time Of Flight Mass Spectrometry; MGIT, Mycobacteria Growth Indicator Tube; PCR, Polymerase Chain Reaction; CO₂, carbon dioxide; rRNA, ribosomal Ribonucleic acid.

Whilst human disease secondary to M. thermoresistibile is rare, it is also possible that it is under‐recognized. M. thermoresistibile is notable for its thermotolerance with its optimal growth occurring between 37 and 45°C, and has been cultured in temperatures up to 60°C. ³ , ⁴ There could be inadequate culturing conditions as laboratories do not routinely incubate samples at temperatures greater than 40°C, ⁵ , ⁶ thereby leading to its lack of identification as the causative organism responsible for infection.

Our patient highlights a case of severe infection caused by this pathogen leading to severe pneumonia and critical illness requiring intensive care intervention. We postulate severe achalasia as the predominant risk factor for this infection. Non‐tuberculous mycobacteria have been recognized as a cause of pneumonia in patients with achalasia, ⁷ perhaps due to recurrent aspiration of gastrointestinal contents in stasis. The association between NTM infections and disorders of oesophageal motility has been documented in Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium abscessus infections. ⁸ To our knowledge, ours is the first case of M. thermoresistibile associated with achalasia.

Periodic environmental exposure may play a role in acquisition of infection given M. thermoresistibile has been reported in food waste, garbage slurry and compost material cultures. ⁹ , ¹⁰ This patient's occupation in refuse collection may have resulted in increased opportunity for infection with this organism. Whilst there was radiological suspicion of lung disease about a year prior to presentation to hospital, concurrent infection with Influenza A may have synergistically contributed to the acute and severe deterioration. ¹¹ , ¹²

The treatment of non‐tuberculous mycobacterial infection is challenging and requires prolonged treatment with multiple antimicrobials. M. thermoresistibile, like other NTM, is well documented to possess intrinsic and acquired antimicrobial resistance mechanisms. ² , ⁹ , ¹⁵ Multidisciplinary involvement of mycobacterial laboratory scientists and clinicians experienced in the management of non‐tuberculous mycobacterial infection warrants consideration for future cases of M. thermoresistibile disease especially when associated with critical illness, as highlighted in our patient.

In our experience, therapeutic drug monitoring was a useful adjunct to treatment. It allowed early dose escalation with subsequent de‐escalation once sustained physiological improvement and clinical stability was achieved.

In summary, although M. thermoresistibile is a rare human pathogen, it has been demonstrated to cause life‐threatening infection in humans requiring prolonged antimicrobial treatment. Conventional laboratory culture techniques may be inadequate to allow detection of this organism due to its eponymous growth characteristics favouring a higher ambient temperature. Therefore, it requires a high degree of clinical suspicion for its diagnosis whilst identification techniques in mycobacterial laboratories continue to evolve.

AUTHOR CONTRIBUTIONS

All authors were involved in the preparation of the manuscript.

CONFLICT OF INTEREST STATEMENT

No conflicts of interest.

ETHICS STATEMENT

The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.

Subramaniam S, Kanhere M, Shephard L, Burke A, Saxon S, Geake J. A case of severe Mycobacterium thermoresistibile pneumonia. Respirology Case Reports. 2024;12(3):e01308. 10.1002/rcr2.1308

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.