Mycobacterium marseillense bloodstream infection combined with skin fungal infection: a case report and literature review

Abstract

Background

Non-tuberculous mycobacteria (NTM) are present widely in the natural environment and can invade the human body through the respiratory tract, gastrointestinal tract, and skin. Immunocompromised patients are particularly prone to infection, which primarily affects multiple organs, including the lungs, lymph nodes, and skin. However, cases of NTM bloodstream infections are rare. Here, we report a rare case of Mycobacterium marseillense bloodstream infection with concurrent skin fungal infection in a patient after kidney transplantation. Related literature was reviewed to enhance the understanding of this rare condition.

Case presentation

A 58-year-old male with a history of long-term steroid and immunosuppressant use after kidney transplantation presented with limb swelling that worsened over the past two months. Physical examination revealed redness and swelling of the skin in all four limbs, with a non-healing wound on the lower left limb. Skin tissue analysis by metagenomic next-generation sequencing (mNGS) and fungal culture indicated infection with Trichophyton rubrum. Blood culture results suggested infection with Mycobacterium marseillense. After receiving anti-NTM treatment, the patient’s symptoms significantly improved, and he is currently undergoing treatment.

Conclusion

Mycobacterium marseillense is a NTM. Gram staining suffered from misdetection, and the acid-fast staining result was positive. This bacterium was identified by mass spectrometry and mNGS analyses. Antimicrobial susceptibility tests for NTM were performed using the broth microdilution method. The results of the susceptibility test showed that Mycobacterium marseillense was sensitive to clarithromycin, an intermediary between moxifloxacin and linezolid. Bacterial clearance requires a combination of drugs and an adequate course of treatment. NTM bloodstream infections are relatively rare, and early identification and proactive intervention are key to their successful management.

Background

Non-tuberculous mycobacteria (NTM) are widely found in natural environments and commonly in water and soil [1]. NTM infections are increasing worldwide, particularly among immunocompromised individuals, such as patients with HIV and those who have undergone solid organ or stem cell transplantation [2]. Reports on bloodstream infections caused by NTM are relatively rare. NTM infections typically manifest as pulmonary or skin infections; however, bloodstream infections are less common. Immunocompromised individuals and those with underlying health conditions are also at risk. In this case report, a rare case of a Mycobacterium marseillense bloodstream infection combined with skin fungal infection is detailed. The infection in the lower limbs was caused by a fungal skin infection in a patient who had undergone a kidney transplant and was receiving long-term immunosuppressant therapy.

Case presentation

A 58-year-old male patient presented to the hospital with a chief complaint of limb swelling for the past 3 years, which worsened over the past 2 months. The patient had undergone renal transplantation 18 years previously because of glomerulonephritis and uremia. He was on a long-term medication regimen including tacrolimus (1 mg bid), mycophenolate mofetil (0.5 g bid), and prednisolone (4 mg bid). Three years earlier, the patient developed a localized swelling in the posterior aspect of the left lower limb following a mosquito bite, which progressively spread to all four limbs. Two months prior to admission, the patient underwent an incision and drainage procedure for the left lower limb; however, the wound did not heal well. The bacterial culture of the drainage fluid revealed Staphylococcus epidermidis. The patient was referred to our hospital for a skin biopsy. Metagenomic next-generation sequencing (mNGS) of the skin tissue revealed positive results for Trichophyton rubrum (1100 reads), Staphylococcus capitis (198 reads), and Corynebacterium tuberculostearicum (28 reads). Fungal cultures confirmed the presence of Trichophyton rubrum. Antimicrobial susceptibility test MIC results were as follows (µg/ml): terbinafine, 0.015; fluconazole, 2; posaconazole, 0.008; voriconazole, 0.015; itraconazole, 0.03; ketoconazole, 0.06; amphotericin B, 0.5. Histopathological examination revealed signs of fungal infection, including diffuse fibroplasia and neovascularization, neutrophilic infiltration, lymphocytes and plasma cells, focal fibrinoid necrosis, and the presence of fungal hyphae and spores.

The patient showed slight improvement after receiving an intravenous infusion of ceftriaxone 2 g qd and intermittent use of itraconazole. He initially presented with worsening pitting edema in all four limbs, along with redness, swelling, and fever in the lower limbs, particularly the left lower limb. Fluid discharge from the wound in the left lower limb was also observed (Fig. 1). His treatment with ceftriaxone and furosemide as an outpatient did not provide satisfactory results, leading to hospital admission for further diagnosis and treatment.

Fig. 1

The patient’s lower limb skin was affected by a fungal infection

Upon admission, the patient presented with normothermia (36.2 ℃), normal pulse rate (76 bpm), respiratory rate (18 breaths/min), and blood pressure (127/77 mmHg). The patient exhibited diffuse peripheral flushing and edema with tenderness in the lower extremities.

Laboratory results revealed leukocytosis (12 × 10⁹/L) with predominantly increased neutrophils (11 × 10⁹/L) and decreased lymphocytes (0.4 × 10⁹/L). Hypoalbuminemia was observed with a serum albumin level of 33.8 g/L. Furthermore, the absolute count of CD4 + T lymphocytes (139/µL) was reduced. C-reactive protein and procalcitonin levels were within the normal ranges. Following admission, the patient received linezolid 600 mg every 12 h and ceftriaxone 2 g once daily to manage the infection. Ten days after topical treatment with terbinafine and mupirocin for skin inflammation, the patient’s symptoms did not improve. Furthermore, there was a progressive decline in blood cell and platelet counts, suggesting a possible adverse reaction to linezolid, which was discontinued. Concurrently, blood culture of Myco/F Lytic Culture Vials yielded a positive result after 250 h, revealing gram-positive bacilli (Fig. 2) and positive acid-fast staining (Fig. 3). Xpert MTB/RIF testing was negative for Mycobacterium tuberculosis complex nucleic acids, suggesting NTM infection. A blood culture postive sample was immediately sent for mNGS analysis to determine the specific NTM subtype, which confirmed Mycobacterium marseillense. After 8 days, the blood agar plate incubated at 37 °C showed neatly edged, dry, and flat colonies (Fig. 4). Mycobacterium marseillense was identified using the matrix-assisted laser flight desorption/ionizationtime-of-mass spectrometry (MAIDI-TOF MS) (Bruker, Germany). Chest computed tomography (CT) scans revealed patchy opacities, nodular shadows, and pleural effusion. We performed acid-fast staining on early skin tissue pathology slides, which revealed a small number of acid-fast bacilli (Fig. 5) and fungal hyphae (Fig. 6) upon microscopic examination. The sputum was cultured several times and Pseudomonas aeruginosa was detected in one of them, whereas no pathogenic bacteria were detected at other time points. The patient may have had a disseminated Mycobacterium marseillense infection with a concurrent fungal infection of the skin. The patient was treated with azithromycin 250 mg qd, ethambutol 1 g qd, moxifloxacin 400 mg qd, contezolid 400 mg bid, and clofazimine 100 mg qd for NTM infection, and terbinafine 250 mg qd for fungal infection.

Fig. 2

Gram-positive bacilli in Gram staining smear from positive blood culture bottle (magnification: x1000)

Fig. 3

Acid-fast bacilli in Acid fast staining smear from positive blood culture bottle (magnification: x1000)

Fig. 4

Mycobacterium marseillense grew on the blood agar plate incubated for 8 days at 37 ℃

Fig. 5

Acid-fast bacilli in Acid fast staining from skin histopathological section (magnification: x1000)

Fig. 6

Fungal hypha in Acid-fast staining from skin histopathological section (magnification: x1000)

Thermo Scientific Sensitivity SLOMYCO2 was used for the antimicrobial susceptibility test (AST). Table 1 presents the results of the study. After 2 months of treatment, the patient’s limb redness and swelling reduced, and the lower limb wound healed. The patient continues to receive the same anti-NTM and antifungal medications, without any changes.

Table 1 Antimicrobial susceptibility testing results for Mycobacterium marseillense using the microbroth dilution method

Literature search and review

We searched the literature on bloodstream infections caused by non-tuberculous mycobacteria. Using specific keywords, we queried the PubMed database and idnetified 103 articles. Among them, we found a literature review published in 2016 that effectively summarized 22 cases of NTM bloodstream infections. [3] We selected 43 articles published between 2017 and the present. Of them, 28 were excluded as they were not case reports. We then carefully read the remaining 15 case reports, extracted data, summarized the characteristics of the 18 cases (Table 2), and compared them with the 22 cases summarized in 2016. The most common pathogen showed a changing trend. Mycobacterium chelonae is the prevailing pathogen from 2017 to the present, whereas Mycobacterium mucogenicum was more frequently reported before 2016. Most patients in both groups were immunocompromised and presented with underlying hematologic disorders, rheumatic diseases, solid tumors, HIV infection, or interstitial pneumonia. Hematologic disorders were the most prevalent underlying conditions, accounting for 37% of the cases since 2017 and 41% before 2016. Our analysis of 18 cases showed that 50% of the patients had received corticosteroid or immunosuppressant therapy, similar to our reported case. The primary organs affected in both groups were the lungs, followed by the endocardium, brain, bone marrow, and soft tissues. This is primarily because NTM is widely present in the environment and can easily cause disseminated NTM infections by initially infecting the respiratory tract and spreading through the bloodstream. Although the chest CT scan of our patient indicated lesions, the clinical symptoms of the patient’s respiratory system were not obvious, and no positive results proved that the lungs were infected with NTM. The mortality rates in the two groups were 11–17% and 23–50% respectively. The lower mortality rate observed since 2017 compared to that before 2016 may be attributed to the diversified identification methods used in recent years. With the availability of various identification methods, the early detection of NTM infections is possible, leading to early treatment and reduced mortality rates. A Canadian study summarized 28 cases of bacteremia caused by NTM [4]. All patients had long-term indwelling vascular access or received intravenous drug injections. Among them, 95% had their central venous catheters removed, and all achieved successful treatment outcomes. The literature suggests that removing indwelling vascular access is a key factor for successful treatment in these patients. Of the 18 reported cases, 44% involved patients with indwelling catheters in their blood vessels or other locations. All patients underwent catheter removal during treatment, and 87.5% achieved successful treatment outcomes. Although our case did not have a catheter inserted, NTM-related catheter-associated bloodstream infections are high. Therefore, it is crucial to consider the importance of catheter removal during treatment.

Table 2 Summary of 18 case reports of bloodstream infection caused by non-tuberculous mycobacterium

Discussion

NTM are classified into two types: rapid-growing and slow-growing. Slow-growing mycobacteria include Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium ulcerans, and Mycobacterium marinum. MAC, an NTM, is the newest species or subspecies discovered. Mycobacterium marseillense is a slow-growing mycobacterium and a member of the MAC complex. In recent years, an increasing number of cases of NTM infections have been reported, with the main sites of infection being the lungs, skin, and soft tissues.

There is currently no literature reporting Mycobacterium marseillense causing bloodstream infections. Because of its slow growth and poor Gram staining, this bacterium can be easily missed in microbiology laboratory analyses. Molecular diagnostic techniques can be used to identify M. marseillense. Identifying the species of NTM is crucial because different species of NTM require different types of antibiotics and treatment durations. ^[2,25] Due to the long-term use of immunosuppressive drugs after kidney transplantation, patients have a weakened immune system and are classified as immunocompromised. Early mNGS of the skin tissue indicated infection with Trichophyton rubrum and Staphylococcus capitis. Clinically, the primary consideration was a fungal infection combined with a Staphylococcus infection on the patient’s skin, without considering the less common pathogen NTM, which can cause bloodstream infection. Clinical cases of bloodstream infections caused by this bacterium are rare, and their clinical features may not be apparent, leading to challenges in diagnosis. However, we successfully diagnosed the patient and initiated combination therapy with anti-NTM and antifungal medications. However, the question is why the acid-fast stain of the patient’s skin tissue was positive but NTM was not detected by mNGS. It is possible that the patient’s skin tissue had a low bacterial load of NTM, making it difficult to lyse the NTM during the nucleic acid extraction process, yielding false-negative results. For mycobacteria in tissue samples, the sensitivity of mNGS may not be very high and, in some cases, even lower than that of traditional culture methods [5]. Unfortunately, neither the patient’s skin tissue nor the wound pus yielded any NTM in the culture. The inability to detect NTM in skin tissue may be due to the low bacterial load and slow growth. The presence of other microorganisms, such as Trichophyton rubrum, may have overshadowed the growth of the NTM. Therefore, it is possible that insufficient NTM colonies were present in the culture for detection. A possible reason for failing to detect NTM in pus cultures could be the short duration of laboratory cultivation, leading to missed detections. Additionally, the clinical suspicion of NTM infection was not communicated to the laboratory in advance, resulting in a standard culture duration that may not have been sufficient to cultivate NTM. In general, detecting NTM in blood cultures is considered a sign of pathogenic bacteria [6]. Among patients undergoing solid organ transplantation, kidney transplant recipients have the highest rate of NTM infection. This could be attributed to the higher frequency of kidney transplantation compared to other solid organ transplants [7]. The risk factors for NTM infection generally include immunodeficiency, genetic defects, monoclonal antibody therapy, and various other factors. Patients with chronic rejection after solid organ transplantation are at increased risk of developing NTM infections [7, 8]. Immunodeficiency can facilitate the progression of NTM infections, and enhanced immunosuppression (such as post-transplant antirejection therapy) further increases the risk of infection [9]. In addition, We believe that the association between skin fungal infections and NTM bloodstream infections was accidental because superficial fungal infections caused by Trichophyton rubrum do not require an underlying disease condition.

Various molecular diagnostic techniques are available for identifying NTM strains, such as mNGS, PCR, direct or indirect homologous genes, and sequence comparison. In clinical settings, implementing MAIDI-TOF MS and mNGS has greatly improved the accuracy of NTM species identification while significantly reducing the identification time. Among them, mNGS is the most advanced and precise method for identifying and distinguishing NTM species [2].

According to relevant studies, combination therapy is superior to monotherapy for NTM bacteremia and is associated with a lower recurrence rate [10]. Currently, breakpoint criteria for the drug susceptibility reference CLSI M24-A2 exist only for clarithromycin, moxifloxacin, and linezolid. However, breakpoints for clinically useful ethambutol, rifampin, rifambutin, streptomycin, and amikacin have not yet been established. In this case, we selected azithromycin, moxifloxacin, ethambutol, clofazimine, and contezolid to combat the NTM infection in our patient. Drug susceptibility testing indicated sensitivity to clarithromycin and intermediate susceptibility to moxifloxacin and linezolid. However, the clinical evaluation confirmed the effectiveness of the chosen treatment. There may be variations in NTM susceptibility between in vivo and in vitro conditions; therefore, there is no recommendation for switching antibiotics. According to the recommended guidelines [2], the treatment course for patients with disseminated MAC requires prolonged medication for one year or even lifelong. In our review of 18 cases, 83% of the patients had a favorable prognosis, highlighting the higher cure rate for disseminated NTM infections. Nonetheless, tailoring the treatment duration based on individual patient circumstances is crucial.

Preventing NTM bloodstream infections is crucial. First, preventing NTM infections in hospitals and avoiding tap water are key steps in the hospital environment. Specifically, it is important to avoid tap water contact with injection sites, venous catheters, and surgical wounds, and refrain from using tap water to rinse medical instruments. Second, personal and household prevention measures involve avoiding water from saunas and hot tubs, regularly replacing shower heads, periodically changing water filter cartridges, using sterilized water in humidifiers, and avoiding contact with patients with NTM [1].