Non-tuberculosis mycobacteria (NTM) (Sharma and Upadhyay, 2020; Pavlik et al., 2022), mycobacteria other than Mycobacterium tuberculosis and Mycobacterium leprae, have emerged as a significant source of infections (Kumar et al., 2021; Nogueira et al., 2021). Among the diverse manifestations of NTM infections, skin and soft tissue involvements are prevalent clinical presentations. Although not posing an immediate life-threatening risk, these infections can result in significant morbidity and adversely affect the quality of life for affected individuals. Notably, there has been a global increase in reported cases of superficial NTM infections (Mei et al., 2019; Philips et al., 2019; Gopalaswamy et al., 2020) with contributing factors including the expanding population of immunocompromised individuals (Blakney et al., 2022; Toth et al., 2022) who face heightened susceptibility during injury or cosmetic procedures (Ahmed et al., 2020; Wang C. J. et al., 2022; Ni et al., 2023). Furthermore, the rise in NTM infections can be attributed, in part, to the ongoing adaptation of NTM to the human host. NTM’s remarkable capacity to thrive within the diverse skin environment, while effectively evading immune responses, also plays a role in the escalating incidence of these infections (Luo et al., 2021).

In light of these observations, understanding and effectively managing NTM skin infections are crucial for public health and patient wellbeing. Regarding treatment choices for NTM infections, various factors come into play due to the unique nature of these infections. Generally, the choice of treatment for NTM infections depends on the specific species and susceptibility pattern of the isolated organisms, as well as the severity and extent of the infection (Pennington et al., 2021). Current treatment strategies often reference the guidelines (Daley et al., 2020) of the Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) on pulmonary NTM-infected diseases. However, it should be noted that the ATS/IDSA guidelines for pulmonary diseases may not be directly applied to all skin-involved cases due to the unique characteristics of cutaneous NTM infections. The invasive or disseminated NTM infections may require a greater variety of drugs and a more extended treatment duration (Liu et al., 2023). When it comes to superficial involved cases, consideration must be given to the potential variations in pathogen types resulting from diverse infection pathways. The unique physiological structures and functions of the skin (Gravitz, 2018), compared to other anatomical sites, may also influence drug absorption and distribution, warranting tailored treatment approaches. In addition, the influence of local microbiota (Grice and Segre, 2011) and differences in host immune responses (Nguyen and Soulika, 2019) should not be underestimated, as they significantly impact treatment outcomes. Surgical interventions, phototherapy (Yang et al., 2022), and heat application (Lee and Lee, 2017) should also be considered as viable alternative treatment options due to anatomical variations in the infected sites. Furthermore, the emergence of newly invented antimycobacterial agents, such as MmpL3 inhibitors and Efflux Pump inhibitors (Rindi, 2020; North et al., 2023), are believed to have potent against slow-growing mycobacteria (SGM) and rapid-growing mycobacteria (RGM), also highlights the need for timely revision of treatment approaches. Finally, although NTM and M. tuberculosis shares similar physiological characteristics, virulence factors, and genetic drug targets (Rifat et al., 2021; Mei et al., 2023), it is still not advisable to fully copy the treatment regimens of TB. Many drugs being developed for treating TB do not exhibit any antimicrobial activity against NTM (Saxena et al., 2021). In summary, those factors highlight the need for updating of targeted treatment approaches to enhance skin-involved patient outcomes.

The management of cutaneous infections caused by various NTM subtypes poses significant challenges, necessitating a careful balance between therapeutic benefits and potential risks. The optimization of diverse treatment approaches, as well as the mitigation of adverse effects and infection recurrence, remain critical objectives. Through this comprehensive review, our aim is to provide an in-depth analysis of the treatment strategies for NTM skin infections and shed light on the complexities involved in addressing these clinical aspects.

Since more and more extrapulmonary NTM-infected cases have been reported recently and no unified treatment proposal could be referred to, a safer, more effective, higher adherent, a broader spectrum of anti-NTM activities, and more cutaneous-specific treatment strategy is needed. Thus, we reviewed the treatment of NTM infections involving skin or soft tissues in recent years to give some suggestions on this topic.

NTM skin involvements exhibit distinctive therapeutic disparities compared to other NTM-infected manifestations, owing to the unique structural characteristics of the skin, variations in drug distribution patterns, diverse modes of infection, relatively confined lesion distribution, milder disease severity, and a greater array of treatment modalities available. The management of NTM infections frequently entails the administration of multiple antimicrobial agents over extended durations, requiring vigilant clinical and laboratory monitoring. Nevertheless, the dearth of well-structured controlled trials investigating first-line treatment regimens, including optimal drug selection, dosage, and duration, poses challenges in formulating evidence-based guidelines for effectively managing a wide array of NTM species and associated diseases. Consequently, regimen selection should generally be guided by drug susceptibility testing. This testing involves assessing the susceptibility of the NTM isolate to various antimicrobial drugs, allowing for informed decisions on the most appropriate therapeutic approach. According to the results of drug sensitivity tests, our recommended treatment choices were summarized in Table 1. The establishment of rigorous clinical trials will be instrumental in addressing these knowledge gaps and facilitating the development of more effective and targeted treatment strategies for NTM skin infections. Waiting for species identification and susceptibility before treatment is reasonable without any delay for most superficial cases. However, the correlation between clinical outcomes and in vitro susceptibility thresholds remains undefined for the majority of NTM species (van Ingen et al., 2012a; Timmins, 2020). Different NTM subspecies have other susceptibility profiles to antimicrobial agents. The susceptible antibiotics against SGM differ from that of RGM (Alffenaar et al., 2021; Sharma et al., 2021). Therefore, subspecies level identification (no higher than the species level) and sensitivity testing of NTM, especially RGM, is recommended. For example, the Clinical and Laboratory Standards Institute (CLSI) recommends (Schoutrop et al., 2018) clarithromycin and amikacin susceptibility testing only for MAC, clarithromycin, and rifampicin for M. kansasii, and clarithromycin for M. abscessus complex. In addition, susceptibility testing should be prolonged as long as 6 weeks for SGM and 2 weeks for macrolides (Dartois and Dick, 2022). Recent advancements in molecular diagnostic techniques have improved the accuracy and speed of identifying NTM species and their drug susceptibilities, allowing for more precise and targeted treatment. However, over time, the stability of some antimycobacterial drugs is gradually affected by the pathogen, leading to a variable minimum inhibitory concentration (MIC), which then affects the final interpretation of the DST result. This partly explains why drug susceptibility testing results do not necessarily translate to a positive clinical response. The local microenvironments (Dey et al., 2010; Dartois and Dick, 2022), which can decrease therapeutic concentrations of drugs at the anatomical sites, might be another reason.

In addition, there is no well-defined treatment endpoint for superficial NTM infections. In contrast to TB or NTM pulmonary diseases, where the treatment endpoint can be determined by sputum specimen culture conversion and imaging results, defining the endpoint of treatment for superficial NTM infections remains uncertain. Typically, a treatment duration of 2–4 months is recommended for skin and soft-tissue NTM infections, while NTM pulmonary diseases often require at least 12 months of therapy after sputum culture reversion. To improve treatment efficacy while minimizing the risk of drug resistance, long-term and multidrug therapy is often necessary for NTM infections. However, this approach may lead to challenges such as drug interactions, drug-related adverse reactions (AEs), and high medication costs, potentially compromising treatment efficacy and patient compliance. Another method for determining the endpoint of treatment involves obtaining post-treatment specimens for culture to assess treatment efficacy, but this invasive procedure carries a heightened risk of reinfection, particularly in individuals with compromised immune systems. Finding a consensus on a specific and effective treatment endpoint for superficial NTM infections is imperative and demands further research and clinical investigation to ensure optimal patient outcomes and successful management of these challenging infections (Haworth et al., 2017; Wi, 2019). Currently, the determination of the treatment endpoint for skin NTM infection primarily relies on the assessment of changes in the patient’s clinical manifestations. These assessments typically involve evaluating the complete or substantial disappearance of preexisting skin lesions, the absence of new skin lesions, and the persistence of unchanged skin lesions after a specific duration of treatment. However, it is important to note that this criterion is subjective and lacks well-defined objective measures. To establish a more standardized and evidence-based approach for defining the treatment endpoint of skin NTM infection, further research and clinical investigations are necessary.

The low susceptibility of NTM to a wide range of antibiotics is attributed to their several characteristics. 1. Intrinsic resistance mechanisms: the first barrier is the unique metabolic condition [hydrophobicity of cell wall, and thereby low permeability (van Ingen et al., 2012a)] and the absence of porin or ABC transporter superfamily of the cell wall, which weakens the uptake and biotransformation of drugs and decreases the affinity with the drug target. 2. Inducible resistance mechanisms (Alffenaar et al., 2021): the second barrier is the genomic mutations of NTM, which could confer high-level resistance. Resistant strains are due to mutations at nucleotides. For instance, the changes of the 23S rRNA (functional erm genes) in M. abscessus isolates and of the RNA polymerase binding protein A (RbpA) in M. smegmatis are linked to the resistance to the macrolides and rifampicin (Dey et al., 2010). Comparative genomics and population genetics studies can provide insights into the genetic variability, evolution, and adaptation of NTM species. 3. Adaptative resistance mechanisms: he adaptability of NTM is the third barrier. NTM has extraordinary abilities in generation-upgrade time, and metabolic capabilities, which means they can adapt to stress before the cells are killed. They can form biofilms on the skin, which are complex microbial communities encased in an extracellular matrix. For example, one of the persistence strategies of NTM is hidden in biofilms (Slany et al., 2016), which generally leads to ten times less susceptibility to antibiotics than their counterparts. Understanding the mechanisms and dynamics of NTM biofilm formation on the skin is an active area of research, aiming to develop strategies to disrupt biofilms for improved treatment outcomes, including the use of biofilm-targeting agents and biofilm-disrupting techniques (such as enzymes, peptides, nanoparticles, and ultrasound). In addition, some studies (Huh et al., 2019) believe that NTM can enter a nonreplicating state and exhibit phenotypic drug resistance. However, up to now, the survey of resistance mechanisms associated with NTM still needs to be completed. Except for macrolides, the resistance mechanisms of many drugs still need to be clarified. It is essential to understand the basis for resistance and, more importantly, how to revise treatment choices to prevent the development of resistance.

For uncomplicated skin-involved cases, primary empirical treatments and antibiotic monotherapy could respond well in most patients. Single-drug or combined (clarithromycin, rifampin, and ethambutol) treatments depend on the specific characteristics of the hosts, location, and identification of species. When a poor response to treatment or rapid progression is found, in vitro susceptibility testing should be addressed throughout the treatment. Compared to antimicrobial agents’ therapy alone, additional surgical operation of the localized infection with medication has proven to have better outcomes for extracutaneous involvement. Regular monitoring of the patient’s clinical response to treatment, as well as laboratory testing to assess the effectiveness of antimicrobial therapy, is important in the management of NTM skin infections. Follow-up appointments with the treating physician should be scheduled as recommended to monitor progress and make any necessary adjustments to the treatment plan. Our recommendations for treating NTM skin infections and recommended procedures are summarized in Table 2 and Figure 1.

Emerging strategies are being explored to overcome drug resistance and improve treatment efficacy of complicated cases. 1. Screen existing drugs and new drugs: Novel antimicrobial drugs have shown promising activity against NTM species and may be considered in the treatment of NTM skin infections, particularly in cases where standard treatment regimens have failed or in the presence of drug-resistant strains. A study (Kaushik et al., 2019) showed that the new β-lactamase inhibitors relebactam and vaborbactam in combination with β-lactams have potent against M. abscessus complex clinical isolates in vitro. Clofazimine (Meir and Barkan, 2020), used for treating leprosy, is repurposed against M. abscessus. Besides, delamanid, pretomanid, and PIPD1 were also tested against M. abscessus. Telacebec is a promising novel drug with the potency of shorter duration and better tolerability (Lee and Pethe, 2022). However, the use of newer drugs may be limited by their potential side effects, higher costs, and availability. 2. Recombination of existing drugs: this is a very economical and efficient option. Previous studies (van Ingen et al., 2012b; Lee and Pethe, 2022) found that some antibiotics could increase cell wall permeability for the uptake of the second drug and accelerate durable cure, which indicates that the synergistic drug interactions could provide additional support in treating NTM infections. 3. Find new drugs according to new targets (Dartois and Dick, 2022): RNA polymerase, DNA gyrase, the ribosome, F-ATP synthase, and several enzymes. For instance, antibiotics that target oxidative phosphorylation energy-generate pathways could be a new choice. Alternatively, MmpL3 (Sethiya et al., 2020), a transporter crucial for exporting trehalose monomycolates to the periplasmic space and outer membrane, could also be a novel target in treating NTM. A study (Swain et al., 2021) found 15 new targets through screening 537 core proteins that researchers could further utilize to design inhibitors for discovering antimicrobial agents. In addition, some new drug research approaches are equally exciting. Macrophage infection assays, persister-specific assays, nonreplicating assays, biofilm assays, animal models, and lesion- or infection-site-specific pharmacokinetic assays, which can help us focus on skin and soft tissue, are instrumental methods to measure and evaluate effects when developing new anti-NTM drugs (Wu et al., 2018). For example, interferon-gamma, a cytokine that plays a role in the immune response against mycobacterial infections, has been used as an adjunct to antimicrobial therapy in some cases of NTM skin infections, particularly in patients with underlying immunosuppressive conditions. Other immune-enhancing agents, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), have also been studied in the management of NTM infections. Fragment-based drug discovery (Togre et al., 2022) (FBDD) can concentrate on designing optimal inhibitors against potential therapeutic targets of NTM. A rabbit model could provide an acceptable surrogate model to study antibiotic penetration and simulate pharmacokinetic-pharmacodynamic tracks in vivo (Kaya et al., 2022).

Our article also has many limitations. First, randomized studies need to be added, and data regarding optimal treatment are limited. Clinical data on the efficacy of different treatment of NTM skin diseases in humans is limited, and further research is needed to determine its safety and effectiveness in clinical practice. Second, the resistance mechanism of NTM (genetic and pathogenic variations among species) infections needs to be understood more.

In summary, a comprehensive understanding of the various aspects discussed in this study is crucial for the effective management of cutaneous involvement caused by NTM. The ideal therapeutic approach should encompass a broader spectrum of anti-NTM activities while simultaneously considering the specific characteristics of cutaneous infections. The optimal treatment approach for NTM infections is still evolving, continuous research, clinical trials, and innovative therapeutic strategies are essential in the quest for safer, more effective, and tailored treatment options to combat NTM cutaneous involvement effectively. By addressing these aspects, clinicians can enhance patient outcomes and reduce the burden of NTM infections in affected populations.