Aspects related to the presentation of NTM infection.
The analysis of patients revealed NTM-EP infection in a high-complexity hospital in Cali, Colombia. Information on NTM-EP in Colombia has been limited. Cases of cutaneous infections in patients undergoing cosmetic procedures, especially those involving M. chelonae [8, 9], Mab and M. fortuitum [9, 10], have been reported. Valvular involvement by M. peregrinum has also been reported [11], along with involvement of the MAI, M. parascrofulaceum, M. terrae [12, 13] and M. fortuitum [14] in the HIV population. Our study contributes to the understanding of the extrapulmonary manifestations of both RGM (M. chelonae, Mab, M. fortuitum) and SGM (M. malmoense, MAI and M. marinum).
In most countries, local studies have estimated the incidence of NTM infection, as it is not considered a notifiable disease. The incidence reported in the United States was 0.011% [15], while in India, it ranged from 0.93% in 2011 to an increase of 1.6% in 2020 [16]. In Colombia, prevalence studies have shown a 1.5% prevalence in respiratory isolates, with M. fortuitum and Mab being the most prevalent [17], and a 5% prevalence in the HIV population [4].
In our study, the presence of M. fortuitum (46%), Mab (31%), M. chelonae (15%), and M. marinum (8%) was detected in patients with cutaneous involvement. This differs from reports in India and Japan, where M. chelonae, Mab, and M. ulcerans are the most reported isolates [16, 18]. In China, the MAI, Mab, and M. kansasii are observed [19], and M. fortuitum is the most common [20], mostly related to trauma.
MAI was identified in 67%, and M. abscessus was identified in the remaining 33%. More than half of the patients were HIV-positive, with MAI being the main isolated mycobacteria. The prevalence of MAI infection in the HIV population is estimated to be 7–12% [2, 6, 21], with disseminated presentation [2]. One of the sites compromised by MAI is the lymphatic system, especially the cervical, mediastinal, and intra-abdominal lymph nodes, as well as the lungs, bones, skin, soft tissues, genital ulcers, and central nervous system [2].
Colombia has become a significant destination for cosmetic surgeries, ranking ninth globally [22]. However, despite its popularity, reports indicate that a considerable number of patients seeking cosmetic procedures in Colombia are from North America, particularly the United States [23]. This raises questions about the quality of care and postoperative complications, especially concerning infectious complications. While cosmetic tourism can offer financial benefits, particularly in Colombia, where costs are often lower than those in other countries, it is crucial to weigh these costs against potential health risks, including the risk of contracting infections such as NTM. Balancing the allure of cosmetic procedures with patient safety remains a critical consideration in the burgeoning cosmetic tourism industry.
Aspects related to diagnosis.
Clinical suspicion guides the approach to NTM infection, with Zielh-Neelsen stains and cultures of lesions or biopsies to detect acid-fast bacilli [24]. The cultures were complemented by molecular tests such as Speed-Oligo Mycobacteria, which identifies up to 12 different species, including the M. tuberculosis complex, M. avium-intracellulare-scrofulaceum complex, M. chelonae-abscessus complex, M. fortuitum, M. kansasii, and M. gordonae [25]. In this case series, mycobacteria were identified using molecular tests, notably the Genotype MTBDR and Speed Oligo.
Aspects related to drug susceptibility
Drug susceptibility in NTM is crucial for effective treatment. In more than 50% of the patients studied, resistance to doxycycline and ofloxacin was identified via drug susceptibility tests. However, NTM strains were sensitive to fluoroquinolones, aminoglycosides, and macrolides in all the tests conducted. It is important to note that NTM are genetically resistant to conventional tuberculosis drugs, especially RGM. A discordance has been observed between in vitro susceptibility and in vivo treatment response, which generates controversy regarding the utility of drug susceptibility tests [26].
Drug susceptibility varies by geographic region, and correlations have been identified between the minimum inhibitory concentration (MIC) of certain drugs and specific genetic mutations in NTM. For example, mutations in the erm 41 and rrl genes confer resistance to macrolides and aminoglycosides, respectively [27, 28]. Various resistance mechanisms have been described in different NTM species, such as efflux pumps associated with aminoglycoside resistance in M. fortuitum and the presence of proteins that protect DNA gyrase from antibiotic action in MAI [4, 27]. M. chelonae exhibits mutations in the 23S rRNA gene that confer resistance to clarithromycin [27]. In M. marinum, resistance mechanisms, such as mutations in the rpoB gene, which encodes the beta subunit of RNA polymerase and is the target of rifampicin, are not fully understood. Given the complexity of drug resistance in NTM, prolonged drug resistance tests are recommended, along with molecular methods to detect specific genetic mutations that may influence treatment response.
Discussion on pharmacological treatment aspects.
The recommendations for the treatment of NTM-EP infection are limited [7, 29]. Current clinical practice guidelines such as those from ATS/ERS/ESCMID/IDSA focus on pulmonary involvement, addressing complex NTM such as MAI, M. Kansasii, M. xenopi, and Mab in patients without cystic fibrosis and without HIV infection [1]. There is debate regarding whether stable patients with extrapulmonary involvement should receive empirical treatment or wait for susceptibility test results considering adverse events, drug interactions, and resistance [1, 4]. The avoidance of monotherapy is recommended to prevent resistance amplification [1, 2].
In our study, we discuss different pharmacological treatment regimens for RGM (Mab, M. chelonae, M. fortuitum) and SGM (MAI, M. malmoense, M. marinum) infections.
Mycobacterium abscessus
Our study agrees with the literature indicating that Mab skin and soft tissue infections (SSTIs) usually occur due to surgical or traumatic inoculation [7, 30]. We observed a significant proportion of middle-aged women, with a median time of presentation after aesthetic procedures of approximately 40 days. In three patients with cutaneous manifestations of Mab susceptibility to clarithromycin, we achieved a cure without relapse using 4–6-month treatment regimens, including clarithromycin and fluoroquinolone, or clarithromycin, aminoglycoside, and fluoroquinolone, with surgery in two of three patients. However, a patient with a clarithromycin-susceptible isolate who received surgical management and clarithromycin monotherapy for 6 months experienced relapse. One patient with lymph node involvement did not continue follow-up, and 50% of patients experienced adverse events during treatment.
It is important to note that Mab subspecies (abscessus, bolletii, and massiliense) are considered highly pathogenic, with high resistance levels and low cure rates [31]. In pulmonary treatment for Mab, a regimen of at least three drugs guided by drug susceptibility testing, including a macrolide, is recommended, even for strains with mutational or inducible (erm gene) resistance [1, 31]. Additionally, the utility of drugs such as cefoxitin or imipenem, linezolid, and tigecycline should be evaluated, although the treatment duration has not yet been established [1, 31]. Minor cutaneous infections can resolve spontaneously, with or without surgical debridement, while for SSTIs, a macrolide regimen along with a parenteral drug for at least 4 months is recommended. In cases of bone infections, treatment extension to 6 months is suggested. Surgery is recommended in cases of extensive disease, abscesses, and the removal of implants or catheters [7].
Mycobacterium chelonae
A patient immunosuppressed by biological therapies who developed joint involvement due to M. chelonae infection was treated for 12 months with clarithromycin combined with moxifloxacin and experienced early relapse, and a patient with an infection associated with cosmetic procedures was treated for 6 months with curative criteria and no relapse. M. chelonae infection is associated with cutaneous infections in immunocompetent patients, and in Colombia, it has been related to infections in HIV-positive individuals [6, 7, 32].
For mild to moderate M. chelonae infections, a two-drug regimen is recommended, and for severe infections, three drugs are suggested. Treatment should include a regimen with two intravenous drugs for 4 to 16 weeks and then two oral drugs selected according to susceptibility test results, with one of them being a macrolide if sensitive, until 12 months after sputum conversion in pulmonary involvement [29]. Drugs such as amikacin, azithromycin, clofazimine, clarithromycin, ciprofloxacin, doxycycline, imipenem, levofloxacin, linezolid, sulfamethoxazole, tigecycline, and tobramycin have demonstrated activity in human studies and in vitro microbiological activity [4, 32].
Mycobacterium avium complex (M. intracellulare, M. chimera and M. avium (subspecies M. avium, M. paratuberculosis, M. silvaticum)
In our study, two HIV patients with adenitis due to MAI were treated for 12 or 6 months. The first case involved a 4-year-old infant with perinatally acquired HIV who developed idiopathic thrombocytopenic purpura and required immunosuppressive management. At the time of NTM infection diagnosis, the patient had a CD4 + T-cell count of 212 cells/mm3, which could be related to her hematological condition. Treatment consisted of clarithromycin, ethambutol, and amikacin. The second case involved an adult HIV patient on antiretroviral therapy with a CD4 + T-cell count of 28 cells/mm3. This patient received treatment with clarithromycin and ethambutol. Both patients achieved a cure with no evidence of relapse during follow-up.
For the treatment of MAI at the pulmonary level in patients with macrolide susceptibility, a three-drug treatment regimen, including a macrolide (azithromycin or clarithromycin) and ethambutol, is suggested. In cases of cavitary disease, bronchiectasis, or macrolide resistance, amikacin is added to the initial treatment for 2 to 3 months, followed by a 12-month regimen after the culture becomes negative [1]. However, up to 40% of patients may experience unfavorable outcomes, requiring modification of their treatment due to adverse events in up to 84% of cases [33]. In situations of pulmonary refractoriness, inhaled liposomal amikacin is recommended [1].
In HIV patients, MAI treatment includes the administration of clarithromycin and ethambutol, with the possibility of adding rifabutin as a third drug. In cases of severe immunosuppression (CD4 + counts less than 50 cells/mm3, bacteremia, and not receiving antiretroviral therapy), the addition of a fluoroquinolone or an aminoglycoside while maintaining treatment for 12 months is considered [2].
Mycobacterium malmoense
our study presents an uncommon case of a patient with endocarditis due to M. malmoense, as most reports are related to pulmonary involvement [7, 34]. Reports on extrapulmonary cases are limited, although lymph node, cutaneous, and articular involvement have been documented [7, 35, 36]. In our case, the patient underwent surgery and received a 12-month treatment including clarithromycin, moxifloxacin, and rifampicin, resulting in a cure and no relapse.
M. malmoense is an SGM with inconsistencies in susceptibility testing. It is intrinsically resistant to isoniazid. For pulmonary involvement, a 12-month treatment regimen involving the use of at least three drugs, rifampicin, ethambutol, and a macrolide (clarithromycin or azithromycin), after sputum culture conversion is recommended [29, 37]. Failure and relapse rates of 10% have been reported, with a related mortality of 4% [29]. In cases of macrolide intolerance or resistance, rifamycin or ethambutol, moxifloxacin, and clofazimine are alternatives. Intravenous amikacin can be considered for cavitary lung lesions. However, there are no specific recommendations for managing extrapulmonary involvement caused by this mycobacterium.
Mycobacterium marinum
A patient who developed SSTIs due to M. marinum after trauma received a 6-month regimen of moxifloxacin combined with rifampicin and achieved a cure with no evidence of relapse. M. marinum has been associated with infections in immunocompromised individuals and SSTIs in immunocompetent patients exposed to aquariums or swimming pools, known as "Fish Fancier's Finger." There is no recommendation for the management of M. marinum infection [4, 38]. In M. marinum, there is demonstrated activity in humans for drugs such as amikacin, clarithromycin, doxycycline, ethambutol, minocycline, rifampicin, and sulfamethoxazole, and in vitro microbiological activity studies for ciprofloxacin, imipenem, isoniazid, levofloxacin, linezolid, moxifloxacin, and tedizolid [4].
The main limitation is related to the sample size, which stems from the inadequate representation of data in the target population. Despite our thorough search for cases in clinical records, many cases were excluded due to the lack of microbiological confirmation of the NTM species. However, our case series still provides valuable information on NTM-EP infections. Notably, NTMP-EP events are not subject to mandatory reporting, making it challenging to clearly define an NTM epidemiological outbreak. It is essential to recognize that certain risk interventions and sources of contamination could signal a potential epidemiological concern and that NTM infections are often mistaken for other diseases.
Additionally, the identification of cases is hindered by the absence of a reference test and inadequate storage of isolates in identification laboratories, leading to a lack of availability for identification in almost half of the cases. One notable weakness identified in our study is the inability to identify the subspecies of M. fortuitum and Mab, which may exhibit distinct drug susceptibility patterns.