Nontuberculous Mycobacteria

Katia Camille Halabi

Lisa Saiman

Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can be isolated from water, soil, dust, and domestic and wild animals.¹ Originally thought to be contaminants or colonizing flora, NTM are wellrecognized human pathogens in both immunosuppressed and immunocompetent patients. Most relevant to this chapter, healthcare-associated infections (HAIs) and outbreaks have been increasingly described for several decades, affecting hundreds of patients. As evidence, from 2009 to 2019, the number of PubMed citations for NTM and human infections increased from 405 to 1395. Outbreaks generally result from patient exposure to NTM-contaminated water within the healthcare environment, such as tap water or ice, or from NTM-contaminated patient care equipment or devices as will be described in more detail below. Prominent examples of the latter include NTM-contaminated endoscopes, bronchoscopes, the systems used to disinfect medical devices, and heater-cooler units used during cardiac bypass surgery.

MYCOBACTERIOLOGY AND LABORATORY IDENTIFICATION

NTM currently consists of almost 200 recognized species and subspecies.¹^,² Many species cause human infections, most commonly Mycobacterium avium complex (MAC, including M intracellulare, M chimaera, and four M avium subspecies) and M abscessus complex (MABSC, including M abscessus subsp. abscessus, M abscessus subsp. massiliense, and M abscessus subsp. bolletii). Other reported human pathogens include M kansasii, M chelonae, M fortuitum, M mageritense, M xenopi, M lentiflavum, M marinum, M simiae, M haemophilum, and M genavense.

Mycobacteria contain mycolic acids in their cell wall, which renders them resistant to decolorization with acid alcohol (hence the term acid-fast). For many years, the Runyon classification of Mycobacteria was utilized to characterize NTM by their rate of growth: rapidly growing NTM require ≤7 days, and slowly growing NTM require >7 days to produce mature colonies on solid media.² While older literature characterized NTM by this terminology, more recent literature (and this chapter) refer to individual NTM species.

The laboratory diagnosis of NTM can be challenging as the number of species continues to increase, different species have genetic and phenotypic similarity, and many NTM grow slowly. The emergence of multidrug-resistant tuberculosis and the increased clinical burden of NTM contributed to the development of rapid and accurate molecular-based methods of identifying mycobacterial species. DNA sequencing of the 16S rRNA gene can identify individual species,³ but this method cannot distinguish closely related species and subspecies. Thus, other targets including rpoB, hsp65, or other genes can be used.⁴

Accurate and rapid identification of NTM is crucial to manage individual patients infected with NTM and to detect potential clusters and outbreaks. While speciation is extremely important, whole genome sequencing (WGS) or analysis of defined sequences can assist with investigating potential outbreaks. However, these advanced methods are not routinely available due to their costs and the complexity of the data analysis. Thus, reference laboratories, water consultants, and the U.S. Centers for Disease Control and Prevention (CDC) are available to assist with outbreak investigations.

EPIDEMIOLOGY OF HUMAN INFECTIONS WITH NTM

NTM most commonly causes pulmonary infections. In addition, bloodstream infections, skin and soft tissue infections, surgical site infections, and disseminated infections are well described. However, NTM infections are not generally reportable since they are not considered communicable diseases. Using culture data to assess disease burden may be inaccurate due to the difficulty distinguishing colonization of patients from contamination of devices, medications, or specimens from true infection. Nonetheless, population-based estimates suggest that the prevalence of pulmonary NTM is increasing in the United States. From 1997 to 2007, an analysis of Medicare beneficiaries revealed an increase in annual NTM prevalence from 20 to 47 cases/100 000 population, and prevalence was higher in women.⁵ From 2008 to 2013, a prevalence study of NTM was conducted in Missouri, Mississippi, Maryland, Ohio, and Wisconsin as these states include NTM as Mycobacteria Disease Other than Tuberculosis (MOTT) on their reportable disease list.⁶ Overall, 24 226 NTM cases were reported during the study period for an estimated annual prevalence of 12.6 cases/100 000 persons. In contrast, in Denmark, only one laboratory has processed mycobacteria cultures
for nearly a century; potentially due to this standardization, data obtained from 1991 to 2015 do not indicate an increased NTM prevalence.⁷

NTM-associated mortality was assessed from 1999 to 2010 using data from the U.S. National Center of Health Statistics; NTM was the cause of 2990 deaths with an overall mean-age adjusted mortality rate of 0.1 per 100 000 person-years.⁸ Increased mortality rates were noted in people 55 years of age and older, women, those living in Hawaii and Louisiana, and those of non-Hispanic White ethnicity. Data from Denmark found the 5-year mortality following NTM-positive cultures to be 40%, although it is uncertain if death was attributed to NTM or to other comorbidities.⁷

PATHOGENESIS OF NTM

NTM have several pathogenic strategies that facilitate HAIs (see Table 24-1). NTM can form biofilms in water pipes and on plastic, silicone, rubber, glass, and metals. Due to their hydrophobic cell wall, NTM are resistant to many low-level disinfectants, many antibiotics, and heavy metals.⁹^,¹⁰ For example, M avium, M intracellulare, and M gordonae are resistant to formaldehyde and alkaline glutaraldehyde (GTA), which previously had been used in the United States.¹¹^,¹²^,¹³^,¹⁴ Today, ortho-phthalaldehyde-based (OPA) products, for example, Cidex OPA, Aldahol, are the high-level disinfectants used in the United States. However, GTA remains widely throughout the world because of its broad-spectrum microbicidal activity, low cost, ease of use, and lack of damage to medical equipment. In experiments of different disinfectants used at different temperatures, GTA and OPA showed variable activity against GTA-resistant strains that appeared to be temperature dependent.¹² Possible mechanisms of resistance to GTA and OPA include porin defects that limit transport of the disinfectant into the mycobacteria.¹⁵

HEALTHCARE-ASSOCIATED INFECTIONS AND OUTBREAKS

Despite numerous publications describing NTM outbreaks for several decades, outbreaks continue to occur. Outbreaks are usually linked to water sources or patient care devices contaminated by water. Outbreaks are often protracted and affect patients distributed across large geographic areas. Outbreaks occur in a variety of healthcare settings, including ambulatory settings performing surgical and cosmetic procedures, which can have less regulatory oversight. These characteristics can make outbreak identification difficult or delayed and can lead to underestimating the number of affected patients. Thus, a high index of suspicion is required to identify HAIs and outbreaks caused by NTM. Even a single NTM case that appears to be healthcare associated should prompt consideration of further investigation and identification of potential sources.

TABLE 24-1 Pathogenic Strategies for Nontuberculous Mycobacteria

Biofilm formation
Resistance to low-level disinfectants
Resistance to antibiotics

SOURCES OF NTM OUTBREAKS

The sources of NTM outbreaks are usually water related and occur when patients are exposed to NTM-contaminated equipment or when patients have direct contact with contaminated water. Prominent examples include M abscessus, M avium, M simiae, M neoaurum, and M genavense contamination of tap water; M chelonae and M porcinum contamination of ice and ice machines; M chimaera contamination of heater-cooler units; M fortuitum contamination of hospital water systems and showers; and M mucogenicum contamination of electronic faucets, sinks, and showers.¹⁶ NTM outbreaks have occurred in a variety of healthcare settings including acute care, outpatient facilities, and surgical suites as well as tattoo parlors; recent outbreaks are described in Table 24-2.

An example of a protracted 5-year outbreak caused by M porcinum contamination of public water supplies resulted in 24 patients with community- and healthcare-associated infections.³⁰ Hospital water, ice machines, and household tap water from the city of Galveston, Texas, were sampled for M porcinum; hospital and residential water isolates were found to be indistinguishable by pulsed-field gel electrophoresis.

Although water is the most common source of NTM, outbreaks due to other sources have also been described. These include an M abscessus subsp. massiliense outbreak of skin and soft tissue infections and bloodstream infections due to contaminated bottles of ultrasound gel.²² An M abscessus outbreak in Colombia affected 232 patients who developed cutaneous lesions following injection of contaminated lidocaine capsules that had been reused.³¹ Multiple NTM species have been linked to Botox injections and fractionated CO₂ laser therapy used for cosmetic procedure to minimize wrinkles and acne scars, piercing, and tattoos; however, in many of these outbreaks, no clear source of contamination was identified.³²

COMMON HEALTHCARE-ASSOCIATED INFECTIONS CAUSED BY NTM

The following section describes the clinical presentations of NTM infections and the relevant outbreak investigations.

Surgical Site Infections

Outbreaks of surgical site infections (SSIs) have been described following cardiothoracic surgery,²⁴ plastic surgery including mammoplasty and liposuction,²⁷^,²⁸ corneal surgery,³³ and knee replacement.³⁴ The clinical presentations of SSIs caused by NTM include failure of surgical site healing or breakdown of healed surgical sites with drainage. Endocarditis may also develop following cardiothoracic surgery. Identification of NTM requires a high index of suspicion due to the need to process the clinical samples on selective media and prolonged incubation as previously described.

TABLE 24-2 Examples of NTM Outbreaks Published From 2015 to 2019

*Type of exposure*	*Mycobacteria species*	*Sources of outbreak*
Water	M abscessus	Tap water exposure to aerodigestive tract of high-risk patients⁹ Waterlines in dental station contaminated pulpotomy procedures¹⁷ M chelonae Distilled water contaminating equipment for LASIK (photorefractive keratectomy) surgery¹⁸
	M marinum	Fish-handling in New York City’s Chinatown^19,20
	M chelonae, M abscessus, and M immunogenum	Ice machines and drinking water on bone marrow transplant unit²¹
Contaminated products or medications	M abscessus subsp. massiliense	Ultrasound gel (intrinsically contaminated during manufacturing)²²
Contaminated products or medications	M abscessus subsp. massiliense	Triamcinolone (steroid) injections of joints²³
Device-related	M chimaera	Heater-cooler device used in cardiothoracic surgery (worldwide outbreak)²⁴
Surgery	M fortuitum and M goodii	Surgical instrument vendor in operating room during prosthetic joint surgery (4 hospital outbreak)²⁵
	M fortuitum	Abdominoplasty in ambulatory surgery center²⁶
Cosmetic surgery	M abscessus and M fortuitum	Cosmetic surgery in the Dominican Republic (multistate outbreak)^27,28
Tattoos	M chelonae	Water cooler water to dilute tattoo ink²⁹

Cardiothoracic Surgery

The first reported outbreak associated with cardiothoracic surgery occurred in 1976 in North Carolina.³⁵ During a 10-week period, sternal wound infections caused by M chelonae were diagnosed in 24% (19/80) of patients who underwent cardiac surgery that included valve replacement with porcine and prosthetic valves as well as saphenous vein graft. Presenting symptoms were pain at the sternotomy incision site or drainage. The source of outbreak was never identified. The second outbreak occurred during a 2-week period in which M fortuitum sternal wound infections developed in 44% (4/9) of patients who underwent cardiac surgery.³⁶ This second outbreak was caused by contaminated porcine valves and resulted in a nationwide outbreak affecting eight patients overall. Relative resistance to 2% formaldehyde, used to sterilize the valves, was implicated in this outbreak.³⁶^,³⁷

In 1981, an outbreak of sternal wound infections and endocarditis occurred in Corpus Christi, Texas, and CDC investigators described the link between NTM-contaminated water and NTM infections.³⁸ This polymicrobial NTM outbreak was linked to two sources: first, M fortuitum contaminated tap water in the operating room and, second, M abscessus contaminated hospital ice water used to cool the cardioplegia solution. It was hypothesized that contamination of the operative field occurred when the bag of cardioplegia solution given to the anesthesiologist contaminated the anesthesiologist’s scissors.³⁸ These findings lead to discontinuing the use of tap water as a coolant in operating rooms.

Perhaps the most striking NTM outbreak associated with devices is the recent worldwide M chimaera outbreak due to contaminated heater-cooler units (HCUs) used during cardiopulmonary bypass to warm and cool patients’ blood. Following a series of reports of M chimaera infections in patients who underwent cardiothoracic procedures in the United States and Europe,³⁹^,⁴⁰^,⁴¹ the CDC issued reports in October 2016 warning of the risk of NTM infections due to HCUs.⁴² The U.S. Food and Drug Administration (FDA) continues its ongoing investigation.⁴³ While many patients exposed to the implicated HCUs remained asymptomatic, clinical presentations included sternal wound infections, prosthetic valve endocarditis, bloodstream infections, and vascular graft infections.⁴⁰ Currently, more than 150 confirmed cases have been diagnosed worldwide.⁴⁴

In this outbreak, transmission occurred due to mycobacterial aerosolization from the HCUs into the operating room with subsequent contamination of the open surgical wound, in situ replication, and subsequent dissemination.²⁴ The proposed route of transmission is displayed in Figure 24-1. Because of the wide geographic distribution of cases, local contamination of the HCUs at individual hospitals seemed unlikely. Instead, the epidemiology implicated a point source outbreak. WGS of more than 100 isolates collected worldwide demonstrated that the isolates were highly related.⁴⁴ M chimaera was cultured from HCUs still in the manufacturing plant as well as water in the pump assembly area of the plant, supporting the claim that contamination occurred during production.⁴³ Several factors contributed to the delay in identifying this outbreak which included the sporadic attack rate, relatively long incubation period of M chimaera, difficulty culturing NTM unless suspected, and the large geographic area involved.

The implications of this outbreak are enormous. Approximately 250 000 cardiothoracic surgical procedures requiring cardiopulmonary bypass are performed each year in the United States. Replacing all of the affected HCUs was not feasible without substantially impacting patient care.²⁴ M chimaera can be eradicated from external surfaces with routine disinfection of the outer surfaces of the HCU. However, the interior surfaces are inaccessible unless the units are dissembled which is not part of the usual maintenance
of HCUs and lead to these units serving as prolonged reservoirs for M chimaera.⁴⁴^,⁴⁵ The FDA and the manufacturer issued updated recommendations for disinfection and use of the involved HCUs.⁴³

Notably, extracorporeal membrane oxygenation (ECMO) devices also run with circulating water. In 2015-2016, an outbreak with M chimaera was linked with potable water faucet used to fill the devices.⁴⁶

FIGURE 24-1 Route of transmission from contaminated heater-cooler units used during cardiothoracic surgery. Heater-cooler units can aerosolize water containing Mycobacterium chimaera into the operating room, including the operative field. The main sites of heater-cooler unit contamination include tubing and water tanks, which subsequently contaminate the cardioplegia circuit. (Printed with permission from Ninh A, Weiner M, Goldberg A. Healthcare-associated Mycobacterium chimaera infection subsequent to heater-cooler device exposure during cardiac surgery. J Cardiothorac Vasc Anesth. 2017;31(5):1831-1835.)

Skin and Soft Tissue Infections

Skin and soft tissue infections (SSTIs) caused by NTM have nonspecific clinical presentations including abscesses, cellulitis, nodules, ulcers, panniculitis, draining sinus tracts, folliculitis, and papules⁴⁷ as described in Table 24-3. The polymorphous presentations of cutaneous NTM make the diagnosis challenging and require a high index of suspicion to ensure that appropriate cultures are sent. Thus, NTM should be considered in all patients presenting with therapy-resistant SSTIs after traumatic injury, surgery, or cosmetic procedures as described further below. SSTIs may also be manifestations of disseminated NTM in immunocompromised patients.

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