Challenges of Nontuberculous Mycobacteria (NTM)

Published on 01/26/2022 | by Waterline Admin
As featured in Waterline Winter 2021-22

Challenges of Nontuberculous Mycobacteria (NTM)

Joseph O. Falkinham, III Ph.D.
Professor of Microbiology

 

Introduction to the Nontuberculous
Mycobacteria (NTM) The nontuberculous mycobacteria (NTM) are members of the Mycobacterium bacterial genus that now includes over 200 distinct species (Tortoli, 2003). The NTM are distinguished from the Mycobacterium tuberculosis group by the fact that that their source is the environment and are not obligate, but rather opportunistic pathogens. All mycobacteria are surrounded by a very thick outer membrane that comprises 30 % of the cellular weight and provides a barrier to the entry of nutrients and antimicrobial compounds from the environment. All Mycobacterium spp. strains can be distinguished from other bacteria by virtue of the fact that they are “acid-fast”. Mycobacterial cells retain red dye carbol fuchsin even after decolorizing with acidic alcohol, due to the high concentration of lipid in the outer membrane. Gram-positive and Gram-negative bacterial cells are decolorized and lose the red color.

 

Although there are now more than 200 species in the genus Mycobacterium, amongst those only a limited number are associated with causing sizeable numbers of human infections. In the United States, infections are caused by Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera (members of the Mycobacterium avium complex, MAC) and members of the Mycobacterium abscessus complex are the most common. The cost of NTM disease is enormous, estimated at over $ 500 million per year in the United States (Collier et al., 2012). Because of their dominance among infected patients, most environmental and pathogenicity studies have been focused on those species.

 

The mycobacterial lipid-rich, outer membrane is a major determinant of the behavior of the cells (Brennan and Nikaido, 1995). One of the costs of synthesizing the lipid-rich outer membrane is that energy is diverted from producing more cells, so the growth rate of the Mycobacterium spp. is quite slow (e.g., 1 generation per day). In addition, the outer membrane serves as a permeability barrier to the influx of nutrients. However, a major benefit of the outer membrane is that Mycobacterium spp. cells are quite resistant to the entry of antimicrobial compounds, particularly disinfectants and antibiotics.

 

Another benefit of the outer membrane is that it makes NTM cells quite hydrophobic. That drives NTM cells to adhere to rocks in rivers and streams and pipe walls in household and hospital plumbing. There the NTM cells grow and produce extracellular slimes that contain lipid, DNA, and protein, called the matrix. Adherence to surfaces means the NTM cells will not be washed out, so they persist in plumbing and instruments. The matrix protects NTM cells from disinfectants, thus increasing their survival in engineered water systems.

 

Nontuberculous Mycobacteria (NTM) are Everywhere
Known sources of the NTM are listed below (Table 1). Basically, the evidence from surveys is that NTM are everywhere. For example, water and biofilm samples from homes of NTM patients (Falkinham, 2011) and non-NTM patients (Nishiuchi et al., 2017) yield high numbers of diverse NTM species. Further, NTM were detected in 70 % of showerheads collected randomly across the United States (Feazel et al., 2009). Humans and NTM share the same habitats. We are exposed to NTM in our homes when we use water, especially when showering as showers generate aerosols (Falkinham et al., 2008). As NTM are in soils, gardening activities can expose a susceptible individual to dusts carrying NTM (De Groote et al., 2006). NTM are oligotrophic, meaning that they can grow at low organic carbon concentrations (George et al., 1980). Further, NTM cells can grow at low oxygen concentrations (Lewis and Falkinham, 2015), meaning they grow in stagnant water in hospital and household plumbing. NTM are well-adapted to growing and persisting in engineered water systems.

 

Table 1. Sources of NTM and NTM-Infection.


Soil, especially peat-rich potting soils
Natural Waters, especially estuaries and coastal swamps
Human-Engineered Water Systems, including distribution systems and building plumbingHospital Water, Ice, and Equipment

Dental Units

Household Water, especially showerheads and tap aerators

Refrigerator Water and Ice

Hot Tubs and Spas

 

One of the challenges to the detection and enumeration of NTM is that in common with other opportunistic pathogens, such as Pseudomonas aeruginosa and Legionella spp., there is no correlation to the standard indicators of water quality; Escherichia coli, coliforms, enterococci, heterotroph plate counts (HPC), and total viable counts (TVC). Other than specifically monitoring for NTM or other waterborne opportunistic pathogens individually, current monitoring provides no information concerning NTM. Even if one could easily monitor for NTM, numbers would not have meaning as the infectious dose for NTM is unknown.

 

NTM Disinfectant-Resistance
As noted above, NTM are resistant to disinfection. Measurements of the susceptibility of representative M. avium complex (MAC) strains showed that they are almost 1,000-fold more tolerant of chlorine, chloramine, ozone, and chlorine dioxide compared to Escherichia coli (Taylor et al., 2000). That is why the NTM dominate the microbial flora of treated drinking water, mostly all contaminating bacteria have been killed by disinfection. Studies have even showed that numbers of NTM increase two-fold between the treatment plant and households (Falkinham et al., 2001). The hydrophobicity of the NTM cells means that the majority of NTM cells are not suspended in the water where they could be washed out, but adhering to pipe walls (Mullis and Falkinham, 2013) where their resistance to disinfectants is increased by virtue of their residence of the extracellular matrix, reducing entry of disinfectants (Steed and Falkinham, 2006). Once resident in a plumbing system, whether in a house, hospital, condominium, or apartment, NTMs are almost impossible to dislodge. Humans have created an ideal environment – namely plumbing – for the survival, growth, and persistence of NTM.

 

NTM Behavior in Plumbing
To illustrate the life of NTM in distribution systems and building plumbing systems, I will follow the behavior of a typical NTM, M. avium from soil to a household. Our M. avium cell is able to grow in soil on available minerals and organic compounds. Their growth is stimulated by the humic and fulvic acids in soils, breakdown products of dark compounds from woody plants (Kirschner et al., 1999). That’s why they are found in high numbers in estuaries and coastal swamps (Kirschner et al., 1992). From surface water, our M. avium cell enters a water treatment plant where its numbers are reduced by precipitation with particles (Falkinham et al., 2001). However, those remaining M. avium cells are resistant to disinfection and thereby are in the treated water entering the distribution system (Taylor et al., 2000; Falkinham et al., 2001; Steed and Falkinham, 2006). As noted above, NTM and our little M. avium cell can grow between the treatment plant and destination water meter at the structure (Falkinham et al., 2001). It is likely that growth is due to the absence of competitors for the available carbon. Once inside the building, water carrying our M. avium cell, might pass through a water heater. That higher temperature will stimulate growth, unless the temperature is too high (Falkinham, 2011; Lande et al., 2019). I view a water heater as a site for increasing numbers of M. avium and other NTM. Drinking water in buildings can be circulated, either due to use and disposal (houses) or due to implementation of pumps to continually recirculate water. Every pipe surface is exposed to M. avium cells in water and those cells can rapidly adhere to pipe surfaces. For example, numbers of 5,000-15,000 cells per cm2 can be achieved on pipe surfaces within 1 hour or less (Mullis and Falkinham, 2013). We have recently found that 99.9 % of cells of M. chimaera are lost from water suspension upon entry into a hospital instrument called a heater-cooler (Falkinham, 2020). Those cells are not killed, but simply lost due to adherence to the surfaces in the instrument. It is important to point out that most NTM cells in drinking water pipe systems are on the pipe surfaces and not suspended in water. Adherence is a terrific way to avoid loss through flushing.

 

The M. avium cell we have been following is perfectly happy to reside in our plumbing or in that of the local hospital. Because of disinfection and selective killing of other microorganisms, there are few competitors for the nutrients. Stagnation does not reduce numbers of M. avium and other NTM as they can grow at low oxygen levels (Lewis and Falkinham, 2015). Growth of M. avium complex and M. abscessus complex strains at 12 % oxygen is the same as at 21 % oxygen. They can even grow, albeit it half the rate, in 6 % oxygen (Lewis and Falkinham, 2015). The cells of M. avium and other NTMs are perfectly adapted to building system plumbing as illustrated below (Table 2).

 

Table 2. NTM Characteristics Leading to Survival, Growth, and Persistence in Plumbing.


Disinfectant-Resistance
Preferential Adherence to Surfaces
Biofilm Formation and GrowthGrowth at Low Organic Concentration

Growth at Low Oxygen Concentration

 

Keeping NTM Numbers in Check
Although an infectious dose of any of the NTM has not been described, it is obvious that high numbers should be avoided. There are a number of approaches that can be applied to plumbing in a building whether a hospital or home, to reduce NTM exposure (Table 3).

 

Table 3. Measures to Reduce NTM Numbers in Premise Plumbing.


Raise Water Heater Temperature to 130°F (55°C)
Avoid Stagnant Regions by Removal of Dead Ends
Avoid Stagnant Water by Regular FlushingPlace 0.2 Micrometer Pore Size Filters on Taps and Showerheads

Remove and Clean Showerheads and Tap Aerators Monthly

Avoid Exposure to Aerosol-Generating Devices

Don’t Drink Refrigerator Water

 

A study of NTM in households of NTM-infected patients led to discovery that NTM numbers were low in homes with a water heater set at 130°F (55°C), but significantly higher in homes with water heaters set at 125 F (51.7°C) or lower (Falkinham, 2011). Based on that information, a subset of 10 of 40 households of M. avium-infected patients in a suburb of Philadelphia (Lande et al., 2019) volunteered to raise their water heater set temperature. The result was that M. avium could no longer be recovered from their water after 8-12 weeks. In that same group of patient households, water samples were collected from two sites; namely the most-often-used and the most-seldomused bathrooms in the residences. The number of NTM, specifically M. avium, were significantly higher in the seldom-used bathroom water samples compared to the most-frequently used (Mantha et al., in preparation). We are urging the patients have someone (not the patient as they are quite susceptible to NTM infection) flush and run water in those bathrooms (or household wings) weekly to reduce stagnation by flushing water weekly. Filters whose pore size is less than 0.2 micrometers in diameter will prevent the passage of NTM and mostly all bacteria. A variety of manufacturers in both North America and Europe manufacture these “medical-grade” filters including those also serving as showerheads. My lab has tested some representative 0.2 micrometer pore size filters and their installation prevents passage of NTM.

 

Following evidence that a strain of M. avium in a patient was linked to the presence of a closely related strain in the patient’s showerhead, (Falkinham et al., 2008), a random, non-NTM-patientdirected survey of showerheads across the United States showed that 70 % yielded NTM (Feazel et al., 2009). Following those reports, it was shown that the presence of NTM in showerheads was the strongest predictor of NTM-infection in residents (Tzou et al., 2020). Thus, I have urged our current NTM-infected patients to remove their showerheads, clean them and then submerge the cleaned showerhead in full strength laundry chlorine bleach. Although such action does not prevent infection, I do feel it would reduce the chance of re-infection. That lesson can be extended to hospital design by not including bathrooms in patient rooms. Further, if a hospital is planning to look after individuals at risk for NTM infections (e.g., transplantation, kidney dialysis, neonatal care; Maras and Daley, 2002), why not design hospital suites with their own, isolated sterile water supply? I make a distinction between cleaning using detergent with disinfection. Often, I read “cleaning” when the meaning is disinfection. For the NTM, both cleaning with detergent and then disinfection (with full-strength chlorine-based bleach) is required. Exposure of a showerhead or a bronchoscope or another piece of medical instrumentation to detergent breaks the hydrophobic bonds holding the NTM cells to the surfaces and will also increase the permeability of NTM cells by disrupting the lipid-rich, outer membrane. Prior treatment with detergent increased the efficacy of bleach in removing biofilms of NTM cells (Falkinham, 2020). Without that dual treatment, NTM cells will rapidly reappear (2 weeks; Falkinham, 2020). Their reappearance is why there are reports of so many NTMremediation programs.

 

Review
Kazda J, Pavlík, I, Falkinham JO III, Hruska K. 2009. The Ecology of Mycobacteria; Kluwer Academic Publisher: Dordrecht, Germany.

 

References available on request

 

A related webinar is available on this topic:

https://www.pall.com/en/medical/webinars/nontuberculous-mycobacteria–ntm—critical-updates-and-strategi.html

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