An Update on Mycobacterium chimaera and Cardiac Surgery Infections

Expires February 2024

  • Image of Nancy Wengenack, Ph.D.Presenter

    Nancy Wengenack, Ph.D., is a Consultant for the Department of Laboratory Medicine and Pathology in Clinical Microbiology at Mayo Clinic in Rochester, Minnesota. She holds the academic rank of Professor of Laboratory Medicine and Pathology.

    Questions?

    Contact us: MMLHotTopics@mayo.edu.

    Transcript and References

    Introduction

    Hi, I’m Matt Binnicker, the Director of Clinical Virology and Vice Chair of Practice in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Currently, an outbreak of Mycobacterium chimaera infections following cardiac surgery is occurring worldwide. The outbreak is associated with contaminated heater-cooler units used for the heart/lung bypass procedure during surgery. In this month’s "Hot Topic," my colleague Dr. Nancy Wengenack will provide you with an overview of the global outbreak situation and discuss what is known regarding the source of Mycobacterium chimaera infection. In addition, she will discuss the clinical features of disease and the recommended laboratory tests that can assist with the diagnosis of Mycobacterium chimaera infections. I hope you enjoy this month’s "Hot Topic," and I want to personally thank you for allowing Mayo Clinic the opportunity to be a partner in your patients’ health care.

    Thank you, Dr. Binnicker. I want to thank Mayo Medical Laboratories for giving me this opportunity to speak with you about the current global outbreak of Mycobacterium chimaera in cardiac surgery patients.

    Disclosures

    I have no disclosures relative to this presentation.

    Utilization Management

    As you view this presentation, consider the following important points regarding testing:

    • How is the test going to be used in your practice?
    • When should the tests be used?
    • How will results impact patient management?

    Objectives

    My objectives today are to discuss the global outbreak of Mycobacterium chimaera infections following cardiac surgery, to describe current knowledge about the heater-cooler units implicated as the cause of the outbreak, and to examine the laboratory diagnostics available for the detection, identification, and susceptibility testing of Mycobacterium chimaera.

    First Report of Cases

    Let’s begin by talking about the first case report on this topic. In 2015, a group from Zurich, Switzerland, reported on a series of cases involving six patients who had prosthetic valve endocarditis or vascular graft infections due to Mycobacterium chimaera. The first case in their institution dated back to a surgery performed in 2012, and the reported period of latency for the six cases ranges from 1.5 to 3.6 years after surgery was performed.

    Mycobacterium chimaera was cultured from blood, cardiac tissue, and other surgical specimens for all cases. Mycobacterium chimaera was also cultured from heater-cooler units used for cardiac bypass during the surgical procedure and from air samples in the surgical suite.

    A Global Outbreak

    Since the first case report, more than 100 cases of Mycobacterium chimaera infection have been reported in Europe, the United States, and Australia. All of the cases are reported from patients who have previously undergone cardiothoracic surgery. All of the cases involve the use of the Sorin Stockert 3T heater-cooler unit manufactured in Germany. In 2015, Sorin and another company merged to form a new company named LivaNova. You will sometimes hear the heater-cooler unit referred to as the LivaNova Stockert 3T system. Since there are more than 250,000 cardiothoracic surgical procedures performed annually in the U.S. alone, and because the latency period for presenting with infection is so long, there is concern that the number of cases detected so far is only the tip of the iceberg for this event.

    What Is a Heater-Cooler Unit and How Is It Used in Cardiac Surgery?

    So, what is a heater-cooler unit and how is it used in cardiac surgeries? Heater-cooler units are used during cardiac surgeries in conjunction with a heart-lung bypass machine. The heater-cooler unit does not have any direct contact with the patient or with patient blood. The heater-cooler unit contains two water tanks and tubing. One water tank uses warm water that through indirect thermal transfer, keeps the patient warm during the surgical procedure often through the use of a warming blanket. The second water tank contains cold water, which is used again indirectly to cool the cardioplegia solution that slows or stops the patient’s heart to allow the surgical procedure to proceed. The working hypothesis early in the outbreak investigation was that the heater-cool unit was somehow responsible for introducing aerosolized bacteria into the surgical field.

    Outbreak Investigation

    Nontuberculous mycobacteria are environmental organisms found in soil and water throughout the world. They are commonly found in household and hospital plumbing, showers, water fountains, ice machines, and any other area where water or water intrusion can be found, and they like to form biofilms, which makes them resistant to cleaning and disinfection practices. Nontuberculous mycobacteria are responsible for numerous reports of device-associated and post-surgical infections and outbreaks. Mycobacterium chimaera has been found in water from the Sorin 3T heater-cooler units used in cardiac surgeries around the world. How can this be? Well, Mycobacterium chimaera has also been recovered from new, unused Sorin 3T heater-cooler units stored at the manufacturing site in Germany and also from water samples taken from the manufacturing site, implicating the manufacturing site as the source of the microbial contamination in these heater-cooler units. Sorin, or now LivaNova, as a company accounts for the manufacture of approximately 60% of the heater-cooler units used in cardiac surgeries in the U.S., and it is a major supplier of heater-cooler units for cardiac surgery units around the world.

    What Happened: Testing of Airflow in Surgical Suite during HCU Operation

    So what do experts believe happened? Well, it’s thought that the contaminated heater-cooler units somehow aerosolized Mycobacterium chimaera. The photographs on this slide show a heater-cooler unit positioned in a surgical suite. See the blue arrows in the photos for the position of the heater-cooler unit. In the photographs on the top row, the exhaust of the heater-cooler unit is directed away from the surgical field, and in the bottom row, the heater-cooler exhaust is directed toward the surgical field. In this study, the authors performed smoke testing of the airflow in the surgical suite when the heater-cooler unit was turned on by placing a small smoke canister on the floor just below the heater-cooler exhaust. As you can see from the photographs, when the heater-cooler unit exhaust is directed away from the surgical field, little smoke is seen in the area of the operating table, but when the heater-cooler exhaust is directed toward the surgical field in the bottom row, the smoke is blown in the direction of the operating table. So, investigators believe that Mycobacterium chimaera was somehow aerosolized from the contaminated heater-cooler unit and was able to contaminate the surgical field during the procedure.

    What Is Being Done?

    So what should be done now that this risk to patients who have previously had cardiac surgeries has been identified? Well, on June 1, 2016, the U.S. Food and Drug Administration (FDA) advised hospitals to determine a method for patient follow-up and establish patient surveillance in case of potential exposure. On October 13, 2016, the Centers for Disease Control and Prevention (CDC) said that hospitals are advised to notify patients who underwent open cardiac surgery involving a Stockert 3T heater-cooler unit that the device was potentially contaminated, possibly putting patients at risk for a life-threatening infection.

    Patient Notification

    Here at Mayo Clinic, more than 17,000 patients who underwent cardiac surgery at any of our sites, whether in Minnesota, Florida, Arizona, or Wisconsin, within the past five years were notified by certified letter of the recently discovered risk. Nursing and physician resources were made available to patients and to their local physicians in case patients or their health care providers had questions or concerns after patients received the notification. The risk of post-surgical infection appears to be low from the early CDC reports at about 1 in 100 patients to 1 in 1,000 patients, but patients may not experience any symptoms for months to years after the surgery, so we may not yet have an accurate risk estimate. The CDC currently reports a range of 3 months to 5 years post-surgery for the manifestation of symptoms with the median time for onset of symptoms being 18 months.

    Clinical Presentation

    Patients with Mycobacterium chimaera infections after cardiac surgery have a range of clinical presentations, but the most common are cardiac manifestations including endocarditis, vascular graft infection, and mycotic aneurysm. Surgical site infections including mediastinitis and sternal wound infections are also common. Other presentations have included abscess formation, bacteremia, osteomyelitis, ocular infections, and granulomatous disease that mimics sarcoid. General symptoms are fairly nonspecific and include fever, night sweats, unexplained weight loss, fatigue, muscle aches, and shortness of breath. One important point to remember is that it is not necessary to test asymptomatic patients just because they have had previous cardiac surgery.

    Preventative Measures with HCUs?

    So what are hospitals doing to prevent any additional infections from occurring during future cardiac surgeries? Well, the exact site or sites of contamination within the heater-cooler units have not been well-defined as yet. You can see from the photographs of an open heater-cooler unit on the right side of the slide that there are many nooks and crannies and water reservoirs where a biofilm may be able to form and which would make decontamination difficult. Indeed, attempts to decontaminate with a variety of agents have been successful in the short-term, but ultimately, the attempts fail to eradicate the organism in the long-term suggesting that inaccessible biofilm formation may be the problem. Strict adherence to the manufacturer’s decontamination protocols and replacement of internal tubing and refurbishment of contaminated units is one possible response, but reliable decontamination remains difficult to achieve.

    Alternative Strategies

    Alternative strategies going forward include the use of heater-cooler units from other manufacturers or LivaNova heater-cooler units manufactured after the dates pinpointed as a concern for manufacturing site contamination. In addition, some authors suggest that positioning of the Sorin 3T heater-cooler unit or any heater-cooler unit outside of the operating suite and/or facing away from the surgical field has been demonstrated to reduce particle counts and disruption of the surgical air curtain. This approach may require some construction as seen in the photos on the right side of this slide where the heater cooler unit is positioned in a separate room with the tubing run through specially constructed ports on the wall into the surgical suite. You can see that care is needed to be taken so that the tubing doesn’t become a tripping hazard in the surgical suite. In addition, just putting the heater-cooler unit in an adjoining room and running the tubing through a cracked open doorway is not recommended since this does not prevent aerosols generated by the heater-cooler unit from reaching the surgical field.

    M. chimaera

    Let’s talk a little bit about Mycobacterium chimaera. Mycobacterium chimaera is a slowly growing nontuberculous mycobacterium that was first proposed for species status by Enrico Tortoli. Mycobacterium chimaera is a member of the Mycobacterium avium complex. It was originally known as a genetic variant called “MAC-A” until Tortoli described it as a distinct species in 2004. Mycobacterium chimaera was the name selected since a chimera in Greek mythology is a mixture of three different animals, with the head of a lion, the body of a goat, and the tail of a serpent. Similarly, Mycobacterium chimaera is a genetic mixture between different Mycobacterium avium complex strains. Mycobacterium chimaera was originally associated with pulmonary infections, but in the last couple of years, M. chimaera has become well-known worldwide as a cause of post-surgical cardiac infections associated with the use of contaminated heater-cooler units during surgery.

    M. avium Complex Species Members

    As I mentioned earlier, Mycobacterium chimaera is a member of the Mycobacterium avium complex, and you can see from the list on this slide that there is now a large number of species beyond Mycobacterium avium and Mycobacterium intracellulare that make up the M. avium complex. They are all slowly-growing mycobacteria, and species identification can be tricky, but it is now often necessary to go beyond the identification of Mycobacterium avium complex because of the worldwide Mycobacterium chimaera event.

    Things to note about some of the less well-known species in this complex are that Mycobacterium avium subspecies hominissuis is not yet a validly recognized subspecies. Also note that Mycobacterium marseillense is the M. avium complex species member, and this can easily be confused with Mycobacterium massiliense, which is a member of the Mycobacterium abscessus species complex. M. marseillense is a slowly-growing mycobacterium while M. massiliense is a rapid-growing mycobacterium, and this distinction becomes important when trying to choose the appropriate antibiotics for patient care.

    Laboratory Diagnostics for M. chimaera

    So let’s talk for a few minutes about laboratory diagnostics for identification of Mycobacterium chimaera. Mycobacterium chimaera is a slowly-growing, non-pigmented, acid-fast mycobacterium. Methods for the direct detection of Mycobacterium chimaera from patient specimens are not available in clinical diagnostic laboratories, at least not at this time. Ordering an acid-fast smear and mycobacterial culture to be performed on patient specimens is the current recommendation for detection of Mycobacterium chimaera. A positive acid-fast smear indicates that a Mycobacterium species is present, but it is not possible to say which Mycobacterium species it is just from examining the acid-fast smear. As mentioned, Mycobacterium chimaera is a slow-growing mycobacterium, so cultures may require 2 to 6 weeks of incubation before visible growth can be detected.

    It should be noted that not all isolates of Mycobacterium chimaera are clinically significant. Isolates from cardiac sources and other normally sterile sites are obviously concerning, but M. avium complex is often isolated from respiratory specimens. Mycobacterium avium complex in respiratory specimens can be a pathogen, or it can be a commensal organism, or it can be a contaminant picked up from the environment. In our experience, approximately one-third of Mycobacterium avium complex isolates from respiratory specimens can be furthered identified to the species level as Mycobacterium chimaera. So finding Mycobacterium chimaera in a respiratory specimen does not necessarily mean it is a pathogen for that patient.

    Common Questions for the Lab

    One common question that the laboratory receives surrounding this outbreak event is, “What type of specimen should I submit if I suspect my patient may have an M. chimaera infection?” Well, the appropriate types of samples to submit depend on the patient’s clinical presentation, and consultation with an infectious diseases specialist can be very helpful in these cases. Common samples that are submitted to the laboratory include blood, purulent drainage, and tissue. Swabs are discouraged as specimens because they collect very little material, and often times, it is difficult to get the material back out of the swab, even with flocked swabs. A needle aspirate is preferred over a swab for the collection of drainage where possible.

    Another question the lab commonly receives is, “Should we perform environmental culturing of our heater-cooler units, or should we perform air sampling in the surgical suite?” The answer to those questions is, “Probably not.” Again, you should consult with your local infection control specialist, but the literature has already firmly established that Sorin 3T heater-cooler units manufactured prior to September 2014 are likely to be contaminated with Mycobacterium chimaera, so there is little point in performing cultures on additional heater-cooler units. In addition, negative environmental cultures will not rule out Mycobacterium chimaera contamination and do not negate the need to consider Mycobacterium chimaera infection in patients with prior cardiac surgery and the appropriate clinical presentation.

    Identification of M. chimaera from Culture Isolates

    Once a mycobacterial culture has grown, Mycobacterium chimaera can be identified using molecular methods. The Hologic/GenProbe nucleic acid hybridization probes for Mycobacterium avium complex and Mycobacterium intracellulare will be positive but will not discriminate to the species level for identification of Mycobacterium chimaera. The Hain GenoType NTM-DR LineProbe assay can differentiate M. chimaera from other M. avium complex members. MALDI-TOF mass spectrometry as used out of the box does not discriminate between M. intracellulare and M. chimaera, but a recent publication by Pranada, et al. in the Journal of Medical Microbiology suggests that a software-based peak-finding algorithm may make species identification possible. Right now, the most reliable way to identify M. chimaera is through the use of DNA sequencing where targets such as the 16S ribosomal RNA gene, the hsp65 gene, or the ITS region are useful.

    Mycobacterial Blood Cultures for M. chimaera

    Mycobacterial blood cultures can be useful for detection of Mycobacterium chimaera bacteremia in suspect patients, but the yield from performing multiple blood cultures is not fully known at this time. The general recommendation is to collect 1 to 3 blood cultures per patient, but you should also consult your microbiology laboratory before collecting too many cultures on multiple patients because there is limited capacity on FDA-cleared instruments for mycobacterial blood cultures, and a bolus of samples could quickly overwhelm available capacity. A big reason for the limited capacity is that mycobacterial blood cultures require prolonged incubation times of up to 42 days.

    Susceptibility Pattern for M. chimaera

    Now, let’s discuss the recommendations for antimicrobial susceptibility testing of M. avium complex members such as M. chimaera. M. avium complex members are generally susceptible to clarithromycin if the patient has not previously had macrolide therapy. The American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the Clinical and Laboratory Standards Institute (CLSI) recommend that clinically significant isolates from patients on prior macrolide therapy should be tested. Also recommended for testing are isolates from patients who develop bacteremia while on macrolide therapy or who relapse while on macrolide therapy. Initial isolates from clinically significant sources like blood or tissue can be tested to establish baseline AST values. Repeat AST can be done after 3 to 6 months of therapy if there is no improvement or if the culture remains positive. There are no CLSI interpretive breakpoints for drugs other than clarithromycin, but amikacin breakpoints may be adopted by the CLSI in 2018. Combination therapy with clarithromycin, rifabutin, and ethambutol is often used. Amikacin can be added to that regimen for the first three months of therapy. The ATS/IDSA guidelines suggest a minimum of 12 months of therapy for disseminated MAC disease, but there has been little outcome data generated as yet for treatment of patients with M. chimaera cardiac infections, so optimum therapy and the duration of therapy is still evolving.

    Summary

    In summary, Mycobacterium chimaera is a nontuberculous mycobacteria that is currently the center of a global outbreak event caused by the use of contaminated Sorin 3T heater-cooler units in cardiac surgery. Patient notification of possible exposure should follow CDC and FDA guidance. The CDC website link is provided on this slide and is a good source of the most up-to-date information on this ongoing event. The CDC site also provides a very helpful toolkit to assist facilities with patient notification. Mycobacterium chimaera is a member of the Mycobacterium avium complex. Identification to the species level and antimicrobial susceptibility testing of isolates should be performed by a qualified laboratory for clinically significant isolates from patients, particularly those who have previously undergone cardiac surgery.

    References

    1. Sax H, Bloemberg G, Hasse B, et al. Prolonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery. Clin Infect Diseases. 2015;61:67-75.
    2. Ninh A, Weiner M, Goldberg A. Healthcare-associated Mycobacterium chimaera infection subsequent to heater-cooler device exposure during cardiac surgery. J Cardiothorac Vasc Anesth. 2015;31(5):1831-1835.
    3. Sommerstein R, Rüegg C, Kohler P, et al. Transmission of Mycobacterium chimaera from heater-cooler units during cardiac surgery despite an ultraclean air ventilation system. Emerg Infect Diseases. 2016;22(6):1008-1013.
    4. Nguyen A, Hook CC, Dearani JA, and Schaff HV. Mycobacterium chimaera: the ethical duty to disclose the minimal risk of infection to exposed patients. J Thoracic and Cardiovasc Surgery. 2017; 153(6):1422-1424.
    5. van Ingen J, Kohl TA, Kranzer K, et al. Global outbreak of severe Mycobacterium chimaera disease after cardiac surgery: a molecular epidemiological study. Lancet Infect Dis. Oct 2017;17(10):1033-1041.
    6. Walker J, Moore G, Collins S, et al. Microbiologic problems and biofilms associated with Mycobacterium chimaera in heater-cooler units used for cardiopulmonary bypass. J Hosp Infect. Jul 2017;96:209-220.
    7. Tortoli E, Rindi L, Garcia MJ, et al. Proposal to elevate the genetic variant MAC-A, included in the Mycobacterium avium complex, to species rank as Mycobacterium chimaera sp. nov. Int J Syst Evol Microbiol. Jul 2004;54(pt 4):1277-1285.
    8. Pranada AB, Witt E, Bienia M, et al. Accurate differentiation of Mycobacterium chimaera from Mycobacterium intracellulare by MALDI-TOF MS analysis. J Med Microbiol. May 2017;66(5):670-677.
    Nancy Wengenack (@nancywengenack)

    Nancy Wengenack