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 occuring
worldwide.
The outbreak is associated with contaminated heater-cooler units used in the heart/lung
bypass procedure during surgery.
In this month’s Hot Topic, my collegue Dr. Nancy Wengenack will provide you with an overview
of the global outbreak situation and discuss what’s known regarding the source of the
infections.
In addition, she’ll 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 partner in your patients’ healthcare.
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.
I have no disclosures relative to this presentation.
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?
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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 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.
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.
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.