The bug in question was Burkholderia cepacia, a type of bacteria that is usually found in soil, water or other liquids. It is not commonly found in blood samples sent to pathology labs but in this case, it had been found in patient blood samples. ¹

The patients in question were in the hospital’s intensive care unit (ICU) and were quite unwell. It was suspected that they had contracted an infection in the ICU, which is why the blood samples were sent for bacterial culture.

However, the characteristics of the B. cepacia organism and the fact that both patients were getting better on antibiotics that wouldn’t have usually treated this organism led to a suspicion that the blood samples had somehow been contaminated.

This is a rare occurrence in pathology labs and an investigation swiftly commenced to find the source of contamination, beginning with testing equipment and materials in the laboratory environment.

Dr Maloney returned from leave and was surprised to discover that despite extensive testing the cause had not been found but several more cases of B. cepacia in blood had arisen.

Professor Ramon Shaban is Clinical Chair in the Department of Infection Control at Gold Coast Health and says staff were working hard to find the cause.

“This is an environmental, water-based organism, so it’s unusual to see it as a bacteraemia (bacteria in the blood). We tested IV fluids and non-sterile gels that have been associated with outbreaks around the world, and were working our way through products to find the cause. We also contacted our peers and soon learned that other cases had been identified across Queensland and interstate, which supported our working hypothesis that this was a point source outbreak.”

A point source outbreak is where patients are exposed to a single source of the bacteria in a brief time period and there is no spread from person to person.

The search intensified and widened, and the culprit was quickly identified, Dr Maloney said:

“Ramon and I went to see a doctor who had been treating one of the patients and put in a central line the day before, when a blood sample was also taken. We asked the doctor to show us what equipment he used and where he had got it. We collected all these items including the ultrasound gel and took everything back to the lab to be tested. The next day I was surprised when Brian Gorman, a senior scientist let me know that we had a suspicious organism growing from the ultrasound gel that was labelled ‘sterile’. This was the gel that was used during ultrasound guided cannulation, and the suspicious organism turned out to be Burkholderia cepacia.”

A central line is a catheter inserted into the vein of a patient needing supply of medication or fluids over an extended period. The process is called cannulation and when ultrasound imaging guides the process a gel is used.

The fact that this product, which was supposed to be sterile but was not, was manufactured internationally was a serious concern to the team, who immediately issued a formal alert to other hospitals across the country.

In-depth microbiological testing was able to establish that the patients from GCUH and the other cases were all affected by the same bacteria and that the ultrasound gel was the common cause.

The Gold Coast Health team notified the Australian Therapeutic Goods Administration (TGA). Approximately 1400 kits containing the gel had been distributed to a dozen hospitals across Australia and within 36 hours the TGA had issued a recall for all these kits.

Ultimately, at least 12 patients tested positive for the bacteria but only one person had symptoms that were directly attributed to B. capacia and they have since recovered.

Dr Maloney said; “In cases like these the doctor is sending a blood sample to pathology because their patient is ill and they need to know why. With an unusual organism like this it is less clear if that is what is causing the illness, so you need to use all the pathology results as well as any other investigations that might be relevant such as diagnostic imaging, to build a full picture of what could be causing symptoms to ensure the patient gets the right treatment.”

Prof Shaban noted that the process was challenging with an unusual bug affecting a range of patients:

“The patients had few common clinical characteristics, which made it more difficult to track down the cause of the infection.”

The fast and systematic approach of the team at Gold Coast Health may well have saved lives. Bacteraemia (bacteria in the blood) is a serious condition and can be life-threatening. Had the contaminated gel not been recalled many more patients would have been affected.

Reference

1. Shaban RZ, Maloney S, Gerrard J, Collignon P, Macbeth D, Cruickshank M, Hume A, Jennison AV, Graham RMA, Bergh H, Wilson HL, Derrington P. (2017). Outbreak of healthcare-associated Burkholderia cenocepacia bacteraemia and infection attributed to contaminated ‘sterile’ gel used for central line insertion under ultrasound guidance and other procedures.  American Journal of Infection Control, Accepted 24 June, 2017.

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A small percentage of blood cultures performed to diagnose infections are contaminated, due to skin fragments containing bacteria that are dislodged during the blood draw.

This contamination can lead to false positive results that can mislead clinicians into thinking a patient has a potentially serious bloodstream infection. This can lead to the unnecessary prescription of antibiotics and subsequently contributes to the growing risk of antibiotic resistance.

The ISDD is a sterile blood collection system that diverts and sequesters the first 1.5 to 2 milliliters of blood – which often carries contaminating skin cells and microbes. This part of the blood is discarded before testing.

The UNMC study involved comparing 1800 blood cultures – one using standard procedures and one using the ISDD for each of the 900 participating patients. The results showed an 88% decrease in false positives with the ISDD compared to standard procedures – from a rate of 1.78% to 0.2%.

Mark Rupp MD, professor and chief of the UNMC Division of Infectious Diseases was the lead author of the study and noted;

“A lot of people think this is a minor problem. However, contaminated blood cultures are a big deal. Physicians can be led astray and patients may be harmed by additional tests and unnecessary antimicrobial therapy.

What is important about this device is it can greatly limit the blood culture from being contaminated, so physicians are rarely fooled by false-positive results. It gives clinicians confidence that results are accurate.”

The accuracy of Australian pathology is extremely high and every mechanism is used by pathologists to minimise the risk of false positives and negatives. However, even when operating at the highest level of quality these issues can occasionally arise. Those working in pathology are constantly seeking ways to minimise the chance of errors and this new research and device may assist them.

The results are published online in the journal Clinical Infectious Diseases.

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If you have a similar Medical Mystery in which pathology plays a similar role, email us at info@knowpathology.com.au

Background

By the time Patient X attended Dr. Hogan’s office, it had been three months since she had felt like herself. Previously completely healthy, the 25-year-old woman had been plagued by shaking chills, fevers, and unremitting fatigue, barely able to drag herself to work. Most troubling, though, was the thin yellow fluid draining from her thighs and the undersides of her breasts.

Patient X’s symptoms had started a little over two weeks after she underwent an operation in the Dominican Republic. The cosmetic surgery – known colloquially as a Brazilian butt lift – had entailed sucking fat out of the belly and low back, then injecting it into the buttocks and thighs. She also underwent breast augmentation.

The clinic had looked pristine. She received a weeklong course of antibiotics after the operation, and the surgical wounds seemed to be healing well. As instructed by the doctor, she kept the incisions clean, and didn’t swim or use hot tubs.

Just a few days after she returned home to Boston, she started draining the fluid from her breasts and thighs.

“My first day back at work, I noticed my shirt felt wet,” Patient X said in an interview with STAT. “I looked in my bra and saw this thin liquid.” Some days, the towels she stuffed into her bra to absorb the fluid became soaked within an hour or two.

Around this same time, Patient X noted large bruises on her legs; these became red and excruciatingly painful, sometimes opening up at night and releasing the same thin fluid.

She’d become extremely fatigued — falling asleep at 5 p.m. some days — and was spiking fevers. She was also losing weight without trying to.

Patient X went to see her General Practitioner, who took samples of this draining fluid and prescribed antibiotics. Over the next few months, the samples would show just a sprinkling of the types of bacteria that normally live on the skin, such as Staphylococcus aureus. Doctors prescribed Patient X various types of antibiotic pills, and although her symptoms sometimes improved temporarily, they always returned.

Alarmingly, the silicone breast implants also eroded through her skin about a month after her surgery; they were visible through the incision. The implants were removed at a hospital; the surgeon told Patient X he thought they might be infected. Although the wounds were rinsed with an antibiotic called cefazolin, no samples were sent for microbiological studies.

Putting it all together

By August 2016, Patient X was fed up. She was then seen by Hogan, a fellow in infectious diseases at Massachusetts General Hospital.

On exam, Hogan noted that the opening in the fold beneath her left breast was draining something that was thinner than pus, but was nevertheless indicative of infection. He was alarmed at the way the infection had bored holes through Patient X’s flesh.

“She had multiple draining ulcers separate from the surgical sites,” said Hogan, who has followed Patient X closely ever since that first appointment. “It looked like a deep infection from within the soft tissue” making its way to the skin, he said.

Full blood count showed slightly high white blood cell and platelet counts, both of which can be high when there’s an infection or inflammation. Her kidney and liver tests were normal. Looking over Patient X’s imaging, Hogan noticed what looked like areas of infection in the parts of her breasts seen in a CT scan of her chest. Hogan thought it might show some smudges indicating a collection of infected fluid.

Hogan felt confident Patient X was infected from the surgery. He ruled out other possible sources of infection: Patient X had no pets. She was not a drug user and never had been. She hadn’t travelled out of the country other than her recent trip for the cosmetic surgery.

The question was which microbe was causing the infection, and why the previous treatments hadn’t gotten rid of it.

Something didn’t quite fit

Patient X’s General Practitioner might have treated her with the wrong antibiotics, or for too short a time, for a commonplace bacterial infection. There also might be a walled-off collection of pus inside of her body that the antibiotics couldn’t reach. Yet if that were the case, the samples collected from the wounds should have grown a lot more bacteria; a mix of a few bugs commonly found on the skin wasn’t exactly a slam-dunk for an infection that just wouldn’t quit.

The other possibility, he thought, was an infection different from the usual ones after surgery in the United States. As opposed to fast-moving staph and strep infections, for example, bacteria in the mycobacterial family could cause chronic, draining infections.

At the forefront of his mind were Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus, which can cause infections of the skin and underlying tissue and are cousins to Mycobacterium tuberculosis, which causes tuberculosis. M. abscessus can cause lung infections, and more rarely meningitis or infections in the brain. Special material is needed to grow mycobacterial species, so it wouldn’t be surprising that previous pathology tests hadn’t revealed these bacteria.

Hogan sent samples of the fluid from her legs and chest for analysis for fungi, mycobacteria, and nocardia, another rare cause of chronic bacterial infections. He also ordered breast and thigh ultrasounds to look for the hidden pockets of infection possibly seen on the CT scan. Finally, he switched Patient X’s antibiotic to better treat staph on the off-chance that this was the cause of her symptoms.

At last, a diagnosis

Hogan and Dr. Raj Gandhi, his more senior colleague on the case, were not surprised when the cultures revealed Mycobacterium abscessus. The defining characteristics of the case — from the chronicity, to the sites and nature of fluid drainage, to the preceding surgery, to the recalcitrance of the infection to many antibiotics — pointed to an infection by this bug.

“It really was classic for mycobacterial disease,” Hogan said.

The tempo of the infection — never disappearing, but never ramping up to the extent that Patient X developed a life-threatening systemic infection — was also typical. If the staph isolated from her wounds had been causing the infection, for example, Patient X likely would have become much sicker, much more quickly — progressing over days, instead of lingering for months. The staph bacteria in her samples were innocent bystanders, not the root of her infection.

Another clue pointing to M. abscessus was the way more and more wounds kept popping up; run-of-the-mill postoperative infections tend to solely entail the area where the surgery was originally performed.

For Patient X, getting a diagnosis after months of searching felt like a breakthrough.

“I was relieved, because at least I had an answer,” she said.

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Up until 2011 fascioliasis was rare in Australia with only a few cases being reported, mostly amongst sheep farmers in Victoria. However, the MJA case series, “Fascioliasis in Australian travellers to Bali” found there were six diagnoses between 2011 and 2014. Given the popularity of Bali as a holiday destination and the specificity of the testing needed to diagnose fascioliasis it is important that Australian GPs are aware of the infection.

Fascioliasis is an infectious disease caused by Fasciola hepatica parasites, which are flat worms known as liver flukes, found in the bile ducts and liver of infected animals such as sheep and cattle.

The flukes are transmitted from animals to people via ingesting contaminated watercress, salads and other freshwater plants or contaminated water, (either by drinking it or by eating vegetables that were washed with it). Up to 40% of Bali cattle are reportedly infected with a form of Fasciola known as Fasciola gigantica, hence the presence of infection in Australians who have visited Bali.

According to the MJA case report pathology plays an important role in correctly diagnosing fascioliasis and therefore ensuring patients receive timely and appropriate treatment. Common symptoms of the infection include fever and abdominal pain, but these could be attributed to a multitude of infections.

Dr Miles Beaman is a pathologist specialising in microbiology who was one of the paper’s authors. Dr Beaman said. “Pathology is able to offer answers that other medical investigations may otherwise miss.

Radiological findings, for example, are often non-specific for fascioliasis. Ultrasonography and CT scans can be used to look for lesions on the patient’s liver caused by the infection. However, images from these are inconclusive in many cases.”

The infection can be diagnosed by examining stool specimens under a microscope (the diagnosis is confirmed if Fasciola eggs are seen) but it takes approximately 4 months for eggs to appear in the stool and therefore this approach is not appropriate for an early diagnosis. In the cases reported in the MJA study, stool microscopy did not yield positive results for any of the six patients.

Instead, the six recent cases of fascioliasis in Australian patients were all diagnosed by specific serology to identify Fasciola antibodies in the blood serum. Results of serological testing may become positive 2–4 weeks after infection, preceding the presence of eggs in the stool. Currently, however, in Australia, serological testing is only available at the Institute for Clinical Pathology and Medical Research at Westmead.

Luckily, fascioliasis is treatable, however an accurate diagnosis is important because the drug used to treat the infection, Triclabendazole, is difficult to obtain in Australia for human use, and therefore has to be either imported or acquired through veterinary supply. Prescription requires Special Access Scheme approval and hospital ethics approval for use in humans.

It is important that doctors in Australia are aware that fasciolasis has now been found in Australian travellers and have an up to date knowledge of the recommendations on testing and treatment. An increased awareness of parasitic causes is important in facilitating timely referral to an infectious diseases or microbiology service for assistance with diagnosis and management and although previously no cases had been reported, our love for Bali doesn’t seem to be shifting. There are likely to be further cases affecting locals and tourists.

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It has the mysterious name MALDI-TOF and to add to its futuristic feel it uses a laser inside a vacuum tube to perform tests on samples prepared with something known as “the matrix”.

(MALDI-TOF stands for Matrix-Assisted Laser Desorption & Ionisation- Time Of Flight.)

In order to operate this intriguing instrument, a scientist prepares a sample on a testing plate, firstly using Formic acid to assist in breaking down cell walls and exposing the proteins.

A liquid called the matrix is then applied and the proteins crystallize as it dries.

This plate of crystalline protein structures is then placed in a ‘well’ inside the large vacuum tube in the machine. A laser at the top of the tube is shot at the sample and measures the ‘peaks’ of the crystals.
This matches them with a database of organisms to determine what the bug in question is and how best to treat it.

So why is this important?

Before going in the machine, the scientist must use the sample to grow the organism.

Prior to the MALDI-TOF, scientists had to grow an organism for between 18 and 24 hours and sometimes up to 40 hours.

Once the organism had grown tests could then be set up but some of these could also take up to 18 hours, meaning the whole process could take days.

Now the MALDI-TOF can use growth 4 hours old to give a result, which only takes 30 seconds inside the machine.

In the case of life-threatening infections like septicaemia, this could save lives.

David Lorenz is a hospital scientist working in microbiology at the St Vincents Hospital pathology laboratory in Sydney.

“If something went wrong with the barrage of biochemical tests set up for the identification of an organism, you wouldn’t necessarily know of the problem until 24 hours later and then you’d have to start again. Although mistakes are rare, with the MALDI-TOF you can know within a minute if there is a problem with the sample and then you can run the test again.”

David says that not only has the MALDI-TOF improved lab turnaround times, which is clearly a benefit to patients and those treating them, it has improved workloads in labs too.

The machine can run up to 96 tests simultaneously every hour and is very accurate.

However, there are still some organisms that the MALDI-TOF cannot tell apart and results need to be interpreted by a skilled medical scientist. If the machine produces a result which is unclear or unusual a scientist can then choose to rerun tests or use alternative methods to identify bacteria.

MALDI-TOF can be used to identify all bacterial illnesses, including bacterial meningitis, E.coli and gonorrhoea. It can also be used on yeast and some fungi.

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