Shortage could disrupt the ability of clinical laboratories in hospitals and health systems to run certain tests for bloodstream infections
US clinical laboratories may soon experience a “disruption of availability” of BACTEC blood culture media bottles distributed by Becton Dickinson (BD). That’s according to the federal Centers for Disease Control and Prevention (CDC) which issued a Health Alert Network (HAN) Health Advisory to all clinical laboratory professionals, healthcare providers and facility administrators, and other stakeholders warning of the potential shortfall of critical testing supplies.
“This shortage has the potential to disrupt patient care by leading to delays in diagnosis, misdiagnosis, or other challenges in the clinical management of patients with certain infectious diseases,” the CDC stated in the health advisory.
The CDC advises healthcare providers and health departments that use the bottles to “immediately begin to assess their situations and develop plans and options to mitigate the potential impact of the shortage on patient care.”
The advisory notes that the bottles are a key component in continuous-monitoring blood culture systems used to diagnose bloodstream infections and related conditions, such as endocarditis, sepsis, and catheter-related infections. About half of all US laboratories use the BD blood culture system, which is compatible only with the BACTEC bottles, the CDC advisory states.
Infectious disease specialist Krutika Kuppalli, MD (above), Chair of the Infectious Diseases Society of America (IDSA) and a Medical Officer for COVID-19 Health Operations at the World Health Organization, outlined the potential impact of the shortage on healthcare providers and clinical laboratories. “Without the ability to identify pathogens or [their susceptibility to specific antibiotics], patients may remain on broad antibiotics, increasing the risk of antibiotic resistance and Clostridium difficile-associated diarrhea,” she told STAT. “Shortages may also discourage ordering blood cultures, leading to missed infections that need treatment.” (Photo copyright: Loyola University Health System.)
FDA Advises Conservation of Existing BACTEC Supplies
The CDC advisory followed a July 10 notice from the US Food and Drug Administration (FDA) that also warned healthcare providers of “interruptions in the supply” of the bottles. The supply disruption “is expected to impact patient diagnosis, follow up patient management, and antimicrobial stewardship efforts,” the FDA’s letter states. “The FDA recommends laboratories and healthcare providers consider conservation strategies to prioritize the use of blood culture media bottles, preserving the supply for patients at highest risk.”
Hospitals have been warned that the bottle shortage could last until September, STAT reported.
BD issued a press release in which BD Worldwide Diagnostic Solutions President Nikos Pavlidis cast blame for the shortage on an unnamed supplier.
“We understand the critical role that blood culture testing plays in diagnosing and treating infections and are taking all available measures to address this important issue, including providing the supplier our manufacturing expertise, using air shipments, modifying BD manufacturing schedules for rapid production, and collaborating with the US Food and Drug Administration to review all potential options to mitigate delays in supply,” Pavlidis said. “As an additional stopgap measure, our former supplier of glass vials will restart production to help fill the intermittent gap in supply.”
Steps Clinical Laboratories Can Take
The CDC and FDA both suggested steps that clinical laboratories and other providers can take to conserve their supplies of the bottles.
Laboratories should strive to prevent contamination of blood cultures, which “can negatively affect patient care and may require the collection of more blood cultures to help determine whether contamination has occurred,” the CDC advised.
In addition, providers should “ensure that the appropriate volume is collected when collecting blood for culture,” the advisory states. “Underfilling bottles decreases the sensitivity to detect bacteremia/fungemia and may require additional blood cultures to be drawn to diagnose an infection.”
Laboratories should also explore alternative options, such as “sending samples out to a laboratory not affected by the shortage.”
The FDA advised providers to collect blood cultures “when medically necessary” in compliance with clinical guidelines, giving priority to patients exhibiting signs of a bloodstream infection.
In an email to STAT, Andrew T. Pavia, MD, Professor of Internal Medicine and Pediatrics at the University of Utah, offered examples of situations where blood culture tests are unnecessary according to clinical guidelines.
“There are conditions like uncomplicated community acquired pneumonia or skin infections where blood cultures are often obtained but add very little,” he told STAT. “It will be critical though that blood cultures are obtained from patients with sepsis, those likely to have bloodstream infections, and very vulnerable patients.”
Hospitals Already Addressing Shortage
STAT reported that some hospitals have already taken measures to reduce the number of tests they run. And some are looking into whether they can safely use bottles past their expiration dates.
Sarah Turbett, MD, Associate Director of Clinical Microbiology Laboratories at Massachusetts General Hospital in Boston, told STAT that her team tested bottles “that were about 100 days past their expiration date to see if they were still able to detect pathogens with the same efficacy as bottles that had not yet expired. They saw no difference in the time to bacterial growth—needed to detect the cause of an infection—in the expired bottles when compared to bottles that had not expired.”
Turbett pointed to a letter in the Journal of Clinical Microbiology and Infection in which European researchers found that bottles from a different brand “were stable for between four and seven months after their expiration dates,” STAT reported.
During a Zoom call hosted by the CDC and the IDSA, hospital representatives asked if the FDA would permit use of expired bottles. However, “a representative of the agency was not able to provide an immediate answer,” STAT reported.
With sepsis being the leading cause of death in hospitals, these specimen bottles for blood culture testing are essential in diagnosing patients with relevant symptoms. This is a new example of how the supply chain for clinical laboratory instruments, tests, and consumables—which was a problem during the SARS-CoV-2 pandemic—continues to be problematic in unexpected ways.
Taking a wider view of supply chain issues that can be disruptive to normal operations of clinical laboratories and anatomic pathology groups, the market concentration of in vitro diagnostics (IVD) manufacturers means fewer vendors offering the same types of products. Consequently, if a lab’s prime vendor has a supply chain issue, there are few options available to swiftly purchase comparable products.
A separate but related issue in the supply chain involves “just in time” (JIT) inventory management—made famous by Taiichi Ohno of Toyota back in the 1980s. This management approach was designed to deliver components and products to the user hourly, daily, and weekly, as appropriate. The goal was to eliminate the cost of carrying large amounts of inventory. This concept evolved into what today is called the “Lean Manufacturing” method.
However, as was demonstrated during the SARS-CoV-2 pandemic, manufacturers and medical laboratories that had adopted JIT found themselves with inadequate numbers of components and finished products.
In the case of the current shortage of BD blood culture media bottles, this is a real-world example of how market concentration limited the number of vendors offering comparable products. At the same time, if this particular manufacturer was operating with the JIT inventory management approach, it found itself with minimal inventories of these media bottles to ship to lab clients while it addressed the manufacturing problems that caused this shortage.
Genomic analysis of pipes and sewers leading from the National Institutes of Health Clinical Care Center in Bethesda, Md., reveals the presence of carbapenem-resistant organisms; raises concern about the presence of multi-drug-resistant bacteria previously undetected in hospital settings
If hospitals and medical laboratories are battlegrounds, then microbiologists and clinical laboratory professionals are frontline soldiers in the ongoing fight against hospital-acquired infections (HAIs) and antibiotic resistance. These warriors, armed with advanced testing and diagnostic skills, bring expertise to antimicrobial stewardship programs that help block the spread of infectious disease. In this war, however, microbiologists and medical laboratory scientists (AKA, medical technologists) also often discover and identify new and potential strains of antibiotic resistance.
Potential Source of Superbugs and Hospital-Acquired Infections
According to the mBio study, “Carbapenemase-producing organisms (CPOs) are a global concern because of the morbidity and mortality associated with these resistant Gram-negative bacteria. Horizontal plasmid transfer spreads the resistance mechanism to new bacteria, and understanding the plasmid ecology of the hospital environment can assist in the design of control strategies to prevent nosocomial infections.”
Karen Frank, MD, PhD (above), is Chief of the Microbiology Service Department at the National Institutes of Health and past-president of the Academy of Clinical Laboratory Physicians and Scientists. She suggests hospitals begin tracking the spread of the bacteria. “In the big picture, the concern is the spread of these resistant organisms worldwide, and some regions of the world are not tracking the spread of the hospital isolates.” (Photo copyright: National Institutes of Health.)
Frank’s team used Illumina’s MiSeq next-generation sequencer and single-molecule real-time (SMRT) sequencing paired with genome libraries, genomics viewers, and software to analyze the genomic DNA of more than 700 samples from the plumbing and sewers. They discovered a “potential environmental reservoir of mobile elements that may contribute to the spread of resistance genes, and increase the risk of antibiotic resistant ‘superbugs’ and difficult to treat hospital-acquired infections (HAIs).”
Genomic Sequencing Identifies Silent Threat Lurking in Sewers
Frank’s study was motivated by a 2011 outbreak of antibiotic-resistant Klebsiella pneumoniae bacteria that spread through the NIHCC via plumbing in ICU, ultimately resulting in the deaths of 11 patients. Although the hospital, like many others, had dedicated teams working to reduce environmental spread of infectious materials, overlooked sinks and pipes were eventually determined to be a disease vector.
In an NBC News report on Frank’s study, Amy Mathers, MD, Director of The Sink Lab at the University of Virginia, noted that sinks are often a locus of infection. In a study published in Applied and Environmental Microbiology, another journal of the ASM, Mathers noted that bacteria in drains form a difficult to clean biofilm that spreads to neighboring sinks through pipes. Mathers told NBC News that despite cleaning, “bacteria stayed adherent to the wall of the pipe” and even “splashed out” into the rooms with sink use.
During the 2011-2012 outbreak, David Henderson, MD, Deputy Director for Clinical Care at the NIHCC, told the LA Times of the increased need for surveillance, and predicted that clinical laboratory methods like genome sequencing “will become a critical tool for epidemiology in the future.”
Frank’s research fulfilled Henderson’s prediction and proved the importance of genomic sequencing and analysis in tracking new potential sources of infection. Frank’s team used the latest tools in genomic sequencing to identify and profile microbes found in locations ranging from internal plumbing and floor drains to sink traps and even external manhole covers outside the hospital proper. It is through that analysis that they identified the vast collection of CPOs thriving in hospital wastewater.
In an article, GenomeWeb quoted Frank’s study, noting that “Over two dozen carbapenemase gene-containing plasmids were identified in the samples considered” and CPOs turned up in nearly all 700 surveillance samples, including “all seven of the wastewater samples taken from the hospital’s intensive care unit pipes.” Although the hospital environment, including “high-touch surfaces,” remained free of similar CPOs, Frank’s team noted potential associations between patient and environmental isolates. GenomeWeb noted Frank’s findings that CPO levels were in “contrast to the low positivity rate in both the patient population and the patient-accessible environment” at NIHCC, but still held the potential for transmission to vulnerable patients.
Since carbapenems are a “last resort” antibiotic for bacteria resistant to other antibiotics, the NIHCC “reservoir” of CPOs is a frightening discovery for physicians, clinical laboratory professionals, and the patients they serve.
The high CPO environment in NIHCC wastewater has the capability to spread resistance to bacteria even without the formal introduction of antibiotics. In an interview with Healthcare Finance News, Frank indicated that lateral gene transfer via plasmids was not only possible, but likely.
“The bacteria fight with each other and plasmids can carry genes that help them survive. As part of a complex bacterial community, they can transfer the plasmids carrying resistance genes to each other,” she noted. “That lateral gene transfer means bacteria can gain resistance, even without exposure to the antibiotics.”
The discovery of this new potential “reservoir” of CPOs may mean new focused genomic work for microbiologists and clinical laboratories. The knowledge gained by the discovery of CPOs in hospital waste water and sinks offers a new target for study and research that, as Frank concludes, will “benefit healthcare facilities worldwide” and “broaden our understanding of antimicrobial resistance genes in multi-drug resistant (MDR) bacteria in the environment and hospital settings.”
Additionally, the device also could help reduce antibiotic-resistant infections and other HAIs and HACs, though this result was not part of the study
Research findings indicate how a new system-in-a-box device that phlebotomists and clinical laboratories would use when drawing blood could reduce contamination of blood cultures and lower patients’ use of antibiotics. In a study involving 1,800 blood cultures done on 904 patients at the University of Nebraska Medical Center (UNMC), use of the device was attributed to an 88% reduction in the blood culture contamination rate.
According to a press release by researchers at UNMC who studied the device, “With traditional blood draws, about 30% to 40% of patients with contaminated blood cultures are prescribed antibiotics unnecessarily. This contributes to antibiotic resistance and undermines nationwide efforts to improve antimicrobial stewardship.” The researchers reported their findings in an article published in the Oxford Academic journal Clinical Infectious Diseases (CID).
Blood Culture Contamination Harms Patients and Increases Cost of Care
The UNMC researchers noted that, during a blood draw, a significant percentage of blood cultures become contaminated when skin fragments containing bacteria are dislodged and mix with the patient’s blood. For the thousands of patients each day who have their blood drawn, contaminated blood cultures, which lead to false positive results for sepsis, often result in unnecessary antibiotic treatment. This in turn can lead to serious and deadly antibiotic-resistant infections with various multi-drug-resistant organisms such as Clostridium difficile infection (C. diff), as well as, other hospital-acquired infections and conditions (HAIs & HACs) due to unnecessary extended length of stay, according to Mark Rupp, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, and Medical Director, Department of Healthcare Epidemiology-Infection Control at UNMC.
In the CID article, Rupp and colleagues reported on a prospective, controlled trial conducted in the emergency department (ED) at UNMC’s partner hospital Nebraska Medicine. Results of the trial showed that the SteriPath ISDD diverts and sequesters the first 1.5 to 2 mL portion of blood. The researchers presumed that these initial drops of blood would contain the contaminating skin cells and microbes.
SteriPath is a self-contained, preassembled, sterile blood collection system. It provides proprietary vein-to-bottle technology that significantly reduces blood culture contamination, according to Magnolia Medical Technologies. This could be useful for helping phlebotomists and clinical laboratories improve the quality of specimens collected for use in blood culture testing. Click on the image above to view videos on the SteriPath ISDD. (Photo copyright: Magnolia Medical Technologies.)
The researchers tested the SteriPath ISDD during standard phlebotomy procedures in patients requiring blood cultures. After drawing 1,808 blood cultures from 904 study subjects, the researchers concluded that the ISDD significantly reduced blood culture contamination compared with standard phlebotomy procedures. The blood culture contamination among phlebotomists who used the ISDD decreased by nearly 90%, compared to phlebotomy procedures conducted by nurses who did not use the ISDD.
“We were able to decrease the false positive rate significantly through use of this device—from 1.78% down to 0.2%, which represents an 88% reduction,” Rupp noted in the UNMC press release. “The 1.78% baseline rate of contamination may seem small, but we should strive to decrease adverse events to the lowest possible level, because of the impact to the patient and the burden to our healthcare system.
“The device is innovative in that it diverts the first couple of milliliters of blood into the sequestration chamber,” Rupp explained. “That’s where we think the contaminants are. The remaining blood being drawn is then diverted into the sterile pathway into the blood culture vial, thereby preventing the contamination.”
Billions of Healthcare Dollars Could Be Saved with SteriPath’s ISDD
During a conference call with reporters, Rupp admitted that cynics might scoff at such a low rate of improvement. “Many of those folks don’t understand that we do tens of millions of blood cultures in this country every year,” he explained. “Every year, we do about 30 million or so blood cultures. That many cultures means a 2% contamination rate equates to somewhere in the neighborhood of about 600,000 contamination events. And 2% is a very respectable level. Usually clinicians are satisfied anywhere below about 3%, which is about 900,000 events each year.”
For about 40% to 50% of patients whose blood is contaminated, physicians will prescribe antibiotics, order another blood test, and require patients to stay several days in the hospital, he added. “All of this results in thousands of extra dollars being spent,” he declared. If each blood contamination case costs about $4,000, then reducing such contamination in potentially 600,000 cases each year could save more than $1 billion healthcare dollars.
According to the researchers, costs associated with blood culture contamination ranged from $1,000 per patient in 1998 to $8,700 per patient in 2009. “If a midpoint cost estimate of $4,850 is used, and the added cost of the device is not taken into account, it equates to a cost avoidance of $1.8 million per year at our institution alone,” Rupp stated. “If the low rate of contamination that we observed in the study, 0.22%, was applied to all blood cultures throughout the country, billions of dollars of excess costs could be avoided.”
This clinical study offers strong evidence that the SteriPath ISDD might prove to be a useful tool that clinical laboratories could use to help prevent unnecessary exposure to antibiotics and hospital stays, lower healthcare costs, and improve patient test outcomes. If the UNMC clinical study outcomes are replicated in future studies, then it is a technology and a solution that has the potential to be adopted by phlebotomists in medical laboratories and hospitals.
Even as the nation’s hospitals embark on efforts to implement effective antimicrobial stewardship programs, researchers continue to seek solutions to the same problem. They are following several paths to combat the growing resistance certain pathogens have to antibiotics. In particular, two approaches are interesting for pathologists and medical laboratory personnel. One involves understanding the processes that lead to antibiotic resistance. The other is to identify useful biomarkers associated with specific strains of pathogens. (more…)
