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ID laboratory stewardship: A concept in need of implementation
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Today we have access to a multitude of new and novel medications, biologic agents, medical devices, imaging modalities, and surgical and nonsurgical invasive procedures, which have transformed the practice of internal medicine from what was essentially a diagnostic profession to one that is now heavily focused on treatment. Although the subspecialty of ID has been treatment oriented for many years, the advent of many new and sophisticated tests means we should turn our attention to potential improper use of the clinical laboratory — a major cost center in any health care system. This brings up the less often addressed but surely relevant concept of laboratory stewardship.
With approximately 13 billion tests performed each year in the United States, use of the clinical laboratory to diagnose, treat, monitor and prevent diseases is the single highest volume medical activity. An estimated 70% of downstream medical decisions are based on pathology and laboratory results. Furthermore, studies have shown that 10% to 30% of laboratory tests ordered and performed each year in the U.S. are either unnecessary or inappropriate.
According to Michael Laposata, MD, PhD, chairman of the department of pathology at the University of Texas Medical Branch-Galveston, laboratory medicine is the medical specialty that nearly every practicing physician relies on every day, yet education and training in medical school and throughout graduate medical education in proper use of the laboratory is limited and inadequate. Although laboratory errors are unusual, about 25% have a negative impact on patient outcomes, providing an incentive to reduce laboratory error to as close to zero as possible. To that end, in an effort to control costs and improve quality of care, the entity known as PLUGS (Patient-Centered Laboratory Utilization Guidance Services) has released guidelines intended to transform laboratory utilization review into laboratory stewardship. The committee members drew attention to the fact that such efforts at stewardship and utilization management and defining best practice are not without precedent in the current health care arena, some of which are now required by the Joint Commission and mandated by CMS. Examples include our area, antimicrobial stewardship; pharmacy and radiology utilization management; blood utilization committees; and the American Board of Internal Medicine’s Choosing Wisely Campaign. In this context, laboratory stewardship is referred to as a health care ethic that embodies responsible planning and management of resources.
A meta-analysis of 15 years of published lab utilization literature showed a 20.6% mean rate of overutilization and a 44.8% mean rate of underutilization. The study also demonstrated overutilization of low-volume tests compared with medium- and high-volume tests (32.2% vs. 19.8% vs. 10.2%), and an overutilization rate during initial testing (43.9%) that was six times higher than the rate during repeat testing (7.4%). Partly as a result of these data, the PLUGS National Committee for Laboratory Stewardship, commissioned in 2016, put forth a template for laboratory stewardship programs consisting of four components: governance; interventions; data extraction and monitoring; and data review and strategies for improvement. It has been shown that the most significant causes of patient harm from laboratory testing are centered on three aspects: ordering the wrong test; failing to retrieve or ignoring a test result; and misinterpreting the test result. Consequently, the committee has recommended that each institution focus on four basic elements for data extraction and monitoring:
- appropriateness of laboratory test orders;
- retrieval of test results;
- appropriateness of test interpretation; and
- impact of each stewardship intervention.
The expectation is that gathering this information will provide the tools for improving the quality of patient care and the allocation of resources.
We as experts in the specialty of ID can and should have a major impact on the success of a laboratory stewardship program, especially in terms of how it closely ties into antimicrobial stewardship. Ideally, before one orders a laboratory test, these questions have been considered:
- What is the purpose of ordering the test and the specific consequences, if any, of not ordering it?
- How well does the particular test differentiate between health and disease?
- Does the person ordering the test possess the knowledge to interpret the results?
- Does the test result play a significant role in the management and/or outcome of the patient?
In addition, to truly have an effective laboratory stewardship, the ordering clinician must be capable of hypothesis deduction (ie, formulating a differential diagnosis) and have a good understanding of the clinical performance characteristics of the tests (ie, prevalence of the disease being tested for, and test sensitivity, specificity, efficiency and predictive value).
Each day, many specimens collected from various tissue and bodily fluids are submitted to clinical microbiology laboratories in hospitals throughout the country with the intended purpose of pathogen isolation, identification and, in most instances, the provision of antimicrobial susceptibility information. In the context of direct patient care — and not for epidemiologic or surveillance reasons — it is assumed that the ordering clinician has made a diagnosis of infection and is hoping to ascertain the etiologic pathogen(s) to determine the best treatment, as well as the need for other interventions (eg, isolation, public health notification, etc.). However, in cases now categorized as “sepsis” and “septic shock,” according to the Sepsis-3 definitions, in only about one-third of cases is the culture positive. Therefore, sepsis is not necessarily defined by the laboratory’s finding of a microorganism. Furthermore, it is incumbent upon the recipient of a positive culture report to be able to distinguish between pathogen, colonizer and contaminant.
The following are examples of “low-hanging fruit” of ID-related laboratory tests that are ordered on a daily basis in hospitals, long-term care and skilled nursing facilities. The best way to improve the utilization of ID laboratory testing is with education by ID specialists or laboratory-based personnel. Furthermore, as pressures mount to develop more guidelines for the use of tests, ID organizations must be at the forefront of the development of those guidelines.
Blood cultures
In one average-sized urban acute-care hospital, only about 6% of the more than 1,000 blood cultures performed each month identified a bacteria or fungus, and up to one-half of the positive findings (within the accepted 3% rate) were considered contaminants. This disappointingly low number confirms the fact that testing for bacteremia serves as a rather poor indicator of active infection, and it is a suboptimal and inefficient method of pathogen identification. In fact, in one study, the diagnostic yield of blood cultures in neutropenic febrile patients was only about 14%. Regardless of whether bacteria gained introduction into the blood primarily (ie, via an intravascular catheter, IV drug use or transiently due to a mucosal-barrier injury) or secondary to a local or deep tissue focus, the blood per se is rarely infected but rather serves as a transient or intermittent conduit. Still, the lab’s report of bacteremia frequently results in unwarranted repeat blood cultures, as well as unnecessary, prolonged parenteral and total days of antibiotic administration based simply on a positive report that is unrelated to how the patient is doing clinically. Moreover, based on the presence of fever alone, blood cultures are reflexively repeatedly ordered or performed as part of a standing order without any new clinical alterations, even though the slow-to-resolve fever may be a known feature of the infection entity responsible for the elevation in temperature (eg, hepatic or lung abscesses).
Blood cultures are frequently ordered as follow-up tests after clear-cut clinical response and even cure of infection, having no benefit. Examples are gram-negative bacterial sepsis that has responded to treatment clinically, or the patient with bacterial endocarditis who remains well after completion of therapy.
Urinalysis and urine cultures
The incessant and uncalled-for treatment of asymptomatic bacteriuria (ASB) is one of the leading initiators of unwarranted antimicrobial prescribing and a major focus of all hospital antimicrobial stewardship programs. Compounding this problem is that, contrary to the knowledge that the presence of pyuria accompanying ASB is not an indication for antimicrobial therapy, leukocytes detected in the urinalysis can mislead practitioners to prescribe antibiotics. Unfortunately, the urinalysis has become part of routine medical practice, and it is often obtained for no clear clinical motive. Sometimes, it is part of the initial “workup” in patients, or it is obtained because of cloudy or “smelly” urine, or because patients present with a variety of signs and symptoms, which on initial evaluation would appear to have no relationship to the urinary system. One way to circumvent this criticized practice is the elimination of reflex urine cultures that are done strictly based on the finding of more than 10 white blood cells (WBCs) and/or more than one type of bacteria and less than five squamous epithelial cells per high-power magnification field, independent of the clinical reason for the ordering of the urinalysis. In hospitals where reflex culturing remains part of the algorithm, adding a comment asking the clinician to call the microbiology laboratory for identification and susceptibility testing if a clinical urinary tract infection is suspected has also proven beneficial in lessening the volume of unjustified cultures and inappropriate antibiotic therapy.
Taking cultures of urine drainage bags from indwelling catheters is another meaningless exercise that can lead to misinformed therapy.
Wound cultures
Nothing better exemplifies the quip “garbage in equals garbage out” than swabbing open wounds and pressure sores and draining sinus tracts in an attempt to either prove the presence of an active soft tissue or bone infection or to identify an organism to treat. Being that surface cultures of such wounds and sinus tracts (with the possible exception of the isolation of Staphylococcus aureus alone) are not valuable and usually denote colonized bacteria and yeast that cannot be differentiated from the true causative pathogen, the submission of such culture samples seems to take place regularly. Additionally, this unjustified practice only encourages the selection and administration of broad-spectrum antibiotics, which drives a potential host of collateral damages. In the best interest of all parties, consideration should be given to instruct the laboratory to reject such samples at the door, or at the least refrain from reporting the results of every microorganism that grows.
Sputum cultures, gram stains, urine antigens and biomarkers for respiratory tract infections
As alluded to in the Infectious Diseases Society of America’s guidelines on the management of community-acquired pneumonia, the low yield and infrequent positive impact of commonly ordered tests on clinical care argue against their routine use. These include blood and sputum cultures, sputum gram stain, urine antigens (eg, pneumococcal and Legionella), and perhaps the biomarker procalcitonin. Other than data collection specifically for epidemiologic and antimicrobial susceptibility study purposes, these tests may best be used when limited to selected groups of patients who have clinical or epidemiologic indications for more extensive diagnostic testing (ie, ICU admission, altered immunologic status or pulmonary anatomy, recent travel, etc.). Randomized studies involving the routine requisition of these tests have failed to demonstrate any significant effect on either mortality or length of stay between patients getting pathogen-directed therapy and those receiving empiric therapy. Furthermore, up until now, most studies have failed to verify a meaningful influence on either the stopping or de-escalation of antimicrobial therapy. However, the same conclusions may not apply in cases of hospital-acquired and ventilator-associated pneumonia. Conceivably, delegating the selection and interpretation of supplemental respiratory tract diagnostic tests to clinicians possessing the greatest degree of knowledge in ID and microbiology would deliver the greatest advantage.
Stool cultures and tests for parasites
If an infectious cause of diarrhea that developed in patients who have been hospitalized for more than 48 hours is considered, testing for Clostridioides difficile is the only diagnostic study that is warranted. A retrospective analysis conducted in a 450-bed acute-care hospital determined that from the several hundred samples submitted for culture with the above-mentioned scenario, on no occasion was a clinically significant pathogen isolated. This finding prompted an automatic cancellation in the computerized ordering system for such test orders. Likewise, fecal leukocyte examination (WBCs) and stool lactoferrin (a surrogate marker for stool WBCs) detection are poor determinants of infectious causes of diarrhea, particularly among inpatients, and they should be eliminated. Similarly, obtaining stool cultures in afebrile outpatients with acute onset of watery diarrhea is highly unlikely to yield positive results for a bacterial pathogen. Also, examination of stool for ova and parasites should be obtained only in patients with diarrhea for more than 2 days plus an appropriate travel history; suspicion of Giardia or Cryptosporidium infection; bloody diarrhea with few or no fecal WBCs; HIV infection; or in men who have sex with men. It should never be obtained in patients who develop diarrhea in the hospital.
C. difficile diagnostic testing
In hospitalized patients, C. difficile is the most common pathogen linked with diarrhea, and it is the leading cause of health care-associated infections. Most, if not all, health care centers have implemented either a two-step algorithm in which glutamate dehydrogenase antigen (GDH) plus toxin A/B immunoassay (EIA) combination testing is followed by PCR only for discrepant GDH/EIA results, or nucleic assay amplification testing (NAAT) is employed alone. In either case, a positive NAAT test does not distinguish colonization from active disease, resulting in a hospital’s C. difficile rate being directly proportional to the number of tests sent. Notwithstanding an incorrect diagnosis, other potentially harmful consequences that may stem from this practice include unnecessary antibiotic treatment and the placement of patients in contact isolation.
Another misuse of the laboratory is sending follow-up studies for C. difficile following response to therapy because tests may remain positive despite clinical response and cure.
Improper timing of vancomycin blood levels
The increased prevalence of MRSA infections has fueled the use of vancomycin — both empirically and for proven infection. As a direct result of increased exposure to this glycopeptide antibiotic, we have experienced a steady and persistent rise in the minimal inhibitory concentration of the agent against a significant proportion of MRSA strains. Based on pharmacokinetic and pharmacodynamic parameters, in order to optimize antimicrobial activity and clinical outcomes, the recommended trough level for vancomycin when treating deep-seated MRSA infections is between 18 and 20 µg/mL, which has led to a substantial upswing in vancomycin-related nephrotoxicity. Therefore, vancomycin trough levels are recommended to both predict vancomycin efficacy and limit acute kidney injury. One retrospective study analyzing 2,597 vancomycin levels determined that 41.3% were drawn too early, providing an overestimation of the patient’s true trough level. Based on this skewed laboratory result, clinicians were more likely to decrease, discontinue or hold a patient’s vancomycin dose with the inherent risk of decreasing treatment efficacy.
Molecular microbiologic tests
Until recently, conventional culture on microbiological media and identification by biochemical tests was the “gold standard” microbial detection method used in clinical microbiology laboratories. Over the past few years, accelerated advancements in technology permitting the identification of genetic material within a microbial cell has provided the microbiology laboratory with several tools at its disposal (eg, 16S rDNA sequencing, matrix-assisted laser desorption ionization time-of-flight mass spectrometry and multiplex-PCR), allowing for rapid and accurate identification of an array of potential bacterial and viral pathogens at one time. Of these, multiplex-PCR testing, which does not require culturing of the sample and has proven to be specific, sensitive, rapid and accurate, has garnered the most attention and is the most frequently used. Available today are panels specifically designed to diagnose respiratory tract, central nervous system, gastrointestinal and bloodstream infections. Simplified modifications have paved the way for molecular point-of-care testing. Proper use of these new techniques will require development of guidelines for their application.
Conclusion
Moving forward, in the interest of effective laboratory utilization, and in the spirit of “evidence-based medical practice,” the question that needs to be asked and answered is, “Does there exist objective evidence that old as well as new technologies in clinical microbiology — irrespective of their focus — have contributed positively to the care of patients with infection?”
Together with our professional laboratory colleagues, we in the ID community need to take the lead in developing, enacting and governing realistic and effective laboratory stewardship interventions, and then educate others. Otherwise, we run the risk of being subjected to and measured by standards put into place by people with less expertise and real-world experience.
- For more information:
- Larry M. Bush, MD, FACP, is an affiliated professor of biomedical sciences at the Charles E. Schmidt College of Medicine, Florida Atlantic University, and affiliated associate professor of medicine at the University of Miami Miller School of Medicine, JFK Medical Center, Palm Beach County, Florida.
- Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
Disclosures: Bush and Kaye report no relevant financial disclosures.