Rapid Diagnostics for Blood Cultures: Supporting Decisions for Antimicrobial Therapy and Value-Based Care

Address correspondence to this author at: Geisinger Health, 100 N Academy Ave., Danville, PA 17822-1930. Fax 570-214-9792; e-mail dmwolk@geisinger.edu.

The Journal of Applied Laboratory Medicine, Volume 3, Issue 4, 1 January 2019, Pages 686–697, https://doi.org/10.1373/jalm.2018.028159

Cite

Donna M Wolk, J Kristie Johnson, Rapid Diagnostics for Blood Cultures: Supporting Decisions for Antimicrobial Therapy and Value-Based Care, The Journal of Applied Laboratory Medicine, Volume 3, Issue 4, 1 January 2019, Pages 686–697, https://doi.org/10.1373/jalm.2018.028159

Abstract

Bacteremia and sepsis are critically important syndromes with high mortality, morbidity, and associated costs. Bloodstream infections and sepsis are among the top causes of mortality in the US, with >600 deaths each day. Most septic patients can be found in emergency medicine departments or critical care units, settings in which rapid administration of targeted antibiotic therapy can reduce mortality. Unfortunately, routine blood cultures are not rapid enough to aid in the decision of therapeutic intervention at the onset of bacteremia. As a result, empiric, broad-spectrum treatment is common—a costly approach that may fail to target the correct microbe effectively, may inadvertently harm patients via antimicrobial toxicity, and may contribute to the evolution of drug-resistant microbes. To overcome these challenges, laboratorians must understand the complexity of diagnosing and treating septic patients, focus on creating algorithms that rapidly support decisions for targeted antibiotic therapy, and synergize with existing emergency department and critical care clinical practices put forth in the Surviving Sepsis Guidelines.

Patients infected with bacteria in their bloodstream can benefit from deployment of laboratory technology that is more rapid and more accurate than historical methods. This review will characterize the current and novel laboratory technology and the potential effect of technology to improve care for patients with blood stream infections. The review provides a snapshot of emerging technologies for laboratorians to consider as they strategize about how best to support quality initiatives focusing on sepsis in their organizations.

DEFINING PRECISION THERAPY BASED ON RAPID DIAGNOSIS OF BLOODSTREAM INFECTIONS

Given the disease severity of bloodstream infections, rapid identification of microbes has become increasingly important, with impact observed in clinical, operational, and financial outcomes in a variety of hospital settings ( 1– 7). Conflicting single-center reports exist ( 8, 9), some originating in centers with strong antimicrobial stewardship presence and others with more limited antimicrobial stewardship. Most reports indicate that faster results can be linked to more timely antibiotic stewardship to optimize the effectiveness of the intervention on downstream outcomes ( 1, 3, 5, 10– 16).

We can use the terms “personalized therapy” or “precision therapy” for bloodstream infections to best describe the practice of antimicrobial deescalation or escalation based on laboratory results. The importance of rapid diagnosis of bacterial and fungal infections is thought to be especially important for high-risk patient groups, but well-designed and well-controlled pragmatic multi-site clinical studies are needed to confirm this assumption and document the clinical utility of rapid reporting.

CLINICAL MICROBIOLOGY LABORATORY'S ROLE IN VALUE-BASED CARE AND PATIENT SAFETY

The clinical microbiology laboratory supports a critical partnership with emergency departments, critical care services, oncology, transplant, antimicrobial stewardship programs, and infection prevention initiatives. The laboratory strives to provide rapid pathogen identification, with which providers can optimize antimicrobial utilization and improve patient outcomes. The use of rapid diagnostics performed on positive blood culture broths revealed the effect on sepsis mortality and operational outcomes for adult and pediatric patients with bacteremia or fungemia ( 2, 3, 15, 17– 21). In other studies, only operations and costs of care were assessed ( 13, 22). In 2008, one study opened a window of opportunity for microbiology laboratories to improve sepsis mortality ( 21); however, the sample size was small. In this study, in a cohort of 99 patients, a 9.1% decrease in mortality occurred when Gram stain results from positive bottles were reported

Microbiology laboratories play a key role in supporting the objectives and operations of an antimicrobial stewardship program. Primary responsibilities include antimicrobial susceptibility testing, rapid testing, and actionable reporting.

• Diagnostic tests should be used wisely to avoid unnecessary antibiotic therapy and unnecessary broad-spectrum therapy (i.e., less antibiotic pressure based on the ability to de-escalate antibiotics, based on diagnostic results).
• Rapid diagnostic tests, biomarkers, and decision rules that have acceptable performance characteristics to differentiate bacterial vs nonbacterial infection should be used to avoid the use of unnecessary antibiotic therapy.
• Bacterial cultures with antimicrobial susceptibility testing (AST) 3 should be collected, handled, and processed promptly and appropriately to identify specific bacteria and facilitate the use of narrow-spectrum antibiotics.
• When available and appropriate for the infection and the bacterial isolate, molecular testing to identify specific resistance genes (for example, mecA or mecC in Staphylococcus spp., vanA or vanB in Enterococcus spp.) or novel nonculture-based phenotypic assays of susceptibility may be used to target antibiotic therapy toward susceptible or resistant isolates.
• Laboratories should avoid diagnostic testing without an appropriate clinical indication—results may have unintended consequences.

The mind-set that the laboratory is merely a cost center completely ignores the fact that delayed laboratory results can diminish care, add expenses, and become the foundation for the loss of reimbursements tied to quality measures from the Centers for Medicare & Medicaid Services when the institute's sepsis mortality rate is higher than expected.

As with all complex diseases, the diagnostic approach to sepsis is multifaceted. Laboratory collaboration with emergency departments and critical care services is essential. Laboratories can participate in healthcare team efforts by providing rapid laboratory testing to maximize the effectiveness of early goal-directed therapy, improve targeted antibiotic therapy, shorten antibiotic treatment duration, avoid development of antibiotic resistance and side effects, decrease mortality and morbidity, decrease the length of stay, and decrease overall hospital costs.

Because the initial diagnosis remains a clinical one ( 25), the clinical microbiology laboratory must help drive antibiotic intervention in partnership with pharmacists and physicians. On presentation of a patient with symptoms of infection, physicians will seek the primary site of infection and attempt to direct therapy to that primary site. This process is known as “source control.” Full patient history is important to define the potential source and risks. For instance, key factors include the source of inflammation, community- or hospital-acquired status, prior or current medications received, recent manipulations or surgery, underlying or chronic diseases, and travel history.

Combining a variety of clinical assessments with various laboratory tests from clinical microbiology, hematology, chemistry, point-of-care testing, and blood gas laboratories is an important aspect of the optimum care and treatment of septic patients. Also, there are several standardized classification systems, created to assess the severity of illness ( 26); one common scoring system is the Acute Physiology and Chronic Health Evaluation (APACHE II SCORE). In summary, because of associated multiple-organ dysfunction in septic patients, death can occur rapidly, so improvements in diagnosis and treatment may require rapid identification and characterization of complex symptoms.

CLINICAL MICROBIOLOGY LABORATORY'S ROLE DOCUMENTING VALUE-BASED CARE AND EVIDENCE-BASED LABORATORY MEDICINE BY PARTICIPATING IN QUALITY INITIATIVES AND OUTCOME STUDIES

Measuring the effect of rapid reporting of pathogens is difficult but important for several reasons. Perhaps the most important is the use of microbiology results to deescalate broad-spectrum antibiotics on the basis of Gram stain or molecular identification of the pathogen or resistance gene. Rapid targeting of antibiotics can minimize unintended consequences of antimicrobial use, such as toxicity, disruptions in the microbiome, and the emergence of resistance. Nevertheless, few studies are designed to characterize the study cohorts fully, and the healthcare infrastructure for pragmatic studies is rarely well defined, making it difficult to generalize study results. In some publications, limited attempts were made to characterize study cohorts regarding demographics and confounders ( 21), and some used dedicated study staff, focused on the function of antimicrobial reassessment ( 27). In part, because of these and other study limitations, the 2016 attempt to create a laboratory medicine guideline for rapid diagnostics met with the limitation of too few data sets to make a laboratory recommendation definitively ( 18). Although a trend was documented in the systematic review and metaanalysis, at the time of publication, no definitive guidelines could be issued ( 18). The study is being repeated to include newly identified data from recently published studies that were unavailable at the time the systematic review was performed.

Relevant outcomes metrics may be categorized into 3 groups: clinical outcome measures, operational or process measures, and financial measures. Examples of clinical measures that affect the quality of life include clinical cure (e.g., “clearance” of a bloodstream infection from blood cultures), incidence of 30-day, 90-day, and 120-day mortality, 30-day readmission, or adverse drug reactions. Examples of process measures include the duration of antimicrobial therapy and time to antimicrobial optimization (e.g., through escalation, in which a narrow-spectrum antimicrobial regimen is broadened, or through deescalation, which involves the reverse). Other examples include the length of stay (LOS) and number of laboratory tests ordered. Examples of financial outcome measures may include total hospital costs per visit, total laboratory costs, or federal reimbursement from sepsis quality measures.

To assess the potential outcomes of rapid diagnostics, one must ensure that the clinical environment remains fixed and that system best practice metrics remain constant during the time of assessment. Antimicrobial therapy choices would need to be informed by the same antimicrobial stewardship instructions for suspected and confirmed cases of sepsis. Examples of outcome metrics and confounding variables can be found in Buehler et al. ( 18).

One of the areas that affect the rapid reporting process is the delay in blood culture transport, which can postpone time to detection for positive blood cultures ( 28) and thus actionable laboratory results. Several laboratory documents cite 4 h as an acceptable transport time ( 29); however, there are no published well-controlled experiments or clear biological proof confirming that time frame is optimal for growth of a diverse variety of microbes or that 4 h delay does not affect patient outcomes. This fact is especially unsettling because new blood culture instruments can flag positive bottles in as little as 6–24 h, so delays in courier transport represent a larger proportion of time when compared to a decade ago.

In cases of sepsis, rapid intervention with appropriate antimicrobial therapy can be critical to patient survival ( 30– 32). In reports describing mortality for bloodstream infection caused by aerobes, anaerobes, and fungi, appropriate antibiotic therapy increases survival by over 25% ( 2, 3, 15, 17– 21, 18). Eliminating delays in appropriate antibiotic administration is said to increase survival by approximately 7%–10% per hour ( 33). Optimized antibiotic care requires intravenous broad-spectrum antibiotics with a daily reevaluation to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs with the goal to discontinue broad-spectrum expediently ( 34).

The Infectious Diseases Society of America published a guidance document describing the role of antimicrobial stewardship programs to be that of “optimizing clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms, and the emergence of resistance” ( 23). Tactics include the use of empirical treatment adherence to published guidelines, deescalation of antimicrobial treatment, a switch from intravenous to oral antibiotics, therapeutic drug monitoring, and the use of restricted antimicrobial lists on clinical outcomes and hospital costs ( 23).

RAPID MOLECULAR METHODS FOR THE DIAGNOSIS OF SEPSIS AND BACTEREMIA

Microbiology detection methods to characterize microbial pathogens and host response patterns are historically too slow, too insensitive, or too nonspecific to support differential diagnosis for early goal-directed therapy strategies. They also do not fully assess the complexities of the host immune response during sepsis, which appears critical to the understanding of associated multiple-organ dysfunction and death. Because of the complex nature of sepsis, there is no single laboratory test that can combine with clinical information to assess health outcomes or describe a time course of certain key biomarkers (i.e., proinflammatory cytokines and chemokines and markers of neutrophil and monocyte activation). Such a multicomponent test will be the key to unraveling the parallel and complex disease processes in sepsis and to providing clinicians with a tool for detection, prognosis, and therapeutic monitoring of sepsis.

Historical immunological and molecular methods are impractical for detecting the complex patterns of immune responses in sepsis. Therefore, given the wide variety of pathogens that can cause disease, clinical microbiology laboratories could benefit from using the approach of “sepsis diagnostic panels” that combine detection of pathogens and key aspects of the patient's innate and systemic immune response. One novel approach is the Immunexpress SeptiCyte LAB assay, which produces a 4-gene expression blood-based signature and discriminates viral and nonviral causes of systemic inflammation ( 35). Full review of this approach is beyond the scope of this review.

Also, sensitive genotypic and phenotypic predictors of antibiotic resistance and pharmacogenomic markers of potential drug toxicity will play a role in the not-too-distant future. It will be critical to offset costs of new rapid methods with overall reductions of hospital costs or improvements in patient care. For the laboratory to effect these changes, a team approach relying on interaction with pharmacists, physicians, and other healthcare staff, to determine the most judicious use of these methods, will be necessary. One approach may include selective testing on only high-risk patients, who may benefit most from rapid testing. Discussion with healthcare finance and reimbursement teams and antimicrobial use teams are critical for the proper test use decisions to be made. Considering the complexity and urgency of the diagnostic challenges we face, this section summarizes the most recent published developments in the diagnosis of sepsis and bacteremia, which affect clinical microbiology laboratories.

One final challenge involves bacterial contamination of blood cultures during collection of samples. Testing a high percentage of skin contaminants in positive blood cultures with rapid diagnostics can be costly, labor-intensive, and lead to unnecessary antimicrobial therapy; therefore, it is prudent to limit the percentage of skin contaminants recovered from blood culture bottles. Skin and line antisepsis is critical to prevent blood culture contamination. Since the advent of chlorhexidine gluconate skin preparation for blood culture collection, a

FOOD AND DRUG ADMINISTRATION–APPROVED MOLECULAR METHODS FOR TESTING BLOOD CULTURE BOTTLES ( TABLE 1)

Characteristics of rapid diagnostics for testing positive blood cultures.