KIMBERLY C. CLAEYS, PHARMD, BCPS*+

Antimicrobial stewardship (AMS) has been recognized at the national level for its importance in stemming the tide of antimicrobial resistance and improving public health through decreased inappropriate antimicrobial use. With accreditation standards and organizationally endorsed guidelines for implementation, the core concepts of AMS have become established within acute care practice.

Diagnostic stewardship, however, is a novel concept that has not been fully defined and elucidated and has, in fact, even been refuted.

 In particular, these interventions target the preanalytic phase (when tests are being ordered), analytic phase (the performance of the diagnostic test itself), and postanalytic phase (reporting of diagnostic results once the test has been complete).

 Interventions related to diagnostic stewardship are meant to alter the processes before antimicrobials are prescribed and thus work synergically with AMS initiatives (

DIAGNOSTIC STEWARDSHIP AND URINARY TRACT INFECTIONS

Urinary tract infections (UTIs) represent one of the most commonly reported infectious diseases; however, inap- propriate diagnosis and management are common.

 Differentiation of UTIs from asymptomatic bacteriuria (ASB) remains a common clinical challenge, as the presence of white blood cells or bacteria in the urine is not, in itself, indicative of a UTI.

 Evidence demonstrates that the presence of a high level of pyuria or a positive urine culture test result, despite a lack of signs and symptoms of infection, are major drivers for antimicrobial prescribing.

 From an AMS perspective, patients are often reviewed after the diagnosis has been made, limiting the ability to alter the course of care. As such, inappropriate treatment of ASB often leads to unnecessary antibiotic exposure and increases the risk of adverse drug events and development of resistance.

Diagnostic stewardship initiatives to decrease inappropriate treatment of ASB target all 3 phases, from preanalytic to postanalytic.

 In the preanalytic phase, it is imperative to limit the unwarranted ordering of urinalyses and urine cultures—in particular, urinalyses that reflex to culture when there was no intent to culture. Decreasing inappropriate ordering of urine cultures can be achieved through a combination of educational initiatives, written guidance, and electronic alerts while ordering. Through a combination of these initiatives and provider feedback, investigators have been able to demonstrate significant reductions in both rates of urine cultures ordered and treatment of ASB.

Additiona lclinical decision support with best practice alerts or requirements for documentation of symptoms in the electronic medical record can also be used to discourage inappropriate ordering of urine cultures.

 Another novel approach is the implementation of conditional urine reflex culture policies. When urinalysis and culture are ordered, the culture is not completed unless meeting specific criteria such as WBC > 10 cells per high-power field.

 Several quasi-experimental studies have shown an immediate decrease in rates of urine cultures performed after implementing conditional urine reflex; however, implica- tions for antimicrobial prescribing have not been extensively studied.

 In the postanalytic phase, there are published methods aimed at decreasing treatment after an inappro- priate urine culture has been ordered—including educational memoranda, selective susceptibility reporting, and complete cessation of urine culture results&mdash;reporting requires a sepa- rate call to the clinical microbiology laboratory.

Health care professionals are increasingly recognizing the importance of differentiating true 

 infection (CDI) from colonization, representing a prime opportunity to implement diagnostic stewardship initiatives.

 For instance, although the gold standard for identifying 

 is cell culture cytotoxicity neutralization assay, it is a labor-intensive method and not commonly employed. Instead, nucleic acid amplification tests (eg, polymerase chain reaction and loop-mediated isothermal amplification) tend to be used in routine clinical practice.

 These molecular tests detect the genes responsible for toxin production and have reported sensitives greater than 99%. These tests with extremely high sensitivity have the risk of low positive predictive values as the prevalence of true infection decreases. As such, when there is low pretest probability, a false-positive test result becomes more likely (Figure 2). This is particularly true in patients with unclear signs and symptoms of infection. The 2016 European Society of Clinical Microbiology and Infectious Diseases and 2018 IDSA guidance for the diagnosis and management of CDI recommend, in conjunction with clin- ical signs and symptoms of infection, a 2-step diagnostic algo- rithm to improve positive predictive performance.

To help differentiate colonization from true infection and decrease diagnosis and treatment of false positives, infection control programs have started to implement these multistep testing algorithms, requiring both a polymerase chain reaction and toxin-positive test result to diagnose true infection.

Other diagnostic stewardship interventions to limit the incorrect diagnosis of CDI have also been successfully imple- mented in the preanalytic phase. Clinical decision support, such as best practice alerts, hard-stops, and requirements to document signs and symptoms of infection while ordering have all shown potential benefit in limiting inappropriate test ordering.

 Best practice alerts and hard-stops can be applied in particular situations, for instance when a test is ordered within 48 hours of laxative use or within 7 days of a previously negative C difficile test result. The most commonly reported interaction is implementing best practice alerts to notify ordering providers of laxative use within 48 hours before ordering the test.

DIAGNOSTIC STEWARDSHIP AND LOWER RESPIRATORY TRACT INFECTIONS

There is considerably less literature specifically focused on diagnostic stewardship initiatives for the management of lower respiratory tract infections (LRTIs).

 A major challenge faced with the treatment of LRTIs is the differentiation of causative pathogens, with organism identification occurring in less than 40% of infections and 50% of infections caused by viral as opposed to bacterial pathogens.

 Treatment of viral LRTIs with antimicrobial agents is likely commonplace. Molecular rapid diagnostic tests, including multiplex syndromic viral panels have been shown to assist in the identification of causative pathogens and implementation of patient isolation; however, their impact on antimicrobial management has been limited.

 Several studies have demonstrated that days of antimicro- bial utilization or the proportion of patients continued on antimicrobials after identifying viral pathogens remain largely unchanged.

 Publications have also examined the impact of rapid diagnostic tests in combination with procalcitonin monitoring, demonstrating the ability to decrease overall antibiotic use in several studies.

 In the postanalytic phase, microbiological nudges have demonstrated success in de-escalating antimicrobial therapy, in particular highlighting the lack of drug-resistant pathogens isolated.

 Selective release of antimicrobial susceptibility information demonstrated the ability to prevent initiation of antimicrobials.

Interventions related to diagnostic stewardship, with and without active AMS involvement, have shown the ability to decrease inappropriate diagnosis of a variety of infections ulti- mately leading to a decline in unnecessary antimicrobial use. Opportunities exist in all 3 phases of diagnostics from pre- to postanalytical, but it remains imperative that an emphasis be placed on ensuring a high pretest probability to increase diagnostic accuracy and ensure appropriate use of diagnostics as well. Collaboration between AMS and the clinical micro- biology laboratory is key to advance best practices in the management of bacterial infections.

Claeys is an assistant professor specializing in infectious diseases at the University of Maryland School of Pharmacy and Antimicrobial Stewardship Pharmacists at University of Maryland Medical Center.

Noval is a second-year pharmacy resident in infectious diseases at the University of Maryland School of Pharmacy. She completed her PGY-1 pharmacy residency at the University of Maryland Medical Center.

*indicates active members of the Society of Infectious Diseases Pharmacists

+ indicates active member of the Making a Difference in Infectious Diseases Research Network

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KIMBERLY C. CLAEYS, PHARMD, BCPS*+

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