Get the content you want anytime you want.

Diagnostic Stewardship: Beyond Managing Bloodstream Infections

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.1,2

Diagnostic stewardship, however, is a novel concept that has not been fully defined and elucidated and has, in fact, even been refuted.3,4 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).3 Interventions related to diagnostic stewardship are meant to alter the processes before antimicrobials are prescribed and thus work synergically with AMS initiatives (Figure).5

Urinary tract infections (UTIs) represent one of the most commonly reported infectious diseases; however, inap- propriate diagnosis and management are common.6,7 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.8 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.9 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.10

Diagnostic stewardship initiatives to decrease inappropriate treatment of ASB target all 3 phases, from preanalytic to postanalytic.11 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.12,13 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.14,15 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.16 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.17-20 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—reporting requires a sepa- rate call to the clinical microbiology laboratory.21-23

Health care professionals are increasingly recognizing the importance of differentiating true Clostridioides difficile infection (CDI) from colonization, representing a prime opportunity to implement diagnostic stewardship initiatives.24,25 For instance, although the gold standard for identifying C difficile 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.26,27 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.28,29 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.30

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.31,32 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.

There is considerably less literature specifically focused on diagnostic stewardship initiatives for the management of lower respiratory tract infections (LRTIs).33 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.34 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.35 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.36-38 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.39,40 In the postanalytic phase, microbiological nudges have demonstrated success in de-escalating antimicrobial therapy, in particular highlighting the lack of drug-resistant pathogens isolated.41 Selective release of antimicrobial susceptibility information demonstrated the ability to prevent initiation of antimicrobials.42

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

1. Antimicrobial Stewardship | Joint Commission. Resources related to antimicrobial stewardship for health care settings. Accessed February 25, 2019.
2. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-e77. doi:10.1093/cid/ciw118.
3.Morgan DJ, Malani P, Diekema DJ. Diagnostic stewardship—leveraging the laboratory to improve antimicrobial use. JAMA. 2017;318(7):607-608. doi:10.1001/jama.2017.8531.
4. Dyar OJ, Moran-Gilad J, Greub G, Pulcini C. Diagnostic stewardship: are we using the right term? Clin Microbiol Infect. 2019;25(3):272-273. doi:10.1016/j.cmi.2018.12.011.
5. Morgan DJ, Croft LD, Deloney V, et al. Choosing wisely in healthcare epidemiology and antimicrobial stewardship. Infect Control Hosp Epidemiol. 2016;37(7):755-760. doi:10.1017/ice.2016.61.
6. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am. 2014;28(1):1-13. doi:10.1016/j.idc.2013.09.003.
7. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284. doi:10.1038/nrmicro3432.
8. Nicolle LE, Gupta K, Bradley SF, et al. Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2019 May 2;68(10):e83-e110. doi: 10.1093/cid/ciy1121.
9. Gupta K, O’Brien W, Gallegos-Salazar J, Strymish J, Branch-Elliman W. How testing drives treatment in asymptomatic patients: level of pyuria directly predicts probability of antimicrobial prescribing [published online ahead of print August 30, 2019]. Clin Infect Dis. 2019 Aug 30. pii: ciz861. doi: 10.1093/cid/ciz861.
10. Leis JA, Gold WL, Daneman N, Shojania K, McGeer A. Downstream impact of urine cultures ordered without indication at two acute care teaching hospitals. Infect Control Hosp Epidemiol. 2013;34(10):1113-1114. doi:10.1086/673151.
11. Claeys KC, Blanco N, Morgan DJ, Leekha S, Sullivan KV. Advances and challenges in the diagnosis and treatment of urinary tract infections: the need for diagnostic stewardship. Curr Infect Dis Rep. 2019;21(4):11. doi:10.1007/s11908-019-0668-7.
12. Egger M, Balmer F, Friedli-Wüthrich H, Mühlemann K. Reduction of urinary catheter use and prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in internal medicine: before-and-after intervention study. Swiss Med Wkly. 2013;143:w13796. doi:10.4414/smw.2013.13796.
13. Trautner BW, Grigoryan L, Petersen NJ, et al. Effectiveness of an antimicrobial stewardship approach for urinary catheter-associated asymptomatic bacteriuria. JAMA Intern Med. 2015;175(7):1120-1127. doi:10.1001/jamainternmed.2015.1878.
14. Keller SC, Feldman L, Smith J, Pahwa A, Cosgrove SE, Chida N. The use of clinical decision support in reducing diagnosis of and treatment of asymptomatic bacteriuria. J Hosp Med. 2018;13(6):392-395. doi:10.12788/jhm.2892.
15.  Shirley D, Scholtz H, Osterby K, Musuuza J, Fox B, Safdar N. Optimizing inpatient urine culture ordering practices using the electronic medical record: a pilot study. Infect Control Hosp Epidemiol. 2017;38(4):486-488. doi:10.1017/ice.2016.301.
16. Jones CW, Culbreath KD, Mehrotra A, Gilligan PH. Reflect urine culture cancellation in the emergency department. J Emerg Med. 2014;46(1):71-76. doi:10.1016/j.jemermed.2013.08.042.
17. Hertz JT, Lescallette RD, Barrett TW, Ward MJ, Self WH. External validation of an ED protocol for reflex urine culture cancelation. Am J Emerg Med. 2015;33(12):1838-1839. doi:10.1016/j.ajem.2015.09.026.
18. Fakih MG, Advani SD, Vaughn VM. Diagnosis of urinary tract infections: need for a reflective rather than reflexive approach. Infect Control Hosp Epidemiol. 2019;40(7):834-835. doi:10.1017/ice.2019.98.
19. Epstein L, Edwards JR, Halpin AL, et al. Evaluation of a novel intervention to reduce unnecessary urine cultures in intensive care units at a tertiary care hospital in Maryland, 2011-2014. Infect Control Hosp Epidemiol. 2016;37(5):606-609. doi:10.1017/ice.2016.9.
20. Stagg A, Lutz H, Kirpalaney S, et al. Impact of two-step urine culture ordering in the emergency department: a time series analysis [published online ahead of print May 3, 2017]. BMJ Qual Saf. 2018 Feb;27(2):140-147. doi:10.1136/bmjqs-2016-006250.
21. Leis JA, Rebick GW, Daneman N, et al. Reducing antimicrobial therapy for asymptomatic bacteriuria among noncatheterized inpatients: a proof-of-concept study. Clin Infect Dis. 2014;58(7):980-983. doi:10.1093/cid/ciu010.
22. Linares LA, Thornton DJ, Strymish J, Baker E, Gupta K. Electronic memorandum decreases unnecessary antimicrobial use for asymptomatic bacteriuria and culture-negative pyuria. Infect Control Hosp Epidemiol. 2011;32(7):644-648. doi:10.1086/660764.
23. McNulty CAM, Lasseter GM, Charlett A, et al. Does laboratory antibiotic susceptibility reporting influence primary care prescribing in urinary tract infection and other infections? J Antimicrob Chemother. 2011;66(6):1396-1404. doi:10.1093/jac/dkr088.
24. Yen C, Holtom P, Butler-Wu SM, Wald-Dickler N, Shulman I, Spellberg B. Reducing Clostridium difficile colitis rates via cost-saving diagnostic stewardship. Infect Control Hosp Epidemiol. 2018;39(6):734-736. doi:10.1017/ice.2018.51.
25. Rock C, Maragakis LL. Diagnostic stewardship for Clostridiodes difficile testing: from laxatives to diarrhea and beyond. Clin Infect Dis. October 2019. doi:10.1093/cid/ciz982.
26. Gerding DN, File TM, McDonald LC. Diagnosis and treatment of Clostridium difficile infection (CDI). Infect Dis Clin Pract (Baltim Md). 2016;24(1):3-10. doi:10.1097/IPC.0000000000000350.
27. Collins DA, Elliott B, Riley TV. Molecular methods for detecting and typing of Clostridium difficile. Pathology. 2015;47(3):211-218. doi:10.1097/PAT.0000000000000238.
28. Crobach MJT, Planche T, Eckert C, et al. European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2016;22(suppl 4):S63-81. doi:10.1016/j.cmi.2016.03.010.
29. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085.
30. Schultz K, Sickbert-Bennett E, Marx A, et al. Preventable patient harm: a multidisciplinary, bundled approach to reducing Clostridium difficile infections while using a glutamate dehydrogenase/toxin immunochromatographic assay/nucleic acid amplification test diagnostic algorithm. J Clin Microbiol. 2018;56(9). doi:10.1128/JCM.00625-18.
31. Madden GR, German Mesner I, Cox HL, et al. Reduced Clostridium difficile tests and laboratory-identified events with a computerized clinical decision support tool and financial incentive. Infect Control Hosp Epidemiol. 2018;39(6):737-740. doi:10.1017/ice.2018.53.
32. White DR, Hamilton KW, Pegues DA, Hanish A, Umscheid CA. The impact of a computerized clinical decision support tool on inappropriate Clostridium difficile testing. Infect Control Hosp Epidemiol. 2017;38(10):1204-1208. doi:10.1017/ice.2017.161.
33. Timbrook TT. Antimicrobial stewardship and implementation of rapid multiplex respiratory diagnostics: is there method in the madness? [published online ahead of print October 22, 2019]. Clin Infect Dis. pii: ciz1046. doi:10.1093/cid/ciz1046. 
34. Pavia AT. What is the role of respiratory viruses in community-acquired pneumonia?: What is the best therapy for influenza and other viral causes of community-acquired pneumonia? Infect Dis Clin. 2013;27(1):157-175.
35. Vos LM, Bruning AHL, Reitsma JB, et al. Rapid molecular tests for influenza, respiratory syncytial virus, and other respiratory viruses: a systematic review of diagnostic accuracy and clinical impact studies. Clin Infect Dis. 2019;69(7):1243-1253. doi:10.1093/cid/ciz056.
36. Mercuro NJ, Kenney RM, Samuel L, Tibbetts RJ, Alangaden GJ, Davis SL. Stewardship opportunities in viral pneumonia: why not the immunocompromised? Transpl Infect Dis. 2018;20(2):e12854. doi:10.1111/tid.12854.
37. Semret M, Schiller I, Jardin BA, et al. Multiplex respiratory virus testing for antimicrobial stewardship: a prospective assessment of antimicrobial use and clinical outcomes among hospitalized adults. J Infect Dis. 2017;216(8):936-944. doi:10.1093/infdis/jix288.
38. Bianchini ML, Mercuro NJ, Kenney RM, et al. Improving care for critically ill patients with community-acquired pneumonia. Am J Health Syst Pharm. 2019;76(12):861-868. doi: 10.1093/ajhp/zxz068.
39. Timbrook T, Maxam M, Bosso J. Antibiotic discontinuation rates associated with positive respiratory viral panel and low procalcitonin results in proven or suspected respiratory infections. Infect Dis Ther. 2015;4(3):297-306. doi:10.1007/s40121-015-0087-5.
40. Moradi T, Bennett N, Shemanski S, Kennedy K, Schlachter A, Boyd S. Use of procalcitonin and a respiratory polymerase chain reaction panel to reduce antibiotic use via an EMR alert [published online ahead of print October 22, 2019]. Clin Infect Dis. pii: ciz1042. doi: 10.1093/cid/ciz1042.
41. Musgrove MA, Kenney RM, Kendall RE, et al. Microbiology comment nudge improves pneumonia prescribing. Open Forum Infect Dis. 2018;5(7):ofy162. doi:10.1093/ofid/ofy162.
42. Cunney R. Interpretative reporting and selective antimicrobial susceptibility release in non-critical microbiology results. J Antimicrob Chemother. 2000;45(5):705-708. doi:10.1093/jac/45.5.705.

>> Read more Stewardsip and Prevention articles:
December 2019: What's on Your Antimicrobial Stewardship "Wish List"?
October 2019: "Antibiotic Never Events": The Ideal Target to Reduce Antimicrobial Exposure
August 2019: Maximize Contact and Minimize Isolation

Advocacy and Research Foundation Partners
Is there a cure? How long until we find it? And will it work for the majority of people living with HIV?