The Confounding Role of Antimicrobial Stewardship Programs in Understanding the Impact of Technology on Patient Care

Abstract

Numerous studies have demonstrated the benefit of the combination of antimicrobial stewardship program (ASP) intervention and rapid diagnostic testing (RDT). However, few studies have attempted to study the incremental benefit of ASP and RDT, making it difficult to understand the true benefits of each intervention. This issue is discussed in the context of an article by S. H. McVane and F. S. Nolte (J Clin Microbiol 54:2476–2484, 2016, http://dx.doi.org/doi:10.1128/JCM.00996-16), with suggestions about how the findings of this study can be applied to other areas of clinical microbiology.

TEXT

The practice of clinical microbiology is classically broken down into three phases: the preanalytical phase, the analytical phase, and the postanalytical phase. The analytical phase of clinical microbiology testing has been so highly standardized that laboratories are able to produce reliable and reproducible results across the United States and around the world. While most resources are dedicated to analytical-phase quality, laboratories are generally less engaged in ensuring quality through the reporting and interpretation (postanalytical) phase. Beyond ensuring that information is communicated accurately for the medical record, little effort is devoted to confirming that that results are actually viewed, much less acted upon appropriately. There are a number of reasons why a clinical microbiology result might fail to have the desired impact on patient care; frequently, though, it is because a result either is not noticed or is misunderstood (1, 2).

At the heart of this issue is the fact that most medical results are communicated passively, through an electronic medical record reporting system. Although these systems are excellent for transmitting information rapidly and accurately, they are also problematic because they present overwhelming quantities of information to providers who may overlook critical results. In addition, the timely observation of microbiology results can be a significant challenge for providers. Unlike many other laboratory results (i.e., chemistry), the timing of microbiology reporting is difficult to predict, and it is therefore impossible for the provider to know when a result will be available in the medical record. This is a tremendous limitation in laboratory reporting and a significant confounder when laboratories implement new technology for improved patient care because, although results may be generated faster, providers may not see them any sooner, thus negating any benefit gained from the improved turnaround time.

Microbiologists are well aware of this limitation, and as a result, we stack the deck in our favor when implementing new diagnostics for the betterment of patient care. A review of studies evaluating the impact of rapid diagnostic testing (RDT) on patient outcomes reveals an important confounding variable: in nearly every case, active reporting was employed in combination with the addition of the new technology. Table 1 summarizes some of these studies and shows that in nearly all cases, the results of the new technology were actively communicated either to the provider directly or to an antimicrobial stewardship program (ASP). In many cases, those results were communicated together with some expert advice as to how they ought to be interpreted and used. This is likely the best way to improve patient care; however, scientifically, we are left to wonder what the true impact of the technology itself was.

TABLE 1.

Summary of outcome-based studies evaluating the impact of rapid diagnostic testing and antimicrobial stewardship program intervention

Laboratory interventionc	Stewardship intervention	Impact on time to laboratory results	Clinical impact	Reference
Rapid verification of identification and AST results	None	AST results reported 5.2 h earlier	Shorter length of hospital stay; lower hospital costs by $2,395 per patient	Barenfanger et al. (3)
Rapid identification and AST (Vitek AutoMicrobic system [Vitek Systems, Inc., Hazelwood, MO, USA]) from positive blood culture bottles	ID fellow intervention	AST results reported 38.2 h earlier	More patients switched to appropriate antibiotic therapy; lowered antibiotic costs by $158 per patient	Trenholme et al. (4)
Rapid identification (Baxter-Microscan WalkAway-96 System, (Sacramento, CA, USA]) and AST from routine culture	Direct notification of physician by laboratory	AST results reported 16.3 h earlier; identification results reported 8.6 h earlier	Significant reduction in 30-day all-cause mortality; fewer laboratory tests; lower hospital costs by ∼$4,000 per patient	Doern et al. (5)
Rapid identification of enterococci (PNA FISH [AdvanDx, Woburn, MA, USA]) from positive blood culture bottles	ID and antimicrobial stewardship team intervention	Final microbiology results 3 and 2.3 days earlier for E. faecalis and E. faecium infections, respectively	Significant reduction in 30-day all-cause mortality for E. faecium infection; faster time to appropriate antibiotics for E. faecium infections	Forrest et al. (6)
Rapid identification of Candida (PNA FISH) from positive blood culture bottles	ID and antimicrobial stewardship team intervention	Candida identification reported 34–51 h earlier	Lower hospital costs by ∼$1,729 per patient	Forrest et al. (7)
Rapid identification (direct MALDI-TOF MSa) of CoNS from positive bloodstream infection	Antimicrobial stewardship team intervention	CoNS identification reported 26 h earlier	Effective therapy started 23 h earlier; significant reduction in 30-day all-cause mortality; reduced overall vancomycin usage	Nagel et al. (8)
Rapid identification of Gram-negative organisms (multiplex PCR panel) from positive blood culture bottles	Antimicrobial stewardship team pharmacist intervention	Organism identification reported 34 h earlier	Shorter length of ICU stay; significant reduction in 30-day all-cause mortality	Walker et al. (9)
Rapid identification of staphylococci with mecA detection (multiplex PCR panel) from positive blood culture bottles	Antimicrobial stewardship team pharmacist intervention	Time to result not reported	Decreased overall hospital costs by ∼$21,000 per patient; increased rate of antibiotic de-escalation	Bauer et al. (10)
Rapid identification (direct MALDI-TOF MSa) and AST (direct ASTb) for Gram-negative organisms from positive blood culture bottles	Notification of ID pharmacist	Organism identification reported 26 h earlier; AST reported 18 h earlier	Effective therapy started 58 h earlier; reduction in 30-day all-cause mortality	Perez et al. (11)
Rapid identification of enterococci and vanA/vanB detection (multiplex PCR panel) from positive blood culture bottles	Antimicrobial stewardship team intervention	AST result for vancomycin resistance reported 48 h earlier	Effective therapy started 23 h earlier; shorter length of hospital stay; decreased overall hospital costs by ∼$58,000 per patient	Sango et al. (12)
Rapid identification (direct MALDI-TOF MSa) and AST (direct ASTb) from positive blood culture bottles	ID pharmacist intervention	Organism identification reported 25 h earlier than routine culture; AST reported 23 h earlier	Effective therapy started 46 h earlier; shorter length of hospital stay; decrease in overall hospital costs by ∼$19,000 per patient	Perez et al. (13)
Rapid identification and AST (multiplex PCR panel) from positive blood culture bottles	ID pharmacist intervention	Organism identification reported 21 h earlier than routine culture; molecular AST result reported ∼47 h earlier	Antibiotic de-escalation 19 h earlier; effective therapy started 14 h earlier; no difference observed in mortality, length of stay, or cost	Banerjee et al. (14)

^aDirect MALDI-TOF MS refers to the identification of organisms directly from positive blood culture broth using MALDI-TOF MS.

^bDirect AST refers to the performance of AST using an inoculum prepared directly from the positive blood culture broth.

^cCoNS, coagulase-negative staphylococcus; FISH, fluorescent in situ hybridization; ICU, intensive care unit; PNA, peptide nucleic acid.

Few studies have controlled for the variable of active reporting as it pertains to the implementation of new technology. With the addition of expensive technologies such as matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), rapid antimicrobial susceptibility testing (AST), and multiplex PCR, we want to believe that the expense of the added resources is justified by improved patient care. Indeed, some studies have demonstrated impressive improvement in care, both in terms of appropriate prescription of antibiotics and in terms of lengths of stay, mortality, and hospital costs (Table 1). However, other studies using much simpler technologies have shown similar improvements (15). For example, Doern et al. showed that the addition of “rapid” disk diffusion testing using positive blood cultures reduced patient mortality (15). Another interesting study showed that simply providing Gram stain results by telephone versus not phoning the results significantly reduced patient mortality (16). It is likely that the improved patient care demonstrated by these studies has more to do with the difference between the old and new diagnostic technologies than it does with the technology itself. Nonetheless, it is difficult to know whether it is the technology or the reporting mechanism that is responsible for improving patient outcomes.

MacVane and Nolte present the results of a unique study in which they evaluated the incremental impact of ASP as well as RDT testing on the care of patients with bloodstream infection (17). In their study, they controlled for active reporting by evaluating an ASP-only period, followed by a period where ASP and RDT were combined. In addition, they included a pre-ASP, pre-RDT control period, which allowed them to draw conclusions about the incremental impact of both ASP and the combination of ASP and RDT.

The most important and most striking finding from the study is that the ASP-plus-RDT period had a significantly reduced time to effective antibiotic therapy (4.9 h) versus both the ASP-only period and the preintervention control period (13 h and 15 h, respectively). In addition, they found no difference between the results from the ASP-only period and those from the preintervention period, which suggests that ASP had little impact on the time to effective antimicrobial therapy. This is an important finding because few studies have included the unique dual-control (no-ASP and ASP-only) study design which would allow this comparison. Most of the studies highlighted in Table 1 represent comparisons between ASP-only interventions and ASP-plus-RDT interventions. If an ASP-only control is not included, then the comparisons are made between a no-ASP control group and an ASP-plus-RDT intervention group. In either case, it is impossible to know the incremental impacts of ASP and RDT.

While the findings of MacVane and Nolte suggest that RDT played a more important role than ASP in reducing the time to effective antibiotic therapy, their analysis of antibiotic de-escalation clearly shows the importance of ASP. These data show that both the ASP-only and the ASP-plus-RDT periods led to de-escalation in 56.7% and 52.4% of cases within the first 96 h, compared with only 33.9% of patients in the no-ASP group. However, the average time to de-escalation was 12 h earlier in the ASP-plus-RDT group than in the ASP-only and the no-ASP groups.

The limitation of the study is that it lacked the RDT-only control period, leaving the reader with an unanswered question: what impact would RDTs have on patient care in the absence of ASP? To answer this question, we can look to the recent publication by Banerjee et al., who, like MacVane and Nolte, included a dual-control group in their study assessing the impact of RDT for positive blood cultures (14). However, their controls differed from those in the study by MacVane and Nolte because they included an RDT-only group rather than an ASP-only group. Interestingly, Banerjee et al. found that RDT-only interventions optimized antibiotic selection but that the addition of ASP to RDT enhanced the effect and had a particularly profound impact on antibiotic de-escalation (14). Taken together, the findings presented by MacVane and Nolte as well as Banerjee et al. suggest an additive relationship between RDT and ASP interventions. This conclusion is somewhat intuitive but one that had not been extensively tested in appropriately controlled studies. In summary, we learn from these studies that positive impacts on patient care are best driven by rapid and accurate diagnostic testing that is efficiently translated to patient intervention through integrated ASPs. Based on the overwhelmingly positive outcomes documented by MacVane and Nolte and the studies highlighted in Table 1, microbiologists and ASPs should be empowered by the knowledge that both play a vital role in improving patient care.

In reviewing the literature, it becomes obvious that most studies of ASP and RDT outcomes focus on improving care for those with bloodstream infection. While this is certainly an important patient population where subtle improvements can mean the difference between life and death, clinical microbiology laboratories seek to improve care for other patient populations where positive outcomes may be more difficult to document. The clinical microbiology community as a whole has invested tremendous resources in adopting newly developed diagnostic technologies, despite a paucity of evidence that they will have a positive impact on patient care. Examples include MALDI-TOF MS identification of organisms isolated from nonblood, clinical specimens; multiplex PCR testing for respiratory, central nervous system, and gastrointestinal pathogens; and many others. Despite the lack of outcome data supporting the use of these technologies, the clinical microbiology and infectious diseases (ID) communities have embraced their use without hesitation because of their superior analytical performance. But how do we justify the cost? Are patients really better off because a multiplex respiratory PCR provided a diagnosis of rhinovirus infection? And how do patients feel about paying over $1,000 for that diagnosis? The unfortunate reality is that we do not yet know whether patients benefit from these technologies. In the majority of cases, they probably do not. But that does not mean that they cannot.

Although most patients affected by new diagnostic technologies are not critically ill, there should be no doubt that their care would be improved by a more accurate and rapid diagnosis. And yet the clinical microbiology and ID community has failed to objectively demonstrate the benefit of such technologies. This reality prompted a recent editorial in the Journal of Clinical Microbiology outlining the need for more outcome-based studies documenting the value of our work (18). After all, if at the end of the day, our efforts, and the resources expended, do not result in better patient care, hospitals will utilize those resources elsewhere. And while the task of proving that we are improving patient care is daunting, the lessons learned from MacVane and Nolte can be used to stack the deck in our favor once again.

Most ASPs focus their efforts on the care of critically ill patients because these interventions have a high likelihood of improving outcomes. What if those same resources could be used to intervene in the care of patients other than those with bacteremia? A compelling argument could be made that no other resource would have a greater impact on patient care than a laboratory stewardship program designed to ensure optimal use of all laboratory results. Such a program should exist separately from, but work closely with, existing ASPs. It should operate under the direction of the clinical microbiology laboratory and focus its efforts on promoting the appropriate and timely utilization of laboratory results because, if we are serious about improving patient care, then we will learn from what MacVane and Nolte, Banerjee et al., and all of researchers who performed the studies listed in Table 1 have found, which is that better outcomes come not just from better diagnostics, and not just from better stewardship, but from the combination of the two.

The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.