impact of a rapid blood culture diagnostic test in a children ...impact of a rapid blood culture...

Impact of a Rapid Blood Culture Diagnostic Test in a Children’sHospital Depends on Gram-Positive versus Gram-NegativeOrganism and Day versus Night Shift

Lillian J. Juttukonda,a Sophie Katz,b Jessica Gillon,c Jonathon Schmitz,d Ritu Banerjeeb

aDepartment of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USAbDivision of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USAcDepartment of Pharmacy, Vanderbilt University Medical Center, Nashville, Tennessee, USAdDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

ABSTRACT Rapid diagnostic tests (RDTs) for bloodstream infections (BSIs) decreasethe time to organism identification and resistance detection. RDTs are associatedwith early deescalation of therapy for Gram-positive BSIs. However, it is less clearhow RDTs influence antibiotic management for Gram-negative BSIs and whetherRDT results are acted on during off-hours. We performed a single-center, retrospec-tive review of children with BSI and Verigene (VG) testing at a children’s hospital.Of the 301 positive cultures included in the study (196 Gram-positive, 44 Gram-negative, 32 polymicrobial, and 29 non-VG targets), the VG result had potential toimpact antibiotic selection in 171 cases; among these, antibiotic changes occurred in119 (70%) cases. For Gram-negative cultures, the Verigene result correlated with un-necessary antibiotic escalation and exposure to broader-spectrum antibiotics thanneeded. In contrast, for Gram-positive cultures, the VG results correlated with appro-priate antibiotic selection. VG results permitted early deescalation for methicillin-susceptible Staphylococcus aureus (MSSA) (19/24 [79%]) and avoidance of antibioticsfor skin contaminants (30/85 [35%]). Antibiotic changes occurred more quickly dur-ing the day than at night (4.6 versus 11.7 h, respectively; P � 0.05), and antibiotic es-calations occurred more quickly than did deescalations (4.1 versus 10.1 h, P � 0.01).In a pediatric institution with a low prevalence of Gram-negative resistance, the VGRDT facilitated antibiotic optimization for Gram-positive BSIs but led to unnecessaryescalation of antibiotics for Gram-negative BSIs. The time to action was slower forRDT results reported at night than during the day. Laboratories should considerthese factors when implementing blood culture RDTs.

KEYWORDS rapid diagnostic tests, antibiotic stewardship, bacteremia, pediatricinfectious diseases, pediatric

Prompt and appropriate antibiotic therapy decreases morbidity and mortality inbloodstream infections (BSIs) and sepsis (1). However, the spread of antibioticresistance and new-found recognition of the role of the microbiota in human healthboth demand that antibiotic therapy be thoughtfully selected to maximize appropriatetherapy and minimize exposure to unnecessary antibiotics. A challenge to antimicrobialstewardship programs (ASP) is the several-day delay from detectable microorganismgrowth in culture to organism identification and antimicrobial susceptibilities throughtraditional phenotypic methods. This lengthy period can lead to inappropriate empir-ical antibiotic therapy for BSIs. Rapid blood culture diagnostic tests (RDTs) have beendeveloped to provide clinicians with more timely microbiologic information and enablefaster, targeted antibiotic therapy for BSIs (2, 3).

Citation Juttukonda LJ, Katz S, Gillon J, SchmitzJ, Banerjee R. 2020. Impact of a rapid bloodculture diagnostic test in a children's hospitaldepends on Gram-positive versus Gram-negative organism and day versus night shift. JClin Microbiol 58:e01400-19. https://doi.org/10.1128/JCM.01400-19.

Editor Carey-Ann D. Burnham, WashingtonUniversity School of Medicine

Copyright © 2020 American Society forMicrobiology. All Rights Reserved.

Address correspondence to Ritu Banerjee,[email protected].

For a commentary on this article, see https://doi.org/10.1128/JCM.02082-19.

Received 25 August 2019Returned for modification 27 September2019Accepted 11 December 2019

Accepted manuscript posted online 18December 2019Published

BACTERIOLOGY

crossm

April 2020 Volume 58 Issue 4 e01400-19 jcm.asm.org 1Journal of Clinical Microbiology

25 March 2020

on April 8, 2021 by guest

http://jcm.asm

.org/D

ownloaded from

https://doi.org/10.1128/JCM.01400-19https://doi.org/10.1128/JCM.01400-19https://doi.org/10.1128/ASMCopyrightv2mailto:[email protected]://doi.org/10.1128/JCM.02082-19https://doi.org/10.1128/JCM.02082-19https://crossmark.crossref.org/dialog/?doi=10.1128/JCM.01400-19&domain=pdf&date_stamp=2019-12-18https://jcm.asm.orghttp://jcm.asm.org/

While some studies report that the use of blood culture RDTs improves the qualityof care, others show no such benefit. Numerous observational studies and a singlerandomized controlled trial of RDT versus standard culture and susceptibility methodshave demonstrated that blood culture RDTs are associated with decreased treatment ofcontaminants (4, 5), reduced use of broad-spectrum antimicrobials (4), earlier initiationof optimal antimicrobial therapy (5–9), decreased hospital length of stay (5, 8, 10), lowercosts (5, 6, 8, 10), and lower mortality (6–8, 11). Furthermore, studies have supportedadditional benefits of combining RDTs with ASP in decreased time to antimicrobialdeescalation (4), decreased mortality (12), and increased cost-effectiveness (13). How-ever, other studies have not observed a reduction in time to first appropriate antimi-crobial escalation and deescalation (14) or impact on mortality or hospital length of stay(15). The joint Infectious Diseases Society of America and the Society for HealthcareEpidemiology of America guidelines for implementing an antimicrobial stewardshipprogram recommend rapid diagnostic testing in addition to conventional culture androutine reporting on blood specimens if combined with active ASP support andinterpretation, but this recommendation is weak with moderate quality of evidence(16). Further study is needed to determine the impact of RDT implementation onantibiotic treatment decisions and clinical outcomes (17). Moreover, given the evidencethat the greatest benefits for RDT occur in conjunction with an ASP, it is unclearwhether to implement RDTs during off-hours and on weekends when ASP providersmay be unavailable (3).

Studies regarding the implementation of RDTs in children are more limited, and RDTevaluations in adults may not be generalizable to children because adults tend to havehigher rates of antibiotic-resistant organisms and more medical comorbidities. Onepre-post intervention study in children demonstrated that RDT implementation with anASP was associated with reduced time to optimal therapy but found no significantdifferences in clinical outcomes compared to those with standard testing methods (18).In another observational study of Gram-positive BSI only, use of an RDT was associatedwith shorter time to antimicrobial changes for Staphylococcus aureus, shorter antibioticduration for probable contaminants, shorter median length of stay, and lower hospitalcosts (19). Whether the impact of RDT testing is similar for Gram-positive and Gram-negative BSI is also unclear. Unlike Gram-positive organisms, Gram-negative organismshave multiple diverse drug resistance mechanisms that cannot all be detected usingcommercially available RDTs which only contain a few resistance gene targets.

The goal of this study was to assess clinical and microbiological factors that mayimpact how RDT results are acted upon in a children’s hospital following the imple-mentation of the Verigene (VG) RDT. The VG nucleic acid test is an FDA-approved RDTwhich identifies select Gram-positive and Gram-negative bacteria and antimicrobialresistance genes and has good test performance in adults (20) and children (21). Weretrospectively evaluated BSI therapy in conjunction with VG results, including (i)overall antibiotic changes, (ii) antibiotic escalation and deescalation, and (iii) antibioticchanges during off-hours. We hypothesized that the VG test would have the greatestimpact on antibiotic changes for Gram-positive infections and that there would be alonger time from test result to antibiotic change on weekends and the night shift.

MATERIALS AND METHODSStudy design. We conducted a retrospective chart review of all Gram-positive blood cultures that

resulted between 19 April 2017 and 19 July 2018 at the Vanderbilt Children’s Hospital in Nashville, TN,and had VG testing followed by pager notification of ASP providers. The study was approved by theVanderbilt institutional review board (IRB) with a waiver of consent.

Microbiologic testing. Blood cultures were processed in the Vanderbilt Clinical MicrobiologyLaboratory using institutional standard of care, the BacT/Alert system, and the BD Phoenix instrument forphenotypic susceptibility testing. During the study period, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-ToF MS) was not in use for organism identification. The VG testwas made clinically available at the start of the study period. The Verigene Gram-negative blood culture(VG-GN) test or Verigene Gram-positive blood culture (VG-GP) test (Luminex Corporation, Austin, TX) wasperformed on all first-episode Gram-positive blood cultures in real time, 24 h a day, 7 days a week. TheVG-GN test detects 4 organisms to the genus level (Acinetobacter spp., Citrobacter spp., Enterobacter spp.,and Proteus spp.), 4 organisms to the species level (Escherichia coli, Klebsiella oxytoca, Klebsiella pneu-

Juttukonda et al. Journal of Clinical Microbiology

April 2020 Volume 58 Issue 4 e01400-19 jcm.asm.org 2


http://jcm.asm

.org/D

ownloaded from

https://jcm.asm.orghttp://jcm.asm.org/

moniae, and Pseudomonas aeruginosa), and 6 antimicrobial resistance genes (CTX-M, IMP, KPC, NDM,OXA, and VIM genes) (22). The VG-GP test detects 3 organisms to the genus level (Staphylococcus spp.,Streptococcus spp., and Listeria spp.), 9 to the species level (Staphylococcus aureus, Staphylococcusepidermidis, Staphylococcus lugdunensis, Streptococcus anginosus group, Streptococcus agalactiae, Strep-tococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus faecium), and 3resistance determinants (mecA, vanA, and vanB) (23). VG testing was not performed on cultures if apatient had a prior positive blood culture of the same Gram stain morphology within the same infectiousepisode. Any antibiotic resistance markers that were detected were reported in the electronic medicalrecord. Resistance markers that were not detected were not reported. Interpretative comments about VGresults (e.g., coagulase-negative staphylococci may be a contaminant and not require treatment) werenot included in the result report. Primary clinicians and ASP providers were paged with VG results at allhours (i.e., 24 h a day, 7 days a week). Stewardship team members additionally reviewed medical recordsof all patients with BSIs and paged primary clinicians 7 days per week from 7 a.m. to 10 p.m. if patientswere not receiving effective antibiotic therapy or were candidates for antibiotic deescalation. Face-to-face, in-person discussions between stewardship and primary services occasionally occurred on week-days during office hours (8 a.m. to 6 p.m.).

Chart abstraction. Electronic medical records (EMR) were accessed for patients with BSIs included inthe study to abstract microbiologic test results, antibiotic selection and timing, and basic clinicalinformation. Antibiotic changes were categorized as escalation if 1 or more additional antibiotics werestarted or if narrow-spectrum agents were changed to broader-spectrum agents. Antibiotic deescalationwas defined as stopping 1 or more antibiotics or changing a broad-spectrum agent to a narrower-spectrum agent (see Table S1 in the supplemental material). Antibiotics were considered to be avoidedonly if a clinician documented in the EMR that he or she elected not to start an antibiotic based on theVG results. Antibiotic deescalation time was defined as the time the antibiotic order was discontinued.Antibiotic escalation time was defined as the time the additional or broader-spectrum antibiotic wasadministered. Immunocompromised patients were defined as patients with solid-organ transplants,severe burns, cystic fibrosis, malignancy, or nephrotic syndrome. Positive blood cultures were defined ascontaminants if the primary clinical team documented in the EMR that the culture was considered acontaminant and the culture grew at least one organism consistent with contamination, includingStaphylococcus epidermidis, coagulase-negative staphylococci (CoNS), viridans group streptococci, Rothiamucilaginosa, Micrococcus species, aerobic diphtheroids, or nutritionally deficient streptococci. Day shiftwas defined as 6 a.m. to 6 p.m. Weekends were defined as Friday at 6 p.m. to Monday at 6 a.m.

Data management and statistical analysis. Mann-Whitney, chi-square, and Fisher’s exact tests wereused to analyze continuous variables, categorical variables, and categorical variables with groupscontaining �5 members, respectively.

RESULTSMicrobiology and Verigene performance. The positive blood culture results are

summarized in Tables 1, S2, and S3. Of the 301 positive blood cultures included in thestudy, 233 (77.4%) cultures were correctly identified by VG testing, with results similarto the manufacturer’s reported test performance (23). For on-panel organisms, concor-dance between standard culture (SC) and VG was 94.4% (185/196) for monomicrobialGram-positive cultures. Likewise, for monomicrobial Gram-negative cultures, the con-cordance between SC and VG was 97.7% (43/44) for on-panel organisms. Discordancewas higher among polymicrobial cultures, with all organisms correctly identified by VGin 5/32 (15.6%) cultures. Twenty-nine cultures were monomicrobial cultures withoff-panel organisms. There was 100% concordance in the identification of resistancegenes by VG and standard phenotypic susceptibility results (Table 1).

Antimicrobial utilization. Of 301 cultures, 85 (28%) were treated as contaminants,and among these, 72 (85%) cultures were correctly identified by VG. Of the patientswith contaminated cultures, 18 (21%) avoided antibiotics altogether, 10 (12%) avoidedthe initiation of one or more antibiotics, and 17 (20%) had antibiotics deescalated.

To best capture the impact of the VG result on antibiotic treatment decisions, wecategorized antibiotic use by time period. Period 1 (P1) was defined as the timebetween culture collection and Gram stain result, period 2 (P2) was defined as the timebetween Gram stain and VG result reporting, period 3 (P3) was defined as thetime between VG result and final culture results, and period 4 (P4) was defined as thetime between the final culture results and completion of antibiotic therapy (Fig. 1A).The overall distribution of antibiotic therapy was similar across periods 1 to 3, with 46to 51% of patients receiving 2 or more antibiotics (Fig. 1A). Following final antimicrobialsusceptibility testing (AST) result reporting at the start of period 4 (P4), the overalldistribution of antibiotic therapy changed, and 78% of patients were on 0 or 1 antibiotic(Fig. 1A). In P4, no antibiotics were received by nearly a quarter of patients with

Verigene Implementation in Pediatrics Journal of Clinical Microbiology



http://jcm.asm

.org/D

ownloaded from


Gram-positive BSIs but only 4% of subjects with Gram-negative BSIs, likely due toGram-positive contaminants that were not treated (Fig. S1). While VG result reportingdid influence antibiotic selection, final AST results had the greatest impact on antibiotictherapy.

Impact of VG result on antibiotic orders. The VG result could have led to anantibiotic alteration in 171/301 cultures (57%), but changes only occurred in 119/171cultures (70%) (Fig. 1B). The most common antibiotic change following the VG resultwas deescalation (61/119 [51%]), followed by avoiding the addition of antibiotics(30/119 [25%]) and antibiotic escalation (28/119 [24%]) (Fig. 1B). No organism wasdetected by the VG panel in 35/301 cultures. In the remaining 266 cultures, change wasmore likely to be possible for Gram-positive organisms (146/214 [68%]) than forGram-negative organisms (24/52 [46%], chi-square, P � 0.0030).

Antibiotic escalation following VG result. For Gram-negative organisms, 10/15(66%) changes that were made based on VG results were escalations, which was asignificantly greater proportion than for Gram-positive organisms, for which only 18/74(24%) of changes were escalations (P � 0.004) (Table 2). This difference in escalation

TABLE 1 Microbiologic characteristics of positive blood cultures

VGa panel ID

No. of culturesidentified by:

%concordancedSCb VGc

Gram positive, single organismEnterococcus faecalis 14 14 100Enterococcus faecium 2 2 100Staphylococcus aureus 52 52 100Staphylococcus epidermidis 62 59e 95.1Other Staphylococcus species 30 27f 90Streptococcus agalactiae 5 5 100Streptococcus anginosus group 1 1 100Streptococcus pneumoniae 9 8 88.9Streptococcus pyogenes 3 3 100Streptococcus species 18 14 77.8Total (Gram positive, single organism, on panel) 196 185 94.4

Gram negative, single organismAcinetobacter species 3 3 100Enterobacter species 6 5 83.3Escherichia coli 22 22 100Klebsiella oxytoca 2 2 100Klebsiella pneumoniae 4 4 100Pseudomonas aeruginosa 7 7 100Total (Gram negative, single organism, on-panel) 44 43 97.7

Total (single organism, target detected) 240 228 95.0

OtherNot on VG panel 29 0 0Polymicrobial 32 5 15.6

Antibiotic resistance genesg

mecA 86 86 100CTX-M 1 1 100

aVG, Verigene.bSC, standard culture.cNumber of cultures correctly identified by VG.dConcordant means that SC and VG provided the same identification of organism and resistance markers.Discordant results included polymicrobial cultures for which VG did not identify all organisms, off-panelorganism for which VG did not provide a result, and organisms for which the incorrect panel was run.

eTwo isolates were incorrectly manually entered into the electronic medical record and reported as S. aureusinstead of S. epidermidis.

fThree cultures were identified by VG as Staphylococcus epidermidis and identified by standard culture ascoagulase-negative staphylococci without further identification.

gAll resistance genes detected by VG were in agreement with phenotype detected by gold standard cultureand susceptibility methods.




http://jcm.asm

.org/D

ownloaded from


rates predominantly occurred due to Gram-negative species included in the ESKAPE(Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter bau-mannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens group, whichare commonly associated with antibiotic resistance (24). Specifically, of the monomi-crobial cultures with Gram-negative ESKAPE pathogens (K. pneumoniae, A. baumannii,P. aeruginosa, and Enterobacter species) detected by VG, 6/21 (28%) resulted in esca-lations, compared to 19/235 (8%) (P � 0.001) for all other organisms (Fig. 2A). Due tolow rates of Gram-negative antibiotic resistance in our study, broad-spectrum Gram-negative antibiotics that were started after the VG result were frequently stoppedfollowing final phenotypic AST results (Fig. 2B and S2). Notably, meropenem wasstarted in 9 patients following the VG result, whereas it was only started in 3 patients

FIG 1 Impact of Verigene result on antibiotic orders. (A) Definition of time periods for study purposes andoverall antibiotic use during time periods. Period 1, time between culture collection and Gram stainresult. Period 2, time between Gram stain and Verigene results. Period 3, time between Verigene resultand final culture results. Period 4, time following final culture results and the completion of antibiotictherapy. Pie chart indicates the percentage (of all 301 cultures included in study) receiving 1, 2, 3�, orno antibiotics for each period. (B) Summary of antibiotic changes following Verigene results.

TABLE 2 Impact of shift and type of antibiotic change on time from Verigene result to antibiotic change

Group 1 Group 2

P valuebShift, time of week,or Gram status

Type of antibioticchange (no.)

Hours to change (median[25th to 75th %ile])a

Shift, time of week,or Gram status

Type of antibioticchange (no.)

Hours to change (median[25th to 75th %ile])a

Day shift All changes (56) 4.6 (1.4–10.30) Night shift All changes (31) 11.7 (8.7–16.4) 0.003Escalation (21) 2.85 (1.3–7.5) Escalation (6) 8.4 (2.9–22.6) 0.14Deescalation (35) 5.3 (1.6–21.5) Deescalation (25) 12.6 (9.7–16.1) 0.06

Weekday All changes (67) 8.2 (2.4–15.8) Weekend All changes (20) 6.1 (1.3–15.0) 0.42Escalation (21) 4.2 (1.9–9.8) Escalation (6) 1.3 (1.0–7.1) 0.11Deescalation (46) 10.1 (2.8–16.9) Deescalation (14) 10.5 (2.6–17.7) 0.99

Gram positive All changes (74) 8.1 (2.3–16.4) Gram negative All changes (15) 5.5 (1.4–10.7) 0.45Escalation (18) 3.2 (1.2–7.5) Escalation (10) 6.9 (1.4–10.9) 0.37Deescalation (56) 10.5 (2.9–18.5) Deescalation (5) 3.0 (1.9–12.4) 0.28

All cultures Escalation (28) 4.1 (1.3–8.4) All cultures Deescalation (61) 10.1 (2.9–16.6) 0.03aTime to escalation in those who had antibiotic escalation.bBy Mann-Whitney test comparing groups 1 and 2. Values significant at a value of �0.05 are in bold type.




http://jcm.asm

.org/D

ownloaded from


following culture collection and 5 patients following the Gram stain result. Meropenemwas discontinued for 8 patients following the final AST results. Likewise, vancomycinstarted following the VG result was commonly discontinued following the final ASTresults (14/22 [64%]; Fig. 2B). These results suggest that escalation following the VGresult led to the receipt of unnecessarily broad-spectrum antibiotics for some patients.

In contrast, when the narrow-spectrum antibiotic agents ampicillin, cefazolin, andnafcillin were started following the VG result, they were rarely discontinued followingfinal AST results (2/29 [7%] discontinued; Fig. 2B). Similarly, the most common antibi-otics that were discontinued after the VG result, vancomycin, cefepime, piperacillin-tazobactam, and ceftriaxone, were rarely restarted following the final AST results (5/99[5%] restarted, Fig. 2C). These results suggest that antibiotic deescalation following theVG result was typically appropriate.

Impact of VG on antibiotic selection for staphylococcal species. Because meth-icillin resistance can be reliably inferred through detection of the mecA gene and thereis a high frequency of vancomycin use as an empirical antibiotic in our institution, wehypothesized that the VG panel would have the most opportunity to impact antibioticorders for staphylococcal species. Compared to all other culture results, antibioticchanges were more likely to be possible for CoNS, methicillin-susceptible S. aureus(MSSA), and methicillin-susceptible S. epidermidis (MSSE), and antibiotic changes wereless likely to be possible for methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 3A).

FIG 2 Antibiotic escalation following Verigene result. (A) Comparison between ESKAPE Gram-negativerods (GNR) (Enterobacter spp., Klebsiella pneumoniae, Acinetobacter spp., Pseudomonas aeruginosa) and allother organisms. Shown are the percentages of antibiotic changes that were escalations versus notescalation (includes deescalation and avoidance of antibiotics) in P3. P � 0.001 by chi-square analysiscomparing the proportion of escalations between ESKAPE GNR and all other organisms. (B) Number ofpatients started on the specified antibiotics in P3, graphed by whether antibiotics were continuedfollowing the final culture results. Black bars indicate number of patients started on the antibiotic in P3and continued on the antibiotic in P4. Gray bars indicate the number of patients started on the antibioticin P3 but the antibiotic order was discontinued in P4. (C) Number of patients with the specifiedantibiotics discontinued in P3, graphed by whether antibiotics were restarted following the final cultureresults. Black bars indicate number of patients for whom the antibiotic was discontinued in P3 and notrestarted in P4. Gray bars indicate the number of patients for whom the antibiotic was discontinued inP3 but restarted in P4. (B and C) Antibiotics are specified on the x axis labels. TZP, piperacillin-tazobactam.




http://jcm.asm

.org/D

ownloaded from


Possible changes were acted on more frequently for MSSA than for all other organisms(Fig. 3B and C), leading to early deescalation to narrow-spectrum antistaphylococcalagents.

Time to antibiotic change following VG results. We hypothesized that the clinicalscenario would impact how quickly antibiotic changes occurred following VG resultreporting. Indeed, antibiotic escalation occurred more quickly than did deescalation(Fig. 4A and Table 2, 4.1 versus 10.1 h, P � 0.01). The median time to escalation forGram-negative organisms was twice that of Gram-positive organisms, and Gram-negative deescalation occurred more quickly than did Gram-positive deescalation,although the interquartile ranges for the two groups were similar. Furthermore, despiteimplementation of the VG test 24 h a day, the median time from the VG result toantibiotic change was faster when VG results were reported during the day than atnight (Fig. 4B and Table 2, 4.6 versus 11.7 h, P � 0.05). Notably, only one escalation andone deescalation occurred between midnight and 6 a.m. (Fig. 4C). There was nostatistically significant difference in the time to antibiotic change on weekdays com-pared to the weekend (Table 2).

DISCUSSION

In this single-center, retrospective study of blood culture characterization using VGin a pediatric hospital, we found that type and timeliness of antibiotic modificationsdiffered by organism type and time of day or night. We found that the VG resultfacilitated antibiotic changes for Gram-positive organisms, including avoidance of

FIG 3 Impact of Verigene on antibiotic selection for staphylococcal species. (A) Organisms (by finalculture identification [ID]) for whom the proportion of cultures with possible antibiotic changes wassignificantly different from all cultures by chi-square analysis (CoNS and MRSA) or Fisher’s exact test(MSSA and MSSE). *, P � 0.05; ***, P � 0.001. All cultures, n � 301; CoNS, n � 31; MRSA, n � 26; MSSA,n � 27 (includes 1 polymicrobial culture with MSSA and CoNS); MSSE, n � 15. (B) Organisms (by finalculture ID) for whom change was possible for at least 4 patients, graphed by the percentage of cases inwhich change was performed when possible. *, P � 0.05 by Fisher’s exact test between proportions ofMSSA versus all other cultures for which change was performed. (C) Utilization of vancomycin, ampicillin,and cefazolin or nafcillin across period 1 (P1), period 2 (P2), period 3 (P3), and period 4 (P4). Bars indicatenumber of patients in each period receiving antibiotics, and shading specifies the antibiotic or antibioticcombination as depicted in the legend.




http://jcm.asm

.org/D

ownloaded from


antibiotics for contaminants and deescalation of therapy for MSSA. However, forGram-negative cultures, VG results often led to inappropriate antibiotic escalation andexposure to unnecessarily broad-spectrum antibiotics.

In our patient population, the VG result led to deescalation from vancomycin andinitiation of narrow-spectrum antistaphylococcal antibiotics, such as cefazolin andnafcillin for MSSA. This result also demonstrates that clinicians were confident in thenegative predictive value of the mecA result in the VG panel, which was validated byhigh rates of agreement between mecA detection and phenotypic methicillin resistancein our study. Previous studies have similarly observed a decreased duration ofvancomycin for coagulase-negative staphylococci and MSSA when using rapiddiagnostic tests that detect mecA (25–27). In a pediatric observational study, thetime to antimicrobial optimization and duration of antibiotics for those withprobable blood culture contamination with coagulase-negative staphylococci de-creased following the implementation of the VG Gram-positive panel (19). Ourstudy adds to the body of work suggesting that rapid diagnostic tests are mostuseful when antibiotic resistance phenotypes are readily predicted by the presenceor absence of a single gene (17).

In contrast to staphylococcal species, for Gram-negative organisms, VG results weremore likely to lead to antibiotic escalation, and many antibiotic escalations were thendeescalated following final phenotypic antibiotic susceptibility results. This findingreflects the fact that Gram-negative antibiotic resistance cannot be predicted by thepresence or absence of a single gene or a few genes. For the VG Gram-negative panel,the lack of a resistance marker can be challenging for clinicians to interpret. In ourstudy, clinicians reacted by initiating broad-spectrum antibiotics, including meropenemand cefepime. However, broadening therapy may not be necessary, as a recent studydemonstrated that a lack of resistance gene detection by VG predicted antibioticsusceptibility for all Gram-negative organisms, except for P. aeruginosa (28). Oneway to aid clinicians with interpreting the Gram-negative VG result is to develop atreatment algorithm based on an institutional antibiogram, evidence-based medi-cine, and RDT results, as recently demonstrated in adults (29). We propose that thedevelopment of such an algorithm should also take into account clinical responseand disease severity. Our results suggest that rapid phenotypic rather than geno-typic resistance detection may be needed to optimize timely therapy for Gram-

FIG 4 Time to antibiotic change following Verigene results. (A and B) Lengths of time between Verigeneresult reporting and antibiotic order discontinuation (for deescalations) or antibiotic administration (forescalations). (A) Deescalations and escalations. (B) Day shift and night shift. (A and B) Bars indicatemedian and 25 to 75% interquartile range, and error bars denote minimum to maximum values. Eachfilled circle represents an individual patient. *, P � 0.05; **, P � 0.01 by Mann-Whitney. (C) Times at whichnew antibiotics were administered (for escalations) or antibiotic orders were discontinued (deescalations)during period 3. Each symbol indicates an individual patient.




http://jcm.asm

.org/D

ownloaded from


negative BSI. One rapid phenotypic method has been recently approved, and othersare in development (30).

The time to antibiotic change was influenced by shift and antibiotic escalationversus deescalation. Antibiotic escalations occurred more quickly than did deescala-tions, suggesting that clinicians considered escalations more urgent than deescalations.While this may not impact patient morbidity or mortality, failure to deescalate promptlyleads to unnecessary antibiotic exposure and may be responsible for increased hospitallength of stay and hospital costs. Strikingly, antibiotic changes occurred more slowly atnight than during the day. One hypothesis for this finding could be that antibioticchanges occurred more quickly when an ASP was available. However, an ASP was notroutinely available over the weekend, and there was no difference in the time toantibiotic change on weekends compared to weekdays. Based on the timing of whenantibiotic orders were changed, we hypothesize that VG results that occurred after 9p.m. were generally not acted on until they could be discussed on morning rounds, asour study took place in a training institution. Clinical microbiology laboratories shouldconsider this result when deciding whether to offer the VG test 24 h a day for allpositive blood cultures.

Our study has limitations, including being retrospective, single center, and notincluding a comparison group, so the impact of the VG test compared to standardtesting methods could not be determined. We did not capture data on ASP recom-mendations or acceptance rates. Our study also took place in a tertiary care children’shospital and may not be generalizable to other settings with different resistance ratesand patient populations, particularly because antibiotic resistance rates were low in ourpatient population. The impact of VG testing is highly dependent on local resistancerates. The retrospective nature of this study made it difficult to determine whetherantibiotic changes were in response to a VG or Gram stain result. Additionally, providerswere unfamiliar with VG early in the study and often waited for standard culture results,potentially reducing impact of the RDT. Despite these limitations, these results open upimportant questions and opportunities regarding RDT implementation. Combining RDTresults with an antibiotic algorithm based on local antibiograms for Gram-negative BSImay help providers make informed decisions regarding antibiotic therapy and avoidunnecessary antibiotic escalation. Second, future studies should consider the risks andbenefits of using narrow-spectrum empirical therapy for Gram-positive infections inclinically stable patients, as the RDT result could be used to escalate therapy should anantibiotic resistance gene be detected. Third, future studies should compare 24-h/daytesting with RDTs versus day shift testing only to determine the clinical impact andcost-effectiveness of RDTs performed at night. Last, the development of rapid pheno-typic susceptibility testing methods for Gram-negative BSI should be prioritized. Im-plementation of rapid blood culture diagnostics can be optimized.

SUPPLEMENTAL MATERIALSupplemental material is available online only.SUPPLEMENTAL FILE S1, PDF file, 0.1 MB.SUPPLEMENTAL FILE S2, PDF file, 0.1 MB.SUPPLEMENTAL FILE S3, PDF file, 0.1 MB.

ACKNOWLEDGMENTSWe thank the clinical microbiology laboratory at Vanderbilt University Medical

Center for their efforts, without which this study would not have been possible.R.B. receives research funding from Roche, bioMérieux, BioFire, and Accelerate

Diagnostics. This work was supported by the American Heart Association (grant15PRE25060007 to L.J.J.), the National Institute of General Medical Studies at theNational Institutes of Health (grant T32 GM07347 to the Vanderbilt Medical-ScientistTraining Program, which supported L.J.J.), the Philanthropic Educational Organization(P.E.O. Scholars Award to L.J.J.), and the National Institute of Allergy and InfectiousDiseases (grant T32 1AI095202-07, which supported S.K.).




http://jcm.asm

.org/D

ownloaded from


REFERENCES1. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips

GS, Lemeshow S, Osborn T, Terry KM, Levy MM. 2017. Time to treatmentand mortality during mandated emergency care for sepsis. N Engl J Med376:2235–2244. https://doi.org/10.1056/NEJMoa1703058.

2. Bauer KA, Perez KK, Forrest GN, Goff DA. 2014. Review of rapid diagnostictests used by antimicrobial stewardship programs. Clin Infect Dis59(Suppl 3):S134 –S145. https://doi.org/10.1093/cid/ciu547.

3. Banerjee R, Ozenci V, Patel R. 2016. Individualized approaches areneeded for optimized blood cultures. Clin Infect Dis 63:1332–1339.https://doi.org/10.1093/cid/ciw573.

4. Banerjee R, Teng CB, Cunningham SA, Ihde SM, Steckelberg JM, MoriartyJP, Shah ND, Mandrekar JN, Patel R. 2015. Randomized trial of rapidmultiplex polymerase chain reaction-based blood culture identificationand susceptibility testing. Clin Infect Dis 61:1071–1080. https://doi.org/10.1093/cid/civ447.

5. Box MJ, Sullivan EL, Ortwine KN, Parmenter MA, Quigley MM, Aguilar-Higgins LM, MacIntosh CL, Goerke KF, Lim RA. 2015. Outcomes of rapididentification for gram-positive bacteremia in combination with antibi-otic stewardship at a community-based hospital system. Pharmacother-apy 35:269 –276. https://doi.org/10.1002/phar.1557.

6. Suzuki H, Hitomi S, Yaguchi Y, Tamai K, Ueda A, Kamata K, Tokuda Y,Koganemaru H, Kurihara Y, Ishikawa H, Yanagisawa H, Yanagihara K.2015. Prospective intervention study with a microarray-based, multi-plexed, automated molecular diagnosis instrument (Verigene system)for the rapid diagnosis of bloodstream infections, and its impact on theclinical outcomes. J Infect Chemother 21:849 – 856. https://doi.org/10.1016/j.jiac.2015.08.019.

7. Huang AM, Newton D, Kunapuli A, Gandhi TN, Washer LL, Isip J, CollinsCD, Nagel JL. 2013. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with anti-microbial stewardship team intervention in adult patients with bactere-mia and candidemia. Clin Infect Dis 57:1237–1245. https://doi.org/10.1093/cid/cit498.

8. Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Peterson LE, MusserJM. 2014. Integrating rapid diagnostics and antimicrobial stewardshipimproves outcomes in patients with antibiotic-resistant Gram-negativebacteremia. J Infect 69:216 –225. https://doi.org/10.1016/j.jinf.2014.05.005.

9. Lockwood AM, Perez KK, Musick WL, Ikwuagwu JO, Attia E, Fasoranti OO,Cernoch PL, Olsen RJ, Musser JM. 2016. Integrating rapid diagnostics andantimicrobial stewardship in two community hospitals improved pro-cess measures and antibiotic adjustment time. Infect Control HospEpidemiol 37:425– 432. https://doi.org/10.1017/ice.2015.313.

10. Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Land GA, PetersonLE, Musser JM. 2013. Integrating rapid pathogen identification and antimi-crobial stewardship significantly decreases hospital costs. Arch Pathol LabMed 137:1247–1254. https://doi.org/10.5858/arpa.2012-0651-OA.

11. Walker T, Dumadag S, Lee CJ, Lee SH, Bender JM, Cupo Abbott J, She RC.2016. Clinical impact of laboratory implementation of Verigene BC-GNmicroarray-based assay for detection of Gram-negative bacteria in pos-itive blood cultures. J Clin Microbiol 54:1789 –1796. https://doi.org/10.1128/JCM.00376-16.

12. Timbrook TT, Morton JB, McConeghy KW, Caffrey AR, Mylonakis E,LaPlante KL. 2017. The effect of molecular rapid diagnostic testing onclinical outcomes in bloodstream infections: a systematic review andmeta-analysis. Clin Infect Dis 64:15–23. https://doi.org/10.1093/cid/ciw649.

13. Pliakos EE, Andreatos N, Shehadeh F, Ziakas PD, Mylonakis E. 2018. Thecost-effectiveness of rapid diagnostic testing for the diagnosis of blood-stream infections with or without antimicrobial stewardship. Clin Micro-biol Rev 31:e00095-17. https://doi.org/10.1128/CMR.00095-17.

14. Tseng AS, Kasule SN, Rice F, Mi L, Chan L, Seville MT, Grys TE. 2018. Is itactionable? An evaluation of the rapid PCR-based blood culture identi-fication panel on the management of Gram-positive and Gram-negativeblood stream infections. Open Forum Infect Dis 5:ofy308. https://doi.org/10.1093/ofid/ofy308.

15. Neuner EA, Pallotta AM, Lam SW, Stowe D, Gordon SM, Procop GW,Richter SS. 2016. Experience with rapid microarray-based diagnostictechnology and antimicrobial stewardship for patients with Gram-positive bacteremia. Infect Control Hosp Epidemiol 37:1361–1366.https://doi.org/10.1017/ice.2016.175.

16. Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus

EJ, Srinivasan A, Dellit TH, Falck-Ytter YT, Fishman NO, Hamilton CW,Jenkins TC, Lipsett PA, Malani PN, May LS, Moran GJ, Neuhauser MM,Newland JG, Ohl CA, Samore MH, Seo SK, Trivedi KK. 2016. Implementingan antibiotic stewardship program: guidelines by the Infectious DiseasesSociety of America and the Society of Healthcare Epidemiology ofAmerica. Clin Infect Dis 62:e51– e77. https://doi.org/10.1093/cid/ciw118.

17. Buehler SS, Madison B, Snyder SR, Derzon JH, Cornish NE, Saubolle MA,Weissfeld AS, Weinstein MP, Liebow EB, Wolk DM. 2016. Effectiveness ofpractices to increase timeliness of providing targeted therapy for inpa-tients with bloodstream infections: a laboratory medicine best practicessystematic review and meta-analysis. Clin Microbiol Rev 29:59 –103.https://doi.org/10.1128/CMR.00053-14.

18. Malcolmson C, Ng K, Hughes S, Kissoon N, Schina J, Tilley PA, Roberts A.2017. Impact of matrix-assisted laser desorption and ionization time-of-flight and antimicrobial stewardship intervention on treatment of blood-stream infections in hospitalized children. J Pediatric Infect Dis Soc6:178 –186. https://doi.org/10.1093/jpids/piw033.

19. Felsenstein S, Bender JM, Sposto R, Gentry M, Takemoto C, Bard JD.2016. Impact of a rapid blood culture assay for Gram-positive iden-tification and detection of resistance markers in a pediatric hospital.Arch Pathol Lab Med 140:267–275. https://doi.org/10.5858/arpa.2015-0119-OA.

20. Aitken SL, Hemmige VS, Koo HL, Vuong NN, Lasco TM, Garey KW. 2015.Real-world performance of a microarray-based rapid diagnostic forGram-positive bloodstream infections and potential utility for antimicro-bial stewardship. Diagn Microbiol Infect Dis 81:4 – 8. https://doi.org/10.1016/j.diagmicrobio.2014.09.025.

21. Vareechon C, Mestas J, Polanco CM, Dien Bard J. 2018. A 5-year study ofthe performance of the Verigene Gram-positive blood culture panel in apediatric hospital. Eur J Clin Microbiol Infect Dis 37:2091–2096. https://doi.org/10.1007/s10096-018-3343-2.

22. Nanosphere. 2014. Verigene Gram-negative blood culture nucleic acidtest (BC-GN). Nanosphere, Northbrook, IL. http://www.nanosphere.us/sites/default/files/support-docs/nanosphere_bcgn_insert_final.pdf. Ac-cessed 16 April 2019.

23. Nanosphere. 2012. Verigene Gram-positive blood culture nucleic acidtest (BC-GP), 027-00030-01, Rev. G. Nanosphere, Northbrook, IL. http://www.nanosphere.us/sites/default/files/support-docs/027-00030-01_g_bc-gp_ivd_package_insert.pdf. Accessed 4 February 2019.

24. Rice LB. 2008. Federal funding for the study of antimicrobial resistancein nosocomial pathogens: no ESKAPE. J Infect Dis 197:1079 –1081.https://doi.org/10.1086/533452.

25. Veesenmeyer AF, Olson JA, Hersh AL, Stockmann C, Korgenski K, ThorellEA, Pavia AT, Blaschke AJ. 2016. A retrospective study of the impact ofrapid diagnostic testing on time to pathogen identification and antibi-otic use for children with positive blood cultures. Infect Dis Ther5:555–570. https://doi.org/10.1007/s40121-016-0136-8.

26. Nguyen DT, Yeh E, Perry S, Luo RF, Pinsky BA, Lee BP, Sisodiya D, BaronEJ, Banaei N. 2010. Real-time PCR testing for mecA reduces vancomycinusage and length of hospitalization for patients infected withmethicillin-sensitive staphylococci. J Clin Microbiol 48:785–790. https://doi.org/10.1128/JCM.02150-09.

27. Pardo J, Klinker KP, Borgert SJ, Butler BM, Giglio PG, Rand KH. 2016.Clinical and economic impact of antimicrobial stewardship interventionswith the FilmArray blood culture identification panel. Diagn MicrobiolInfect Dis 84:159 –164. https://doi.org/10.1016/j.diagmicrobio.2015.10.023.

28. Pogue JM, Heil EL, Lephart P, Johnson JK, Mynatt RP, Salimnia H,Claeys KC. 2018. An antibiotic stewardship program blueprint foroptimizing Verigene BC-GN within an institution: a tale of two cities.Antimicrob Agents Chemother 62:e02538-17. https://doi.org/10.1128/AAC.02538-17.

29. Claeys KC, Schlaffer KE, Heil EL, Leekha S, Johnson JK. 2018. Validation ofan antimicrobial stewardship-driven Verigene blood culture Gram-negative treatment algorithm to improve appropriateness of antibiotics.Open Forum Infect Dis 5:ofy233. https://doi.org/10.1093/ofid/ofy233.

30. Marschal M, Bachmaier J, Autenrieth I, Oberhettinger P, Willmann M,Peter S. 2017. Evaluation of the Accelerate Pheno system for fast iden-tification and antimicrobial susceptibility testing from positive bloodcultures in bloodstream infections caused by Gram-negative pathogens.J Clin Microbiol 55:2116 –2126. https://doi.org/10.1128/JCM.00181-17.




http://jcm.asm

.org/D

ownloaded from

https://doi.org/10.1056/NEJMoa1703058https://doi.org/10.1093/cid/ciu547https://doi.org/10.1093/cid/ciw573https://doi.org/10.1093/cid/civ447https://doi.org/10.1093/cid/civ447https://doi.org/10.1002/phar.1557https://doi.org/10.1016/j.jiac.2015.08.019https://doi.org/10.1016/j.jiac.2015.08.019https://doi.org/10.1093/cid/cit498https://doi.org/10.1093/cid/cit498https://doi.org/10.1016/j.jinf.2014.05.005https://doi.org/10.1016/j.jinf.2014.05.005https://doi.org/10.1017/ice.2015.313https://doi.org/10.5858/arpa.2012-0651-OAhttps://doi.org/10.1128/JCM.00376-16https://doi.org/10.1128/JCM.00376-16https://doi.org/10.1093/cid/ciw649https://doi.org/10.1093/cid/ciw649https://doi.org/10.1128/CMR.00095-17https://doi.org/10.1093/ofid/ofy308https://doi.org/10.1093/ofid/ofy308https://doi.org/10.1017/ice.2016.175https://doi.org/10.1093/cid/ciw118https://doi.org/10.1128/CMR.00053-14https://doi.org/10.1093/jpids/piw033https://doi.org/10.5858/arpa.2015-0119-OAhttps://doi.org/10.5858/arpa.2015-0119-OAhttps://doi.org/10.1016/j.diagmicrobio.2014.09.025https://doi.org/10.1016/j.diagmicrobio.2014.09.025https://doi.org/10.1007/s10096-018-3343-2https://doi.org/10.1007/s10096-018-3343-2http://www.nanosphere.us/sites/default/files/support-docs/nanosphere_bcgn_insert_final.pdfhttp://www.nanosphere.us/sites/default/files/support-docs/nanosphere_bcgn_insert_final.pdfhttp://www.nanosphere.us/sites/default/files/support-docs/027-00030-01_g_bc-gp_ivd_package_insert.pdfhttp://www.nanosphere.us/sites/default/files/support-docs/027-00030-01_g_bc-gp_ivd_package_insert.pdfhttp://www.nanosphere.us/sites/default/files/support-docs/027-00030-01_g_bc-gp_ivd_package_insert.pdfhttps://doi.org/10.1086/533452https://doi.org/10.1007/s40121-016-0136-8https://doi.org/10.1128/JCM.02150-09https://doi.org/10.1128/JCM.02150-09https://doi.org/10.1016/j.diagmicrobio.2015.10.023https://doi.org/10.1016/j.diagmicrobio.2015.10.023https://doi.org/10.1128/AAC.02538-17https://doi.org/10.1128/AAC.02538-17https://doi.org/10.1093/ofid/ofy233https://doi.org/10.1128/JCM.00181-17https://jcm.asm.orghttp://jcm.asm.org/

MATERIALS AND METHODSStudy design. Microbiologic testing. Chart abstraction. Data management and statistical analysis.

RESULTSMicrobiology and Verigene performance. Antimicrobial utilization. Impact of VG result on antibiotic orders. Antibiotic escalation following VG result. Impact of VG on antibiotic selection for staphylococcal species. Time to antibiotic change following VG results.

DISCUSSIONSUPPLEMENTAL MATERIALACKNOWLEDGMENTS

impact of a rapid blood culture diagnostic test in a children ...impact of a rapid blood culture...

Documents