8
Original Contributions WOULD EARLIER MICROBE IDENTIFICATION ALTER ANTIBIOTIC THERAPY IN BACTEREMIC EMERGENCY DEPARTMENT PATIENTS? Lisa R. Stoneking, MD, Asad E. Patanwala, PHARMD, BCPS, John P. Winkler, MD, Albert B. Fiorello, MD, Elizabeth S. Lee, MS III, Daniel P. Olson, MPH, and Donna M. Wolk, PHD(ABMM) Department of Emergency Medicine, University of Arizona, Tucson, Arizona Reprint Address: Lisa R. Stoneking, MD, Department of Emergency Medicine, University of Arizona, 1609 N. Warren Ave., Room 118, PO Box 245057, Tucson, AZ 85724 , Abstract—Background: Although debate exists about the treatment of sepsis, few disagree about the benefits of early, appropriately targeted antibiotic administration. Study Objectives: To determine the appropriateness of em- piric antimicrobial therapy and the extent to which therapy would be altered if the causative organism for sepsis was known at the time of administration. Methods: This was a retrospective cohort study, conducted in an academic Emergency Department (ED), on consecutive positive blood cultures between November 1, 2008 and February 1, 2009. Blood cultures and the appropriateness of administered an- timicrobial therapy were evaluated. Therapy choices were categorized based on whether or not a physician, complying with antimicrobial guidelines, would have made changes to empiric antibiotic therapy had the causative organism ini- tially been known. Results: There were 90 positive blood cul- tures obtained from 84 patients. Of these, 21.1% (n = 19) were considered contaminants. The final categorization of empiric antibiotics given in the ED for the remaining blood culture results were: 1) therapy would be changed to narrower-spectrum antibiotics (n = 34, 55.7%); 2) therapy would be changed because the organism was not covered (n = 13, 21.3%); and 3) therapy would remain the same (n = 14, 23.0%). There was 90.2% inter-rater agreement for these classifications (p < 0.0001), with a kappa of 0.84. Polymerase chain reaction analysis had a statistically signif- icant advantage (p < 0.0001) over Infectious Disease Society of America protocols in facilitating accurate antimicrobial therapies. Conclusion: This study confirms the need for more rapid and accurate laboratory methods for blood- stream pathogen identification. Ó 2013 Elsevier Inc. , Keywords—sepsis; antimicrobial therapy; blood cul- tures; intensive care unit; microbiology INTRODUCTION Sepsis is a leading cause of death worldwide and the main cause of death in non-coronary intensive care units (ICUs), occurring in up to 75% of ICU patients (1–4). The fatalities due to sepsis equal those from myocardial infarction (5). The definition of sepsis is clear, but repre- sents a gradient of disease, which is subject to interpreta- tion. Defined as a known or suspected infection leading to a systemic inflammatory response syndrome (SIRS), sep- sis is a disease state that progresses to severe sepsis when end-organ dysfunction is present. Septic shock occurs when sepsis is present in addition to hypotension, refrac- tory to fluid resuscitation. Thus, criteria for diagnosis can often be complicated and symptoms can overlap with other diseases, often leading to treatment delay and in- creased mortality. SIRS may be caused by a number of disease mechanisms, and clinicians may not suspect in- fection unless a fever is present at the time of presentation. When bloodstream infection as a source of sepsis is suspected, routine blood cultures are performed but may not yield specific results for several days. Although blood cultures remain the reference standard for diagno- sis of bacteremia, culture methods have many inherent limitations. Blood cultures may be slow to yield RECEIVED: 1 August 2011; FINAL SUBMISSION RECEIVED: 29 November 2011; ACCEPTED: 26 February 2012 1 The Journal of Emergency Medicine, Vol. 44, No. 1, pp. 1–8, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter doi:10.1016/j.jemermed.2012.02.036

Would Earlier Microbe Identification Alter Antibiotic Therapy in Bacteremic Emergency Department Patients?

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The Journal of Emergency Medicine, Vol. 44, No. 1, pp. 1–8, 2013Copyright � 2013 Elsevier Inc.

Printed in the USA. All rights reserved0736-4679/$ - see front matter

doi:10.1016/j.jemermed.2012.02.036

RECEIVED: 1 AuACCEPTED: 26 F

OriginalContributions

WOULD EARLIER MICROBE IDENTIFICATION ALTER ANTIBIOTIC THERAPY INBACTEREMIC EMERGENCY DEPARTMENT PATIENTS?

Lisa R. Stoneking, MD, Asad E. Patanwala, PHARMD, BCPS, John P. Winkler, MD, Albert B. Fiorello, MD,Elizabeth S. Lee, MS III, Daniel P. Olson, MPH, and Donna M. Wolk, PHD(ABMM)

Department of Emergency Medicine, University of Arizona, Tucson, ArizonaReprint Address: Lisa R. Stoneking, MD, Department of Emergency Medicine, University of Arizona, 1609 N. Warren Ave., Room 118, PO Box

245057, Tucson, AZ 85724

, Abstract—Background: Although debate exists aboutthe treatment of sepsis, few disagree about the benefits ofearly, appropriately targeted antibiotic administration.Study Objectives: To determine the appropriateness of em-piric antimicrobial therapy and the extent to which therapywould be altered if the causative organism for sepsis wasknown at the time of administration. Methods: This wasa retrospective cohort study, conducted in an academicEmergency Department (ED), on consecutive positive bloodcultures between November 1, 2008 and February 1, 2009.Blood cultures and the appropriateness of administered an-timicrobial therapy were evaluated. Therapy choices werecategorized based on whether or not a physician, complyingwith antimicrobial guidelines, would have made changes toempiric antibiotic therapy had the causative organism ini-tially been known. Results: There were 90 positive blood cul-tures obtained from 84 patients. Of these, 21.1% (n = 19)were considered contaminants. The final categorization ofempiric antibiotics given in the ED for the remaining bloodculture results were: 1) therapy would be changed tonarrower-spectrum antibiotics (n = 34, 55.7%); 2) therapywould be changed because the organism was not covered(n = 13, 21.3%); and 3) therapy would remain the same(n = 14, 23.0%). There was 90.2% inter-rater agreementfor these classifications (p < 0.0001), with a kappa of 0.84.Polymerase chain reaction analysis had a statistically signif-icant advantage (p < 0.0001) over Infectious Disease Societyof America protocols in facilitating accurate antimicrobialtherapies. Conclusion: This study confirms the need formore rapid and accurate laboratory methods for blood-stream pathogen identification. � 2013 Elsevier Inc.

gust 2011; FINAL SUBMISSION RECEIVED: 29 Noveebruary 2012

1

, Keywords—sepsis; antimicrobial therapy; blood cul-tures; intensive care unit; microbiology

INTRODUCTION

Sepsis is a leading cause of death worldwide and the maincause of death in non-coronary intensive care units(ICUs), occurring in up to 75% of ICU patients (1–4).The fatalities due to sepsis equal those from myocardialinfarction (5). The definition of sepsis is clear, but repre-sents a gradient of disease, which is subject to interpreta-tion. Defined as a known or suspected infection leading toa systemic inflammatory response syndrome (SIRS), sep-sis is a disease state that progresses to severe sepsis whenend-organ dysfunction is present. Septic shock occurswhen sepsis is present in addition to hypotension, refrac-tory to fluid resuscitation. Thus, criteria for diagnosis canoften be complicated and symptoms can overlap withother diseases, often leading to treatment delay and in-creased mortality. SIRS may be caused by a number ofdisease mechanisms, and clinicians may not suspect in-fection unless a fever is present at the time of presentation.

When bloodstream infection as a source of sepsis issuspected, routine blood cultures are performed butmay not yield specific results for several days. Althoughblood cultures remain the reference standard for diagno-sis of bacteremia, culture methods have many inherentlimitations. Blood cultures may be slow to yield

mber 2011;

2 L. R. Stoneking et al.

a causative organism, andmay have limited sensitivity fororganisms that do not grow well in blood culture media(6). The typical time needed to achieve a positive bloodculture result ranges between 12 and 48 h, leading to de-lays in correct antibiotic treatment (7). Furthermore, sen-sitivity is far from ideal for diagnosing a diseasewith suchhigh mortality. Sensitivity is partly based on blood vol-ume collected. An adequate volume may be difficult tocollect in pediatric patients, elderly patients, and hypo-tensive patients (8). One recent study at a children’s hos-pital showed that over half of blood cultures hadinadequate volume and were < 50% as likely to yielda positive result than adequate volume in similar patients(9). Another study showed increased sensitivity with in-creasing numbers of blood cultures drawn: 1 blood cul-ture (73%), 2 blood cultures (89–93%), 3 blood cultures(96–98%), and 4 blood cultures (up to 99%). At our insti-tution, a quality assurance project is used to monitorblood volume to ensure compliance with volume require-ments in > 90% of blood cultures collected.

These blood cultures were collected in the first fewdays of symptom onset, with the higher percentage beingcollected in the first 24 h (10). Collecting blood culturesbefore antibiotics are administered is one of the immedi-ate surviving sepsis campaign guidelines. Additional lim-itations occur for fastidious pathogens, which are noteasily cultivated in routine cultures (11). In fact, up to20–55% of bloodstream infections are not identified byroutine blood culture methods (12,13).

Thus, the diagnosis of sepsis is often clinical and theinitial antibiotic treatment remains empiric for a longertime (14). Recommendations for empiric treatment in-clude the use of broad-spectrum agents until a definitivepathogen is isolated. Without timely narrowing of antimi-crobial spectrum, this practice has the potential to in-crease resistance and lead to adverse side effects. Inaddition, the possibility of false-positive blood culturesincreases unnecessary antibiotic use.

Althoughmuchprogress has beenmade in technologiesfor rapid discovery of specific bacteria and antibiotic resis-tance genes, blood culture remains the gold standard due tothe perceived need for live bacteria for susceptibility test-ing (8). However, there are many types of non-culture-based bacterial identification studies, and the numbersare rapidly expanding as many areas of molecular biologyare being applied to clinical medicine (6,8). Some of thecurrent available technology includes peptide nucleicacid fluorescence in situ hybridization (PNA-FISH),polymerase chain reaction (PCR), real-time PCR, multi-plex PCR,DNA sequencing,mass spectrometry combinedwith PCR, microarray pyrosequencing, and others (6,8).

For culture-negative fungemia, PCRwas reported to bepositive in 56%of cases (15). In one study, limited to caseswith severe sepsis, 34.7% of PCRs were positive com-

pared to 16.5% of blood cultures (p < 0.001) (16). Thesedata indicate that the presence of a pathogen-associatedDNA is a meaningful event in severe sepsis and warrantsfurther investigation for its suitability to guide anti-infective therapy. Although these new technologies havenot replaced blood cultures, many have been shown tobe valuable adjuvants, helping to choosemore appropriateantibiotics early in the disease course of sepsis.

The Surviving Sepsis Campaign published treatmentguidelines for immediate resuscitation (6 h) and subse-quent management (24 h) of patients with sepsis (17).Of these, one variable, the time to antibiotics, was shownto be the most crucial factor in preventing mortality (18).In a multivariate analysis, Kumar et al. show that every1-h delay in appropriate antibiotic treatment increasesmortality by 7–10% (18). Subsequently, there is an urgentneed for rapid diagnostic tests to establish the presence ofbacteremia and the genus and species of the pathogen sothat earlier administration of appropriately targeted anti-biotics can be initiated.With projected increases in the in-cidence of sepsis, even small improvements in diagnosticcapabilities could lead to decreased mortality from sep-sis, translating into thousands of saved lives each yearand a significant public health benefit (19).

The objective of this study was to determine the appro-priateness of initial empiric antimicrobial therapy and theextent to which therapy would be altered if the causativeorganism was known at time of prescribing in the Emer-gency Department (ED). This information is useful to de-termine the utility of non-culture-based diagnostic testingsuch as PCR.

METHODS

Study Design and Setting

A retrospective cohort study of consecutive blood cul-tures obtained from patients presenting to the ED be-tween November 1, 2008 and February 1, 2009 wasperformed after approval by the Human Subjects Protec-tion Program. The study was performed in a 61-bed,academic, tertiary care ED in the United States, desig-nated as a level I trauma center, with an annual censusof approximately 70,000 patients.

The data extraction process from medical records wasperformed after the patient’s visit was finalized. Extractionwas followed by review and audit of all cases to determinethe presence of contaminants and the category of antibiotictreatment. Review included physicians, laboratory ex-perts, and a pharmacist. In addition, after adjudication ofeach blood culture, a pharmacist and physician indepen-dently categorized antibiotic status. Any discrepancieswere evaluated for final categorization by an arbitrationcommittee. Finally, microbial distributions, antibiograms,and drug therapy selection processes were compared to

Early Microbe Identification 3

ensure similar microbial distribution, susceptibility pat-terns, and treatment patterns still existing in 2011.

Data Collection and Analyses

A list of patients with positive blood cultures obtained inthe ED during the study time frame was generated fromelectronic medical records. All patients were included,with no specific exclusion criteria. Data were collectedusing a uniform data extraction template by investigatorswith medical training (medical student E.L., residentJ.W., and attending physician L.S.). Data extractedfrom electronic medical records included patient demo-graphics, vital signs on arrival to the ED, comorbidities,blood culture results and antibiotic susceptibilities, infec-tion site, timing of blood cultures in relation to antibioticadministration, type and dose of antibiotics administeredto the patient, time to administration of antibiotics, vol-ume of intravenous (i.v.) fluids administered while inthe ED, laboratory results that supported the diagnosisof sepsis or bacteremia (erythrocyte sedimentation rate,lactic acid, white blood cell count, C-reactive protein),initial diagnosis, number of days the patient spent in theICU, and requirements for mechanical ventilation.

After data collection was complete, the investigatorscollectively reviewed case histories to document theblood cultures that were defined as contaminants. Con-taminated cultures were defined as those reported as con-taminants according to clinical laboratory guidelines orphysicians, that is, those that were considered to be skinflora and were positive in only one of multiple sets ofblood cultures and were not isolated from a secondarysite. The cultures determined to be contaminants by theinvestigators were excluded from final data analysis.

For the remaining cultures, empiric antimicrobial ther-apy was evaluated using a retrospective observationalcase series study design, and defining ‘‘what-if’’ criteria.The investigators categorized therapy choices based onwhether or not they would have made changes to initialantimicrobial therapy if they had known the causative or-ganism at the time of initial prescribing in the ED. Thefollowing categorizations were determined a priori: 1)therapy would be changed to narrower spectrum antibi-otics; 2) therapy would be changed because organismwas not covered (this group included those given antibi-otics that did not cover the microbe and those not givenantibiotics); and 3) therapy would remain the same. Cat-egorization was based on the Infectious Disease Societyof America Clinical Practice Guidelines (http://www.idsociety.org/IDSA_Practice_Guidelines/). One pharma-cist (A.P.) and one physician (A.F.), who were not in-volved in the data collection process, independentlyperformed categorization. Inter-rater reliability of the cat-egorizations between the pharmacist scores and the phy-

sician scores were performed using the kappa measurecoefficient of agreement. Discrepancies between thetwo reviewers then went to an arbitration committee,which consisted of the two original reviewers and anotherEmergency Medicine attending physician (L.S.). Thethird reviewer made the final decision. Statistical analy-ses were performed using Stata 11.0 (College Station,TX) and JMP 9 statistical software (Cary, NC).

Blood Culture Method

Chlorhexidine antisepsis of the blood collection skin sitewas used (20). Eight to 10 mL of blood was collectedaccording to standard phlebotomy methods for bloodcultures (21). Blood was inoculated into fast actingneutralization-aerobic and fast acting neutralization-anaerobic blood culture bottles (bioMerieux, Durham,NC) and incubated in the BacT-Alert 3D instrument (bio-Merieux), which flags bottles as positivewhen CO2 levelsrise and are indicative of bacterial growth.

Reference Standard Methods for Identification

Positive bottles were removed from the system for iden-tification of pathogens according to reference methods.Briefly, aliquots of positive blood culture bottles weresubjected to Gram stain and plating on Trypticase Soyagar supplemented with 5% sheep blood (TSA, Remel,Lenexa, KS) and Chocolate agar (CHOC, Remel); Mac-Conkey agar (MAC; Remel) and Sabouraud Agar(SAB; Remel) were also inoculated, if the result of theGram stain indicated Gram-negative bacilli or yeast.The organisms were incubated in either ambient air, 5%CO2, or in an anaerobic environment using the Gas-Pak�EZ Anaerobe Container System with Indicator(Becton-Dickinson, Franklin Lakes, NJ). Post-subculture, colony morphology was used as the basisfor additional phenotypic testing, based on determinativeprotocols described in the Manual of Clinical Microbiol-ogy and in accordance with guidelines issued by the Clin-ical Laboratory Standards Institute (CLSI), and ClinicalLaboratory Improvement Act (CLIA ’88) regulations(42CFR493.1251) (21–24). Microorganisms wereidentified according to standard clinical laboratorymethods, including Vitek 2 Gram-Positive Identification,Gram Negative Identification, and Vitek 2 Yeast identifi-cation card (bioMerieux) (21). Susceptibility testing wasperformed with the GPS (Gram-positive susceptibility)card and GNS (Gram-negative susceptibility) card (bio-Merieux) or disk diffusion methods (CLSI) (23,24).

RESULTS

During the 3-month study period, there were 103 recordsof positive blood cultures obtained. After eliminating

21.3%

55.7%

23.0%

Antibiotic Therapy

Altered Broader Altered Narrower Unchanged

Figure 1. Therapy distribution.

4 L. R. Stoneking et al.

duplicate values and missing records, there were 90 pos-itive blood cultures obtained from 84 patients in the ED.Of these cultures, 21.1% (n = 19) were considered to becontaminants. The final categorization of empiric antibi-otics given in the ED for the remaining blood cultureresults were: 1) therapy would be changed to narrower-spectrum antibiotics (n = 34, 55.7%); 2) therapy wouldbe changed because organism was not covered (n = 13,21.3%); and 3) therapy would remain the same (n = 14,23.0%) (Figure 1). There was 90.2% agreement for theseclassifications between the investigators, with a kappa of0.84 (p < 0.0001). This high inter-rater reliability be-tween pharmacist and physician increased the strengthof our classification. Note that in 4 of 13 cases wherethe organism was not covered, no antibiotics were admin-istered to the patient in the ED. Patient demographics andinitial vital signs obtained in the ED are provided inTable 1. The most common presumed sites of infectionwere genitourinary (33.3%), respiratory (33.3%), skin(14.0%), and other (19.3%). The five most common or-

Table 1. Patient Demographics and Vital Signs

Demographic Variable Altered Therapy Means (9

Age (years) 56 (50–63)Sex (% male) 64Weight (kg) 62.8 (54.3–71.2Vital signs

Temperature (�C) 37.6 (37.3–37.9Systolic blood pressure (mm Hg) 121.8 (114.1–12Diastolic blood pressure (mm Hg) 63.9 (59.6–68.2Heart rate (beats per min) 115 (108–123)Respiratory rate (breaths per min) 23 (21–25)Oxygen saturation (%) 93.2 (91.0–95.4Lactate 2.0 (1.6–2.4)White blood cell count (�1000) 13.0 (10.8–15.2

CI = confidence interval.

ganisms isolated were Escherichia coli (23.0%), Staphy-lococcus aureus (19.7%), Streptococcus pneumoniae(13.1%), Enterococcus spp. (9.8%), and Klebsiella spp.(6.6%). Although this review was performed in 2008and 2009, the top 5 microbes by percentage are still com-parable to the most common bloodstream pathogens re-covered from ED patients in 2010 by the UniversityMedical Center Microbiology Laboratory (Escherichiacoli, Staphylococcus aureus, Klebsiella pneumoniae,Enterococcus spp, Pseudomonas aeruginosa-in order ofprevalence). The proportion of infections considered tobe health care-associated vs. community-acquired were60.6% vs. 39.3%, respectively, as defined by a data ab-stractor who determined the status based on recent(< 30 days) hospitalizations, residence at a nursing careor other health care facility, or receiving dialysis. Themean time to receiving antibiotics from initial patient tri-age was 4.0 h (SD 3.5 h). The majority of patients in thesample set were admitted to the hospital (88.5%) vs. di-rectly discharged from the ED (11.5%). Overall, rate ofmortality was 6.6%.

The Infectious Disease Society of America (IDSA)empiric guidelines assist physicians in improving carethrough consistent evidence-based practices. However,the potential identification of pathogens by moleculartesting has a statistically significant advantage(p < 0.0001) over IDSA protocols alone according toa McNemar test (25). The McNemar test is a paired testwith an approximate c

2 distribution, which was used todetermine the symmetry of disagreement between the ac-curacy of prescribing the ideal medication by IDSA pro-tocols alone vs. a ‘‘what if’’ scenario where PCRidentification could have been utilized. Awareness ofpathogen identification via molecular analysis was almostthree times more likely to change therapy to a moremicrobial-specific antibiotic (broader coverage or nar-rower spectrum) than empiric guidelines. In fact, molec-ular methods would have helped physicians to use

5% CI) or % Unchanged Therapy Means (95% CI) or %

47 (32–62)50

) 69.5 (52.8–86.2)

) 38.0 (37.3–38.7)9.4) 132.3 (125.6–139.0)) 70.8 (64.1–77.5)

117 (108–127)20 (18–22)

) 96.1 (94.9–97.3)2.0 (0.8–3.2)

) 15.5 (11.2–19.7)

Early Microbe Identification 5

a narrower spectrum of antibiotic therapy > 16 timesmore often and a broader spectrum seven times more of-ten than following IDSA protocols alone (p < 0.0001).

DISCUSSION

Bloodstream infections, which lead to sepsis, the body’sresponse to overwhelming infection, are among the topcauses of death in the United States. Despite technologi-cal advances, mortality rates still fall between 30% and50% for patients with severe sepsis (26–28). Substantialmortality is attributed to testing delays in determinationof the microbial cause(s) and selection of theappropriate antibiotic. As a result, empiric, broad-spectrum treatment is common; a costly approach thatmay fail to effectively target the correct microbe, may in-advertently harm patients via antimicrobial toxicity, andmay contribute to the evolution of drug-resistant mi-crobes. Current laboratory methods for identificationand characterization of bloodstream pathogens are slowto produce useful results and are ineffective for detectionof some pathogens (11).

Themost important finding from this study is that ther-apy would remain the same in only 23% of patients, hadthe organism identification been known to EmergencyPhysicians. This fact supports a strong argument for bet-ter technology and identification methods for blood-stream infections. Our data are supported by one largestudy that found 18.8% and 28.4% of community-acquired and nosocomial septic shock cases were initiallytreated with inadequate antimicrobial therapy (29).Reports of inadequate therapy range between 24% and35% (30–33). Inappropriate initial antimicrobialtherapy reduces survival from septic shockapproximately five-fold, from 50% to about 10% (29).However, we realize that even if testing was available,providing organism identification within a few hours ofpresentation, the initial antibiotic choice might not be al-tered in critically ill patients. It would still be advisable toadminister broad-spectrum coverage initially becausemortality significantly increases if appropriate antibioticsare not given early (13). In this situation, early organismidentification would allow for rapid de-escalation andtailored antibiotic therapy within hours, not days, as isstandard today, providing improved effectiveness, anti-microbial stewardship, and lower toxicity.

It is reported that molecular methods have the poten-tial to double accurate organism identification comparedto blood cultures (34). Another report details the varietyof uncultivable microbes, for which molecular methodswould be beneficial (11). It is becoming evident that tech-nology is evolving to the point where we can imagine fullidentification of pathogens via molecular methods; thetechnology already exists for full identification from

blood culture bottles (35). Although currently a researchmethod, lower costs and adaptation to random-accesswhole-blood testing could render existing multiplex mo-lecular methods feasible for identification of all blood-stream infections (35).

Several methods for rapid molecular identification ofpathogens from blood cultures bottles are currently avail-able; however, few are cleared by the U.S. Food and DrugAdministration. The development of molecular diagnos-tic assays, such as PNA-FISH, for detection of singlepathogens from blood culture bottles, have already beenshown to have impact on reducing mortality and costs(36). These methods can reduce the time it takes to con-firm bacterial and fungal identity by over 1–4 days (37).In the near future, tests that can identify many pathogens,such as pyrosequencing, PCR electrospray mass spec-trometry, and Maldi-TOF mass spectrometry, could char-acterize Gram-positive, Gram-negative, and fungalinfections, and can enable more rapid and targeted anti-microbial interventions for those with severe disease(6,8).

Our ED contaminant percentage (number of ED con-taminants/number of hospital-wide contaminants) duringthe study time frame initially appeared high. This con-taminant percentage was therefore compared to the over-all ED contaminant percentage during the same timeperiod and found to be comparable at 33%. November2008, December 2008, and January 2009 had ED contam-inant percentage of 24%, 27%, and 44%, respectively.The laboratory and Infection Prevention at our hospitalhas focused attention to this high percentage rate andhas now instituted a centralized phlebotomy team in theED as of September 2010.

Limitations

Several limitations were considered when performingthis study. First, it is a retrospective chart review duringa very brief time frame. A prospective analysis of molec-ular tests on whole blood within a 4- to 6-h window isnecessary to better determine the number of patientswho would truly have antibiotic therapy altered due toearly pathogen identification. This study used only posi-tive blood culture results from a microbiology repositoryand did not take into consideration blood culture resultsthat were false negatives, which may have underesti-mated our overall number of patients that would havehad antibiotic therapy altered. Also, the documentationwas not always adequate to extrapolate the desired infor-mation. For example, discrepancies between nursing doc-umentation and physician documentation as towhether ornot an ordered antibiotic was actually given or how muchi.v. fluids were administered made classification moredifficult. When these discrepancies occurred, our team

6 L. R. Stoneking et al.

used nursing documentation totals. Both nursing and phy-sician handwritten documentation was often illegible.Though potentially useful, the future molecular methods,such as PCR testing methods, have limitations. For exam-ple, PCR can differentiate between methicillin-sensitiveS. aureus and methicillin-resistant S. aureus based ona drug-resistance gene target, but does not have the capac-ity to determine susceptibility results for all microbes. Inour data set, one study patient was placed on ciprofloxa-cin for an E. coli infection. Typically, this would havebeen an appropriate antibiotic choice. However, in thissituation, the E. coli was resistant to ciprofloxacin. Thispatient was still categorized into the ‘‘no alteration wouldoccur’’ category, as molecular methods would have failedto identify the resistance.

CONCLUSION

Overall, the results of this study confirm the need formore rapid and accurate laboratory methods for identifi-cation of bloodstream pathogens and support the needfor more collaboration between microbiology laborato-ries, ED physicians, and pharmacists to improve the earlycare of patients with bacteremia. It is evident that moreattention to collection of blood cultures to avoid skin con-tamination is required, and that perhaps an ED-specificantibiogram may be useful to fine tune IDSA guidelinesfor treatment of bloodstream infections until the timethat molecular methods are available for whole bloodtesting. Future research is needed to support developmentof whole blood DNA extraction methods and supportmultiplex molecular methods for early identification ofbloodstream pathogens.

Acknowledgment—Special thanks to Rebecca Landreth, RN,CIC, Infection Preventionist, for providing our research teamwith ED blood culture and contaminant rates.

REFERENCES

1. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving SepsisCampaign: results of an international guideline-based performanceimprovement program targeting severe sepsis. Crit Care Med 2010;38:367–74.

2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J,Pinsky MR. Epidemiology of severe sepsis in the United States:analysis of incidence, outcome, and associated costs of care. CritCare Med 2001;29:1303–10.

3. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology ofsepsis in the United States from 1979 through 2000. N Engl J Med2003;348:1546–54.

4. Esper A, Martin GS. Is severe sepsis increasing in incidence ANDseverity? Crit Care Med 2007;35:1414–5.

5. Wenzel RP, Edmond MB. Severe sepsis-national estimates. CritCare Med 2001;29:1472–4.

6. Wolk DM, Fiorello AB. Code sepsis: rapid methods to diagnosesepsis and detect hematopathogens Part II: challenges to the labora-tory diagnosis of sepsis. Clin Microbiol Newsl 2010;32:41–9.

7. Riest G, Linde HJ, Shah PM. Comparison of BacT/Alert and BAC-TECNR 860 blood culture systems in a laboratory not continuouslystaffed. Clin Microbiol Infect 1997;3:345–51.

8. Mancini N, Carletti S, Ghidoli N, Cichero P, Burioni R, ClementiM.The era of molecular and other non-culture-based methods in diag-nosis of sepsis. Clin Microbiol Rev 2010;23:235–51.

9. Connell TG, Rele M, Cowley D, Buttery JP, Curtis N. How reliableis a negative blood culture result? Volume of blood submitted forculture in routine practice in a children’s hospital. Pediatrics2007;119:891–6.

10. Lee A, Mirrett S, Reller LB, Weinstein MP. Detection of blood-stream infections in adults: how many blood cultures are needed?J Clin Microbiol 2007;45:3546–8.

11. Fenollar F, Raoult D.Molecular diagnosis of bloodstream infectionscaused by non-cultivable bacteria. Int J Antimicrob Agents 2007;30(Suppl 1):S7–15.

12. Leibovici L, Konisberger H, Pitlik SD, Samra Z, Drucker M. Bac-teremia and fungemia of unknown origin in adults. Clin InfectDis 1992;14:436–43.

13. Heffner AC, Horton JM, Marchick MR, Jones AE. Etiology of ill-ness in patients with severe sepsis admitted to the hospital fromthe emergency department. Clin Infect Dis 2010;50:814–20.

14. Hunfeld KP, Bingold T, Brade V, Wissing H. Molecular biologicaldetection of pathogens in patients with sepsis. Potentials, limita-tions and perspectives [German]. Anaesthesist 2008;57:326–37.

15. Ahmad S, Khan Z, Mustafa AS, Khan ZU. Seminested PCR for di-agnosis of candidemia: comparison with culture, antigen detection,and biochemical methods for species identification. J Clin Micro-biol 2002;40:2483–9.

16. Bauer M, Reinhart K. Molecular diagnostics of sepsis—where arewe today? Int J Med Microbiol 2010;300:411–3.

17. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Cam-paign: international guidelines for management of severe sepsisand septic shock. Crit Care Med 2008;2008(36):296–327.

18. KumarA,RobertsD,WoodKE, et al.Durationof hypotension beforeinitiation of effective antimicrobial therapy is the critical determinantof survival in human septic shock. Crit Care Med 2006;34:1589–96.

19. Institute for Healthcare Improvement. Sepsis. Available at: http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis. Accessed May28, 2009.

20. Mimoz O, Karim A, Mercat A, et al. Chlorhexidine compared withpovidone-iodine as skin preparation before blood culture. A ran-domized, controlled trial. Ann Intern Med 1999;131:834–7.

21. Baron EJ, Weinstein MP, Dunne WM Jr, Yagupsky P, Welch DF,Wilson DM. Cumitech 1C, Blood cultures IV. Washington, DC:ASM Press; 2005.

22. Institute. CLS. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standard -Eight Edition CLSI Document M07–A8 (2009).

23. Clinical and Laboratory Standards Institute. Performance standardsfor antimicrobial disk susceptibility tests; approved standard—11th

edition. Wayne, PA: Clinical and Laboratory Standards Institute;2012.

24. Clinical and Laboratory Standards Institute. Performance standardsfor antimicrobial susceptibility testing; twentieth informational sup-plement. Wayne, PA: Clinical and Laboratory Standards Institute;2010.

25. McNemarQ.Note on the sampling error of the difference betweencor-related proportions or percentages. Psychometrika 1947;12:153–7.

26. SchlichtingD,McCollam JS.Recognizing andmanaging severe sep-sis: a common and deadly threat. South Med J 2007;100:594–600.

27. Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of com-pliance with 6-hour and 24-hour sepsis bundles on hospital mortal-ity in patients with severe sepsis: a prospective observational study.Crit Care 2005;9:R764–70.

28. Lee CC, Chen SY, Tsai CL, et al. Prognostic value of mortality inemergency department sepsis score, procalcitonin, and C-reactiveprotein in patients with sepsis at the emergency department. Shock2008;29:322–7.

29. Kumar A. Optimizing antimicrobial therapy in sepsis and septicshock. Crit Care Clin 2009;25:733–51. viii.

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30. Rello J, Gallego M, Mariscal D, Sonora R, Valles J. The value ofroutine microbial investigation in ventilator-associated pneumonia.Am J Respir Crit Care Med 1997;156:196–200.

31. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicro-bial treatment of infections: a risk factor for hospital mortalityamong critically ill patients. Chest 1999;115:462–74.

32. Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL data onthe therapy and outcome of ventilator-associated pneumonia. Chest1997;111:676–85.

33. Alvarez-Lerma F. Modification of empiric antibiotic treatment inpatients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Med 1996;22:387–94.

34. Bloos F, Hinder F, Becker K, et al. A multicenter trial to compareblood culture with polymerase chain reaction in severe human sep-sis. Intensive Care Med 2010;36:241–7.

35. Kaleta EJ, Clark AE, Johnson DR, et al. Use of PCR coupled withelectrospray ionizationmass spectrometry for rapid identification ofbacterial and yeast bloodstream pathogens from blood culture bot-tles. J Clin Microbiol 2011;49:345–53.

36. Gamage DC, Olson DP, Stickell LH, et al. Significant decreases inmortality and hospital costs after laboratory testing with PNA FISH.Poster D-1302b, 51st Interscience Conference of AntimicrobialAgents and Chemotherapy. Chicago, IL; 2011.

37. Forrest GN. PNA FISH: present and future impact on patient man-agement. Expert Rev Mol Diagn 2007;7:231–6.

8 L. R. Stoneking et al.

ARTICLE SUMMARY

1. Why is this topic important?Substantial mortality is attributed to testing delays in

determination of the microbial cause(s) and selection ofthe appropriate antibiotic in patients with bloodstream in-fections. As a result, empiric, broad-spectrum treatment isa common, costly approach that may fail to effectively tar-get the correct microbe, may inadvertently harm patientsvia antimicrobial toxicity, and may contribute to the evo-lution of drug resistant microbes.2. What does this study attempt to show?

More rapid and accurate laboratory methods for identi-fication of bloodstream pathogens are necessary. In-creased collaboration between microbiologylaboratories, emergency department (ED) physicians,and pharmacists could improve the early care of patientswith bacteremia.3. What are the key findings?

a) Empiric antibiotics given in the ED for positiveblood culture results would have changed tonarrower-spectrum antibiotics 55.7% of the time,would have changed because the organism was notcovered 21.3% of the time, and would haveremained the same 23.0% of the time had themicrobe been known at the time of antibioticadministration.

b) Polymerase chain reaction would have helpedphysicians to use a narrower spectrum of antibiotictherapy > 16 times more often and a broaderspectrum 7 times more often than followingInfectious Disease Society of America protocolsalone (p < 0.0001).

c) The five most common organisms isolated wereEscherichia coli (23.0%), Staphylococcus aureus(19.7%), Streptococcus pneumoniae (13.1%),Enterococcus spp. (9.8%), and Klebsiella spp.(6.6%).

4. How is patient care impacted?This study highlights the need for alternatives to blood

culture such as molecular methods for organism identifi-cation. It impacts care by enabling the use of new technol-ogies that will lead to more appropriate antimicrobialtherapy.