Would Earlier Microbe Identification Alter Antibiotic Therapy in ...

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

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

, Keywords—sepsis; antimicrobial therapy; blood cultures; intensive care unit; microbiology

, 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 empiric 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 antimicrobial 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 initially been known. Results: There were 90 positive blood cultures 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 significant 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 bloodstream pathogen identification. Ó 2013 Elsevier Inc.

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 represents a gradient of disease, which is subject to interpretation. Defined as a known or suspected infection leading to a systemic inflammatory response syndrome (SIRS), sepsis 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, refractory to fluid resuscitation. Thus, criteria for diagnosis can often be complicated and symptoms can overlap with other diseases, often leading to treatment delay and increased mortality. SIRS may be caused by a number of disease mechanisms, and clinicians may not suspect infection 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 diagnosis 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

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a causative organism, and may have limited sensitivity for organisms that do not grow well in blood culture media (6). The typical time needed to achieve a positive blood culture result ranges between 12 and 48 h, leading to delays in correct antibiotic treatment (7). Furthermore, sensitivity is far from ideal for diagnosing a disease with such high mortality. Sensitivity is partly based on blood volume collected. An adequate volume may be difficult to collect in pediatric patients, elderly patients, and hypotensive patients (8). One recent study at a children’s hospital showed that over half of blood cultures had inadequate volume and were < 50% as likely to yield a positive result than adequate volume in similar patients (9). Another study showed increased sensitivity with increasing numbers of blood cultures drawn: 1 blood culture (73%), 2 blood cultures (89–93%), 3 blood cultures (96–98%), and 4 blood cultures (up to 99%). At our institution, a quality assurance project is used to monitor blood volume to ensure compliance with volume requirements in > 90% of blood cultures collected. These blood cultures were collected in the first few days of symptom onset, with the higher percentage being collected in the first 24 h (10). Collecting blood cultures before antibiotics are administered is one of the immediate surviving sepsis campaign guidelines. Additional limitations occur for fastidious pathogens, which are not easily cultivated in routine cultures (11). In fact, up to 20–55% of bloodstream infections are not identified by routine blood culture methods (12,13). Thus, the diagnosis of sepsis is often clinical and the initial antibiotic treatment remains empiric for a longer time (14). Recommendations for empiric treatment include the use of broad-spectrum agents until a definitive pathogen is isolated. Without timely narrowing of antimicrobial spectrum, this practice has the potential to increase resistance and lead to adverse side effects. In addition, the possibility of false-positive blood cultures increases unnecessary antibiotic use. Although much progress has been made in technologies for rapid discovery of specific bacteria and antibiotic resistance genes, blood culture remains the gold standard due to the perceived need for live bacteria for susceptibility testing (8). However, there are many types of non-culturebased bacterial identification studies, and the numbers are rapidly expanding as many areas of molecular biology are being applied to clinical medicine (6,8). Some of the current available technology includes peptide nucleic acid fluorescence in situ hybridization (PNA-FISH), polymerase chain reaction (PCR), real-time PCR, multiplex PCR, DNA sequencing, mass spectrometry combined with PCR, microarray pyrosequencing, and others (6,8). For culture-negative fungemia, PCR was reported to be positive in 56% of cases (15). In one study, limited to cases with severe sepsis, 34.7% of PCRs were positive com-

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pared to 16.5% of blood cultures (p < 0.001) (16). These data indicate that the presence of a pathogen-associated DNA is a meaningful event in severe sepsis and warrants further investigation for its suitability to guide antiinfective therapy. Although these new technologies have not replaced blood cultures, many have been shown to be valuable adjuvants, helping to choose more appropriate antibiotics early in the disease course of sepsis. The Surviving Sepsis Campaign published treatment guidelines for immediate resuscitation (6 h) and subsequent management (24 h) of patients with sepsis (17). Of these, one variable, the time to antibiotics, was shown to be the most crucial factor in preventing mortality (18). In a multivariate analysis, Kumar et al. show that every 1-h delay in appropriate antibiotic treatment increases mortality by 7–10% (18). Subsequently, there is an urgent need for rapid diagnostic tests to establish the presence of bacteremia and the genus and species of the pathogen so that earlier administration of appropriately targeted antibiotics can be initiated. With projected increases in the incidence of sepsis, even small improvements in diagnostic capabilities could lead to decreased mortality from sepsis, translating into thousands of saved lives each year and a significant public health benefit (19). The objective of this study was to determine the appropriateness of initial empiric antimicrobial therapy and the extent to which therapy would be altered if the causative organism was known at time of prescribing in the Emergency Department (ED). This information is useful to determine the utility of non-culture-based diagnostic testing such as PCR. METHODS Study Design and Setting A retrospective cohort study of consecutive blood cultures obtained from patients presenting to the ED between November 1, 2008 and February 1, 2009 was performed after approval by the Human Subjects Protection Program. The study was performed in a 61-bed, academic, tertiary care ED in the United States, designated as a level I trauma center, with an annual census of approximately 70,000 patients. The data extraction process from medical records was performed after the patient’s visit was finalized. Extraction was followed by review and audit of all cases to determine the presence of contaminants and the category of antibiotic treatment. Review included physicians, laboratory experts, and a pharmacist. In addition, after adjudication of each blood culture, a pharmacist and physician independently categorized antibiotic status. Any discrepancies were evaluated for final categorization by an arbitration committee. Finally, microbial distributions, antibiograms, and drug therapy selection processes were compared to

Early Microbe Identification

ensure similar microbial distribution, susceptibility patterns, and treatment patterns still existing in 2011. Data Collection and Analyses A list of patients with positive blood cultures obtained in the ED during the study time frame was generated from electronic medical records. All patients were included, with no specific exclusion criteria. Data were collected using a uniform data extraction template by investigators with medical training (medical student E.L., resident J.W., and attending physician L.S.). Data extracted from electronic medical records included patient demographics, vital signs on arrival to the ED, comorbidities, blood culture results and antibiotic susceptibilities, infection site, timing of blood cultures in relation to antibiotic administration, type and dose of antibiotics administered to the patient, time to administration of antibiotics, volume of intravenous (i.v.) fluids administered while in the ED, laboratory results that supported the diagnosis of sepsis or bacteremia (erythrocyte sedimentation rate, lactic acid, white blood cell count, C-reactive protein), initial diagnosis, number of days the patient spent in the ICU, and requirements for mechanical ventilation. After data collection was complete, the investigators collectively reviewed case histories to document the blood cultures that were defined as contaminants. Contaminated cultures were defined as those reported as contaminants according to clinical laboratory guidelines or physicians, that is, those that were considered to be skin flora and were positive in only one of multiple sets of blood cultures and were not isolated from a secondary site. The cultures determined to be contaminants by the investigators were excluded from final data analysis. For the remaining cultures, empiric antimicrobial therapy was evaluated using a retrospective observational case series study design, and defining ‘‘what-if’’ criteria. The investigators categorized therapy choices based on whether or not they would have made changes to initial antimicrobial therapy if they had known the causative organism at the time of initial prescribing in the ED. The following categorizations were determined a priori: 1) therapy would be changed to narrower spectrum antibiotics; 2) therapy would be changed because organism was not covered (this group included those given antibiotics that did not cover the microbe and those not given antibiotics); and 3) therapy would remain the same. Categorization was based on the Infectious Disease Society of America Clinical Practice Guidelines (http://www. idsociety.org/IDSA_Practice_Guidelines/). One pharmacist (A.P.) and one physician (A.F.), who were not involved in the data collection process, independently performed categorization. Inter-rater reliability of the categorizations between the pharmacist scores and the phy-

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sician scores were performed using the kappa measure coefficient of agreement. Discrepancies between the two reviewers then went to an arbitration committee, which consisted of the two original reviewers and another Emergency Medicine attending physician (L.S.). The third reviewer made the final decision. Statistical analyses 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 site was used (20). Eight to 10 mL of blood was collected according to standard phlebotomy methods for blood cultures (21). Blood was inoculated into fast acting neutralization-aerobic and fast acting neutralizationanaerobic blood culture bottles (bioMe´rieux, Durham, NC) and incubated in the BacT-Alert 3D instrument (bioMe´rieux), which flags bottles as positive when CO2 levels rise and are indicative of bacterial growth. Reference Standard Methods for Identification Positive bottles were removed from the system for identification of pathogens according to reference methods. Briefly, aliquots of positive blood culture bottles were subjected to Gram stain and plating on Trypticase Soy agar supplemented with 5% sheep blood (TSA, Remel, Lenexa, KS) and Chocolate agar (CHOC, Remel); MacConkey agar (MAC; Remel) and Sabouraud Agar (SAB; Remel) were also inoculated, if the result of the Gram stain indicated Gram-negative bacilli or yeast. The organisms were incubated in either ambient air, 5% CO2, or in an anaerobic environment using the GasPakÔEZ Anaerobe Container System with Indicator (Becton-Dickinson, Franklin Lakes, NJ). Postsubculture, colony morphology was used as the basis for additional phenotypic testing, based on determinative protocols described in the Manual of Clinical Microbiology and in accordance with guidelines issued by the Clinical Laboratory Standards Institute (CLSI), and Clinical Laboratory Improvement Act (CLIA ’88) regulations (42CFR493.1251) (21–24). Microorganisms were identified according to standard clinical laboratory methods, including Vitek 2 Gram-Positive Identification, Gram Negative Identification, and Vitek 2 Yeast identification card (bioMe´rieux) (21). Susceptibility testing was performed with the GPS (Gram-positive susceptibility) card and GNS (Gram-negative susceptibility) card (bioMe´rieux) or disk diffusion methods (CLSI) (23,24). RESULTS During the 3-month study period, there were 103 records of positive blood cultures obtained. After eliminating

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21.3%

23.0%

55.7%

Antibiotic Therapy Altered Broader

Altered Narrower

Unchanged

Figure 1. Therapy distribution.

duplicate values and missing records, there were 90 positive blood cultures obtained from 84 patients in the ED. Of these cultures, 21.1% (n = 19) were considered to be contaminants. The final categorization of empiric antibiotics given in the ED for the remaining blood culture results were: 1) therapy would be changed to narrowerspectrum antibiotics (n = 34, 55.7%); 2) therapy would be 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 these classifications between the investigators, with a kappa of 0.84 (p < 0.0001). This high inter-rater reliability between pharmacist and physician increased the strength of our classification. Note that in 4 of 13 cases where the organism was not covered, no antibiotics were administered to the patient in the ED. Patient demographics and initial vital signs obtained in the ED are provided in Table 1. The most common presumed sites of infection were genitourinary (33.3%), respiratory (33.3%), skin (14.0%), and other (19.3%). The five most common or-

ganisms isolated were Escherichia coli (23.0%), Staphylococcus aureus (19.7%), Streptococcus pneumoniae (13.1%), Enterococcus spp. (9.8%), and Klebsiella spp. (6.6%). Although this review was performed in 2008 and 2009, the top 5 microbes by percentage are still comparable to the most common bloodstream pathogens recovered from ED patients in 2010 by the University Medical Center Microbiology Laboratory (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus spp, Pseudomonas aeruginosa-in order of prevalence). The proportion of infections considered to be health care-associated vs. community-acquired were 60.6% vs. 39.3%, respectively, as defined by a data abstractor who determined the status based on recent (< 30 days) hospitalizations, residence at a nursing care or other health care facility, or receiving dialysis. The mean time to receiving antibiotics from initial patient triage was 4.0 h (SD 3.5 h). The majority of patients in the sample set were admitted to the hospital (88.5%) vs. directly discharged from the ED (11.5%). Overall, rate of mortality was 6.6%. The Infectious Disease Society of America (IDSA) empiric guidelines assist physicians in improving care through consistent evidence-based practices. However, the potential identification of pathogens by molecular testing has a statistically significant advantage (p < 0.0001) over IDSA protocols alone according to a McNemar test (25). The McNemar test is a paired test with an approximate c2 distribution, which was used to determine the symmetry of disagreement between the accuracy of prescribing the ideal medication by IDSA protocols alone vs. a ‘‘what if’’ scenario where PCR identification could have been utilized. Awareness of pathogen identification via molecular analysis was almost three times more likely to change therapy to a more microbial-specific antibiotic (broader coverage or narrower spectrum) than empiric guidelines. In fact, molecular methods would have helped physicians to use

Table 1. Patient Demographics and Vital Signs Demographic Variable

Altered Therapy Means (95% CI) or %

Unchanged Therapy Means (95% CI) or %

Age (years) Sex (% male) Weight (kg) Vital signs Temperature ( C) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats per min) Respiratory rate (breaths per min) Oxygen saturation (%) Lactate White blood cell count (1000)

56 (50–63) 64 62.8 (54.3–71.2)

47 (32–62) 50 69.5 (52.8–86.2)

37.6 (37.3–37.9) 121.8 (114.1–129.4) 63.9 (59.6–68.2) 115 (108–123) 23 (21–25) 93.2 (91.0–95.4) 2.0 (1.6–2.4) 13.0 (10.8–15.2)

38.0 (37.3–38.7) 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)

CI = confidence interval.

Early Microbe Identification

a narrower spectrum of antibiotic therapy > 16 times more often and a broader spectrum seven times more often than following IDSA protocols alone (p < 0.0001). DISCUSSION Bloodstream infections, which lead to sepsis, the body’s response to overwhelming infection, are among the top causes of death in the United States. Despite technological advances, mortality rates still fall between 30% and 50% for patients with severe sepsis (26–28). Substantial mortality is attributed to testing delays in determination of the microbial cause(s) and selection of the appropriate antibiotic. As a result, empiric, broadspectrum treatment is common; a costly approach that may fail to effectively target the correct microbe, may inadvertently harm patients via antimicrobial toxicity, and may contribute to the evolution of drug-resistant microbes. Current laboratory methods for identification and characterization of bloodstream pathogens are slow to produce useful results and are ineffective for detection of some pathogens (11). The most important finding from this study is that therapy would remain the same in only 23% of patients, had the organism identification been known to Emergency Physicians. This fact supports a strong argument for better technology and identification methods for bloodstream infections. Our data are supported by one large study that found 18.8% and 28.4% of communityacquired and nosocomial septic shock cases were initially treated with inadequate antimicrobial therapy (29). Reports of inadequate therapy range between 24% and 35% (30–33). Inappropriate initial antimicrobial therapy reduces survival from septic shock approximately five-fold, from 50% to about 10% (29). However, we realize that even if testing was available, providing organism identification within a few hours of presentation, the initial antibiotic choice might not be altered in critically ill patients. It would still be advisable to administer broad-spectrum coverage initially because mortality significantly increases if appropriate antibiotics are not given early (13). In this situation, early organism identification would allow for rapid de-escalation and tailored antibiotic therapy within hours, not days, as is standard today, providing improved effectiveness, antimicrobial stewardship, and lower toxicity. It is reported that molecular methods have the potential to double accurate organism identification compared to blood cultures (34). Another report details the variety of uncultivable microbes, for which molecular methods would be beneficial (11). It is becoming evident that technology is evolving to the point where we can imagine full identification of pathogens via molecular methods; the technology already exists for full identification from

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blood culture bottles (35). Although currently a research method, lower costs and adaptation to random-access whole-blood testing could render existing multiplex molecular methods feasible for identification of all bloodstream infections (35). Several methods for rapid molecular identification of pathogens from blood cultures bottles are currently available; however, few are cleared by the U.S. Food and Drug Administration. The development of molecular diagnostic assays, such as PNA-FISH, for detection of single pathogens from blood culture bottles, have already been shown to have impact on reducing mortality and costs (36). These methods can reduce the time it takes to confirm 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 spectrometry, and Maldi-TOF mass spectrometry, could characterize Gram-positive, Gram-negative, and fungal infections, and can enable more rapid and targeted antimicrobial interventions for those with severe disease (6,8). Our ED contaminant percentage (number of ED contaminants/number of hospital-wide contaminants) during the study time frame initially appeared high. This contaminant percentage was therefore compared to the overall ED contaminant percentage during the same time period and found to be comparable at 33%. November 2008, December 2008, and January 2009 had ED contaminant percentage of 24%, 27%, and 44%, respectively. The laboratory and Infection Prevention at our hospital has focused attention to this high percentage rate and has now instituted a centralized phlebotomy team in the ED as of September 2010. Limitations Several limitations were considered when performing this study. First, it is a retrospective chart review during a very brief time frame. A prospective analysis of molecular tests on whole blood within a 4- to 6-h window is necessary to better determine the number of patients who would truly have antibiotic therapy altered due to early pathogen identification. This study used only positive blood culture results from a microbiology repository and did not take into consideration blood culture results that were false negatives, which may have underestimated our overall number of patients that would have had antibiotic therapy altered. Also, the documentation was not always adequate to extrapolate the desired information. For example, discrepancies between nursing documentation and physician documentation as to whether or not an ordered antibiotic was actually given or how much i.v. fluids were administered made classification more difficult. When these discrepancies occurred, our team

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used nursing documentation totals. Both nursing and physician handwritten documentation was often illegible. Though potentially useful, the future molecular methods, such as PCR testing methods, have limitations. For example, PCR can differentiate between methicillin-sensitive S. aureus and methicillin-resistant S. aureus based on a drug-resistance gene target, but does not have the capacity to determine susceptibility results for all microbes. In our data set, one study patient was placed on ciprofloxacin for an E. coli infection. Typically, this would have been an appropriate antibiotic choice. However, in this situation, the E. coli was resistant to ciprofloxacin. This patient was still categorized into the ‘‘no alteration would occur’’ category, as molecular methods would have failed to identify the resistance. CONCLUSION Overall, the results of this study confirm the need for more rapid and accurate laboratory methods for identification of bloodstream pathogens and support the need for more collaboration between microbiology laboratories, ED physicians, and pharmacists to improve the early care of patients with bacteremia. It is evident that more attention to collection of blood cultures to avoid skin contamination is required, and that perhaps an ED-specific antibiogram may be useful to fine tune IDSA guidelines for treatment of bloodstream infections until the time that molecular methods are available for whole blood testing. Future research is needed to support development of whole blood DNA extraction methods and support multiplex molecular methods for early identification of bloodstream pathogens. Acknowledgment—Special thanks to Rebecca Landreth, RN, CIC, Infection Preventionist, for providing our research team with ED blood culture and contaminant rates.

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7 34. Bloos F, Hinder F, Becker K, et al. A multicenter trial to compare blood culture with polymerase chain reaction in severe human sepsis. Intensive Care Med 2010;36:241–7. 35. Kaleta EJ, Clark AE, Johnson DR, et al. Use of PCR coupled with electrospray ionization mass spectrometry for rapid identification of bacterial and yeast bloodstream pathogens from blood culture bottles. J Clin Microbiol 2011;49:345–53. 36. Gamage DC, Olson DP, Stickell LH, et al. Significant decreases in mortality and hospital costs after laboratory testing with PNA FISH. Poster D-1302b, 51st Interscience Conference of Antimicrobial Agents and Chemotherapy. Chicago, IL; 2011. 37. Forrest GN. PNA FISH: present and future impact on patient management. Expert Rev Mol Diagn 2007;7:231–6.

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ARTICLE SUMMARY 1. Why is this topic important? Substantial mortality is attributed to testing delays in determination of the microbial cause(s) and selection of the appropriate antibiotic in patients with bloodstream infections. As a result, empiric, broad-spectrum treatment is a common, costly approach that may fail to effectively target the correct microbe, may inadvertently harm patients via antimicrobial toxicity, and may contribute to the evolution of drug resistant microbes. 2. What does this study attempt to show? More rapid and accurate laboratory methods for identification of bloodstream pathogens are necessary. Increased collaboration between microbiology laboratories, emergency department (ED) physicians, and pharmacists could improve the early care of patients with bacteremia. 3. What are the key findings? a) Empiric antibiotics given in the ED for positive blood culture results would have changed to narrower-spectrum antibiotics 55.7% of the time, would have changed because the organism was not covered 21.3% of the time, and would have remained the same 23.0% of the time had the microbe been known at the time of antibiotic administration. b) Polymerase chain reaction would have helped physicians to use a narrower spectrum of antibiotic therapy > 16 times more often and a broader spectrum 7 times more often than following Infectious Disease Society of America protocols alone (p < 0.0001). c) The five most common organisms isolated were Escherichia 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 identification. It impacts care by enabling the use of new technologies that will lead to more appropriate antimicrobial therapy.