Hippocratic Medicine No.1: Blood Culture or No Blood Culture, That is the Question.

Welcome to the first installment of our new column here at Everyday EBM - Hippocratic Medicine.  

Modeled after the Do No Harm project pioneered at the University of Colorado, the aim of this (hopefully) monthly installment will be on the avoidance of avoidable care i.e. raising awareness for how medical overuse has the potential to do patient harm.   Because every test or intervention we do has the potential for not just benefit but also harm, we should seek that our patients do better because of the care we provide instead of despite it.  

Clinical Scenario: It is a regular day in the emergency department and along with the regular smattering of chest pain rule-outs, vaginal bleeders, and abdominal pain, you have two patients who need to be admitted for IV antibiotics. One has a diffuse cellulitis of the left leg and the other pyelonephritis, unable to tolerate oral meds. Both have an elevated white count but no other SIRS criteria. When giving sign-out, the inpatient medicine team asks for blood cultures on both patients.  Is there any value for blood cultures in patients with cellulitis and pyelonephritis? Does this value outweigh the potential harms?

Literature Review:The ACEP article [1] “The evidence against blood cultures” presented interesting data regarding cost and benefit of blood cultures. According to the article, in 2010 $151 million dollars was spent on blood cultures. Only 4% to 7% of blood cultures were true positives. Alarmingly, blood cultures are almost as likely to give you a false positive as a true one: 40% of all "positive" cultures are false positives. For cellulitis, only 2% of patients are likely to develop a bacteremia and skin infections are almost always due to Staph or Strep. For uncomplicated pyelonephritis, the urine culture is what is used to target treatment, and if blood cultures are positive, it is almost always with the same organism and does not alter treatment course.
 

With regard to their recommendations for pyelonephritis, the ACEP article draws on a retrospective chart review of 212 patients admitted for uncomplicated pyelonephritis [2] . Blood cultures were performed for 105 of these patients, only 16% of which grew out an organism. Of the 11 positive cultures, all but 2 had the same organism that was identified in the urine and no change was made in treatment. The other 2 were found to have a second infectious source for their bacteremia.
 
With regard to cellulitis, a retrospective review of 710 patients admitted for cellulitis, of which 553 had blood cultures drawn. Of these patients, only 11 cultures (2%) were positive [3]. A 2012 review article in the Journal of infection found 7.9% of patients with cellulitis had positive cultures, all with Staph or Strep identified as the source organism [4]. 

These findings are not limited to the adult population [5].  A retrospective cohort study of blood culture results and microbiology laboratory charges for pediatric cases of community-acquired pneumonia and skin/soft tissue infection found that only 9/279 cultures (3.2%) grew an organism and only 5/9 (55%) were deemed to be true positives.  The main subsequent intervention?  Repeat cultures.  4/9 of these were deemed to be false-positives, leading to a smattering repeat cultures, ID consultation, prolonged LOS, and vancomycin initiation:

Table 2 from Parikh et. al. (Ref 5)

But are there clinical indicators that increase the diagnostic or therapeutic yield of blood cultures? The answer is yes. In a 1996 study, SIRS criteria was found to be 96% sensitive for positive blood cultures and this has been corroborated by other studies [6]. This indicates that in the absence of SIRS criteria aka in the absence of sepsis (2 SIRS + a known infectious source) blood cultures are more likely to be false positives than true positives, and do not meet standards for an indicated test.

As alluded to in the pediatric data, we may be doing more harm than good when ordering blood cultures in patients with uncomplicated [or shall we say SIRS(-) ?] pneumonia, cellulitis or UTI. Just like an incidental finding on an imaging study, false positive blood cultures have the power to beget further testing and intervention. Since we have learned above that the results are unlikely to change treatment course, we know that there are limited benefits. But what about the costs?

- Blood cultures increased cost and hospital length of stay: A retrospective study from Ireland [7] compared "cases" of false-positive blood cultures [defined as a single blood culture set positive for micro-organisms commonly thought of as contaminants or multiple blood cultures positive for different organisms] with "controls" matched for comorbidity via the Charlson index with "true negative" blood cultures. They found an overall false positive rate of 4.7%, and that patients with false positive blood cultures stayed in the hospital for 5.4 days ( 95% CI 2.8 - 8.1 days) longer at a cost of $7502.20 more (95% CI: $4,925.80 - $10, 078.60) compared to counterparts matched for diagnosis and comorbidity. A similar study from Brigham and Women's Hospital published in 1991 [8] found essentially the same results (average increased LOS of 4.5 days and increased total cost of $4,385). 


-  Blood cultures increase unnecessary antibiotic use: In addition to adding to hospital length of stay, part of the additional costs incurred by false positive blood cultures are unnecessary antibiotics [8]. 
A prospective, blood culture cohort study [9] evaluated all blood culures positive for skin flora during a three month period at a US medical center.  In this study, they found 59 false positives aka contaminants with Coagulase Negative Staph in 3, 276 collections (compared with 20 cases of "true bacteremia" with the same organism).  Among the 59 patients in the false positive category, 24 (41%) were treated with antimicrobial agents, predominantly vancomycin.  It is unclear from reading the paper if this was a direct result of the positive blood culture, or due to continuation of empiric treatment; however, the results described by Alahmadi [7] and Bates [8] suggest that the culture results are at least in part responsible.  Beyond the aspect of monetary cost alone, there are a number of harms, including renal injury and spread of antibiotic resistance, that make unnecessary antibiotic use particularly troubling.


It has been written [8] that  "The true costs of a blood culture may greatly exceed the costs of the test itself".   How do we change this?  In the same way we make all clinical tests better - by using them in the appropriate situation and maximizing specificity.
 
                I. Decrease blood culture contamination rates:  The nationwide average for blood culture contamination is thought to be in the range of 3-5%.  At our own hospital (BJH), the blood culture contamination rate was within this range, with a rate of 3-4% for the emergency department compared with 1-2% for the ICU for 2014.  Several studies have demonstrated that increased nursing education and standardization of protocols can have significant impact on contamination rates. For example, one study for multiple centers in Sacramento saw a sustained drop from a 12% to 3% after instituting (and intensively educating about) a protocol of chlorhexidine-based skin cleaner and sterile glove technique in which a sterile glove is used for repalpating the site [10].
           
               II.  Use it in the appropriate clinical situation:  If you are admitting a patient with SIRS(-) pneumonia, UTI, or SSTI just don't do it.  However, make sure to send the urine culture before antibiotics (patient has not gone yet?  That's what a straight cath is for!). If the inpatient medicine team asks you to, use it as an opportunity for education.  Floridly septic?  Go ahead.  Think its endocarditis?  Sure.  


Submitted by Alicia Oberle, PGY-3 and Maia Dorsett (@maiadorsett), PGY-3
Reviewed by Ryan Schneider and Stephen Liang. 
Thank you to Maureen Keating and Carey-Ann Burnham of BJC Micro for our own contamination rate data.

References:
1. Lin MP, Schurr JD. Arm Yourself for the “Cultural” Debate: The Evidence Against Blood Cultures. ACEP Now. Sept 2014 Vol 33 Number 9.
2. Pasternak EL, Topink MA. Blood Cultures in Pyelonephritis: do results change therapy? Acad Emerg Med. 2000; 7:1170.
3. Perl B, Gottehrer NP, Raveh D, et. al. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis. 1999; 29:1483-1488.
4. Gunderson CG, Martinello RA. A systematic review of bacteremias in cellulitis and erysipelas. Journal of Infection. 2012 Feb. 
5.Parikh, K., Davis, A. B., & Pavuluri, P. (2014). Do we need this blood culture?. Hospital pediatrics, 4(2), 78-84.
 6. Jones GR, Lowes JA. The systemic inflammatory response syndrome as a predictor of bacteremia and outcome from sepsis. QJM. 1996; 89:515-522. 7. Alahmadi, Y. M., Aldeyab, M. A., McElnay, J. C., Scott, M. G., Darwish Elhajji, F. W., Magee, F. A., ... & Kearney, M. P. (2011). Clinical and economic impact of contaminated blood cultures within the hospital setting. Journal of Hospital Infection, 77(3), 233-236.
8. Bates, D. W., Goldman, L., & Lee, T. H. (1991). Contaminant blood cultures and resource utilization: the true consequences of false-positive results. JAMA, 265(3), 365-369
9. Souvenir, D., Anderson, D. E., Palpant, S., Mroch, H., Askin, S., Anderson, J., ... & Campbell, D. M. (1998). Blood cultures positive for coagulase-negative staphylococci: antisepsis, pseudobacteremia, and therapy of patients. Journal of clinical microbiology, 36(7), 1923-1926.
10. Denno, J., & Gannon, M. (2013). Practical Steps to Lower Blood Culture Contamination Rates in the Emergency Department. Journal of Emergency Nursing, 39(5), 459-464.