Healthcare-Associated Bloodstream Infections (Non-device related)

Healthcare-Associated Bloodstream Infections (Non-device related)

Richard J. Hankins

Mark E. Rupp

Healthcare-associated bloodstream infections (HA-BSIs) are a substantial and continuing problem in our present day healthcare system. A variety of factors, including central venous catheterization, predispose patients toward development of infections involving the bloodstream. Pathogens causing these infections vary according to the primary site of infection and a variety of patient factors. Preventive efforts are generally directed at the primary site of invasion. This chapter summarizes general issues related to healthcare-associated bacteremia. Due to the importance of BSI related to the use of intravascular devices, they will be discussed further in Chapter 12 More specific information can be found in chapters covering specific primary infections and pathogens.


HA-BSIs result in substantial morbidity, mortality, and economic cost. From 1975 to 1998, the proportion of healthcare-associated infections accounted for by BSIs increased from 5% to 17%.1,2 A review of data from the U.S. Nationwide Inpatient Sample estimated the rate of BSIs at 21.6 episodes/1000 admissions.3 Recently multicenter studies in Australia, France, and Italy found the HA-BSI rate to be 0.55-0.64, 0.99-1.31, and 1.6 per 1000 patient-days, respectively.4,5,6 It is estimated that each year in the United States between 250 000 and 500 000 patients experience a HA-BSI and between 30 000 and 100 000 die from these infections.3,7 An encouraging development in recent years has been a decrease in methicillin-resistant Staphylococcus aureus (MRSA) BSI.8,9,10,11 A U.S. Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report found that from 2005 to 2012, hospital-acquired MRSA BSI decreased 17.1% per year (P < .001).10 Similar findings were noted in an observational cohort study across 132 hospitals in Australia, which saw a yearly decrease of MRSA BSI of 9.4% from 2002 to 2013.8 The reason for this decline is not completely defined, but possible explanations include changes in S aureus epidemiology, the impact of hospital policies designed to decrease MRSA transmission, and widespread efforts to decrease rates of central venous catheter (CVC) infection. In an effort to decrease MRSA hospital-onset infections, Jain et al. instituted an “MRSA bundle,” consisting of surveillance for nasal colonization, contact precautions for patients with MRSA colonization or infection, hand hygiene, and focus on changing the culture to make infection prevention everyone’s responsibility. After beginning the initiative in 2007, they saw a decrease in non-device-related MRSA BSI of 79% (P < .001).9

The crude mortality associated with HA-BSI varies in published reports and depends on the microbial etiology and the underlying condition of the patient. Over a 7-year observational period from 1995 to 2002, the Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) investigators analyzed over 24 000 cases of HA-BSI from 49 medical centers and noted a crude mortality rate of 27%, ranging from 21% for coagulase-negative staphylococci to 40% for Candida sp.12 Since then, mortality rates have not substantially changed. A systematic review in 2013 found the case fatality rate ranged from 12% to 32% following HA-BSI.13 However, attributable mortality is more difficult to ascertain. In some studies that controlled for confounding variables such as severity of illness, BSI was not noted to increase mortality, while other investigators noted substantial increased mortality.14,15 Similarly, mortality associated with hospital-acquired S aureus BSI has not varied. A study monitoring S aureus BSI in Denmark noted a relatively constant rate of mortality of 27% in 1995 and 23% in 2008.16 Similar findings in the Premier and Cerner Electronic Health Record Databases showed no changes in unadjusted mortality rates for hospital-acquired S aureus BSI in the United States from 2012 to 2017.10

Healthcare-associated BSI results in dramatic increases in economic cost. The length of hospital stay is extended by 1-4 weeks at a cost of up to $40 000 per survivor.15,17 There is no doubt that HA-BSI is a very significant problem associated with the current healthcare system and that efforts to better understand and prevent this devastating complication are warranted.


The diagnosis of BSI is dependent on the capacity to recover microbes from the blood. Most large laboratories utilize various automated blood culture systems that are reasonably comparable and are often continuously monitored. These automated systems have been reviewed elsewhere, and an extensive discussion is beyond the scope of this chapter. Unfortunately, despite advances in clinical microbiology and improvement in the sensitivity of blood cultures to detect bacteremia, contamination of blood cultures continues to be problematic.28,29

Blood Culture Contamination or Pseudobacteremia

Pseudobacteremia, false-positive blood cultures, and blood culture contamination all refer to the problem in which microbes from a site outside the bloodstream are introduced into a sample of blood obtained for culture. This is a widespread phenomenon and occurs in 1%-5% of cultures even under optimal conditions, and up to 40% of positive cultures may represent contamination.28,30,31 The implications of blood culture contamination are substantial and include increased cost due to additional cultures and tests needed to investigate culture positivity, unnecessary antibiotics, side effects and toxicity due to the antibiotics, increased length of hospital stay, and inappropriate admission to the hospital. The total excess cost associated with blood culture contamination was $4100-$8720 per patient, while the median length of stay also increased a full day due to contamination.32,33,34,35

Differentiating contamination from true bacteremia must be done clinically by consideration of the microbe recovered from the blood, clinical presentation, number of cultures, source of positive cultures (line vs peripheral), and incubation time to positivity. It should be noted, however, that discounting single positive cultures with skin flora microbes (coagulase negative staphylococci) may lead to misdiagnosis in up to 25% of clinically significant bacteremic episodes due to these microorganisms, particularly in patients with CVCs.36,37 The cause of blood culture contamination is multifactorial, with multiple factors needing to be addressed in order to minimize its occurrence. Poor disinfection of the skin prior to obtaining culture and acquisition of blood cultures through vascular catheters are two well-known causes for blood culture contamination.38,39

Skin Preparation and Culture Technique

Inadequate skin preparation has been reported to be the most frequent cause of blood culture contamination.30 A variety of disinfectants are available for skin preparation. The use of iodine tincture results in lower rates of contamination when compared to povidone iodine, which is thought to be due to the shorter drying time and rapidity of antimicrobial activity associated with the alcohol in iodine tincture.32 Similarly, it has been observed that skin disinfection with alcoholic chlorhexidine resulted in fewer contaminated blood cultures than povidone iodine.40 However, Calfee and Farr observed no significant differences in contamination rates among four different skin antiseptics including povidone iodine, povidone iodine with 70% alcohol, isopropyl alcohol, and tincture of iodine.41 Washer et al. similarly evaluated povidone iodine, iodine tincture, and chlorhexidine gluconate and found no significant differences in reduction of contamination.42 This same conclusion was confirmed by Story-Roller et al. as no significant difference was found in blood culture contamination rates between the use of chlorhexidine and iodine tincture for skin antisepsis prior to blood culture acquisition. Based on these studies, guidelines published by both the Infectious Disease Society of America (IDSA) and the American College of Critical Care Medicine recommend using either alcohol alone, chlorhexidine with alcohol, or tincture of iodine for skin decontamination.43,44 A new needle should be utilized for each attempt at venipuncture. Blood should be promptly inoculated into culture bottles following disinfection of culture bottle top septums as the bottle tops are not sterile. Recently it was shown that utilizing an initial specimen diversion device (ISDD) could assist in further reducing blood culture contamination.45

Blood Volume Sampled

To maximize the diagnostic yield from blood cultures, an adequate amount of blood must be sampled. In many cases, the concentration of microorganisms in the bloodstream is ≤1 colony-forming unit (CFU)/mL, and therefore at least 40 mL of blood in adults should be sampled to reliably detect bacteremia.46 Mermel and Maki found that the yield from blood cultures in adults increased 3% per milliliter of blood obtained. In addition to rendering a low yield
from blood cultures, inadequate blood volume has also been associated with increased rates of culture contamination.47 Unfortunately, the inadequate sampling of blood volume is frequent in many clinical centers.48 Volume of sampling has also been shown to vary significantly between peripheral blood samples and samples acquired through a central line. Jones et al. found that blood culture vials contained ˜2.5 mL more blood when the culture was obtained via a CVC compared to peripheral phlebotomy (P < .001).49 It was hypothesized that ease of blood procurement via a catheter resulted in a larger volume being sampled.


The microbial profile of HA-BSI has changed markedly over the past several decades in response to changes in patient population and antibiotic use. Throughout the 1970s, Enterobacteriaceae were the most common cause of HA-BSI.61 During the 1980s, a relative decrease in bacteremia due to Escherichia coli and Klebsiella pneumoniae was observed, whereas the contribution due to coagulase-negative staphylococci, enterococci, and Candida albicans increased.62 These changes were attributed to the widespread use of antibiotics with activity against Enterobacteriaceae and the increased utilization of indwelling medical devices, particularly intravascular catheters. Another trend observed during the 1980s was a shift toward more antibiotic-resistant pathogens. Increased prevalence of antibiotic resistance was observed in Pseudomonas aeruginosa and Enterobacter cloacae resistant to third-generation cephalosporins, S aureus and coagulase-negative staphylococci resistant to methicillin, and enterococci resistant to high levels of aminoglycosides.62

These trends continued in the 1990s. BSI accounted for ˜14% of healthcare-associated infections with Gram-positive cocci including coagulase-negative staphylococci, S aureus, and enterococci responsible for 56% of HA-BSIs.2 Unfortunately, since the mid-1990s, due to limitations in time and personnel resources, fewer and fewer hospitals participated in the hospital-wide surveillance component of the CDC’s National Nosocomial Infections Surveillance (NNIS) system, and it was discontinued in 1999. However, the NNIS system continued to track healthcare-associated infections from targeted surveillance in ICUs. There was little change in the relative rank order of bloodstream isolates observed in ICU patients from 1990 to 1999.63 Pathogens varied by type of ICU with Gram-negative pathogens such as Enterobacter sp. or P aeruginosa causing BSI more frequently in burn ICUs than other types of ICUs (11.2% and 9.5%, respectively). Conversely, BSI due to S aureus and coagulase-negative staphylococci occurred with greater frequency in coronary care and cardiothoracic ICU patients (23.2% and 42.7%, respectively) than in other ICUs.63

NNIS transitioned into the NHSN, and while NHSN includes a much larger number of institutions, it no longer reports HA-BSI data. Reports on overall HA-BSIs have been less frequent as both national surveys and focused reports have described specific syndromes responsible for BSI such as intravascular catheter infection, pneumonia, and urinary tract infection (UTI). A nationwide surveillance study (SCOPE), which described over 24 000 HA-BSIs from 1995 to 2002, noted12 that Gram-positive pathogens such as coagulase-negative staphylococci, S aureus, and enterococci were most common in both ICU and non-ICU setting (62.5% and 59.3%, respectively). Coagulase-negative staphylococci, Enterobacter sp., Serratia sp., A baumannii, and Candida sp. were more common in the ICU, while S aureus, Klebsiella sp., and E coli were more common in the general ward (P < .001). A notable finding in this study was the high incidence of BSIs due to Candida species, accounting for nearly 10% of HA-BSIs and increasing significantly from 8% in 1995 to 12% in 2002 (P < .001, trend analysis). C albicans was the most common species isolated (54%), and C glabrata (19%), C parapsilosis (11%), and C tropicalis (11%) were also frequently isolated.12 Other centers have noted similar trends with candidal BSIs making up 10% or more of healthcare-associated BSIs.64 Some institutions have recently described a re-emergence of Gram-negative pathogens causing HA-BSIs. In a tertiary care center in the United States from 1999 to 2003, the number of BSIs caused by Gram-negative organisms significantly increased from 15.9% to 24.1% (P < .001), while infections due to coagulasenegative staphylococci and S aureus decreased over the same time period (P < .007).64 In some centers, Gram-negative pathogens have eclipsed Gram-positives as the most common organisms causing HA-BSIs, while other locations are seeing near equivalence between the two.4,65 Chaftari et al. noted this change in the epidemiology of BSI in oncology patients, in comparing infection control data from September 1999 to November 2000 to BSI data from January 2013 to March 2014. BSI due to Gram-negative organisms increased from 24% in their earlier cohort, to 52% over a decade later (P < .0001).66 A cohort study including 24 countries evaluating HA-BSI in ICUs found similar results, with Gram-negative organisms being responsible for 57.6% of blood culture isolates.67 Factors possibly contributing to the increase in Gram-negative pathogens include improved practices in the placement and maintenance of CVCs leading to decreased line-related Gram-positive infections, increasing antimicrobial resistance in Gram-negative isolates, and the emergence of organisms such as A baumannii as major pathogens in the ICU (Table 13-2). These trends in the etiology of HA-BSIs are described in Table 13-3.

TABLE 13-2 Pathogens Isolated from Intensive Care Unit Healthcare-Associated Bloodstream Infections, the EUROBACT International Cohort Study, 2009 (n = 1317)


Number (%)

Acinetobacter sp.

160 (12.2)

Klebsiella sp.

156 (11.9)

Pseudomonas sp.

150 (11.4)

Enterococcus sp.

144 (10.9)

Coagulase-negative staphylococci

141 (10.7)

S aureus

119 (9.0)


98 (7.4)

Enterobacter sp.

88 (6.7)

C albicans

56 (4.3)


205 (15.6)

Data from Tabah A, Koulenti D, Laupland K, et al. Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med. 2012;38(12):1930-1945.

As previously mentioned, during the 1980s a trend was observed indicating that healthcare-associated BSIs were increasingly being caused by antibiotic-resistant pathogens. This trend continued in the 1990s and worsened in the first decade of the 21st century. Klevens and colleagues compared NNIS microbiologic data for the period 1990-1994 to 2000-2004 and noted significant increases in MRSA BSIs (27.0%-54.1%), ceftazidime-resistant P aeruginosa pneumonias (16.6%-22.7%), and ciprofloxacin-resistant E coli UTIs (0.9%-9.8%).68 The latest published data from the NNIS system, summarized bacterial isolates from ICU and non-ICU inpatient areas from January 1998 to June 2004, indicated an alarming prevalence of antimicrobial resistance.69 These data are shown in Table 13-4. Using data from the SCOPE study which included HA-BSI from 49 hospitals from 1995 to 2002, Wisplinghoff et al. described significant increases in the isolation of MRSA (22%-57%), ceftazidime-resistant P aeruginosa (12%-29%), and vancomycin-resistant Enterococcus faecium (47%-70%).12 The rise of resistant pathogens is a global phenomenon. A survey of over 81 000 BSI from three continents noted two- to threefold higher rates of vancomycin-resistant enterococci (13.3%), ESBL Klebsiella sp. (24.6%), and multidrug-resistant P aeruginosa (9.0%) in HA-BSIs compared to community BSIs.70 The EUROBACT study found in intensive care patients with HA-BSI the two most common Gram-negative isolates of Acinetobacter sp. and Klebsiella sp. were multidrug resistant in at least 70% of strains.67 The rate of HA-BSI due to MRSA appears to be decreasing with studies showing a reduction ranging
from 31.5% to 76.6%.8,71 While MRSA HA-BSI appears to be decreasing, the rate of HA-BSI due to resistant Gram-negative organisms appears to be increasing.

TABLE 13-3 Pathogens Isolated from Healthcare-Associated Bloodstream Infections, 1995-2012

Si et al.4 2008-2012, n = 8092

Wisplinghoff et al.12 1995-2002, n = 24,179

Corona et al.81a 2002-2003, n = 1,266

Coagulase-negative staphylococci




S aureus




Enterococcus sp.




E coli




Candida sp.




Viridans streptococci




Pseudomonas sp.




Klebsiella sp.




Enterobacter sp.




Other GNR












Values represent percentage of total bloodstream isolates for pathogen in specific study.

a Total percentage >100% as more than one microorganism may be reported as cause of bacteremia. NR, not reported; GNR, Gramnegative aerobic rods. (Data from Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309-317; Si D, Runnegar N, Marquess J, Rajmokan M, Playford EG. Characterising healthcare-associated bloodstream infections in public hospitals in Queensland, 2008-2012. Med J Aust. 2016;204(7):276-276; and Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). J Antimicrob Chemother. 2010;65(6):1276-1285.)

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Jun 8, 2021 | Posted by in INFECTIOUS DISEASE | Comments Off on Healthcare-Associated Bloodstream Infections (Non-device related)
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