RESEARCH ARTICLE Cost Attributable to Nosocomial Bacteremia. Analysis According to Microorganism and Antimicrobial Sensitivity in a University Hospital in Barcelona Marta Riu1,2*, Pietro Chiarello1,2, Roser Terradas2,3, Maria Sala1,4,5, Enric Garcia-Alzorriz1, Xavier Castells1,4,5, Santiago Grau2,6, Francesc Cots1 1 IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain, 2 Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 3 School of Nursing, Hospital del Mar, Barcelona, Spain, 4 Department of Epidemiology and Evaluation, Hospital del Mar, Barcelona, Spain, 5 Redissec (Red de Investigación en Servicios Sanitarios en enfermedades crónicas), Madrid, Spain, 6 Department of Pharmacy, Hospital del Mar, Barcelona, Spain * 20138@hospitaldelmar.cat Abstract OPEN ACCESS Aim Citation: Riu M, Chiarello P, Terradas R, Sala M, To calculate the incremental cost of nosocomial bacteremia caused by the most common Garcia-Alzorriz E, Castells X, et al. (2016) Cost organisms, classified by their antimicrobial susceptibility. Attributable to Nosocomial Bacteremia. Analysis According to Microorganism and Antimicrobial Sensitivity in a University Hospital in Barcelona. PLoS Methods ONE 11(4): e0153076. doi:10.1371/journal. We selected patients who developed nosocomial bacteremia caused by Staphylococcus pone.0153076 aureus, Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa. These Editor: Delmiro Fernandez-Reyes, University microorganisms were analyzed because of their high prevalence and they frequently pres- College London, UNITED KINGDOM ent multidrug resistance. A control group consisted of patients classified within the same all- Received: June 17, 2015 patient refined-diagnosis related group without bacteremia. Our hospital has an established Accepted: March 23, 2016 cost accounting system (full-costing) that uses activity-based criteria to analyze cost distri- Published: April 7, 2016 bution. A logistic regression model was fitted to estimate the probability of developing bac- Copyright: © 2016 Riu et al. This is an open access teremia for each admission (propensity score) and was used for propensity score matching article distributed under the terms of the Creative adjustment. Subsequently, the propensity score was included in an econometric model to Commons Attribution License, which permits adjust the incremental cost of patients who developed bacteremia, as well as differences in unrestricted use, distribution, and reproduction in any this cost, depending on whether the microorganism was multidrug-resistant or multidrug- medium, provided the original author and source are credited. sensitive. Data Availability Statement: All relevant data are within the paper and its Supporting Information file. Results Funding: The authors have no support or funding to A total of 571 admissions with bacteremia matched the inclusion criteria and 82,022 were report. included in the control group. The mean cost was € 25,891 for admissions with bacteremia Competing Interests: The authors have declared and € 6,750 for those without bacteremia. The mean incremental cost was estimated at € that no competing interests exist. 15,151 (CI, € 11,570 to € 18,733). Multidrug-resistant P. aeruginosa bacteremia had the PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 1 / 12 Cost Attributable to Nosocomial Bacteremia highest mean incremental cost, € 44,709 (CI, € 34,559 to € 54,859). Antimicrobial-suscepti- ble E. coli nosocomial bacteremia had the lowest mean incremental cost, € 10,481 (CI, € 8,752 to € 12,210). Despite their lower cost, episodes of antimicrobial-susceptible E. coli nosocomial bacteremia had a major impact due to their high frequency. Conclusions Adjustment of hospital cost according to the organism causing bacteremia and antibiotic sensitivity could improve prevention strategies and allow their prioritization according to their overall impact and costs. Infection reduction is a strategy to reduce resistance. Introduction Bacteremia is a severe infection with high mortality rates. Nosocomial bacteremia constitutes an important part of healthcare related infections. In a study conducted in 12 Spanish hospitals that aimed to evaluate the costs of adverse events, healthcare infections were the group with highest incremental costs, representing 64.2% of the total cost of episodes with adverse events [1]. Nosocomial bacteremia increases length of stay, hospital costs and mortality rates, as it can trigger more serious events such as septic shock, occasionally with multiple organ failure, and death. The incidence rate of nosocomial bacteremia has been estimated to be between 113 and 189/100,000 inhabitants per year, with an associated mortality of between 21 and 38/100,000 per year [2]. The additional per-patient cost at hospital level has been estimated at € 14,735 [3] or € 12,853 [4]. In a systematic review that analyzed variations in analytical methods to esti- mate the incremental costs of nosocomial infections, the results for nosocomial bacteremia var- ied from $ 5,875 to $ 86,500 [5]; this disparity reflects differences in patient characteristics, the type of infection, the causative microorganisms, and the calculation methods. Bacteremia caused by multidrug-resistant microorganisms has a worse prognosis than that is caused by antimicrobial-susceptible microorganisms, because multidrug resistance delays and reduces the choice of appropriate treatment. Consequently, adverse effects could be more frequent and the selected antimicrobials are usually more expensive and, due to their broader spectrum, could promote the development of new antimicrobial resistances [6–8]. Population- based studies have estimated the additional costs of antimicrobial resistance at $ 20 billion in the USA [9] and 1.5 billion annually in Europe, of which more than 900 million are direct hos- pital costs [10]. In the case of bacteremia, the excess cost of multidrug resistance has been esti- mated at $16,918 per patient [11]. Unfortunately, the prevalence of multidrug resistant microorganisms is constantly growing, despite various strategies for prevention, which is a concern for health professionals [9,10]. The excess cost associated with nosocomial bacteremia is avoidable and can be used as a measure of the impact of these infections. However, some authors have suggested that tradi- tional methods overestimate the incremental cost due to the presence of various types of bias. First, the possibility of developing nosocomial bacteremia is due, in part, to length of exposure. Consequently, a longer hospital stay increases the risk of acquiring an infection. In addition, a hospital-acquired infection increases the length of stay, converting the length of stay into a var- iable directly related to a time-dependent bias [12–14]. Further biases can also be related to the lack of complete information on all confounding variables (default variable bias) or if the sam- ple analyzed does not include adequate control cases (selection bias) [13–15]. The main source of cost is hospital analytical cost accounting, which includes the cost of all activities conducted in the process of providing healthcare to hospitalized patients and all rele- vant cost typologies [14,16]. PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 2 / 12 Cost Attributable to Nosocomial Bacteremia Due to the difficulty of identifying the multitude of activities performed in a hospital, cur- rently few hospitals have developed detailed per patient cost accounting. Consequently, most studies analyzing bacteremia costs are based on secondary estimates rather than real costs [5, 17,18]. These methodologies lose sensitivity in showing the variability of costs due to the spe- cific circumstances that affect the type and number of activities performed in the treatment of each patient according to their characteristics and needs. The use of costs based on analytical cost accounting systems ensures that the variability of clinical practice is sufficiently captured in terms of resource use. A recently published study on the economic impact of adverse events showed the advantages and strengths of the use of activity-based costing and full costing tech- niques in healthcare economic evaluation [1]. Differentiating the incremental cost of bacteremia by microorganisms according to their antimicrobial sensitivity or resistance would contribute to a better understanding of the mag- nitude of the economic burden of resistance. In addition, such an analysis would help to eval- uate the effectiveness of initiatives attempting to antimicrobial resistance and would provide valuable information on the areas that should be prioritized to control healthcare infections [19–22]. Objective The main aim of the study was to calculate the incremental cost of nosocomial bacteremia caused by the most common organisms, classified by antibiotic sensitivity. Material and Methods A retrospective study was conducted at Hospital del Mar, Barcelona, a teaching hospital equipped with 400 beds that provides medical and surgical care and has a catchment area of 300,000 inhabitants. The study population consisted of patients admitted to the hospital from 2005 to 2012. All discharges were classified with the all-patient refined-diagnosis-related group (APR-DRG) v. 24.0 grouper. Admitted patients who developed nosocomial bacteremia caused by Staphylococ- cus aureus, Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa and all control patients classified within the same APR-DRG groups were selected. These microorganisms were analyzed because of their high prevalence, and, in our environment, often have multidrug resistance. Nosocomial bacteremia was defined according to the Center for Disease Control definitions [23]. Magiorakos[24] criteria were used to identify multidrug resistant microorganisms (Table 1). Admissions grouped into non-specific APR-DRG were excluded. Patients with two or more episodes of bacteremia during the same hospital stay were also excluded because of their spe- cific risk factors [25]. The dependent variable was the cost of the hospitalization episode. The main explanatory variable was the presence of nosocomial bacteremia. Additional study variables were age and sex, type of admission (emergency or elective), type of treatment (medical or surgical), dis- charge status (alive or deceased), admission diagnosis, the presence of complications, level of comorbidities as measured by the Elixhauser index [1], intensive care unit (ICU) admission, per-patient cost previous to the bacteremia as a weighted measure of length of hospital stay prior to bacteremia detection and the cost weight of the adjacent APR-DRG group. The total costs of hospital admissions with nosocomial bacteremia caused by the selected microorganisms were analyzed by taking into account the antimicrobial susceptibility of each microorganism. This group of patients was compared with the control group. PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 3 / 12 Cost Attributable to Nosocomial Bacteremia Table 1. Criteria used to identify multidrug-resistant microorganisms. Microorganisms Antimicrobial category Antimicrobial agents Aminoglycosides Amikacin Gentamicin Tobramycin Carbapenems Ertapenem E. coli* Imipenem K. pneumoniae* Meropenem 1st or 2nd generation cephalosporins Cefazoline Cefuroxime 3rd or 4th generation cephalosporins Cefotaxime Ceftazidime Cefepime Aminoglycosides Amikacin Gentamicin Tobramycin Monobactams Aztreonam Cephalosporins with antipseudomonal activity Ceftazidime P. aeruginosa* Cefepime Quinolones Ciprofloxacin Levofloxacin Ureidopenicillins Piperacillin + Tazobactam Carbapenems Imipenem Meropenem Polymyxins Colistin Penicillins Oxacillin S. aureus** Cloxacillin Methicillin Glycopeptides Vancomycin * Microorganisms were considered to be multidrug-resistant if identified as such by the microbiologist or if they had developed resistance to three or more antibiotics family. ** Microorganisms were considered to be multidrug-resistant if they developed resistance to one antibiotic family. doi:10.1371/journal.pone.0153076.t001 Clinical information on the hospitalization process of each patient included in the study was obtained from the minimum dataset of hospital discharges and from the hospital informa- tion system, which has an established cost accounting systems (full-costing) in which cost dis- tribution is based on activity-based criteria[26]. All costs were adjusted to 2012 price levels according to the national price index published by Spain’s National Institute of Statistics [27]. Admissions with bacteremia were identified using the dataset collected by the infection control department, which prospectively follows up all episodes of bacteremia. A descriptive analysis was performed of all variables of admissions with and without bacter- emia and of microorganism sensitivity. The Chi-square test was used to compare categorical variables and the comparison of mean values was performed using ANOVA test. A generalized linear model with binomial distribution and logit function was fitted to estimate, for each admission, the probability of developing bacteremia (propensity score) and was used for propensity score matching adjustment [14,28]. The model was specified the variables previously described with logarithmic transformations for the APR-DRG cost weight and for cost previous to the bacteremia. Subsequently, the propensity score was included in a generalized linear models PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 4 / 12 Cost Attributable to Nosocomial Bacteremia with the Gamma distribution and the log link function to adjust the incremental cost of patients who developed bacteremia, as well as differences in this cost, depending on whether the microor- ganism was multidrug-resistant or multidrug-sensitive. The econometric model included the same variables used for the estimation of the propensity score (see S1 File for details). The study was approved by the Ethics Committee for Clinical Research of Hospital del Mar, Parc de Salut Mar. Any patient-level data was anonymized, and no additional informed con- sent was required. Results There were 177,378 discharges in the study period, of which 0.96% had an episode of bacter- emia (n = 1,703). Of these, 669 (39.3%) were episodes of nosocomial bacteremia caused by the above-mentioned microorganisms. Finally, 571 admissions with bacteremia met the inclusion criteria and 82,022 treated in the same period and grouped in the same APR-DRG who did not develop nosocomial bacteremia were included in the control group. Table 2 shows the charac- teristics of the selected episodes. At hospital admission, patients from both groups had similar levels of comorbidities (Elixhauser index) and requirements for surgical intervention, although patients who developed bacteremia were more likely to be admitted to the ICU and had higher mortality and resource consumption (measured by APR-DRG weight and average cost). Among the 571 episodes with bacteremia, the most frequently isolated microorganism was E. coli (184 episodes), followed by S. aureus (108 episodes). The least frequent microorganism was P. aeruginosa (86 episodes), which nevertheless showed the highest percentage (40.7%) of episodes with multidrug resistance. Overall, 29.2% of microorganisms showed multidrug resis- tance (Table 3). About 16% of nosocomial bacteremia were polymicrobial. The total cost was € 568,464,250. The 571 admissions with bacteremia represented 0.69% of analyzed admissions and 2.6% of total observed cost (Table 4). The mean cost of admissions with bacteremia was € 25,891. Nosocomial bacteremia caused by multidrug-resistant P. aeruginosa was the most costly with a mean observed cost of € 38,872; episodes caused by multidrug-resistant E. coli had the lowest mean cost, € 16,754 (Table 4). The mean incremental cost was estimated at € 15,151 (CI, € 11,570 to € 18,733) and was related to an Table 2. Patients without and with bacteremia, characteristics, and average cost of the episode. Patients Patients with bacteremia without bacteremia multidrug-sensitive multidrug-resistent P-value Number of patients 82,022 404 167 Male sex (N, %) 43,256 52.7 249 61.6 101 60.5 <0.000 Age (mean, SD) 67.1 17.0 64.7 15.8 67.2 14.7 0.017 Urgent admission (N, %) 53,171 64.8 291 72.0 126 75.4 <0.000 Surgical patient (N, %) 34,534 42.1 193 47.8 67 40.1 0.062 Intensive care unit admission (N, %) 4,508 5.5 128 31.7 51 30.5 <0.000 Exitus (N, %) 3,852 4.7 112 27.7 52 31.1 <0.000 Elixhauser index (mean, SD) 2.6 1.9 2.6 1.7 2.8 1.9 0.428 APR-DRG weight (mean, SD) 1.1539 0.8405 1.9435 2.2947 1.8310 2.0532 <0.000 Length of hospital stay (mean, SD) 10.8 10.3 32.2 28.0 37.2 24.4 <0.000 Length of hospital stay prior to bacteremia (mean, SD) - 14.5 15.2 18.5 13.4 - Total cost observed (mean, SD) 6,750 7,619 24,960 31,154 28,143 23,964 <0.000 Abbreviation: APR-DRG = all-patient refined-diagnosis related group. doi:10.1371/journal.pone.0153076.t002 PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 5 / 12 Cost Attributable to Nosocomial Bacteremia Table 3. Distribution of bacteremia according to the causative organism and its antibiotic sensitivity. Multidrug-sensitive Multidrug-resistant N % N % Total S. aureus 70 64.8 38 35.2 108 E. coli 145 78.8 39 21.2 184 K. pneumoniae 69 67.6 33 32.4 102 P. aeruginosa 51 59.3 35 40.7 86 Polimicrobial 69 75.8 22 24.2 91 Total 404 70.8 167 29.2 571 doi:10.1371/journal.pone.0153076.t003 increase of € 8,651,221 in total hospital costs. As shown in Table 5, multidrug-resistant P. aerugi- nosa bacteremia had the highest incremental cost, € 44,709 (CI € 34,559 to € 54,859). Despite being one of the less common microorganisms, P. aeruginosa had a substantial impact on total costs, amounting to € 1,564,817. The mean incremental cost was € 8,872 for multidrug-resistant E. coli bacteremia and was € 10,481 (CI € 8,752 to € 12,210) for antimicrobial-susceptible E. coli nosocomial bacteremia, which represented the second highest total cost (€ 1,519,735). Despite its lower mean incremental cost compared with other causative agents, antimicrobial-susceptible E. coli nosocomial bacteria had a major impact due to its high frequency. Multidrug-sensitive nosocomial polymicrobial bacteremia also had a major impact on cost, amounting to € 19,009 (CI € 14,917 to € 23,100 IC), and represented a total incremental cost of € 1,311,987. Discussion The 571 admissions developing nosocomial bacteremia during the 8 years analyzed increased total hospital costs by € 8,651,221, more than € 1,000,000 per year. The mean additional cost Table 4. Average and total cost among all patients according to the causative organism and its antibiotic sensitivity. Observed cost Patients N % mean total Without bacteremia 82,022 99.3 6,75 553,680,489 With bacteremia 571 0.69 25,891 14,783,761 Total 82,593 100.0 6,883 568,464,250 Microorganism group S. aureus (MDSM) 70 12.3 22,851 1,599,541 S. aureus (MDRM) 38 6.7 24,468 929,792 E. coli (MDSM) 145 25.4 21,883 3,173,003 E.coli (MDRM) 39 6.8 16,754 653,392 K. pneumoniae (MDSM) 69 12.1 25,222 1,740,292 K. pneumoniae (MDRM) 33 5.8 35,100 1,158,312 P. aeruginosa (MDSM) 51 8.9 30,201 1,540,266 P. aeruginosa (MDRM) 35 6.1 38,872 1,360,505 Polymicrobial (MDSM) 69 12.1 29,431 2,030,733 Polymicrobial (MDRM) 22 3.9 27,179 597,938 Total number of patients with bacteremia 571 100.0 25,891 14,783,775 MDSM = multidrug-sensitive microorganism; MDRM = multidrug-resistant microorganism. doi:10.1371/journal.pone.0153076.t004 PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 6 / 12 Cost Attributable to Nosocomial Bacteremia Table 5. Average incremental cost and impact on cost of the distinct causative organisms and their antibiotic sensitivity. Patients Incremental cost Impact on costs Microorganism group N % Mean Confidence interval Total % S aureus (MSSA) 70 12,3 9.350 7.215 11.485 654.500 7,6 MRSA 38 6,7 14.372 10.426 18.317 546.136 6,3 E coli (MDSM) 145 25,4 10.481 8.752 12.210 1.519.745 17,6 E coli (MDRM) 39 6,8 8.872 6.588 11.155 346.008 4 K pneumoniae (MDSM) 69 12,1 13.864 11.019 16.709 956.616 11,1 K pneumoniae (MDRM) 33 5,8 18.208 12.663 23.754 600.864 6,9 P aeruginosa (MDSM) 51 8,9 16.042 11.956 20.127 818.142 9,5 P aeruginosa (MDRM) 35 6,1 44.709 34.559 54.859 1.564.815 18,1 Polymicrobian (MDSM) 69 12,1 19.009 14.917 23.100 1.311.621 15,2 Polymicrobian (MDRM) 22 3,9 15.138 6.932 23.344 333.036 3,8 Total 571 100 15.151 11.570 18.733 8.651.221 100 MDSM = multidrug-sensitive microorganism; MDRM = multidrug-resistant microorganism. doi:10.1371/journal.pone.0153076.t005 was € 15,151 per admission. Substantial differences were found between organisms. Multidrug- resistant P. aeruginosa bacteremia had the highest economic impact, with a mean incremental cost of € 44,709. The characteristics and implications of the S. aureus bacterium have been constantly studied since the first epidemic of methicillin-resistant S. aureus (MRSA) in the 1960s [29]. The observed costs related to multidrug-sensitive S aureus (MSSA) ranged from $ 9,839 to $ 59,245. Reported costs for MRSA have ranged from $ 11,045 to $ 84,436 [30,31]. A study ana- lyzing patients with S. aureus bacteremia in 27 Spanish hospitals [31] reported that the cost of MSSA was € 9,839 and the cost of MRSA was € 11,044, slightly lower than those found in the present work. Two previous studies have evaluated the cost of MRSA bacteremia compared with MSSA bacteremia using propensity score matching techniques, although their findings are not clearly comparable with those of this study. The first [32] included community-acquired bacteremia in selected cases; the estimated cost was $ 8,355 (MSSA) vs. $ 9,369 (MRSA). The second [33] analyzed the cost of patients with and without ICU admission separately; among the former, those who developed MRSA bacteremia were associated with higher costs (with an odds ratio of 2 relative to MSSA), while non-ICU patients showed no significant difference in cost. E. coli was the most frequent bacteremia found in this study (32.2% of total episodes) and showed the lowest multidrug resistance (21.2%). Its mean incremental cost estimate was lower than those of other microorganisms but it had the second highest total economic impact due to its high frequency. The adjusted cost of multidrug-resistant E. coli was lower than that for mul- tidrug-sensitive episodes. E. coli is one of the most frequent microorganisms causing bacteremia, whether hospital- or community-acquired [34–36], and has an increasing share of multidrug resistance [13, 36]. Nevertheless, very few studies have analyzed the impact of this microorganism on hospital cost. This could be because E. coli bacteremia usually results from urinary tract infections, which are generally low-severity and produce few complications. However, because of its fre- quency, this microorganism warrants study. In a systematic review of the economic impact of multidrug resistance [18], only one of the studies described the costs of E. coli bacteremia and found observed mean costs of € 13,709 for PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 7 / 12 Cost Attributable to Nosocomial Bacteremia multidrug-resistant microorganism, € 8,683 for multi-sensitive microorganism and € 5,026 for those related to multidrug resistance; these costs are lower than those observed in our cohort with this organism, which can be explained by the inclusion of community-acquired bacter- emia episodes. Other studies mentioned in the same review analyzed the costs of infections caused by E. coli and K. pneumoniae and included different types of infections, not only bacteremia. In our study, the mean observed cost was € 21,883 for E. coli multidrug-sensitive episodes, € 16,754 for multidrug-resistant episodes, € 25,222 for multidrug-sensitive K. pneumoniae episodes and € 35,100 for multidrug-resistant episodes. The results were considerably higher for K. pneumo- niae episodes; consequently, although both microorganisms belong to the same family, their inclusion in the same study does not seem an appropriate strategy. The cost described in the above-mentioned review and attributable to multidrug resistance for both microorganisms ranged from $ 1,587 to $ 30,093. The authors attribute this substantial disparity to the differ- ences in cost of living among the countries included in the study. We believe that this may explain some of the differences but that differences in the patients enrolled and in calculation methods may also have had an influence. An analysis of the cost of infections (except urinary tract infections) caused by E. coli and K. pneumoniae also found high incremental costs, with a mean cost of $ 41,353 for multidrug- resistant and $ 24,902 for multidrug-sensitive microorganisms [37]. Likewise, in patients with multidrug-resistant E. coli or K. pneumoniae nosocomial infection, Roberts et al [8] found a mean cost of $ 39,403, similar to our results for bacteremia caused by multidrug-resistant K pneumoniae (€ 35,100) but clearly higher than the mean cost of bacteremia caused by multi- drug-resistant E. coli (€ 16,754). P. aeruginosa was the microorganism with the highest proportion of multidrug resistance and also showed a higher estimated incremental cost for both multidrug-sensitive episodes (€ 16,042) and multidrug-resistant episodes (€ 44,709). These results are consistent with those found by our team in a previous study, in which the cost of infection/colonization by P. aerugi- nosa was € 4,933 for multidrug-sensitive episodes and € 12,351 for multidrug-resistant epi- sodes, despite the lower costs in our study; however, in that study, bacteremia as well as infection and colonization were included in the cost analysis [22]. Findings from other studies show higher costs in patients infected with or colonized by P. aeruginosa. For episodes with imipenem-resistance the mean hospital post-culture cost was $ 251,495 for multidrug-resistant microorganisms and was $ 166,196 for multidrug-sensitive microorganisms [21]. Neidell et al [38] found an incremental cost of $ 25,300 for infection with multidrug-resistant P. aeruginosa compared to multidrug-sensitive P aeruginosa. These results are very similar to the findings of the present study, since the estimated cost of nosocomial episodes of multidrug-resistant P. aer- uginosa bacteremia was € 28,667 higher than that of multidrug-sensitive P. aeruginosa bacter- emia. Nevertheless, the high levels of cost found in these analyses may be because most infections caused by P. aeruginosa occur in advanced stages of illness or in immunocompro- mised patients [21]. There is evidence that a significant proportion of nosocomial infections could be avoided. Findings from a review article suggest that the figure could be higher than 20% [39]. Some authors believe that the ability of experts to properly compare the effectiveness of prevention strategies for nosocomial infections is severely limited by the multiplicity of pathogens and the changing epidemiology of multidrug resistance in different centers [40]. As clearly shown in lit- erature, several strategies to prevent nosocomial infections and reduce antibiotic resistance have been implemented [41–44]. Nevertheless, most of the reported experiences have been conducted in strongly controlled environments, such as ICUs, where, in the USA [45], a 58% reduction in nosocomial catheter-related bacteremia was estimated in 2008 compared with PLOS ONE | DOI:10.1371/journal.pone.0153076 April 7, 2016 8 / 12 Cost Attributable to Nosocomial Bacteremia 2004. In addition, after application of specific hospital programs, two studies found decreases of 41.7% [42] and 73.9% [43] in bacteremia associated with central venous catheters. The success of clinical measures in reducing antimicrobial resistance has varied [9,10, 19] and some measures have had substantial success, such as in Denmark, where the rate of MRSA bacteremia decreased from 32% in 1968 to less than 2% in the last few years [29]. This study analyzed the hospital costs of all nosocomial bacteremia caused by the most com- mon organisms in a tertiary-care teaching hospital in Barcelona. The aim was to expand the findings of other studies that included only a single microorganism in the analysis and which were often based on a single outbreak of bacteremia or on bacteremia in a single hospital area. The analytical structure of our study has limitations: first, we used information from a single hospital center, which could affect extrapolation of the results. Second, we excluded health care-associated bacteremia, which is always the result of a previous contact with the hospital. Thus, the episode of hospitalization represents an entirely avoidable cost. Finally, costs were calculated from the perspective of the hospital and inpatient care. The strength of this study lies in the exhaustiveness and thoroughness of the process of identifying bacteremia. Episodes were selected according to the protocols of the professionals involved in the infection control program and not by using administrative databases, as often occur in similar studies. It has been estimated that administrative-only information identifies only 20% of infections [46]. Importantly, this study analyzed real hospital costs elaborated with an activity-based costing system instead of tariffs or estimates from other sources. In line with the results of other authors [12,13], our results showed that length of hospital stay is an important factor that should always be taken into account and controlled for. Admis- sions with bacteremia, on average, developed the infection on the 14th day of stay while admis- sions without bacteremia had a mean length of stay of 10 days; in other words, admissions without bacteremia are discharged before the date when bacteremia usually develops. In this analysis we used a propensity-score matching approach to minimize potential time-dependent bias and selection bias. This study also highlights the importance of conducting interventions to control multidrug resistance, as conducted in some hospitals by implementing specific programs [47]. The adjustment of hospital cost for the organism causing bacteremia and for antibiotic sen- sitivity allows prevention strategies to be improved and prioritized according to their global impact and costs. Importantly, infection reduction is a strategy to reduce antimicrobial resistance. Supporting Information S1 File. Supporting information. (DOCX) Acknowledgments The authors would like to thank professionals from the hospital and, especially, everyone at the infection control and at the microbiology laboratory. Their work was essential for gathering information necessary for this study. Author Contributions Conceived and designed the experiments: MR PC RT FC. 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