Costs of Bloodstream Infections Caused by Escherichia coli and ...

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2010, p. 4085–4091 0066-4804/10/$12.00 doi:10.1128/AAC.00143-10 Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Vol. 54, No. 10

Costs of Bloodstream Infections Caused by Escherichia coli and Influence of Extended-Spectrum-␤-Lactamase Production and Inadequate Initial Antibiotic Therapy䌤 Mario Tumbarello,1* Teresa Spanu,2 Rossella Di Bidino,3 Marco Marchetti,3 Matteo Ruggeri,4 Enrico Maria Trecarichi,1 Gennaro De Pascale,1 Enrica Maria Proli,5 Roberto Cauda,1 Americo Cicchetti,4 and Giovanni Fadda2 Institutes of Infectious Diseases1 and Microbiology,2 Faculty of Medicine, Health Technology Assessment Unit,3 Faculty of Economics,4 and Hospital Pharmacy,5 Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy Received 1 February 2010/Returned for modification 17 May 2010/Accepted 21 July 2010

Escherichia coli is the leading cause of bloodstream infections (BSIs) caused by Gram-negative bacteria. The increasing prevalence of antibiotic-resistant E. coli strains, particularly those producing extendedspectrum ␤-lactamases (ESBLs), increases the odds that empirically prescribed antimicrobial therapy for these infections will be inadequate, but the economic impact of this risk has not been fully evaluated. In the present retrospective 1-year analysis of 134 consecutive E. coli BSIs in our hospital, we explored the clinical and economic impacts of (i) inadequate initial antimicrobial treatment (IIAT) (i.e., empirical treatment with drugs to which the isolate had displayed in vitro resistance) of these infections and (ii) ESBL production by the bloodstream isolate. Cost data were obtained from the hospital accounting system. Compared with the 107 (79.8%) adequately treated patients, the 27 (20.1%) who received IIAT had a higher proportion of ESBL BSIs (74.0% versus 15.8%), longer (ⴙ6 days) and more costly (ⴙEUR 4,322.00) post-BSI-onset hospital stays, and higher 21-day mortality rates (40.7% versus 5.6%). Compared with the 97 non-ESBL infections, the 37 (27.6%) ESBL BSIs were also associated with longer (ⴙ7 days) and more costly (ⴙEUR 5,026.00) post-BSI-onset hospital stays and increased 21-day mortality (29.7% versus 6.1%). These findings confirm that the hospital costs and mortality associated with E. coli BSIs are significantly increased by ESBL production and by IIAT. antimicrobial therapy (IIAT) has been shown to increase hospitalization costs related to intra-abdominal and other sterilesite infections caused by methicillin-resistant Staphylococcus aureus (33), but this issue has not been specifically explored with reference to BSIs caused by E. coli. This information is essential for identifying/developing cost-effective measures for curbing the spread of antimicrobial-resistant isolates (7). We conducted a retrospective cohort study to explore the clinical and economic impacts of ESBL production and IIAT of E. coli BSIs.

Escherichia coli is the leading cause of bloodstream infections (BSIs) involving Gram-negative bacteria (16, 37). The last 20 years have witnessed a striking increase in the number of infections caused by antibiotic-resistant strains of E. coli, and this has had an important impact on the outcomes of BSIs (24). Multidrug-resistant (MDR) E. coli strains and particularly those that produce extended-spectrum ␤-lactamases (ESBL) not only are endemic in many health care settings but also have become an important cause of communityacquired infections (1, 27, 28). These organisms are resistant to many of the antimicrobial agents usually recommended for the treatment of infections caused by E coli, so the odds are quite high that empirically prescribed antimicrobial therapy will be ineffective against these infections (4, 9, 18, 22, 23, 25, 26, 29, 32, 35). Our previous studies showed that failure to provide prompt, effective antimicrobial therapy for BSIs caused by ESBL-producing E. coli is associated with increased mortality and longer hospital stays (35, 36). Similar findings have been reported by others (15, 18, 20, 24, 31, 32). Length of stay (LOS) has been identified as the single most important determinant of costs related to inpatient care for bacteremia (3). Inadequate initial

MATERIALS AND METHODS Study design and patient population. We conducted a retrospective cohort study of adult inpatients with E. coli BSIs treated at the Catholic University Hospital in Rome, Italy (1,600 beds, approximately 60,000 admissions/year), between 1 January 2006 and 31 December 2006. Cases were identified through a search of the microbiology laboratory database. The following exclusion criteria were applied: age ⬍18 years, polymicrobial BSI, non-E. coli infection at another site at BSI presentation, and recurrent E. coli BSI (i.e., only information on the first episode recorded for each patient was included in our analysis). To identify the clinical and economic impacts of IIAT, we compared the subgroup of patients who received IIAT with those whose antimicrobial therapy was adequate from the outset (adequate initial antimicrobial therapy [AIAT]). The impact of ESBL production on the same outcomes was estimated by comparing the subgroups of patients with ESBL-producing isolates causing BSIs (ESBL BSIs) and non-ESBL-producing isolates causing BSIs (non-ESBL BSIs). Definitions. The terms listed here were defined prior to data analysis. A BSI was defined by the presence of at least one blood culture growing E. coli, together with clinical features compatible with the systemic inflammatory response syndrome (e.g., fever, tachycardia, tachypnea, and leukocytosis) (30). The date of BSI onset was the date of collection of the first blood sample yielding the

* Corresponding author. Mailing address: Istituto Malattie Infettive, Universita` Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy. Phone: 39-06-30155373. Fax: 39-06-3054519. E-mail: [email protected]. 䌤 Published ahead of print on 26 July 2010. 4085

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study isolate by culture (index blood culture). An infection at any site caused by the same E. coli strain isolated from the blood was considered the BSI source (12). Septic shock was defined as sepsis associated with organ dysfunction and persistent hypotension following volume replacement (30). BSIs were classified as nosocomial if the index blood sample for culture had been drawn 48 h or more after admission to our hospital. Nonnosocomial infections were classified as health care associated or community acquired, as defined by Friedman et al. (11). Prior hospitalization was defined as an inpatient stay of at least 2 days during the 12 months preceding the index hospitalization. Prior antimicrobial therapy was defined as use of any antimicrobial for ⬎48 h during the 3 months preceding the index admission. The term initial antibiotic treatment refers to the drugs administered empirically before in vitro susceptibility test results were available. Analysis of this variable was limited to antimicrobial agents with potential activity against E. coli; other types of antimicrobials used during this period (e.g., glycopeptides, anti-anaerobic organism agents, and antifungals) were excluded from all analyses. The initial treatment was classified as inadequate if any of the following was true: (i) no antibiotics were prescribed, (ii) the infecting pathogen displayed in vitro resistance (as defined below) to the drug(s) being administered, and/or (iii) the regimen used was not in accordance with the current recommendations in The Sanford Guide to Antimicrobial Therapy (13). Post-BSI-onset hospital stay was defined as the difference (in days) between the date of the index blood culture and the date of discharge or death (whichever came first). For outcome assessment, all patients were evaluated from the day of the index blood culture to the day of discharge/death. The clinical outcomes measured were the initial response to treatment (assessed 72 h after BSI onset) and the 21-day mortality rate (calculated as the percentage of cases ending in death ⱕ21 days after BSI onset). The initial response was classified as treatment failure if signs of the infection persisted without improvement or worsened or if death occurred within the first 72 h after the BSI onset. Charlson comorbidity indexes (5) were calculated for each case, and the overall severity of the patient’s illness was expressed as the Acute Physiology and Chronic Health Evaluation (APACHE) score (17). Microbiology studies. Isolates were identified to the species level with the Vitek 2 (bioMe´rieux, Inc., Hazelwood, MO) and Phoenix (Becton Dickinson Microbiology Systems) automated systems. The ESBL status of each isolate was determined as described elsewhere (34, 35). The MICs of the antimicrobials tested were determined with the Etest (AB Biodisc, Solna, Sweden), as described previously (34, 35), and classified according to the Clinical and Laboratory Standards Institute (CLSI) breakpoints and guidelines (6). Cost analysis. In Italy, National Health Service (NHS) coverage extends to all members of the population. Public hospitals are reimbursed by the NHS for all expenses related to inpatient care, which is reported in the form of DiagnosisRelated Group (DRG) codes. In our study, the costs of BSIs were expressed from the perspective of the hospital as direct health care costs, i.e., total expenditures incurred by the hospital to provide services or goods for each patient with a BSI. The costs of post-acute care (i.e., the care provided after discharge) and those related to the loss of productivity for the patients themselves were not considered. For each case, the cost of the post-BSI-onset hospital stay was retrieved from the database of the hospital’s financial and administrative department. All costs were expressed in euros. The basic cost differences related to ESBL production (versus non-ESBL production) by the bloodstream isolate and to IIAT (versus AIAT) were also converted to U.S. dollars using the official exchange rates for 2006 (United States Federal Reserve Statistical Release, Annual Foreign Exchange Rates; release date, 2 January 2009; http://www .federalreserve.gov/releases/g5a). Statistical analysis. Statistical analyses were performed with the Intercooled Stata program, version 8, for Windows (Stata Corporation, College Station, TX). Given the asymmetrical distribution of costs and times to discharge (verified with the Shapiro-Wilks test), continuous variables were evaluated with the WilcoxonMann-Whitney test. Categorical variables were evaluated using the chi-square or Fisher exact test. Values are expressed as group means ⫾ standard deviations (SDs) (continuous variables) or percentages (categorical variables). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations that emerged. The Kaplan-Meier method was used for survival analysis. Two-tailed tests were used to determine statistical significance; a P value of ⬍0.05 was considered significant. Multivariate probabilistic sensitivity analysis (PSA) was performed to generalize study results. We considered the combined effect on total costs of the variations in resource use. A gamma distribution was assumed for each cost, based on a Monte Carlo simulation that involved 1,000 iterations. The PSA allowed us to define 95% CIs for disaggregated and total costs. The interquartile range (25th percentile to 75th percentile) was also reported as an indicator of the variations in cost observed in the multivariate sensitivity analysis.

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RESULTS Our search revealed 143 patients with blood cultures that were positive for E. coli in 2006. Nine of these cases were excluded because the BSI was polymicrobial, the patient had a concomitant non-E. coli infection at another site, or complete medical records were not available for review. The remaining 134 patients had documented E. coli BSIs that met the clinical and microbiological criteria for inclusion in the study. Characteristics of E. coli isolates. All 134 isolates displayed in vitro susceptibility to imipenem, meropenem, amikacin, and tigecycline. Thirty-seven (27.6%) of the isolates were ESBL producers. All 37 displayed in vitro resistance to oxyiminocephalosporins, and most were also resistant to one or more of the following antimicrobials/antimicrobial combinations: ciprofloxacin, 86.5%; amoxicillin-clavulanic acid, 56.7%; gentamicin, 51.3%; trimethoprim-sulfamethoxazole, 29.7%; and piperacillin-tazobactam, 21.6%. A total of 48 ESBL genes were identified in these 37 isolates. The majority of the genes (62%) encoded CTX-M-type enzymes. Most (26/37, 70.3%) of the ESBL isolates produced CTX-M-15, and 4 produced CTXM-1. SHV-12 production was detected in 18 isolates. The 97 non-ESBL-producing isolates displayed resistance to ampicillin (61.8%), amoxicillin-clavulanic acid (1%), ciprofloxacin (32%), gentamicin (6.2%), piperacillin-tazobactam (1%), and/or trimethoprim-sulfamethoxazole (44.3%). Characteristics of patients and antimicrobial treatment. The mean age of the patient cohort was 62 ⫾ 17 years, 65 (48.5%) of the patients were men, and 41 (30.6%) had some form of neoplastic disease. At the time of BSI onset, 79 (58.9%) patients were in a medical ward, 46 (34.3%) were in a surgical ward, and 9 (6.7%) were in the intensive care unit. Half of the BSIs (67/134, 50%) were nosocomial; the other half were equally divided between health-care-associated (34/134, 25.4%) and community-acquired (33/134, 24.6%) infections. The most common primary site of infection was the urinary tract (66/134, 49.2%), followed by the pancreaticobiliary tract (36/134, 26.9%). Table 1 summarizes the characteristics of the patient cohort according to the ESBL status of the bloodstream isolate. ESBL BSIs were more frequently hospital acquired (23/37, 62.1%), and the patients who had them were more likely to have solid tumors (17/37, 45.9%), histories of recent antimicrobial therapy (20/37, 54.1%) or hospitalization (29/37, 78.3%), and infection sources in the pancreaticobiliary tract (18/37, 48.6%). A higher proportion also received IIAT (20/37, 54.1%). Patients with non-ESBL BSIs had higher frequencies of community-acquired infection (30/97, 30.9%). Over 60% of the index blood cultures in this group had been drawn in medical units (62/97, 63.9%), and the most common source of infection was the urinary tract (54/97, 55.6%). Within a few hours of the index blood culture, all but two of the patients were receiving empirically prescribed treatment with currently recommended doses of one or more of the following antimicrobials: aminoglycosides (amikacin or gentamicin; n ⫽ 11), ␤-lactam–␤-lactamase inhibitor combinations (amoxicillin-clavulanic acid or piperacillin-tazobactam; n ⫽ 32), carbapenems (imipenem or meropenem; n ⫽ 33), fluoroquinolones (ciprofloxacin or levofloxacin; n ⫽ 37), or oxyimino-cephalosporins (ceftriaxone or ceftazidime; n ⫽ 36). Twenty-seven (20.1%) of the 134 cases received therapy that

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TABLE 1. Clinical characteristics of patients with E. coli bloodstream infections stratified by ESBL production and inadequate initial antimicrobial therapya Infection Characteristic

No. (%) of patients with: ESBL BSI (n ⫽ 37)

Demographics Males Mean ⫾ SD age (yr)

Therapy

Non-ESBL BSI (n ⫽ 97)

No. (%) of patients administered: P

IIAT (n ⫽ 27)

AIAT (n ⫽ 107)

P

18 (48.6) 59 ⫾ 18

43 (48.4) 63 ⫾ 17

0.98 0.34

16 (59.2) 62 ⫾ 15

49 (45.7) 62 ⫾ 18

0.21 0.88

4 (10.8) 4 (10.8) 4 (10.8) 3 (8.1) 17 (45.9) 6 (16.2) 2.28 ⫾ 2.10

7 (7.2) 17 (17.5) 18 (18.5) 16 (16.4) 24 (24.7) 19 (19.6) 2.35 ⫾ 2.16

0.49 0.33 0.27 0.21 0.01 0.65 0.88

3 (11.1) 4 (14.8) 5 (18.5) 2 (7.4) 12 (44.3) 3 (11.1) 2.33 ⫾ 1.86

8 (7.5) 17 (15.9) 17 (15.9) 17 (15.9) 29 (17.1) 22 (20.5) 2.29 ⫾ 2.17

0.53 9.89 0.74 0.25 0.08 0.26 0.93

Epidemiological category Hospital acquired Health care associated Community acquired

23 (62.1) 11 (29.7) 3 (8.2)

44 (45.3) 23 (23.7) 30 (30.9)

0.08 0.47 0.006

14 (51.8) 10 (37.4) 3 (11.1)

53 (49.5) 24 (22.4) 30 (28.1)

0.82 0.11 0.06

Ward at BSI onset Medicine Surgery Intensive care unit

17 (45.9) 17 (45.9) 3 (8.1)

62 (63.9) 29 (29.9) 6 (6.1)

0.05 0.08 0.69

14 (51.8) 11 (40.7) 2 (7.4)

65 (60.7) 35 (32.7) 7 (6.5)

0.40 0.43 0.87

History Previous antimicrobialsb Previous hospitalizationc

20 (54.1) 29 (78.3)

31 (31.9) 57 (58.7)

0.01 0.003

11 (40.7) 20 (74.1)

40 (37.3) 66 (61.6)

0.74 0.23

6 (16.2) 29 (78.3)

7 (7.2) 80 (82.4)

0.11 0.58

6 (22.2) 23 (85.1)

7 (6.5) 86 (80.3)

0.01 0.56

1 (2.7) 0 18 (48.6) 1 (2.7) 1 (2.7) 6 (16.2) 12 (32.4)

3 (3.1) 3 (3.1) 18 (18.5) 3 (3.1) 0 18 (18.5) 54 (55.6)

0.90 0.27 ⬍0.001 0.90 0.10 0.75 0.01

0 0 9 (33.3) 1 (3.7) 1 (3.7) 7 (25.9) 10 (37)

4 (3.7) 3 (2.8) 27 (25.2) 3 (2.8) 0 17 (15.8) 56 (52.3)

0.30 0.37 0.39 0.80 0.04 0.22 0.15

20 (74.1)

17 (15.9)

⬍0.001

Comorbidity Chronic liver disease Chronic renal insufficiency Diabetes mellitus Hematological malignancy Solid tumor Immunosuppression Mean ⫾ SD Charlson index

Clinical presentation Septic shock APACHE score ⬎ 15 Primary source of BSId Central venous catheter Lower respiratory tract Pancreaticobiliary tract Skin and soft tissues Surgical wound Unknown Urinary tract ESBL production IIAT

20 (54.1)

7 (7.2)

⬍0.001

a

Results are numbers (percentages) of patients, unless otherwise indicated. b During the 3 months prior to the index blood culture. c During the 12 months prior to the index blood culture. d Four patients had multiple sources of infection.

met our definition of IIAT, and these patients were compared with the 107 who received AIAT to identify significant differences between the two groups (Table 1). The IIAT patients were significantly more likely to have solid tumors (12/27, 44.3%) and septic shock (6/27, 22.2%) and were less likely to have community-acquired BSIs (3/27, 11.1%). Most were infected by ESBL-producing E. coli isolates (20/27, 74.1%). The IIAT for patients with ESBL BSIs included oxyimino-cephalosporins in seven cases, fluoroquinolones in seven cases, ␤-lactam–␤-lactamase inhibitor combinations in seven cases, and an aminoglycoside in one case. As for those with non-ESBLproducing E. coli isolates, five received IIAT with fluoroquino-

lones, and in two others the initial therapy did not include any agents with potential activity against E. coli. Five of the 27 IIAT patients died while they were receiving the empirically prescribed therapy. The other 22 were switched to appropriate therapy (carbapenems in 16 [77.2%] cases, ␤-lactam–␤-lactamase inhibitors in 4 [18.2%] cases, and fluoroquinolones in 2 [9.1%] cases) 72 ⫾ 96 h (mean, 74 h) after the index blood culture. Influence of ESBL production and IIAT on costs of hospitalization. The mean post-BSI-onset hospital stay was significantly longer in patients who had ESBL BSIs (20 ⫾ 17 days versus 13 ⫾ 9 days for those with non-ESBL BSIs; P ⫽ 0.02)

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TABLE 2. Costs of hospitalization for patients with E. coli bloodstream infections stratified by ESBL production and inadequate initial antimicrobial therapy Infection Cost

Medical care Nursing care Pharmacy services Diagnostic testinga Support servicesb Othersc Total a b c

Therapy

Mean cost ⫾ SD (EUR)

Mean cost ⫾ SD (EUR)

ESBL BSI (n ⫽ 37)

Non-ESBL BSI (n ⫽ 97)

P

IIAT (n ⫽ 27)

AIAT (n ⫽ 107)

P

1,964 ⫾ 417 3,894 ⫾ 1,078 933 ⫾ 1,706 2,373 ⫾ 2,734 1,674 ⫾ 1,983 2,869 ⫾ 2,676

1,134 ⫾ 83 2,001 ⫾ 163 848 ⫾ 1,434 1,760 ⫾ 1,974 1,016 ⫾ 723 1,921 ⫾ 2,152

0.04 0.03 0.75 0.10 0.01 0.02

1,801 ⫾ 281 3,956 ⫾ 1,219 803 ⫾ 1,040 1,956 ⫾ 2,037 1,655 ⫾ 1,546 3,351 ⫾ 3,234

1,253 ⫾ 149 2,162 ⫾ 262 889 ⫾ 1,608 1,924 ⫾ 2,271 1,082 ⫾ 1,125 1,888 ⫾ 1,963

0.02 0.005 0.72 0.68 0.007 0.02

13,709 ⫾ 16,312

8,683 ⫾ 6,683

0.03

13,524 ⫾ 2,610

9,201 ⫾ 914

0.04

Diagnostic testing included laboratory and imaging studies. Support services included food service, laundry, maintenance, security, etc. Other costs included utilities, admission/discharge cost, depreciation, and overhead costs.

and in those who received IIAT (20 ⫾ 15 days versus 14 ⫾ 10 days for those in the AIAT group; P ⫽ 0.02). Total hospital costs were significantly higher for a patient with an ESBL BSI than for patients with non-ESBL BSIs (means ⫾ SDs, EUR 13,709 ⫾ 16,312 and EUR 8,683 ⫾ 6,683, respectively) and for one whose initial antimicrobial therapy was inadequate than for patients who were adequately treated (means ⫾ SDs, EUR 13,524 ⫾ 2,610 and EUR 9,201 ⫾ 914, respectively); total and disaggregated costs of hospitalization for patients with E. coli bloodstream infection stratified by ESBL production and inadequate initial antimicrobial therapy are shown in Table 2. The overall cost of pharmacy services (i.e., all types of drug therapy) was not significantly affected by the ESBL status of the isolate (P ⫽ 0.75) or the adequacy of the initial treatment (P ⫽ 0.72). However, the specific cost of antimicrobial drug therapy was increased 1.6-fold by ESBL production (means ⫾ SDs, EUR 763 ⫾ 437 versus 474 ⫾ 270 for non-ESBL BSIs; P ⬍ 0.001) and 1.4-fold by IIAT (means ⫾ SDs, EUR 715 ⫾ 437 versus 513 ⫾ 311 for AIAT; P ⫽ 0.02) (Fig. 1). Using Monte Carlo simulation based on a gamma distribution, we evaluated the effect of simultaneous variation of each resource uptake on the cost differences related to ESBL production (versus non-ESBL production) and to IIAT (versus AIAT) (Fig. 2). According to our basic case analysis, these

FIG. 1. Cost of antimicrobial drug therapy in subgroups defined by the infecting pathogen’s ESBL status and by the adequacy of the initial antibiotic therapy. The mean ⫾ SD cost of antimicrobial treatment was EUR 763 ⫾ 437 for ESBL BSIs versus EUR 474 ⫾ 270 for non-ESBL BSIs (P ⬍ 0.001), and it was EUR 715 ⫾ 437 for patients with IIAT versus EUR 513 ⫾ 311 for those with AIAT (P ⫽ 0.02).

differences amounted to EUR 5,026 and EUR 4,322, respectively (US$6,314 and US$5,429, respectively). These values correspond to the median of the gamma distribution results in the Monte Carlo simulation. In 90% of the cases, multivariate sensitivity analysis revealed a difference associated with ESBL production amounting to EUR 4,838 (⫹55%) or more and an interquartile range of EUR 4,933 to 5,137 (corresponding to a cost increase of 56.5% to 59.4%). As for the costs related to IIAT, in 90% of the cases the difference exceeded EUR 4,126, which corresponds to a cost increase of at least 44%. The interquartile range was EUR 4,228 to 4,424, which corresponds to an increase of 45.7% to 48.4%. Influence of ESBL production and IIAT on patient outcomes. Treatment failure rates after the first 72 h of therapy were about 3 times higher among patients with ESBL BSIs (45.9% versus 11.3% in the non-ESBL BSI group; OR ⫽ 3.21; 95% CI ⫽ 1.96 to 5.27; P ⬍ 0.001). The initial treatment failure was about 22 times more frequent among patients in the IIAT

FIG. 2. Box plot showing percent differences between the costs of ESBL and non-ESBL E. coli BSIs and between the costs of IIAT and AIAT E. coli BSIs. The results are based on a Monte Carlo simulation with 1,000 iterations. Boxes represent interquartile ranges (lower border, 25th percentile; upper border, 75th percentile), and the horizontal lines within the boxes indicate the medians (50th percentile). Whiskers indicate minimum and maximum values.

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FIG. 3. Kaplan-Meier curves showing the impact on 21-day mortality of ESBL production (solid line) versus non-ESBL production (dashed line) by the bloodstream isolate (P ⬍ 0.001) (a) and inadequate (solid line) versus adequate (dashed line) initial antibiotic therapy (P ⬍ 0.001) (b).

group (85.1% versus 4.6% in the AIAT group; OR ⫽ 21.76; 95% CI ⫽ 8.19 to 57.80; P ⬍ 0.001). Twenty-one days after BSI onset, 17 (12.7%) of the 134 patients had died. This group included 29.7% (11 of 37) of the ESBL BSI group and only 6.1% (6 of 97) of those with nonESBL infections (OR ⫽ 4.43; 95% CI ⫽ 2.46 to 7.95; P ⬍ 0.001). The 21-day mortality rates were also significantly different between the IIAT group (11/27, 40.7%) and the AIAT group (6/107, 5.6%) (OR ⫽ 3.09; 95% CI ⫽ 1.92 to 4.98; P ⬍ 0.001). Survival curve analysis confirmed the higher risks of mortality associated with ESBL production (P ⬍ 0.001) and with IIAT (P ⬍ 0.001) (Fig. 3). DISCUSSION The present retrospective review of 134 E. coli BSIs revealed a high prevalence of ESBL-producing isolates (28%) and frequent prescription of inadequate antimicrobial therapy in the initial phase of the infection (20%). The IIAT group included only 7.2% of the non-ESBL BSIs but over half (54.1%) of the ESBL BSIs. ESBL production increased the mean post-BSI-onset hospital stay by about 50% (from ⬃13 to ⬃20 days) and mean hospital costs by EUR 5,026 (a 1.5-fold increase over the cost of non-ESBL BSIs). Our findings are clearly in line with data

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reported by other groups. In terms of costs, for example, Lautenbach and colleagues found that the median hospital charge for care delivered after the onset of infection with an ESBLproducing isolate of E. coli or Klebsiella pneumoniae was 2.9 times higher than that for infections caused by non-ESBL producers (18). In a study by Schwaber and colleagues, bacteremia caused by ESBL-positive Enterobacteriaceae family members was associated with an adjusted 1.6-fold increase in hospitalization costs with respect to the costs for non-ESBL BSIs (31). Lee and coworkers showed that the cost of nonurinary-tract infections caused by ESBL-producing E. coli and Klebsiella species was 1.7 times the cost of similar infections caused by non-ESBL producers (20). It is well-known that inadequate or delayed therapy is a major determinant of the adverse clinical outcomes of infections caused by antimicrobial-resistant organisms (7, 8, 14). Our previous work has clearly demonstrated that IIAT has a negative impact on mortality and time to discharge in patients with ESBL-producing E. coli BSIs, and similar findings have been reported by others (14, 24, 35). In the present study, IIAT prolonged post-BSI-onset hospital stays by a mean of 6 days (or 40%) compared with the stays for patients who received AIAT. Very little information about the impact of IIAT on the cost of hospitalization is available. Recently, Shorr et al. evaluated the impact of IIAT on hospital costs and LOS in 291 patients with sterile-site infections caused by methicillin-resistant Staphylococcus aureus (33). Only one out of four infections was initially treated with an appropriate antibiotic, but the median LOS for this subgroup was over 2 days shorter than that for the group who initially received inappropriate antibiotics, and the median cost of hospitalization for the IIAT group was 1.4 times higher than that for the AIAT group (US$19,427 and US$13,688, respectively, a difference of US$5,739). To the best of our knowledge, there are no published hospital-based data on the costs associated with IIAT for E. coli BSIs. Our study provides a quantitative estimate of the added resource utilization required for E. coli BSIs characterized by IIAT (⫹47% compared with that required for adequately treatment), and these significant differences were confirmed by the results of a Monte Carlo simulation. In any evaluation of hospital costs, it is important to distinguish between microcost-based use of resources (i.e., the total expenditures required of the hospital to provide the services or goods in question) and reimbursement (i.e., the amount that the hospital receives from all payers, which comprise the patient, national health care system, private insurance companies, etc., depending on the country being investigated). Because microcosting provides a more accurate picture of the economic resources used to treat infected patients, we conducted our analysis from the cost perspective of the hospital. Few studies have analyzed the overall cost of BSIs caused by ESBL-producing strains of Enterobacteriaceae, but all were conducted from the perspective of third-party payers; i.e., the cost of the hospitalization was defined on the basis of bills sent to a third party payer (18, 20, 31). Moreover, only one of these studies (20) compared both the total and disaggregated costs of hospitalization for patients with infections caused by ESBLproducing and non-ESBL-producing Enterobacteriaceae. The cost of drugs, antimicrobials in particular, is often cited

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as the main driver of rising inpatient health care costs. In our cohort, the overall costs of drug therapy were apparently similar in all groups, but expenditures for antibiotic therapy were significantly higher for the ESBL BSI (almost 75%) and IIAT (nearly 40%) groups than for their respective control groups. These findings are in line with those of Lee and colleagues, who reported no significant differences between the total pharmaceutical costs of infections caused by ESBL-producing and non-ESBL-producing Enterobacteriaceae (20). They also found significantly higher expenditures for antibiotic therapy for BSIs caused by MDR Acinetobacter baumannii isolates than for therapy caused by non-MDR A. baumannii isolates (19). However, the findings of our study confirms previous reports indicating that antimicrobial treatment accounts for less than 10% of the overall costs of hospital care for patients with serious infections (20, 21). In addition, a recent cost analysis of hospitalizations for pneumonia indicates that efforts aimed at limiting the LOS may be more effective in reducing hospital expenditures than measures designed to limit antimicrobial drug acquisition costs (10). As for mortality, increased risks among patients with infections caused by ESBL-producing Enterobacteriaceae have been associated with the delayed administration of antibiotics and with the administration of drugs to which the infecting pathogen is resistant (15, 18, 22, 24, 27–29, 31, 35). In a meta-analysis conducted in 2007, ESBL production by Enterobacteriaceae bloodstream isolates markedly increased the likelihood of ineffective treatment and mortality (pooled relative risks, 5.56 and 1.85, respectively) (32). In our cohort, patients who received IIAT, regardless of whether they had ESBL or nonESBL BSIs, were 3 times more likely to develop septic shock and 7 times more likely to die by day 21 than those treated from the outset with appropriate drugs. In previous studies, we found that failure to provide adequate antimicrobial therapy in the initial stages of an ESBL BSI strongly increased the risk of 21-day mortality (35, 36). Even in the absence of a direct effect on mortality, microbiologically inadequate antibiotic therapy influenced the rate of initial treatment failure, which occurred in 85% of the inadequately treated patients. In conclusion, antimicrobial drug resistance is on the rise, and the likelihood that empirically prescribed treatment will prove ineffective is increasing. These trends can have adverse effects not only on clinical outcomes but also on the use of health care resources (8, 14, 15, 18, 20, 24, 32, 35, 36). Expenditure data can vary widely, depending on the population studied and the type of health care facility considered. Generalizations are therefore difficult, but there is little doubt that LOS after infection onset is the most important determinant of hospital costs for an episode of bacteremia (3). Therefore, increasing the chances that empirically prescribed treatment will be effective can also be regarded as a strategy for minimizing the high costs of hospitalizations involving BSIs. Awareness of current bacterial resistance patterns and a sound understanding of the risk factors for antibiotic-resistant E. coli infection can improve the efficacy of empirical treatment protocols; and in this context, close collaboration between physicians, clinical microbiologists, and infectious disease consultants should produce significant positive effects (2). In addition, hospitals can probably save money by increasing efforts to control antibiotic resistance. More accurate risk assessment

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and the use of new molecular methods for identifying drugresistant pathogens could reduce the frequency of inadequate empirical antibiotic therapy and allow substantial savings in terms of morbidity/mortality and the use of health care resources. ACKNOWLEDGMENTS This work was partially supported by grants from the Italian Ministry for Universities and Research (Ministero dell’Istruzione, dell’Universita` e della Ricerca) (Fondi Ateneo Linea D-1 2008– 2009). We thank Marian Everett Kent for assistance with editing the manuscript. REFERENCES 1. Ben-Ami, R., J. Rodríguez-Ban ˜ o, H. Arslan, J. D. Pitout, C. Quentin, E. S. Calbo, K. Azap, C. Arpin, A. Pascual, D. M. Livermore, J. Garau, and Y. Carmeli. 2009. A multinational survey of risk factors for infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in nonhospitalized patients. Clin. Infect. Dis. 49:682–690. 2. Blot, S., K. Vandewoude, D. De Bacquer, and F. Colardyn. 2002. Nosocomial bacteremia caused by antibiotic-resistant Gram-negative bacteria in critically ill patients: clinical outcome and length of hospitalization. Clin. Infect. Dis. 34:1600–1606. 3. Brun Buisson, C., F. Roudot-Thoraval, E. Girou, C. Grenier-Sennelier, and I. Durand-Zaleski. 2003. The costs of septic syndromes in the intensive care unit and influence of hospital-acquired sepsis. Intensive Care Med. 29:1464– 1471. 4. Canto ´n, R., and T. M. Coque. 2006. The CTX-M beta-lactamase pandemic. Curr. Opin. Microbiol. 9:466–475. 5. Charlson, M. E., P. Pompei, K. L. Ales, and C. R. MacKenzie. 1987. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis. 40:373–383. 6. Clinical and Laboratory Standards Institute. 2009. Performance standards for antimicrobial susceptibility testing; 19th informational supplement. M100-S19. Clinical and Laboratory Standards Institute, Wayne, PA. 7. Cosgrove, S. E., and Y. Carmeli. 2003. The impact of antimicrobial resistance on health and economic outcomes. Clin. Infect. Dis. 36:1433–1437. 8. Cosgrove, S. E. 2006. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin. Infect. Dis. 42(Suppl. 2):S82–S89. 9. Falagas, M. E., and D. E. Karageorgopoulos. 2009. Extended-spectrum betalactamase-producing organisms. J. Hosp. Infect. 73:345–354. 10. Frei, C. R., and D. S. Burgess. 2005. Cost-effectiveness of 4 empiric antimicrobial regimens in patients with community-acquired pneumonia. Formulary 40:298–303. 11. Friedman, N. D., K. S. Kaye, J. E. Stout, S. A. McGarry, S. L. Trivette, J. P. Briggs, W. Lamm, C. Clark, J. MacFarquhar, A. L. Walton, L. B. Reller, and D. J. Sexton. 2002. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann. Intern. Med. 137:791–797. 12. Garner, J. S., W. R. Jarvis, T. G. Emori, T. C. Horan, and J. M. Hughes. 1988. CDC definitions for nosocomial infections, 1988. Am. J. Infect. Control 16:128–140. 13. Gilbert, N. D., R. C. Moellering, G. M. Eliopoulos, H. F. Chambers, and M. S. Saag (ed.). 2006. The Sanford guide to antimicrobial therapy. Antimicrobial Therapy, Inc., Sperryville, VA. 14. Giske, C. G., D. L, Monnet, O. Cars, Y. Carmeli, and ReAct-Action on Antibiotic Resistance. 2008. Clinical and economic impact of common multidrug-resistant Gram-negative bacilli. Antimicrob. Agents Chemother. 52: 813–821. 15. Hyle, E. P., A. D. Lipworth, T. E. Zaoutis, I. Nachamkin, W. B. Bilker, and E. Lautenbach. 2005. Impact of inadequate initial antimicrobial therapy on mortality in infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: variability by site of infection. Arch. Intern. Med. 165: 1375–1380. 16. Javaloyas, M. D., D. Garcia-Somoza, and F. Gudiol. 2002. Epidemiology and prognosis of bacteremia: a 10 year study in a community hospital. Scand. J. Infect. Dis. 34:436–441. 17. Knaus, W. A., D. P. Wagner, E. A. Draper, J. E. Zimmerman, M. Bergner, P. G. Bastos, C. A. Sirio, D. J. Murphy, T. Lotring, A. Damiano, et al. 1991. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 100:1619–1636. 18. Lautenbach, E., J. B. Patel, W. B. Bilker, P. H. Edelstein, and N. O. Fishman. 2001. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin. Infect. Dis. 32:1162–1171. 19. Lee, N. Y., H. C. Lee, N. Y. Ko, C. M. Chang, H. I. Shih, C. J. Wu, and W. C.

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