Adjustment of antibiotic treatment according to the results of blood cultures leads to decreased antibiotic use and costs

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1 Journal of Antimicrobial Chemotherapy (2006) 57, doi: /jac/dki463 Advance Access publication 29 December 2005 Adjustment of antibiotic treatment according to the results of blood cultures leads to decreased antibiotic use and costs Dag Berild 1 *, Atefeh Mohseni 1, Lien My Diep 2, Mogens Jensenius 1 and Signe Holta Ringertz 3 1 Department of Internal Medicine, Aker University Hospital, N-0514 Oslo, Norway; 2 Research Centre, Aker University Hospital, N-0514 Oslo, Norway; 3 Department of Microbiology, Aker University Hospital, N-0514 Oslo, Norway Received 27 September 2005; returned 21 October 2005; revised 23 November 2005; accepted 29 November 2005 Introduction: To avoid the use of unnecessary broad-spectrum antibiotics, empirical therapy of bacteraemia should be adjusted according to the results of blood cultures. Objectives: To investigate whether the results of blood cultures led to changes in antibiotic use and costs in a tertiary-care university hospital in Norway. Methods: Medical records from all patients with positive blood cultures in 2001 were analysed retrospectively. Factors predisposing to infections, results of blood cultures, antibiotic use and outcome were recorded. The influence of blood culture results on antibiotic treatment and costs were analysed. Results: The antibiotic use in 226 of bacteraemia in 214 patients was analysed. According to the guidelines empirical antibiotic treatment should be adjusted in 166. Antibiotic use was adjusted in 146 (88%) of these 166, which led to a narrowing of therapy in 118 (80%). Compared with empirical therapy there was a 22% reduction in the number of antibiotics. Adjustment of therapy was more often performed in Gram-negative bacteraemia and polymicrobial cultures than in Gram-positive bacteraemia. In bacteraemia caused by ampicillin-resistant Escherichia coli, ampicillin was mostly replaced by ciprofloxacin. The cost for 7 days adjusted therapy in 146 was d (23%) less than for 7 days of empirical therapy. Conclusions: Adjustment of antibiotic therapy according to the results of blood cultures led to a reduction in the number of antibiotics and a narrowing of antibiotic therapy. The costs for antibiotics decreased. Keywords: bacteraemia, septicaemia, resistance, guidelines, therapy Introduction Owing to a high mortality in bacteraemia, empirical broadspectrum antibiotic therapy is justified to cover potentially dangerous pathogenic bacteria. 1 To limit the emergence and spread of antibiotic resistance, broad-spectrum therapy should be narrowed according to the results of blood cultures as soon as they are available. 2,3 However, the results of blood cultures are often ignored because the patients are doing well on empirical therapy. 4 8 We wanted to study how the results of blood cultures influenced antibiotic use and costs in the treatment of bacteraemia. The only significant resistance problem in our hospital is in Escherichia coli where 30% of all isolates are resistant to ampicillin. We therefore particularly studied the antibiotic use in E. coli bacteraemia. Materials and methods The hospital Aker University Hospital (Aker) is a 450-bed tertiary care hospital with departments of surgery, internal medicine and intensive care. In 2001, there were admissions with an average duration of hospital stay of 6.6 days. Antibiotic guidelines In 1994 written guidelines (a pocket book) on antibiotic use was issued and distributed to all physicians at our hospital. The guidelines were implemented mainly by educational outreach visits 3 4 h weekly by one specialist in infectious diseases. 9 The infectious disease personnel were also available on the telephone for consultation on antibiotic issues. 10 The expenses for printing the guidelines were around d *Corresponding author. Tel: ; Fax: ; dag.berild@medisin.uio.no Ó The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Adjusting antibiotic treatment according to results of blood cultures These guidelines recommend the use of penicillin plus aminoglycoside as empirical therapy in cases of suspected bacteraemia. In seriously ill patients it is recommended that antibiotics are given intravenously in the first days, and early transfer to oral therapy is encouraged in patients who improve clinically and have a functioning gastrointestinal tract. If an intra-abdominal focus of infection is suspected, one is advised to replace penicillin with ampicillin and to add metronidazole. In cases of drug allergy, renal failure or other contraindications, alternative regimens are recommended. The guidelines emphasize the importance of adjusting the empirical treatment according to the microbiological results. That is, unless complicating factors are present (e.g. neutropenia, intra-abdominal infections, infective endocarditis and Pseudomonas infection), a rapid change of therapy to one narrow-spectrum or semi-broad antibiotic is recommended (see the Definitions section). Penicillin G monotherapy is recommended as the first drug of choice for uncomplicated pneumococcal and streptococcal bacteraemia. Dicloxacillin monotherapy is recommended in uncomplicated Staphylococcus aureus bacteraemia, and ampicillin monotherapy is recommended for uncomplicated ampicillin-susceptible E. coli bacteraemia. In enterococcal bacteraemia it is recommended that ampicillin is combined with gentamicin. Recommendations for duration of therapy are given. Blood cultures Blood culture (Bactec 9249; Becton Dickinson, USA) is performed with a set of at least one aerobic bottle and one anaerobic bottle. During the daytime, growth in blood cultures is reported immediately by telephone to the nurses or doctors on the wards. Growth that has occurred during the evening and night is reported, with the result of Gram s stain, by the microbiologist directly to the physician in charge at the morning conference at the department of internal medicine. Preliminary results on typing and susceptibility testing of isolates are given within 24 h after the report of growth. Clinical information Records from all patients with bacteraemia in 2001 were studied retrospectively. Demographic data, initial diagnoses, reported antibiotic allergy, factors predisposing for infections, antibiotic treatment, duration of treatment, duration of hospital stay and mortality (for all reasons) were recorded. The date blood cultures were obtained as well as the date of blood culture reporting to the clinician were recorded. Definitions An episode of bacteraemia was defined as growth of bacteria in one or more blood culture bottles. If a patient had repeated positive blood cultures with the same or a different microbe, these bacteraemias were considered as separate if more than 7 days apart. Episodes of bacteraemia caused by coagulase-negative staphylococci (CoNS), Bacillus species, Micrococcus, Diptheroides or other likely contaminants, and fungi were not evaluated further. If there was growth of contaminants or fungi plus another bacterium, the episode was considered as an episode of true bacteraemia. A patient was excluded if transferred to another hospital or dead before the blood culture results were available. A polymicrobial culture was defined as growth of two or more organisms in the same bottle. Hospital-acquired bacteraemia was defined as growth in a blood culture obtained more than 48 h after hospital admission. As narrow-spectrum antibiotics we considered penicillin G, dicloxacillin, cloxacillin, macrolides, metronidazole and fusidic acid; as semi-broadspectrum antibiotics we considered ampicillin (co-amoxiclav is not used), first- and second-generation cephalosporins, co-trimoxazole and clindamycin; and as broad-spectrum antibiotics we considered third-generation cephalosporins, carbapenems, fluoroquinolones and aminoglycosides. Analysis of treatment Empirical treatment was treatment before the results of blood cultures were available. Culture-based treatment was defined as treatment adjusted within 48 h after the clinicians had obtained the results of blood cultures. Culture-based treatment was considered as appropriate if the isolated bacterium was in vitro susceptible to the antibiotic given, insufficient if the bacterium was in vitro resistant to the treatment and superfluous if broad-spectrum antibiotics were continued in uncomplicated bacteraemia despite a possibility to streamline therapy to a more narrow-spectrum antibiotic. Two specialists in infectious diseases (D. B. and M. J.) first assessed the appropriateness of therapy independently. There were a few initial disagreements that were solved by consensus. Costs The doses used for calculation of the costs were equal to the DDD for most antibiotics, but for penicillin G the dose was 4.8 g, for ampicillin 8 g, dicloxacillin 4 g, cefotaxime and ceftazidime 3 g and meropenem 3 g. For doxycycline, ciprofloxacin, fusidic acid and co-trimoxazole only the cost for oral therapy was calculated. The daily cost for each antibiotic was multiplied by seven and again by the number of empirical courses and summarized. The same procedure was performed for adjusted therapy. The cost savings were calculated by subtracting the sum of costs for adjusted therapy from the costs for empirical therapy. Only the cost of the drug itself was included. Statistical analysis For categorical variables we used the c 2 test or Fisher s exact test. For comparison of two independent groups the t-test or Mann Whitney test was used. The 95% confidence intervals (95% CIs) for median were given using the bootstrap method. Univariate and multivariate logistic regressions were performed for dichotomous outcomes. Analysis was carried out for the following factors: age (15 69 years, 70 years or older), male of female, predispositions to infections or not, hospital- or community-acquired infections, surgical or medical department, and duration of hospital stay (0 7 days, 8 14 days, days, 22 days or more). Odds ratios are given with 95% CIs. The statistical software for the Social Sciences 12.0 was used. For count data and repeated count data we used poisson and xtpoisson commands in the statistical software Stata/SE 8.0 for epidemiology. P values <0.05 were considered statistically significant. Results General results In 2001, blood culture bottles were obtained from 2002 patients, usually a set of two aerobe and two anaerobe bottles per episode. There was growth of microorganisms in 354 in 332 patients. One hundred and twenty-eight were excluded leaving 226 of true bacteraemia in 214 patients to be included in the study (Figure 1). Two hundred and two patients had a single episode of bacteraemia, and 12 patients had two. Fourteen (6%) were polymicrobial (Table 1). One hundred and thirty-nine (61%) were in men. The median age was 74 years (quartiles 59 82). 327

3 354 of positive blood cultures Berild et al Empirical Adjusted 92 with CoNS, other contaminants, and fungi excluded Appropriate therapy according to guidelines continued in of true bacteraemia. Adjustment of therapy recommended according to guidelines in 166 Treatment adjusted in 146. Therapy not adjusted in where the patients died or were discharged before blood cultures were available were excluded Cost of final therapy 23% less than empirical therapy Figure 1. Adjustment of antibiotic treatment in bacteraemia according to the bacteriological findings. Other contaminants are Diphteroides, Micrococcus and Bifidobacterium. CoNS, coagulase-negative staphylococci. Table 1. Microbiological findings in 226 blood cultures including 14 polymicrobial cultures Organism Number of isolates Gram-positive bacteria S. aureus 39 Streptococcus pneumoniae 29 Other streptococci 22 Enterococcus 9 Listeria 1 Gram-negative bacteria E. coli 84 Klebsiella pneumonia 18 Proteus mirabilis 11 Enterobacter 4 Pseudomonas 7 Salmonella/Shigella 5 Morganella 2 Serratia marcecens 1 Haemophilus influenzae 1 Anaerobe organisms 7 Total 240 In 176 (78%) there were one or more predisposing factors for infections. One hundred and eighty-two (81%) were community-acquired. One hundred and forty-six (65%) were at the department of medicine. The geometric mean duration of hospital stay for all was 11.5 days (95% CI 10.31, 12.82). The mean time from when the blood cultures were sampled from the patient to when the results of the blood cultures were reported to the clinicians was 3.0 days (95% CI 2.8, 3.2). Number of courses Ampicillins Penicillin G and V Dicloxacillin Aminoglycosides Cephalosporins Fluoroquinolones Metronidazole Others Figure 2. Use of empirical and adjusted antibiotics in 226 with true bacteraemia. Others are doxycycline, 4; carbapenem, 1; co-trimoxazole, 16; macrolides and clindamycin, 9; fusidic acid, 2; chloramphenicol, 2; and nitrofurantoin, 2. Therapy At the time of the blood culture report empirical treatment was given in 220 (97%) with an average 1.9 antibiotics. In 60 (26%) empirical therapy was considered as appropriate and continued without changes. According to the blood cultures results, empirical antibiotic therapy should have been adjusted in 166. Therapy was adjusted in 146 (88%) (Figure 1). Of these 146 therapy was narrowed in 118, and was changed due to reported in vitro resistance to the antibiotic in 34 (24 with E. coli,3klebsiella,2proteus,2enterococcus, 2 S. aureus and 1 Salmonella). The mean duration of empirical therapy in the adjusted group was 4 days. Aminoglycoside and metronidazole use was halved and quinolone use doubled after the results of blood cultures were available (Figure 2). The frequency of adjustment of therapy was independent of age, gender, department, or if the patient had factors predisposing to infections. Insufficient therapy according to the in vitro susceptibility testing was given in 4 of 44 of hospital-acquired bacteraemia, and in 6 out of 182 of community-acquired infections. Superfluous therapy was given in 9 out of 80 at the department of surgery versus 8 out of 146 at the department of medicine (OR 2.2; 95% CI ; P = 0.1). In nine caused by ampicillin-susceptible E. coli, superfluous therapy with cefotaxime or ciprofloxacin was given. Adjustment of therapy according to the bacterium (Figure 3) In 19 out of 28 due to ampicillin-resistant E. coli empirical ampicillin therapy was replaced by ciprofloxacin. Compared with pneumococci, the OR for changing therapy in E. coli was 1.77 (95% CI ; P = 0.2), in other Gram-negative bacilli 1.67 (95% CI ; P = 0.3) and in S. aureus 1.8 (95% CI ; P = 0.25). In 14 with two bacteria, therapy was changed in 10, and in the other therapy was changed in 5 out of

4 Adjusting antibiotic treatment according to results of blood cultures No. of positive blood cultures Outcome All 28 patients with fatal bacteraemia (12%) received appropriate therapy. There were no deaths in the 10 where insufficient therapy was registered. For all 226 mortality was significantly higher in hospital-acquired bacteraemia than in community-acquired bacteraemia (OR 4.4; 95% CI ; P = 0.03) and in patients 70 years of age or older (OR 3.7; 95% CI ; P = 0.03). In the 146 where the treatment had been adjusted, the mortality was also higher in hospital-acquired than in community-acquired (OR 5.0; 95% CI ; P = 0.002). There was no significant difference in the duration of hospital stay between the group who received appropriate therapy (13.2 days) and the group who received inappropriate therapy (14.6 days). Costs E. coli The cost for 7 days adjusted therapy in 146 was d (23%) less than for 7 days of empirical therapy. Discussion Other Gramnegative bacilli Streptococci Pneumococci Therapy continued Therapy changed S. aureus Others Figure 3. Change of antibiotic therapy according to the bacteriological findings in 226 of bacteraemia. Others are as follows: 1 Listeria; 1 Haemophilus influenzae; 4 anaerobes; 7 enterococci; and 14 with polymicrobial cultures. The usefulness of blood cultures has been questioned, 11 but in the present era of increasing antibiotic resistance it is more important than ever to avoid unnecessary broad-spectrum antibiotic therapy. 5,6,12 The main finding in this study was the high proportion of in which antibiotic therapy was adjusted according to the blood culture findings, which led to a narrowing of therapy and a low use of broad-spectrum antibiotics. This high rate of adjustment is in contrast to other studies where a more frequent neglect of antibiotic susceptibility data led to a greater proportion of patients receiving superfluous therapy and high use of broad-spectrum antibiotics. 2,7,13 In our hospital, the changes were mainly performed to adjust therapy according to the antibiotic guidelines, and to adjust for resistance in E. coli. Aminoglycosides and metronidazole, which in our hospital are primarily used in empirical combination therapy, were the antibiotics most frequently discontinued. The antibiotic guidelines were actively promoted by the infectious disease personnel, and the recommendations are in line with the perception of rational antibiotic use in Scandinavia. This may explain the good compliance with the guidelines particularly at the department of medicine where superfluous therapy was rare. We have no explanation why there was a tendency to ignore the results of blood cultures in hospital-acquired compared with community-acquired. Other investigators have proposed that the longer the patient stays in the hospital, the more difficult it may be to interpret blood culture results. 2 We found that the higher mortality in hospital-acquired bacteraemia could not be ascribed to insufficient antibiotic treatment and that the deaths could be attributed to non-infectious diseases. Treatment was most often adjusted in infections due to Gramnegative organisms and polymicrobial. In E. coli this is partly due to ampicillin resistance, but it could indicate that it was more difficult to predict the focus and to give correct empirical therapy in abdominal and urinary tract infections than in respiratory tract and skin infections. The replacement of ampicillin by ciprofloxacin and other antibiotics in ampicillin-resistant E. coli bacteraemia may have contributed to the equal mortality in ampicillin-susceptible and -resistant E. coli bacteraemia. 1,14,15 However, for unknown reasons the possibility to narrow therapy was ignored most often in E. coli bacteraemia. The Scandinavian policy with the use of old fashioned antibiotics has been criticized, but in one Danish study, this policy increased long-term survival compared with the use of newer antibiotics. 1 The patients who died in our study had all received appropriate therapy, which confirms that factors other than antibiotic coverage influence mortality in bacteraemia. 16 The change of therapy also led to decreased costs for antibiotics, which exceeded the costs for implementing the guidelines. This is important in times with increased focus on cost-effectiveness in hospitals. 17 The true cost savings in this study are probably higher than the reported figures. Only the expenses for oral ciprofloxacin are given in the cost calculations even if many of the patients surely were given the more expensive parenteral ciprofloxacin initially. In addition we are aware that higher doses than recommended, particularly of the penicillins and cephalosporins, are used in bacteraemia, 10 and the cost calculations in our study were based on moderate daily doses of these antibiotics. Because of a low level of antibiotic resistance we could use cheap antibiotics as empirical therapy, but in settings with a higher level of antibiotic resistance physicians are forced to use the newer and expensive broad-spectrum antibiotics for empirical treatment. In these hospitals adjustment of therapy with older and cheaper narrow-spectrum antibiotics may lead to greater savings than in our study if the bacteria should turn out to be susceptible to these antibiotics. The present study has demonstrated that adjusting antibioic therapy according to the results of blood culture findings leads to a narrowing of antibiotic therapy. Thereby, the emergence of antibiotic resistance can be avoided or delayed. 18 Antibiotic resistance 329

5 Berild et al. may be reversed if the antibiotic use is decreased. Therefore, narrowing therapy according to the blood culture findings may be even more important in settings with a higher frequency of antibiotic resistance than currently is the case in our hospital. Our goal is to avoid the situation of high-level resistance seen in many countries. Transparency declarations None to declare. References 1. Hanon FX, Monnet DL, Sorensen TL et al. Survival of patients with bacteraemia in relation to initial empirical antimicrobial treatment. Scand J Infect Dis 2002; 34: Arbo MD, Snydman DR. Influence of blood culture results on antibiotic choice in the treatment of bacteremia. Arch Intern Med 1994; 154: Cunney RJ, McNamara EB, Alansari N et al. The impact of blood culture reporting and clinical liaison on the empiric treatment of bacteraemia. J Clin Pathol 1997; 50: Campo L, Mylotte JM. Use of microbiology reports by physicians in prescribing antimicrobial agents. Am J Med Sci 1988; 296: Dunagan WC, Woodward RS, Medoff G et al. Antimicrobial misuse in patients with positive blood cultures. Am J Med 1989; 87: Dunagan WC, Woodward RS, Medoff G et al. Antibiotic misuse in two clinical situations: positive blood culture and administration of aminoglycosides. Rev Infect Dis 1991; 13: Elhanan G, Sarhat M, Raz R. Empiric antibiotic treatment and the misuse of culture results and antibiotic sensitivities in patients with community-acquired bacteraemia due to urinary tract infection. J Infect 1997; 35: Maki DG, Schuna AA. A study of antimicrobial misuse in a university hospital. Am J Med Sci 1978; 275: Berild D, Ringertz SH, Lelek M et al. Antibiotic guidelines lead to reductions in the use and cost of antibiotics in a university hospital. Scand J Infect Dis 2001; 33: Berild D, Ringertz SH, Lelek M. Appropriate antibiotic use according to diagnoses and bacteriological findings: report of 12 pointprevalence studies on antibiotic use in a university hospital. Scand J Infect Dis 2002; 34: Waterer GW, Wunderink RG. The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures. Respir Med 2001; 95: Bryan CS. Blood cultures for community-acquired pneumonia: No place to skimp! Chest 1999; 116: Kumarasamy Y, Cadwgan T, Gillanders IA et al. Optimizing antibiotic therapy-the Aberdeen experience. Clin Microbiol Infect 2003; 9: Herchline T, Gros S. Improving clinical outcome in bacteremia. J Eval Clin Pract 1998; 4: Olesen B, Kolmos HJ, Orskov F et al. Bacteraemia due to Escherichia coli in a Danish university hospital, Scand J Infect Dis 1995; 27: Zaragoza R, Artero A, Camarena JJ et al. The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit. Clin Microbiol Infect 2003; 9: Howard D, Cordell R, McGowan JE, Jr et al. Measuring the economic costs of antimicrobial resistance in hospital settings: summary of the Centers for Disease Control and Prevention-Emory Workshop. Clin Infect Dis 2001; 33: Turnidge J. Impact of antibiotic resistance on the treatment of sepsis. Scand J Infect Dis 2003; 35: