Clinical characteristics and outcomes of patients with Burkholderia cepacia bacteremia in an intensive care unit

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Diagnostic Microbiology and Infectious Disease 70 (2011) 260 – 266 www.elsevier.com/locate/diagmicrobio

Clinical Outcomes

Clinical characteristics and outcomes of patients with Burkholderia cepacia bacteremia in an intensive care unit Chun-Hsing Liaoa , Hou-Tai Changa , Chih-Cheng Laib , Yu-Tsung Huangc,d , Meng-Shuian Hsua , Chia-Ying Liua , Chia-Jui Yanga , Po-Ren Hsuehc,d,⁎ a Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei County, Taiwan R.O.C. Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan R.O.C. c Department of Internal Medicine, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan R.O.C. d Department of Laboratory Medicine, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan R.O.C. Received 26 November 2010; accepted 16 January 2011 b

Abstract The purpose of this study was to investigate a cohort of patients with Burkholderia cepacia bacteremia in the intensive care unit (ICU) at our institution. A large outbreak of B. cepacia bacteremia involving 95 patients lasted for 4 years in an ICU in northern Taiwan. The clinical characteristics and antimicrobial treatment responses of these patients were analyzed. Minimal inhibitory concentrations were determined and pulse-field gel electrophoresis was performed for the 73 available isolates. Overall, the in-hospital mortality rate was 53.8% and the 14-day mortality rate was 16.8%. Most patients (95.6%) had several underlying diseases and all but 1 patient had tracheal intubation. Malignancy (37.5% versus 13.9%, P = 0.02) and higher Sequential Organ Failure Assessment (SOFA) scores at the onset of bacteremia (11.9 ± 4.7 versus 7.9 ± 3.6, P b 0.001) were significant risk factors for 14-day mortality. In contrast, treatment with ceftazidime (76.0% versus 43.7%, P = 0.02) and diabetes (51.9% versus 13.8%, P = 0.01) were associated with decreased mortality. In the multivariate analysis, malignancy and higher SOFA score were significant risk factors for mortality [odds ratio (OR) 12.45, 95% confidence interval (CI) 2.35–65.94; OR 1.20, 95% CI 1.00–1.45, respectively]. Meropenem, ceftazidime, and piperacillin–tazobactam were the most active agents (susceptible rate 100%, 97.3%, and 97.3%, respectively). Pulsed-field gel electrophoresis results indicated 49 of the 73 isolates could be classified as outbreak-related strains. There was no significant difference in the clinical characteristics and outcomes of patients with bacteremia due to outbreak-related and non–outbreak-related strains. In conclusion, malignancy and a higher SOFA score at onset of bacteremia predicted increased mortality, but the clinical presentation and outcome of patients with outbreak and non-outbreak strains were similar. © 2011 Elsevier Inc. All rights reserved. Keywords: Burkholderia cepacia; Bacteremia; Outbreak; Antimicrobial susceptibility; Treatment outcomes

1. Introduction Burkholderia cepacia, originally described as the cause of soft rot of onions, can be recovered from the natural and hospital environment (Goldmann, & Klinger, 1986; Gregory, & McNabb, 1986). Over the past 2 decades, B. cepacia has been recognized as an important pathogen in patients with cystic fibrosis (CF) (Fitzsimons, 1996; Isles et al., 1984).

⁎ Corresponding author. Tel.: +886-2-23123456x65355; fax: +886-223224263. E-mail address: [email protected] (P.-R. Hsueh). 0732-8893/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2011.01.008

However, its pathogenicity is not limited to CF patients and some studies found that the organism can also infect patients without CF with resultant morbidity (Holmes et al., 1999; Reboli et al., 1996). B. cepacia is an emerging pathogen in patients acquiring nosocomial infections and may cause outbreaks via different sources (Goven et al., 1996; Hamill et al., 1995; Jarvis et al., 1987; Lu et al., 1997a). Several studies suggest that patients with debilitating underlying diseases, particularly those with an indwelling invasive device or intensive unit stay, are at risk of acquiring B. cepacia in the hospital (Jarvis et al., 1987; Jones et al., 2001; Yu et al., 1999). Antimicrobial therapy for B. cepacia infections is a challenge, because this pathogen is intrinsically resistant to many antimicrobial

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agents (Chang et al., 1998; Jarvis et al., 1987; Lu et al., 1997b; Spencer, 1995; Yu et al., 1999). However, poor correlation between in vitro susceptibility tests and clinical outcomes has been reported (Spencer, 1995). We investigated a cohort of patients with B. cepacia bacteremia who were identified in the intensive care unit (ICU) at our institution over a 4-year period. The aim of this study was to evaluate the potential outbreaks of B. cepacia bacteremia in the ICUs and investigate the predictors to clinical response and to determine whether the outbreak strain carried an increased risk of mortality compared to the non-outbreak strain.

2. Materials and methods 2.1. Hospital setting Far Eastern Memorial Hospital (FEMH) is a 1040-bed hospital located in northern Taiwan and has 22 ICU beds in the medical unit. The surveillance of nosocomial infections at FEMH has been performed by the Nosocomial Infection Control Committee since 1985. 2.2. Clinical characteristics of patients All patients with B. cepacia bacteremia identified from records of the microbiology laboratory were consecutively included from January 2004 to December 2007. Data on demographic characteristics, underlying illness, Sequential Organ Failure Assessment (SOFA) scores at onset of bacteremia, invasive procedures, and antimicrobials administered after the bacteremic episodes (including all used for more than 48 h) were collected (Vincent et al., 1998). When a catheter-related bloodstream infection was suspected by physicians in charge, catheters were removed and tip cultures were performed. The semi-quantitative tip culture (≥15 colonies) method was used to diagnose catheter-related infection. The 14-day mortality was used to evaluate treatment response since many patients had intractable underlying diseases or developed further nosocomial infections (n = 22). Septic shock was defined as the criteria of Bone et al. (1992). 2.3. Bacterial isolates All positive blood culture isolates were identified to the species level by a commercial system (API 20NE, bioMerieux, Vitek, Hazelwood, MO, USA) and further characterized biochemically by conventional tests (positive for lactose, maltose, and sucrose, but negative for urease and lysine reaction) (Gilligan, 1991). These isolates were further confirmed to be B. cepacia using polymerase chain reaction–restriction fragment length polymorphism (RFLP) analysis of the 16S rDNA as previously described (Segonds et al., 1999; Teng et al., 2001).

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2.4. Antimicrobial susceptibility testing Susceptibility of bacterial isolates to antimicrobial agents was initially determined by the routine disk diffusion method and interpreted in accordance with the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS) (2004). The disk susceptibility NCCLS interpretive criteria for Pseudomonas aeruginosa were applied for B. cepacia isolates in the hospital (Gilligan, 1991). A total of 73 isolates of B. cepacia from these patients were preserved. Minimum inhibitory concentrations (MICs) of these isolates were then determined by the recommended agar dilution method in 2010 [Clinical and Laboratory Standards Institute (CLSI), 2010]. Antimicrobial agents used for susceptibility testing were obtained from their corresponding manufacturers. The antimicrobial agents tested were incorporated into Mueller–Hinton agar (BBL, Becton Dickinson, USA) in serial twofold concentration that ranged from 0.03 to 128 μg/mL. Escherichia coli ATCC 25922 and P. aeruginosa ATCC 27853 were used as controls in each set of tests. Interpretive MIC breakpoints of ceftazidime, meropenem, minocycline, trimethoprim–sulfamethoxazole (TMP-SMX), and levofloxacin for B. cepacia obtained from CLSI were used to define the susceptibility categories of the isolates (Clinical and Laboratory Standards Institute, 2010). There was no CLSI MIC breakpoint for piperacillin–tazobactam, imipenem, tetracycline, moxifloxacin, tigecycline, and colistin at the time of this study (Clinical and Laboratory Standards Institute, 2010). 2.5. Molecular typing Pulsed-field gel electrophoresis (PFGE) was performed for the 73 available B. cepacia isolates to investigate their molecular epidemiology. Five unrelated B. cepacia isolates from National Taiwan University Hospital in 2005 were also included in this study as control strains for PFGE analysis. The detailed method used to perform PFGE has been described previously (Tenover et al., 1995). For restriction endonuclease digestion of the DNA plug, the restriction enzyme XbaI (Takara Shuzo, Kyoto, Japan) was applied (Ouchi et al., 1995). The PFGE results were analyzed with Gelcompar for Windows version 3.1. Band pattern similarity above 80% was considered as a probable cluster indicating the presence of an outbreak. 2.6. Statistical analysis In the statistical analysis, means and standard deviations (SD) were calculated as summaries of continuous variables. Comparisons were performed with the Mann–Whitney U method for continuous variables and with the chi-square test or Fisher's exact test for categorical variables. Factors associated with 14-day mortality were further evaluated with a multivariate analysis. The survival curves for patients treated with or without ceftazidime were depicted using the

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Kaplan–Meier method. The reason why we analyzed the association between ceftazidime use and outcome of the patients was that this agent was the most commonly used drug in the ICUs for empirical treatment of nosocomial infections. Data were collected in a Microsoft Excel database (Microsoft Excel 2001, Microsoft Corporation, Seattle, WA, USA) and analyzed with SPSS software for Windows (release 10.0, SPSS, Chicago, IL, USA). 3. Results 3.1. Clinical characteristics of patients with B. cepacia bacteremia Over the 4-year period, a total of 95 patients with B. cepacia bacteremia were identified. All the isolates were identified as B. cepacia based on results by conventional identification, commercial kit system, and comparable RFLP profile. Of them, 58 (61.1%) were men and the ages ranged from 55 to 87 years. Respiratory tract infection was the most common presentation (49.5%), followed by catheter-related infection and urinary tract infection. As for underlying illness, 44 (46.3%) patients had chronic lung diseases and diabetes mellitus and 41 (43.2%) patients had chronic kidney disease, 40 (42.1%) patients had cardiovascular diseases, and Table 1 Characteristics and 14-day mortality of 95 patients with B. cepacia bacteremia Variable

Survivors (n = 79)

Age 71.2 ± 1.3 Male 47 (59.5) SOFA 7.9 ± 3.6 Underlying diseases Chronic pulmonary disease 35 (44.3) Cardiovascular disease 34 (43.0) Chronic renal disease 34 (43.0) Malignancy 11 (13.9) Diabetes mellitus 41 (51.9) Stroke 26 (32.9) Liver cirrhosis 1 (1.3) Steroid use 22 (27.9) Source of bacteremia Respiratory tract 41 (51.9) Urinary tract 4 (21.1) Catheter 19 (24.1) Primary bacteremia 15 (19.0) Complications Septic shock 34 (43.0) Fever 74 (93.7) Predisposing factors Central venous catheter 74 (93.7) Foley 75 (94.9) Ventilator 78 (98.7) Double lumen catheter 27 (34.2) Total parenteral nutrition 22 (27.9) Antibiotic use after B. cepacia bacteremia Ceftazidime 60 (76.0) Meropenem 17 (21.5) Piperacillin-tazobactam 32 (40.5)

Non-survivors (n = 16)

P value

66.5 ± 4.3 11 (68.8) 11.9 ± 4.7

0.19 0.58 b0.001

9 6 7 6 3 5 2 3

(56.3) (37.5) (43.8) (37.5) (18.8) (31.3) (12.5) (18.8)

0.38 0.68 0.96 0.02 0.01 0.90 0.07 0.55

6 (37.5) 0 3 (18.8) 7 (43.5)

0.41 1.00 0.76 0.05

11 (68.8) 14 (87.5)

0.06 0.39

14 16 16 7 5

(87.5) (100) (100) (43.8) (31.3)

0.27 0.36 1.00 0.47 0.78

7 (43.8) 0 (0.0) 5 (31.3)

0.02 0.06 0.78

25 (26.3%) patients had received daily steroid ≥10-mg treatment. Eighty-eight (92.6%) patients had fever and 45 (47.4%) had septic shock when bacteremia developed. Most of the patients had an intravascular catheter (92.6%), respiratory failure with tracheal intubation (98.9%), or Foley catheterization (95.8%). The overall in-hospital mortality rate was 51.6%. There were 16 patients who died within 14 days after the onset of bacteremia (Table 1). There were no significant differences between 14-day survivors and non-survivors in age, gender, primary source of bacteremia, some comorbidities (chronic lung, kidney, or cardiovascular disease and the use of steroid), and the prevalence of a foreign body, including a central venous catheter, endotracheal tube, double lumen catheter, or Foley catheter. Mortality was more common in patients with higher SOFA scores at the onset of bacteremia (11.9 ± 4.7 versus 7.9 ± 3.6; P b 0.001) and in those with underlying malignancy (37.5% versus 13.9%; P = 0.02). Diabetes mellitus (51.9% versus 18.8%; P = 0.02) and the use of ceftazidime after culture results were available (76.0% versus 43.8%; P = 0.02) and were more common in survivors. Multivariate analysis revealed that malignancy was significantly associated with mortality [odds ratio (OR) and 95% confidence interval (CI) were 12.5, 2.35–65.94], while SOFA score was of borderline significance (OR 1.20, 95% CI 1.00–1.45) (Table 2). The survival curves of patients with and without ceftazidime treatment are compared in Fig. 1. The log rank test result was 0.065. 3.2. Antimicrobial susceptibilities The rates of susceptibility for the 73 B. cepacia isolates to ceftazidime and meropenem were 97.3% and 100%, respectively (Table 3). The susceptible rates of minocycline and levofloxacin were both 5.5%. All isolates were resistant to TMP-SMX. If MIC interpretive breakpoints for P. aeruginosa were applied, the susceptibility rate of B. cepacia to piperacillin–tazobactam was 97.3% (Clinical and Laboratory Standards Institute, 2010). The MIC90s of moxifloxacin, tigecycline, and colistin were 16, 4, and N32 mg/L, respectively. 3.3. Outbreak investigation The outbreak of patients with B. cepacia bacteremia was first suspected in January and February 2004 (5 cases in 2 Table 2 Multivariate analysis of factors associated with 14-day mortality among 95 patients with B. cepacia bacteremia Factors

Odds ratio

95% Confidence interval

P value

Age Male SOFA score Septic shock Ceftazidime treatment Underlying malignancy

0.99 0.85 1.20 4.03 0.18 12.45

0.95–1.04 0.21–3.45 1.00–1.45 0.81–20.1 0.04–0.80 2.35–65.94

0.71 0.82 0.05 0.09 0.24 0.003

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decreased, but we could still find patients colonized with B. cepacia occasionally. The outbreak was finally controlled in 2009 after discontinuing all reusable ventilator circuits, including tubing, connectors, and humidifiers, which were considered the culprit of this outbreak. 3.4. Clinical manifestations and molecular epidemiology of outbreak isolates PFGE analysis of the 73 preserved isolates indicated that 49 (67.1%) isolates were cluster (outbreak-related) strains (Fig. 2). The PFGE profiles of the 5 isolates from the unrelated hospital were different from those of the cluster strains. The clinical characteristics and outcome of patients with outbreak-related and non–outbreak-related B. cepacia isolates are compared in Table 4. There was no significant difference between these 2 groups in underlying condition or disease, treatment, and outcome.

Fig. 1. Comparison of the survival curves of patients with B. cepacia bacteremia with and without ceftazidime treatment (log rank 0.065).

months, compared to 3 patients who had B. cepacia bacteremia in the whole year of 2003). The control of this outbreak was difficult since no single factor was found to be responsible for the spread of the organisms, similar to previous reports (Abe et al., 2007; Bressler et al., 2007; Woods et al., 2004). In 2005, repeated environmental surveillance cultures were performed but no obvious transmission route was found. In 2006, we enhanced environmental cleaning and launched a program to decrease the use of central catheters and carbapenems, but the effect was not obvious. In 2007, we started to implement contact isolation of all patients carrying B. cepacia in the units (Bressler et al., 2007). The number of bacteremic patients Table 3 Minimum inhibitory concentrations of the 73 preserved bacteremic B. cepacia isolates Antimicrobial agent

MIC (mg/L) Range

MIC50

MIC90

Ceftazidime TMP/SMX Tigecycline Tetracycline Minocycline Imipenem Meropenem Piperacillin/tazobactam Levofloxacin Moxifloxacin Colistin

2–16 8/152–32/608 0.12–8 64–N128 1–N128 16.0–32 4–4 4–N128 2–32 1–16 N32–N32

2 16/304 2 N128 8 16 4 8 4 4 N32

2 16/304 4 N128 8 32 4 16 16 16 N32

Susceptible (%) 97.3 0 NA NA 5.5 NA 100 NAa 5.5 NA NA

a If MIC interpretive breakpoints for P. aeruginosa were applied, the susceptibility rate of B. cepacia to piperacillin–tazobactam was 97.3% (Clinical and Laboratory Standards Institute, 2010).

4. Discussion This study examined the clinical characteristics and outcome of 95 patients who acquired B. cepacia bacteremia in a medical ICU during a 4-year period. Malignancy and higher SOFA score at the onset of bacteremia were predictors of increased mortality. Among the 73 available isolates, 49 were considered to be part of an outbreak. There was no significant difference in the clinical characteristics and outcomes of patients with bacteremia due to outbreakrelated and non–outbreak-related strains. Previous studies found that most patients with B. cepacia bacteremia had serious underlying diseases, including malignancy, diabetes mellitus, and chronic lung disease (Fitzsimons, 1996; Holmes et al., 1999; Isles et al., 1984). The present study, one of the largest reported investigations of B. cepacia bacteremia in non-CF patients, showed a similar finding that most patients (95.6%) had more than 1 underlying disease. Several predisposing factors, such as staying in an ICU and invasive catheter use, have been suggested as the major determinants for developing B. cepacia bacteremia (Goldmann et al., 1986; Isles et al., 1984). All of the patients in this study were staying in the ICU and most of them had undergone intubation or tracheotomy with ventilator support and were using intravascular and Foley catheters. Because B. cepacia colonizes the respiratory tract, it is not surprising that a compromised respiratory status, such as the need for intubation with mechanical ventilator support, emerged as a significant risk factor for B. cepacia bacteremia. B. cepacia exhibits broad-range resistance to many antimicrobial agents in vitro. Ceftazidime has the lowest MIC50 and MIC90, and only 2 B. cepacia isolates were found to be resistant to this agent in this study. Treatment with ceftazidime was associated with lower mortality. All of the isolates were susceptible to meropenem, and no patient who received meropenem died within 14 days (not statistically

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Pulsotypes 55

60

65

70

75

80

85

90

95

100

Designation of isolates 37 69 74 76 40 72 56 58 61 62 63 66 70 65 67 60 1 10 11 12 13 14 2 20 39 7 8 5 3 55 34 4 41 42 45 46 47 54 84 49 68 50 52 53 57 18 19 51 64 86 91 87 83 85 81 82 77 25 26 31 27 28 33 30 29 15 22 35 36 17 75

Fig. 2. Pulsotypes of 73 preserved bacteremic isolates of B. cepacia.

significant due to the small case number). By contrast, percentages of patients receiving piperacillin–tazobactam (n = 37) were similar in survivors and non-survivors. A recent review of antimicrobial treatment for B. cepacia infection found favorable outcomes in 68.4% to 100% of patients treated with ceftazidime, 66.7% with meropenem, and 75% with piperacillin (Avgeri et al., 2009). In the present study, these percentages were 89.6%, 100%, and 86.5%, respectively. TMP/SMX has been suggested for the treatment of B. cepacia infection (Avgeri et al., 2009; Isles et al., 1984). However, the disc susceptibility tests in the present study showed that most of the isolates were resistant to TMPSMX. Only 5 patients received this antimicrobial and their 14-day mortality rate was 20%. The MICs of TMP-SMX were 8–32 mg/L in this study, with a MIC90 of 16 mg/L. Woods et al. (2004) showed that some outbreak-related strains were associated with poor outcome in patients with B. cepacia bacteremia. However, in this study we could not

demonstrate any difference in outcome between patients with outbreak and non-outbreak strains. This study had several limitations. First, although conventional identification methods, commercial kit identification system, and RFLP of the 16S rDNA were used to identify the isolates as B. cepacia, further molecular work (i.e., analysis of the recA gene) to further speciation (genomovars) of these isolates (B. cepacia complex) is needed (Mann et al., 2010). Second, since evaluating the treatment response among these patients was difficult due to complex variations in underlying illness, we used 14-day mortality as the end point (Woods et al., 2004). Third, because many of these patients had received several antimicrobial agents and these drugs were adjusted frequently, we included all major medications for the treatment of B. cepacia infection in the analysis, as long as the agent was used for more than 48 hours. However, the analysis was complicated by the fact that 5 patients died within 3 days after bacteremia onset, 2 of them had a mean

C.-H. Liao et al. / Diagnostic Microbiology and Infectious Disease 70 (2011) 260–266 Table 4 Comparison of clinical characteristics and outcomes of patients with bacteremia caused by outbreak and non-outbreak B. cepacia strains Outbreak-related Non–outbreak-related P strains (n = 49) strains (n = 24) value Age 68.8 ± 14.1 Male 27 (55.1) SOFA score 8.5 ± 4.6 Underlying illness Chronic pulmonary 27 (55.1) disease Cardiovascular disease 19 (38.8) Chronic renal disease 24 (49.0) Malignancy 11 (22.4) Diabetes mellitus 21 (42.9) Stroke 16 (32.7) Steroid 14 (28.6) Liver cirrhosis 1 (2.0) Source of infection Respiratory tract 28 (57.1) Catheter 11 (22.4) Urinary tract 1 (2.0) Primary bacteremia 9 (18.4) Predisposing factors Central venous 43 (87.8) catheter Ventilator 49 (100.0) Foley 48 (98.0) Double lumen catheter 17 (34.7) Total parenteral 17 (34.7) nutrition Complications Fever 45 (91.8) Shock 22 (44.9) In-hospital mortality 27 (55.1) 14-day mortality 13 (26.5) Antibiotic use after B. cepacia bacteremia Ceftazidime 36 (73.4) Meropenem 6 (12.2) Piperacillin-tazobactam 8 (16.3)

72.0 ± 12.8 16 (66.7) 9.0 ± 4.0

0.32 0.35 0.60

11 (45.8)

0.46

11 (45.8) 13 (54.2) 5 (20.8) 12 (50.0) 8 (33.3) 8 (33.3) 1 (4.2)

0.57 0.68 0.88 0.57 0.95 0.68 1.00

12 (50.0) 4 (16.7) 1 (4.2) 7 (29.2)

0.57 0.76 1.00 0.30

23 (95.8)

0.17

24 (100.0) 24 (100.0) 11 (45.8) 4 (16.7)

1.00 1.00 0.44 0.17

21 (87.5) 11 (45.8) 11 (45.8) 3 (12.5)

0.68 0.94 0.46 0.23

18 (75.0) 6 (25.0) 20 (83.3)

1.00 0.18 0.49

SOFA score of 23.4 and only 3 of them received adequate empirical therapy judged from the results by the disk diffusion method. Although meropenem, piperacillin– tazobactam, and ceftazidime were still the most potent agents, it is possible that a concomitant microorganism might have affected the choice of medications and treatment response. Furthermore, the outbreak persisted for 4 years, and the bacteria could possibly evolve during this period, which might limit the efficacy of PFGE to determine the clonality of outbreak strains. Finally, this is a retrospective study which might limit its accuracy in assessing risk factors. In summary, this study found that B. cepacia bacteremia in critically ill patients carried a high mortality rate. Malignancy and a higher SOFA score at the onset of bacteremia were predictors of increased mortality. Treatment with effective agents such as ceftazidime, meropenem, and piperacillin–tazobactam was associated with a favorable 14-day survival rate.

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