Original Article

Risk Factors for Burkholderia cepacia Complex Bacteremia Among Intensive Care Unit Patients Without Cystic Fibrosis: A Case‐Control Study

Adam M. Bressler, MD; Keith S. Kaye, MD; John J. LiPuma, MD; Barbara D. Alexander, MD; Christopher M. Moore, MD; L. Barth Reller, MD; Christopher W. Woods, MD  

From the Infectious Disease Specialists of Atlanta and the Clinical Microbiology Laboratory, Dekalb Medical Center, Atlanta, Georgia (A.M.B.); the Department of Medicine (K.S.K., L.B.R., C.W.W.) and the Clinical Microbiology Laboratory (B.D.A., L.B.R., C.W.W.), Duke University School of Medicine, Durham, and the Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill (C.W.W.), North Carolina; the Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor (J.L.L.); and the University of Virginia School of Medicine, Charlottesville (C.M.M.).

Address reprint requests to Christopher W. Woods, Clinical Microbiology Laboratory, 113 Durham Veterans Affairs Medical Center, Durham, NC 27705 (woods004@mc.duke.edu).

Background. The Burkholderia cepacia complex is associated with colonization or disease in patients with cystic fibrosis (CF). For patients without CF, this complex is poorly understood apart from its presence in occasional point source outbreaks.

Objective. To investigate risk factors for B. cepacia bacteremia in hospitalized, intensive care unit patients without CF.

Methods. We identified patients with 1 or more blood cultures positive for B. cepacia between May 1, 1996, and March 31, 2002, excluding those with CF. Control patients were matched to case patients by ward, duration of hospitalization, and onset date of bacteremia. Matched analyses were used to identify risk factors for B. cepacia bacteremia.

Results. We enrolled 40 patients with B. cepacia bacteremia into the study. No environmental or other point source for B. cepacia complex was identified, although horizontal spread was suspected. Implementation of contact precautions was effective in decreasing the incidence of B. cepacia bacteremia. We selected 119 matched controls. Age, sex, and race were similar between cases and controls. In multivariable analysis, renal failure that required dialysis, recent abdominal surgery, 2 or more bronchoscopic procedures before detection of B. cepacia bacteremia, tracheostomy, and presence of a central line before detection of B. cepacia bacteremia were independently associated with development of B. cepacia bacteremia, whereas presence of a percutaneous feeding tube was associated with a lower risk of disease.

Conclusions. B. cepacia complex is an important emerging group of nosocomial pathogens in patients with and patients without CF. Nosocomial spread is likely facilitated by cross‐transmission, frequent pulmonary procedures, and central venous access. Infection control measures appear useful for limiting the spread of virulent, transmissible clones of B. cepacia complex.

Received November 26, 2006; accepted March 5, 2007; electronically published June 29, 2007.

The Burkholderia cepacia complex represents a group of at least 9 distinct species.1 These gram‐negative rods are motile, aerobic, nonfermenting, and often resistant to multiple drugs. Colonization and infection with B. cepacia complex in patients with cystic fibrosis (CF) have been associated with a progressive decrease in pulmonary function and rapidly fatal septicemia and death.2,3 Some authors have also reported increased case‐fatality ratios after lung transplantation among patients with CF and B. cepacia complex infection. As a result, in many centers, colonization and infection with B. cepacia complex are criteria that exclude patients with CF from lung transplantation.4‐6 Furthermore, it appears that certain strains of Burkholderia cenocepacia (formerly known as genomovar III of the B. cepacia complex) may be associated with increased transmissibility and/or poor outcomes in the CF population.7‐13

Outside the CF population, infection with B. cepacia complex is poorly understood apart from its presence in occasional point source outbreaks. Several studies have documented outbreaks among patients with and patients without CF in which patient‐to‐patient cross‐transmission is thought to have occurred.14‐17 Elsewhere, we described the clinical outcomes and molecular aspects of a prolonged outbreak of B. cepacia complex bacteremia among 53 patients, most of whom did not have CF, at a university hospital.18 That study reported a high overall case‐fatality rate and a significant association between infection with certain epidemic strains of B. cenocepacia and death. These data suggest that species‐specific and/or strain‐specific transmissibility and virulence may also be seen in non‐CF populations.

Risk factors for acquiring B. cepacia complex in the CF population have been reported.8,19,20 However, risk factors for B. cepacia bacteremia in non‐CF populations have not been well characterized. We performed a case‐control study to determine risk factors for B. cepacia bacteremia in a non‐CF population and describe the epidemiology of B. cepacia complex infection in our institution.

Methods

 

Setting and Design

Duke University Medical Center is a 750‐bed tertiary care medical center in Durham, North Carolina. The hospital has 80 intensive care unit (ICU) beds distributed in medical, cardiac, surgical, thoracic surgical, neurological, bone marrow transplantation, pediatric, and neonatal units. The medical center also has a large lung transplantation program that performs procedures on patients with CF. During the study period, patients with CF and B. cepacia complex colonization were not considered for lung transplantation.

In 2000, the infection control program at Duke University Medical Center initiated an investigation of a prolonged outbreak of B. cepacia complex infections. As a component of that investigation, we performed a case‐control study to determine the risk factors for developing B. cepacia bacteremia in critically ill hospitalized patients who did not have CF. The Duke University Medical Center institutional review board approved all components of this study and determined that informed patient consent was not indicated.

Case and Control Definitions

A case was defined as any ICU patient during the study period with at least 1 blood culture yielding an isolate confirmed as B. cepacia complex. Patients with CF were excluded because the aim of the study was to define risk factors for acquisition in patients without CF. Case ascertainment was accomplished through a review of the records for all blood cultures with positive results between May 1, 1996, and March 31, 2002, archived in the Clinical Microbiology Laboratory at Duke University Medical Center. Patients with multiple cultures with positive results or episodes of B. cepacia bacteremia were only enrolled once, at the time of their initial positive culture result or bacteremia episode.

Controls were defined as patients who had spent at least 7 days in the ICU within 2 weeks of the primary episode of B. cepacia bacteremia for their matched case but did not have B. cepacia complex isolated during the study period. Controls were matched to case patients in a 3:1 ratio on the basis of ICU type and date of onset of B. cepacia bacteremia for the matched case.

Databases and Study Variables

All microbiology laboratory records from July 1992 through June 2002 were reviewed for both blood and nonblood isolates of B. cepacia complex. Transplantation program databases were also examined to determine the total number of lung transplantations performed on patients with and patients without CF and to identify patients with a history of previous colonization with B. cepacia complex. Demographic, clinical, and laboratory data and hospital interventions were abstracted from medical records and electronic databases of study patients. Study data were collected using a standardized questionnaire and entered into a database (Epi Info, version 6.0).

Environmental Investigation

The epidemic curve (Figure) suggested an endemic problem related to cross‐transmission, rather than to a point source outbreak. A single evaluation for environmental reservoirs of B. cepacia complex was performed at the peak of the outbreak in September 2000. This investigation included ICUs (ie, thoracic surgery, surgery, and medical ICUs) that had patients with B. cepacia bacteremia. Samples from multiple surfaces, including handrails, sinks, ventilators, and in‐room computer surfaces, were obtained and inoculated onto B. cepacia selective agar (Remel).

Figure.  Time line depicting an increase in the number of lung transplantations (LTs) along with an outbreak of clinical Burkholderia cepacia colonization, followed by a decrease in the number of colonizations after initiation of contact isolation for all patients found to have B. cepacia complex. CF, cystic fibrosis.

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Microbiological and Molecular Analysis

Blood isolates of B. cepacia complex were prospectively collected and processed according to standard practice. Environmental specimens were incubated at 35°C, and cultures were evaluated daily for 5 days. Gram‐negative, oxidase‐positive, nonfermenting rods were putatively identified as B. cepacia complex by cell wall analysis, using gas‐liquid chromatography (MIDI System; Microbial ID). All isolates were frozen and stored at −70°C. Confirmation of bacterial species was based on 16S rDNA and recA species‐specific polymerase chain reaction analysis, as described elsewhere.21,22

We performed macrochromosomal pulsed‐field gel electrophoresis restriction fragment length polymorphism analysis on all isolates, using protocols described elsewhere, with SpeI endonuclease digestion followed by electrophoresis in 1% agarose for 19.5 hours on a CHEF Mapper system (Bio‐Rad Laboratories).23 Additionally, representative sputum specimens from 40 patients with CF who were colonized with B. cepacia complex between June 1999 and June 2002 were also submitted for pulsed‐field gel electrophoresis analysis. Strain characterization based on pulsed‐field gel electrophoresis patterns was determined visually by the method of Tenover et al.24 Antimicrobial susceptibility testing was performed using commercial dry broth microdilution plates on an automated system (MicroScan; Dade Behring).

Statistical Analysis

Data analysis was performed using SAS statistical software, version 8.2 (SAS). Comparative exposure variables before the date of onset of B. cepacia bacteremia were measured for cases and controls. Bivariate analysis for categorical variables included calculation of 2‐sided P values and odds ratios (ORs) with 95% confidence intervals (CIs), using the Mantel‐Haenszel χ2 test for matched analyses. Continuous variables were compared using 2‐sided Wilcoxon rank sum or Student t tests. To determine independent associations between select variables and acquisition of B. cepacia bacteremia, multivariable logistic regression was performed. Covariates were included in the model if bivariate analysis revealed that they were significantly associated with B. cepacia bacteremia at an α of <.10. Other variables that were reported as risk factors in prior studies or were considered to be important by the study investigators were also included in the model. A final multivariable model was achieved using a stepwise selection procedure. All covariates were checked for confounding and colinearity, and confounding variables were included in the final model. Effect measures in the final model were recorded as ORs with 95% CIs. All P values were 2‐sided.

Results

 

From 1992 through 2002, the Duke Clinical Microbiology Laboratory detected B. cepacia complex in cultures of nonblood specimens from 286 patients and in cultures of blood from 77 patients with and without CF (Figure). Of patients with B. cepacia bacteremia, 47 (61%) also had B. cepacia complex isolated from a respiratory tract specimen, and 3 had the pathogen isolated from the urinary tract specimen.

Outbreak Investigation

In 1996, the frequency of recovery of B. cepacia complex isolates from respiratory tract specimens and blood increased dramatically from previous years at our institution, peaking in 1999 (Figure). This finding corresponded to an increase in the number of lung transplantations performed, including transplantations performed in patients with CF who were previously infected with B. cepacia complex. From September 1992 through December 2002, a total of 82 patients with CF underwent lung transplantation at Duke University Medical Center. Of these, 20 had B. cepacia complex isolated within 1 year before transplantation. Ten of these 20 patients were infected with B. cenocepacia, 9 were infected with other B. cepacia complex species, and 1 was unavailable for molecular analysis. As reported elsewhere, the increase of B. cepacia bacteremia at our institution was attributed primarily to 2 different clones of B. cenocepacia.18 However, the molecular characterization of representative B. cepacia complex isolates from both hospitalized and nonhospitalized patients with CF did not identify a source for either of the outbreak‐associated strains. Thus, although we suspected that the CF population was responsible for the introduction of the B. cepacia complex strains associated with the outbreak of B. cepacia bacteremia among patients without CF, we were unable to prove that this was the case.

Control of Outbreak

Infection control measures, including the use of contact precautions for all patients with B. cepacia complex, were implemented in September 2000. Contact precautions included gowning and gloving on entering the rooms of patients infected with B. cepacia complex and handwashing after contact. These practices were only applied to patients with documented infection or colonization, not to units as a whole. Furthermore, the institution placed a moratorium on all transplantations for B. cenocepacia–infected patients with CF. As shown in the Figure, the frequency of B. cepacia complex recovery, including the 2 outbreak‐associated clones, rapidly decreased after these interventions. The environmental investigation performed concurrently with implementation of the outbreak control measures in 2000 identified only a single isolate of an outbreak‐associated strain in a workstation sink drain in an ICU caring for a patient with B. cepacia bacteremia.

Case‐Control Study

We reviewed case histories for all 60 patients hospitalized at our facility with 1 or more blood cultures positive for B. cepacia complex between May 1, 1996, and April 1, 2002. Of these, 20 patients were excluded from the case‐control study for the following reasons: molecular analysis established an alternative organism identification (2 Pandoraea species, 1 Ralstonia species), 6 patients were not in an ICU at the time of bacteremia, and 10 patients had CF. An additional patient was excluded from the analysis when we were unable to identify controls with appropriate matching criteria. Compared with included case patients, excluded patients were younger, had fewer comorbid conditions, and were more likely to be white, as might be expected for patients with CF. The remaining 40 patients were included as cases in our analysis.

The median age of cases was 52 years (range, 20‐82 years). Cases were predominantly women (55%) and white (70%). Most of the 40 cases were identified in the medical ICU (12 cases), surgical ICU (11), or thoracic ICU (10), with the remainder coming from oncology, cardiac, and neurological ICUs. Thirty‐three cases (83%) had bloodstream infections with B. cenocepacia. Of these 33 cases, 2 dominant clones (outbreak strains 1 and 2) accounted for 18 and 10 isolates, respectively. Among the 16 available isolates from the 20 excluded patients, only 7 were B. cenocepacia, and none were either of the 2 epidemic clones. Clusters of infections caused by the same clone in the same unit at the same time were interspersed with sporadic infections caused by both outbreak and unique clones.

In matched, bivariate analysis (Table 1), no difference was found in mean age, sex, or race between cases and controls. Patients in both groups had extensive preexisting comorbid conditions as evidenced by their similar baseline Charlson comorbidity indexes ( for cases vs for controls; ). Of the individual comorbidities, only end‐stage renal disease that required hemodialysis was more common among cases, compared with controls (OR, 7.9 [95% CI, 2.5‐25.3]).

Table 1. 
Table 1.  Association Between Baseline Characteristics and Comorbid Conditions and the Risk of Burkholderia cepacia Bacteremia Among Case Patients and Control Patients

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Comparisons of hospital course, sequelae, and interventions between cases and controls are presented in Table 2. Both groups had complex hospitalizations, but cases had longer ICU stays preceding the date of B. cepacia bacteremia (median duration, 27 vs 20 days; ). By all measures, respiratory compromise was more severe among cases than controls, as shown by the need for mechanical ventilation (OR, 5.7 [95% CI, 0.9‐37.5]), the duration of mechanical ventilation (median, 20 vs 11 days [ ), and subsequent receipt of a tracheostomy (OR, 1.9 [95% CI, 0.9‐3.7]). Cases were also more likely to have undergone bronchoscopy (OR, 5.4 [95% CI, 2.03‐14.5]) and had more bronchoscopic procedures performed (median number, 4.4 vs 2.2; ). Although most patients in both groups had some type of indwelling venous catheter, temporary and permanent vascular lines were still associated with B. cepacia bacteremia (OR, 18.0 [95% CI, 1.2‐268.5]). Abdominal surgery was associated with B. cepacia bacteremia (OR, 3.1 [95% CI, 1.07‐9.1]), but, surprisingly, percutaneous endoscopic gastrostomy (PEG) placement was associated with a decreased risk for B. cepacia bacteremia (OR, 0.3 [95% CI, 0.1‐0.9]). No association was found between exposure to a particular class of antimicrobials or glucocorticoids and the development of B. cepacia bacteremia.

Table 2. 
Table 2.  Association Between Hospital Interventions and Procedures and the Risk of Burkholderia cepacia Bacteremia Among Case Patients and Control Patients

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Multivariate analysis revealed that multiple bronchoscopic procedures (OR, 7.99 [95% CI, 1.60‐39.95]), tracheostomy at the time of B. cepacia bacteremia (OR, 7.68 [95% CI, 2.12‐27.85]), presence of an indwelling central venous catheter (OR, 21.72 [95% CI 1.8‐261.78]), end‐stage renal disease that required hemodialysis (OR, 3.77 [95% CI, 1.17‐12.18]), and recent abdominal surgery (OR, 6.58 [95% CI, 1.03‐41.91]) were independently associated with the development of B. cepacia bacteremia (Table 3). In multivariable analysis, ICU patients with PEG tubes remained at decreased risk for developing B. cepacia bacteremia (OR, 0.11 [95% CI, 0.02‐0.65]).

Table 3. 
Table 3.  Significant Risk Factors for Burkholderia cepacia Complex Bacteremia, by Multivariable Logistic Regression Analysis

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Antimicrobial susceptibility testing was performed on all 40 bloodstream isolates. Drugs with activity against the greatest number of isolates were ceftazidime (37 isolates [93%]) and trimethoprim‐sulfamethoxazole (38 [95%]). Fewer isolates were susceptible to imipenem‐cilastin (5 isolates [13%]), piperacillin‐tazobactam (13 [33%]), and ciprofloxacin (19 [48%]). All isolates were resistant to aminoglycosides, which is consistent with the inherent properties of B. cepacia complex.

Discussion

 

We experienced a prolonged outbreak of B. cepacia bacteremia at our institution that involved hospitalized patients with and patients without CF. Along with our previous report,18 these data represent one of the largest evaluations of B. cepacia complex bacteremia among patients without CF. The investigation and analysis of this outbreak identified several independent predictors of B. cepacia bacteremia.

Because B. cepacia complex colonizes the respiratory tract, it is not surprising that factors associated with compromised respiratory status, including the need for tracheostomy and multiple bronchoscopic procedures, emerged as significant risk factors for B. cepacia bacteremia. These findings are markers for severely ill patients who require frequent healthcare interventions and invasive procedures and have multiple exposures to resistant nosocomial organisms. Nosocomial bacteria are frequently transmitted to patients via the contaminated hands of healthcare workers, equipment, or reagents. Although contaminated bronchoscopic equipment has been documented as a cause of nosocomial outbreaks of tuberculosis and Pseudomonas aeruginosa infection,25‐29 the persistence of infection after terminal cleaning of our instruments, the use of multiple bronchoscopes among case patients, and the diversity of strains recovered from study patients are not supportive of an equipment point source for this outbreak.

In this study, abdominal surgery was a significant risk factor for B. cepacia bacteremia. However, we also demonstrated a protective effect of PEG tube insertion. Taken together, these findings suggest that aspiration, especially among patients who received postoperative ventilatory assistance, may contribute to B. cepacia bacteremia. In addition to decreasing aspiration, PEG tube insertion may have decreased exposure to nasogastric tubes, which limits respiratory colonization by B. cepacia complex and subsequent bacteremia.

The presence of an indwelling vascular catheter was significantly associated with B. cepacia bacteremia. This finding is consistent with previous data concerning the risk for bloodstream infections with B. cepacia complex and other organisms.30‐36 The association of end‐stage renal disease and bacteremia with B. cepacia complex and other nosocomial organisms has also been demonstrated elsewhere. Both the immunosuppressed state of dialysis patients and the requirement for vascular access likely contribute to the increased risk of bacteremia among this population.36,37

Although the overall outbreak was polyclonal, 2 strains of B. cenocepacia constituted most of the nosocomial cases of infection in ICU patients without CF. We were not able to trace either of these clones to an environmental source. Furthermore, the spatiotemporal pattern was more consistent with cross‐transmission by healthcare workers. This assumption is supported by the fact that implementation of strict isolation procedures curtailed the outbreak. Other investigators have also described B. cepacia complex pneumonia outbreaks among hospitalized patients without CF and without an apparent point source in which the institution of strict infection control measures limited spread.15‐17,35

Previous data suggest that, among patients with CF, certain B. cenocepacia strains may be associated with cross‐transmission and higher mortality rates among infected patients before and after lung transplantation.2,3,7,9,13 There is a growing body of literature documenting B. cepacia complex as a cause of nosocomial outbreaks among patients without CF and without a clear point source.15‐18,35 Prior data and this study implicate B. cenocepacia particularly as causing serious disease in this population.18,35,38 Whether these associations are an epidemiological phenomenon or in fact related to differences in virulence remains to be determined. Further research and effective models are required to better delineate these possibilities. Although we were unable to document a specific patient source for the outbreak, the increase in cases of nosocomial B. cepacia bacteremia paralleled the increase in the number of colonized patients who underwent lung transplantation and suggests transmission from the CF transplantation population to other ICU populations.

This study illustrates the importance and efficacy of infection control practices in controlling B. cepacia spread in hospital settings. After the implementation of contact isolation for all patients, irrespective of CF status, who were colonized or infected with B. cepacia complex, spread of B. cepacia complex decreased at our hospital. These measures have been maintained at our hospital, and since April 2002 (the end of the study period), there have been 6 cases of B. cepacia bacteremia in patients with CF and 6 cases in patients without CF.

Our study has several limitations. Overall, the outbreak was difficult to investigate because it occurred during a long period. Furthermore, we only extensively studied B. cepacia bacteremia and not infection or colonization at other body sites. Therefore, we have characterized only a small burden of the overall problem. Furthermore, our environmental investigation was limited and only occurred after the severity of outbreak had already peaked and was decreasing.

Species within the B. cepacia complex are important emerging nosocomial pathogens in both the CF and non‐CF populations. Infection control practices, including contact isolation, are useful in limiting the spread of virulent, transmissible clones of B. cepacia complex.

Acknowledgments

 

Financial support. Durham Veterans Affairs Medical Center Health Services Research and Development Field Program (C.W.W.) and Cystic Fibrosis Foundation (J.J.L.).

Potential conflicts of interest. All authors report no conflicts of interest relevant to this article.

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  • Presented in part: 41st annual meeting of the Infectious Diseases Society of America; San Diego; October 2003 (abstract 577).

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