| | Incidence, Risk Factors, and Outcomes of Klebsiella pneumoniae BacteremiaAbstract BackgroundAlthough Klebsiella pneumoniae is the second most common cause of Gram-negative bloodstream infections, its epidemiology has not been defined in a nonselected population. We sought to describe the incidence of, risk factors for, and outcomes associated with K. pneumoniae bacteremia. MethodsPopulation-based surveillance for K. pneumoniae bacteremia was conducted in the Calgary Health Region (population 1.2 million) from 2000 to 2007. ResultsA total of 640 episodes of K. pneumoniae bacteremia were identified for an overall annual population incidence of 7.1 per 100,000; 174 (27%) were nosocomial, 276 (43%) were healthcare-associated community onset, and 190 (30%) were community acquired. Elderly patients and men were at highest risk for K. pneumoniae bacteremia. Dialysis, solid-organ transplantation, chronic liver disease, and cancer were the most important risk factors for acquiring K. pneumoniae bacteremia. Rates of resistance to trimethoprim/sulfamethoxazole increased significantly during 2000 to 2007. The case fatality rate was 20%, and the annual population mortality rate was 1.3 per 100,000. Increasing age, nosocomial acquisition, non-urinary and non-biliary focus of infection, and several comorbid illnesses were independently associated with an increased risk of death. ConclusionThis is the first population-based study to document the major burden of illness associated with K. pneumoniae bacteremia and identifies groups at increased risk of acquiring and dying of these infections. Klebsiella pneumoniae is the second most common cause (behind Escherichia coli) of community- and hospital-acquired Gram-negative bloodstream infection.1, 2, 3 K. pneumoniae bloodstream infections usually arise as a complication of focal urinary, gastrointestinal, or respiratory tract infections, although occasionally they can arise without a definable source.4 The importance of K. pneumoniae as an invasive pathogen seems to be increasing. In the past 2 decades, highly invasive hypermucoid strains associated with liver abscesses and septic metastasis have been described and have emerged as a leading cause of pyogenic liver abscesses in several Asian countries.5, 6, 7, 8 In addition, the recent years also have witnessed increasing rates of antimicrobial resistance in K. pneumoniae, most notably strains producing extended spectrum b-lactamases (ESBL).9 Although several hospital-based studies have noted a high rate of occurrence of comorbid illnesses10, 11, 12, 13 and a case fatality rate of 20% to 40%,3, 10, 12, 13, 14 the mortality rate and risk factors for acquiring and dying of K. pneumoniae bacteremia have not been defined in nonselected population. Clinical Significance•Dialysis, solid-organ transplantation, chronic liver disease, and cancer are the most important risk factors for acquiring Klebsiella pneumoniae bacteremia. •Increasing age, nosocomial acquisition, non-urinary and non-biliary focus of infection, heart disease, stroke, alcoholism, and rheumatoid arthritis are risk factors for death. •Population incidence and mortality rates are 7.1 per 100,000 per year and 1.3 per 100,000 per year, respectively. To best define the occurrence and determinants of an infectious disease, population-based studies are needed. Such designs enable the determination of population incidence and mortality rates by including all cases occurring within a defined population to minimize selection bias. The objective of this study was to conduct population-based surveillance in a large Canadian health region during 2000 to 2007 to define the incidence, risk factors for acquisition, and outcomes of K. pneumoniae bacteremia. Materials and Methods  Study Population The Calgary Health Region (CHR) administers virtually all medical and surgical care to the residents of the cities of Calgary and Airdrie and a large surrounding area (population 1.2 million) in the Province of Alberta, Canada. Only patients requiring acute liver, heart, or lung transplantation surgery are routinely referred elsewhere. All persons who resided in the CHR and who developed bacteremic K. pneumoniae infection between January 1, 2000, and December 31, 2007 were included in the study. The Conjoint Health Research Ethics Board at the University of Calgary and CHR approved the study. Study Protocol An active, retrospective, population-based surveillance cohort design was used. Surveillance for bacteremic K. pneumoniae infections was conducted by Calgary Laboratory Services, a regional laboratory system that receives more than 95% of all blood samples submitted for culture from hospitals, nursing homes, and clinics in the CHR. Further clinical and outcome details were obtained on all patients admitted to any of the 4 major acute care hospitals (representing ≥95% CHR admissions) using data available from the regional corporate data warehouse. Definitions Bacteremic K. pneumoniae infection was defined by its isolation from 1 or more sets of aseptically obtained blood culture bottles. Clinical isolates were cultured, confirmed as K. pneumoniae, and tested for antimicrobial susceptibility by standard techniques. At Calgary Laboratory Services, all K. pneumoniae isolates are routinely screened for ESBL production as previously described.15, 16 The presence or absence of K. pneumoniae cultures obtained from non-blood sites within ±48 hours of the index incident blood culture draw also was assessed. Incident cases were defined by the new first isolation of K. pneumoniae from the blood of a CHR resident; repeated isolation within 365 days after the first isolation was deemed to represent the same incident infection. Residency status was established using the 2003 boundaries of the CHR.17 Nosocomial bacteremias were those in which the first positive culture was obtained 48 hours or more after hospital admission or within 48 hours of discharge from the hospital. Community-onset infections were those in which the first positive culture was obtained less than 48 hours after hospital admission or more than 48 hours after discharge from the hospital. At least one of the following was true for a patient with healthcare-associated, community-onset K. pneumoniae bacteremia: attended a hospital clinic or emergency department within the previous 5 to 30 days before bloodstream infection; admitted to CHR acute care hospital for 2 or more days within the previous 90 days before bloodstream infection; a sample was submitted from a nursing home or long-term care facility; or received outpatient hemodialysis. Data on dialysis were not available for children, in which case data were assumed to be absent. Community-acquired infections were those community-onset bacteremias that were not healthcare associated. Statistical Analysis Analysis was performed using Stata version 9.0 (Stata Corp, College Station, Tex). Non-normally distributed variables were reported as medians with interquartile ranges (IQRs) and compared using the rank-sum test for pairs or median test for multiple groups. Differences in proportions among categoric data were assessed using Fisher's exact test for pairwise comparisons and the χ2 test for multiple groups. The incidence of bacteremic K. pneumoniae infection was calculated by dividing the number of incident cases by the regional population. Population-based risk factors for developing K. pneumoniae bacteremia were quantified by dividing the incidence of these infections among those with a given factor by those without the factor. Regional demographic data were used to determine the population at risk for assessment of age and gender.18 For other potential risk factors, the population at risk was ascertained or estimated using local patient registry data,19, 20, 21 regional or Canadian survey data,22, 23, 24, 25, 26, 27, 28, 29 or published North American epidemiology studies.30, 31, 32, 33, 34 Risks were expressed as incidence rate ratios and reported with 95% confidence intervals. A logistic regression model was developed to assess independent factors associated with in-hospital death. Factors found to be significant at the P<.1 level in univariate analysis were included in the initial model, and backward stepwise variable elimination was then performed to develop the final model. Model calibration was assessed using the Hosmer–Lemeshow goodness-of-fit test, and discrimination was assessed using the area under the receiver operating characteristic curve. For all statistical comparisons, a P value less than .05 represented statistical significance. Results During the 8-year study, 640 incident bacteremic K. pneumoniae infections occurred among 633 CHR residents; 6 patients had 2 incident episodes, and 1 patient had 3 incident episodes. Basic demographic (age, gender, residency) and microbiologic data were available for all patients, and further clinical and outcome details were available for the 584 of 640 incident cases (91%) managed at 1 of the 4 major acute care centers in the CHR. Among the 640 incident bacteremic K. pneumoniae infections, 174 (27%) were classified as nosocomial, 276 (43%) were classified as healthcare associated, and 190 (30%) were classified as community acquired. Nosocomial infections represented a rate of 0.2 per 1000 total hospital discharges and 0.3 per 1000 hospital discharges for which admission to the hospital was more than 48 hours. Incidence The annual incidence of bacteremic infection was 7.1 per 100,000 population. Moderate variability in the year-to-year incidence was observed during the 8 years of the study (Figure 1). The median patient age was 68.9 years (IQR, 53.0-79.3 years) and was significantly (P=.001) lower for patients with nosocomial (62.9; IQR, 48.4-77.0 years) compared with community-acquired (69.8; IQR, 54.6-78.3 years) and healthcare-associated (70.7; IQR, 55.0-81.1 years) infections. The risk for development of K. pneumoniae bacteremia was closely related to age, with the elderly at highest risk (Figure 2). Of the 640 incidence cases, 370 (58%) occurred in men (rate ratio, 1.4; 95% confidence interval,, 1.2-1.6; P=.0001), with the excess risk in men most notable in the elderly (Figure 2). Clinical Characteristics and Risk Factors Among the 584 patients with detailed clinical information available for analysis, a focal source of K. pneumoniae infection was recorded in 408 patients (70%) (Table 1). The overall median length of stay was 11.0 days (IQR, 5.9-27.4 days) and was significantly (P<.0001) longer for nosocomial (30.1; IQR, 16.7-57.1 days) compared with healthcare-associated (8.1; IQR, 4.9-17.7 days) and community-acquired (7.8; IQR, 4.6-11.9 days) infections. The time from admission to development of nosocomial bacteremia was a median of 11.4 days (IQR, 4.9-23.0 days). | | |  | Source of Infection | Median Age | Nosocomially Acquired (%) N=174 | Health Care Associated (%) N=244 | Community Acquired (%) N=166 | Total (%) N=584 | |
|---|
| Primary bacteremia | 60.7 | 90(51) | 66(38) | 18(10) | 176(30) | | | Biliary tract | 73.3 | 13(11) | 47(40) | 56(48) | 116(19) | | | Genitourinary tract | 70.8 | 21(14) | 73(50) | 53(36) | 147(25) | | | Intra-abdominal | 59.7 | 20(33) | 23(38) | 16(27) | 59(10) | | | Pancreatitis | 78.1 | 4(40) | 2(20) | 4(40) | 10(1.7) | | | Pneumonia | 69.6 | 20(38) | 24(46) | 8(15) | 52(8) | | | Skin or soft tissue | 74.0 | 3(50) | 3(50) | 0 | 6(1) | | | Primary liver abscess | 67.1 | 2(14) | 3(21) | 9(64) | 14(2.3) | | | Central nervous system | 64.1 | 1(33) | 0(0) | 2(66) | 3(<1) | | | Bone | 76.6 | 0(0) | 1(100) | 0(0) | 1(<1) | | | | |
Solid-organ transplantation, chronic liver disease, renal dialysis, and cancer were identified as the most important risk factors for acquiring K. pneumoniae bacteremia (Table 2). Among the 22 transplant recipients (3%), 10 were kidney recipients, 6 were bone marrow recipients, and 6 were liver recipients. Cancer was present in 198 of 584 patients (33%). Gastrointestinal malignancies were the most common, affecting 80 of 584 of all patients (13%): pancreatic cancer in 19, colon cancer in 18, and biliary cancer in 13. Hematologic malignancies affected 49 of 584 patients (8%): acute myelogenous leukemia in 22, non-Hodgkin's lymphoma in 8, acute lymphocytic leukemia in 5, and multiple myeloma in 4. Genital–urinary malignancies affected 38 of 584 patients (6%): prostate cancer in 11 and bladder cancer in 10. The remaining 27 of 584 patients (4%) had lung, central nervous system, breast, skin, thyroid, and unknown primary cancers. Metastatic disease was present in 71 of 198 patients (36%) with cancer, which represents 12% of all patients. | | | | Factor | Age Groupa | No. (%) | RR (95% CI) | P Value | |
|---|
| Dialysis | 20+ | 18(2) | 57.8(34.0-92.1) | <.0001 | | | Chronic liver disease | All | 44(7) | 54.2(38.9-73.8) | <.0001 | | | Organ transplant | All | 16(2) | 43.3(24.5-70.9) | <.0001 | | | Cancer | 20+ | 191(34) | 28.1(23.5-33.6) | <.0001 | | | Diabetes | 12+ | 123(21) | 8.3(6.8-10.2) | <.0001 | | | Multiple sclerosis | All | 14(2) | 7.1(3.9-12.1) | <.0001 | | | Heart disease | 12+ | 127(22) | 6.9(5.6-8.4) | <.0001 | | | Crohn's disease | All | 10(1) | 6.1(2.9-11.3) | <.0001 | | | HIV | All | 2(<1) | 4.9(0.5-17.8) | .0722 | | | Parkinson's disease | 20+ | 7(1) | 3.8(1.5-7.9) | .0036 | | | Stroke | 12+ | 19(3) | 3.4(2.0-5.4) | <.0001 | | | Ulcerative colitis | All | 3(<1) | 2.7(0.5-8.1) | .1197 | | | Systemic lupus erythematosus | 20+ | 5(<1) | 2.4(0.7-5.6) | .0802 | | | Chronic obstructive pulmonary disease | 12+ | 39(6) | 2.3(1.6-3.3) | <.0001 | | | Rheumatoid arthritis | 20+ | 9(1) | 1.6(0.7-3.0) | .1729 | | | Alcoholism | 20+ | 31(5) | 1.4(0.9-2.0) | .0768 | | | Hepatitis B | All | 8(1) | 1.3(0.5-2.7) | .3691 | | | Hepatitis C | All | 6(1) | 1.1(0.4-2.5) | .7047 | | | Asthma | 12+ | 6(1) | 1.1(0.4-2.5) | .7047 | | | Chronic renal disease (not dialysis) | 20+ | 55(9) | 0.7(0.5-0.9) | .0205 | | | | |
Cancer was the most common risk factor among patients with a focal biliary source of infection (30/116 [25%]), intra-abdominal source (15/59 [25%]), or pneumonia (22/52 [42%]). Diabetes was the most common risk factor among patients with a focal genitourinary tract infection (42/147 [28%]) or primary liver abscess (4/14 [28%]). Cancer was more common among patients with nosocomial-acquired and health care-associated infections, with 191 of 418 patients (45%) affected, compared with 7 of 166 patients (4%) with community-acquired infections (P<.0001). Cardiovascular disease occurred more frequently in patients with nosocomial-acquired infections, affecting 51 of 174 patients (29%), compared with patients with health care-associated or community-acquired infections (81/410 [19%]) (P=.012). Alcoholism was more common among patients with nosocomial-acquired infections, affecting 18 of 174 patients (10%), compared with patients with health care-associated or community-acquired infections (13/410 [3%]) (P<.0001). The remaining conditions selected as risk factors were evenly distributed among patients with nosocomial, health care-associated, and community-acquired infections. Microbiology Antimicrobial susceptibility testing results were retrievable for 635 of 640 incident K. pneumoniae blood isolates (99%). Reduced susceptibility (intermediate or resistant) to ampicillin occurred in all 635 isolates (100%), to trimethoprim/sulfamethoxazole in 43 of 635 isolates (6%), to gentamicin in 6 of 635 isolates (<1%), to cefazolin in 60 of 635 (9%) isolates, and to amoxicillin/clavulanate in 33 of 635 (5%) isolates. Among isolates tested, reduced susceptibility to ciprofloxacin occurred in 23 of 590 (3%), to ceftriaxone in 5 of 584 (<1%), to piperacillin in 47 of 555 (8%), to piperacillin/tazobactam in 21 of 591 (3%), and to imipenem in 1 of 433 (<1). ESBL-producing isolates were identified in only 4 of 640 (<1%) incident cases (2 healthcare associated and 2 nosocomially acquired). During the 8 years of study, rates of resistance to all of the antimicrobials did not significantly vary annually other than for trimethoprim/sulfamethoxazole (P=.01). This was due to higher rates: 13 of 91 (14%) in 2003 and 10 of 82 (12%) in 2005, compared with 20 of 437 (5%) collectively during the other years. Discussion Although hospital-based case series and clinicians have recognized that K. pneumoniae is a major cause of bacteremia, our observation of an incidence rate of 7.1 per 100,000 per year is novel, and there are no previous studies for comparison. By placing this rate in context with other important causes of bacteremia, it is lower than for E. coli (30/100,000 per year) and Staphylococcus aureus (28/100,000 per year), comparable to Pseudomonas aeruginosa (6.4/100,000 per year) and Streptococcus milleri group (8.65/100,000 per year), but significantly higher than for other pyogenic Streptococcus species (4.3, 3.1, 0.41, 1.83/100,000 per year combined for groups A, B, C, G, respectively) and other Enterobacteriaceae, such as Serratia species (0.9/100,000 per year) and Hafnia alvei (0.13/100,000 per year).35, 36, 37, 38, 39, 40 Numerous hospital-based studies have suggested several comorbidities as risk factors for the development of K. pneumoniae bacteremia, including diabetes mellitus, cancer, chronic liver disease, and biliary disease.10, 11, 12 In contrast with prior investigations, we found that the risk associated with diabetes mellitus was lower compared with chronic liver disease, cancer, and solid-organ transplantation. These observations may reflect differences in the selected populations studied. It is not surprising that advanced age was associated with an increased risk because this has been a fairly consistent observation across many previous studies and may be reflective of an age-associated increased risk in general for the comorbid illnesses highly associated with increased risk.1, 2, 41 There are no studies in the literature to date to compare the overall annual population mortality rate of 1.3 per 100,000 per year found in our study. Case fatality in hospital-based case series report rates varying from 22% to 46%.3, 10, 12 The widely variable case fatality rates likely reflects the inherent differences in these studies in terms of case mix, selection bias of the referral centers, and geographic distribution. Nosocomial acquisition of infection carried a higher mortality rate compared with community-acquired infection in these studies, which also was found in our study. The overall antibiotic resistance rates of K. pneumoniae isolates in our study are low when compared with observations from other studies worldwide. Hospital-based studies from Taiwan and South Korea have shown rates of resistance to ciprofloxacin ranging from 6% to 21% compared with 3% in our study, to trimethoprim/sulfamethoxazole of 31% compared with 6% in our study, and to ceftriaxone ranging from 8% to 33% compared with less than 1% in our study.10, 11 It is not clear why resistance rates among of K. pneumoniae have remained so low in our region, because we have experienced major problems with many other resistant organisms not limited to metalo-β-lactamase–producing P. aeruginosa, methicillin-resistant S. aureus, and ESBL-producing E. coli. Notably, there were few ESBL-producing isolates in our study (<1%) compared with E. coli isolates from the CHR during a similar time period (2%).39 ESBL-producing isolates of K. pneumoniae have been increasing worldwide. Paterson et al.42 found 85 of 455 (18%) K. pneumoniae bloodstream isolates detected in 7 countries produced the ESBL enzyme. ESBL rates have reached as high as 50% of all K. pneumoniae isolates, as was found in several eastern European countries in 2000.43 The distinctive syndrome of K. pneumoniae bacteremia in association with liver abscesses has been well described in several Asian countries; however, there are few reports outside of Asia.44 Our study identified 14 incident cases of bacteremia associated with primary liver abscesses, including 4 diabetic patients and a majority of community-acquired cases. Of the 2 nosocomial cases, 1 was diagnosed 4 days after admission and may have truly represented a community-acquired case, whereas the other case was first isolated 1 month after admission and was clearly of nosocomial acquisition. We did not have adequate data to assess ethnicity in these patients or whether they might have recently traveled to Asia. These cases were distributed evenly over the study duration, and there was no significant difference in their antimicrobial susceptibility profile compared with other cases. The case fatality in this patient group (1/14 [7%]) was less than the overall case fatality rate (20%). The capsular serotypes were not determined for these isolates because the serum is not routinely available for testing. Studies from Asia have shown serotypes 1 and 2 to be the most commonly identified serotypes involved in this syndrome.5, 6, 7, 8 Study Limitations Several study limitations warrant discussion. Only cases of K. pneumoniae infection associated with positive blood cultures were included in the study. Patients with significant infections who may have been bacteremic but who did not have blood samples submitted for culture were not included in the study; as a result, the reported incidence of K. pneumoniae bacteremia is likely a conservative estimate of the burden of invasive disease. Only a retrospective analysis was used to assess clinical features, and patients were not interviewed or clinically examined at the time of the study to determine the source of infection. Therefore, the number of cases of primary bacteremia with no identified source is most likely an overestimate of the true number. Finally, we did not assess certain clinical features and potential risk factors for acquisition, such as severity of disease, intensive care intervention, central venous catheter access, and indwelling bladder catheter use. Inclusion of these variables would further improve the predictive capacity of disease acquisition and mortality. Conclusions This is the first investigation to define the burden of disease and risks for morbidity and mortality associated with K. pneumoniae bacteremia on a large, population-based scale. Several different factors were found to be associated with a significantly increased risk of acquiring and dying of these infections. These data demonstrate the importance of K. pneumoniae as an invasive pathogen and support ongoing surveillance efforts aimed at tracking their occurrence and designing means of reducing their impact. Acknowledgments We thank Sansira Seminowich, Southern Alberta Transplant Program, Sophia Niu, Quality Safety and Health Information, and Marilyn Greene, Health Information Reporting, for providing transplant and hospital admission and discharge data. References 1. 1Skogberg K, Lyytikainen O, Ruutu P, et al. Increase in bloodstream infections in Finland, 1995-2002. Epidemiol Infect. 2008;136:108–114. 2. 2Uslan DZ, Crane SJ, Steckelberg JM, et al. Age- and sex-associated trends in bloodstream infection: a population-based study in Olmsted County, Minnesota. Arch Intern Med. 2007;167:834–839. MEDLINE |
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44. 44Ko WC, Paterson DL, Sagnimeni AJ, et al. Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical patterns. Emerg Infect Dis. 2002;8:160–166. MEDLINE a Department of Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada b Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada c Department of Critical Care Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada  Requests for reprints should be addressed to Kevin B. Laupland, MD, MSc, FRCPC, Room 719, North Tower, Foothills Medical Centre, 1403 29th Street NW, Calgary, Alberta, Canada T2N 2T9
Funding: This study was funded in part by an unrestricted research grant from Pfizer Canada. The authors had complete autonomy of the design, acquisition, analysis, and reporting of the study. Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript. Authorship: All authors had access to the data and played a role in writing this manuscript. PII: S0002-9343(09)00524-5 doi:10.1016/j.amjmed.2009.03.034 © 2009 Elsevier Inc. All rights reserved. | |
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