Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Influence of Delayed Receipt of Effective Antimicrobial Therapy on Clinical Outcome

Clinical Infectious Diseases, Sep 2003

Among the nosocomial pathogens, Pseudomonas aeruginosa is recognized as a major cause of morbidity and mortality. Data on 136 patients with P. aeruginosa bacteremia were retrospectively analyzed to evaluate risk factors for mortality. The median age of the patients was 55 years (range, 15–85 years), 78.7% of the cases were hospital-acquired, and the 30-day mortality rate was 39% (53 of 136 patients). Multivariate analysis demonstrated that risk factors for mortality included severe sepsis, pneumonia, delay in starting effective antimicrobial therapy, and an increasing APACHE II score (all P values <.05). In 123 of the 136 patients (excluding 13 patients treated with inadequate definitive antibiotics), 30-day mortality was 27.7% (13 of 47 patients) in the group of patients who received initially effective empirical antimicrobial therapy, and 43.4% (33 of 76) in the group of patients who received delayed effective antimicrobial therapy (P = .079). There was a trend toward higher mortality as the length of delay increased. Delay in starting effective antimicrobial therapy for P. aeruginosa bacteremia tended to be associated with higher mortality.

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Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Influence of Delayed Receipt of Effective Antimicrobial Therapy on Clinical Outcome

Cheol-In Kang 0 Sung-Han Kim 0 Hong-Bin Kim 0 Sang-Won Park 0 Young-Ju Choe 0 Myoung-don Oh 0 Eui-Chong Kim 0 1 Kang-Won Choe 0 0 Received 28 October 2002; accepted 25 April 2003; electronically published 23 August 2003. Presented in part: 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy , San Diego, CA , September 2002 (abstract K-85). Seoul National University College of Medicine , 28 Yongon-dong Chongno-gu, Seoul, 110-744, Republic of Korea 1 Laboratory Medicine, Seoul National University College of Medicine , Seoul, Republic of Korea Among the nosocomial pathogens, Pseudomonas aeruginosa is recognized as a major cause of morbidity and mortality. Data on 136 patients with P. aeruginosa bacteremia were retrospectively analyzed to evaluate risk factors for mortality. The median age of the patients was 55 years (range, 15-85 years), 78.7% of the cases were hospital-acquired, and the 30-day mortality rate was 39% (53 of 136 patients). Multivariate analysis demonstrated that risk factors for mortality included severe sepsis, pneumonia, delay in starting effective antimicrobial therapy, and an increasing APACHE II score (all P values !.05). In 123 of the 136 patients (excluding 13 patients treated with inadequate definitive antibiotics), 30-day mortality was 27.7% (13 of 47 patients) in the group of patients who received initially effective empirical antimicrobial therapy, and 43.4% (33 of 76) in the group of patients who received delayed effective antimicrobial therapy (P p .079). There was a trend toward higher mortality as the length of delay increased. Delay in starting effective antimicrobial therapy for P. aeruginosa bacteremia tended to be associated with higher mortality. - Pseudomonas aeruginosa is an important nosocomial pathogen, especially in individuals with neutropenia and those who are immunocompromised [13]. During the 1960s, when P. aeruginosa first emerged as a common cause of gram-negative bacteremia and effective antipseudomonal antibiotics were unavailable, the mortality rate was 90% [4, 5]. As antipseudomonal antibiotics were introduced, treatment outcomes in cases of P. aeruginosa bacteremia improved. However, P. aeruginosa continues to be a serious cause of infection, associated with a high rate of morbidity and a mortality rate ranging from 18% to 61% [611]. Pseudomonas infection is clinically indistinguishable from other forms of gram-negative bacterial infection. For this reason, patients with Pseudomonas infection might receive empirical antibiotics that are inactive against Pseudomonas, especially before antibiotic susceptibility results become available [1214]. It has been well documented that inappropriate antimicrobial therapy is associated with adverse outcome [911], but little information exists about whether ineffective empirical antimicrobial therapy given during the first 4872 h, when results of microbiological testing are unavailable, affects the outcome adversely. We aimed to evaluate the risk factors for mortality and to determine the influence of delayed effective antimicrobial therapy on the clinical outcome of patients with P. aeruginosa bacteremia. PATIENTS AND METHODS Patients. A review was conducted of the clinical microbiological laboratory results and medical records of 150 individuals diagnosed from January 1998 to December 2001 at Seoul National University Hospital (Seoul, Republic of Korea), a 1500-bed tertiary care university hospital and referral center. This review identified 145 patients with clinically significant P. aeruginosa bacteremia. Only the first bacteremic episode for each patient was included in the analysis. Nine patients with cases of polymicrobial bacteremia were excluded, and, therefore, 136 patients were enrolled in this study. Microbiological testing. Identification of P. aeruginosa was performed with a Vitek-GNI Card (bioMerieux), and antibiotic susceptibility testing was performed using the disk diffusion method, following the recommendations of the NCCLS [15, 16]. Study design and data collection. A retrospective cohort study was conducted to evaluate the risk factors for mortality and the influence of a delay in receiving effective antimicrobial therapy on patient outcome. Thirty-day mortality was the main outcome measurement. We reviewed the medical records of patients retrospectively. Data collected included: age; sex; underlying disease; source of bacteremia; severity of illness (as calculated by the APACHE II score [17]); duration of hospital stay before bacteremia; antimicrobial therapy regimen; the time of administration of antibiotics and blood culture sample acquisition; and antimicrobial therapy during the 30 days prior to bacteremia. The presence of the following comorbid conditions was documented: neutropenia; presentation with septic shock; receipt of intensive care unit (ICU) care; use of an immunosuppressive agent within 30 days prior to bacteremia; history of prior corticosteroid use; being in a postoperative state; and history of an invasive procedure within 72 h prior to bacteremia. In addition, the presence of a central venous catheter, urinary catheter, or mechanical ventilation was noted. The time at which antibiotics were administered and blood samples for culture were obtained was evaluated. Antimicrobial therapy regimens. Patients with cancer who were febrile and neutropenic were initially treated with an empirical regimen that consisted of an antipseudomonal penicillin and tobramycin. After 4872 h, the antibiotic regimen was modified, depending on the clinical response of the patient and/or the susceptibility of the isolated organism. If there was a favorable response, the initial antibiotic regimen was continued for most of the patients. However, if the response was unfavorable, it was recommended that empirical antibiotics be switched to broad-spectrum cephalosporin and amikacin. The patients with P. aeruginosa bacteremia received antimicrobial therapy for 12 weeks. The patients who had secondary complications, such as abscess, received prolonged therapy for 14 weeks and, if needed, surgical drainage. This study was retrospective; therefore, the patients physicians, not the researchers, decided the antimicrobial therapy regimens. Definitions. The presence of P. aeruginosa bacteremia was defined as the identification of P. aeruginosa in a blood culture [16]. Clinically significant P. aeruginosa bacteremia was defined as 1 positive blood culture and clinical features compatible with sepsis. Empirical administration of antimicrobial therapy was classified as effective initial antimicrobial therapy or delayed effective antimicrobial therapy according to the initial antimicrobial therapy regimens that were administered within 24 h after blood culture samples were obtained. Effective initial antimicrobial therapy was defined as therapy administered within 24 h after blood culture samples were obtained and consisting of an initial empirical regimen containing antipseudomonal antibiotics (such as antipseudomonal penicillin, ceftazidime, carbapenem, or fluoroquinolone) that were later proved to be active in vitro against blood isolates of P. aeruginosa. Delay in effective antimicrobial therapy was defined as the administration of empirical antibiotics ineffective against the P. aeruginosa isolate prior to the availability of the results of antibiotic susceptibility testing, with a delay of 124 h after blood culture samples were obtained. Regardless of the empirical therapy, effective definitive antimicrobial therapy was defined as treatmentafter determining the antibiotic susceptibility of the blood isolateswith an antibiotic regimen containing antipseudomonal antibiotics active in vitro against the blood isolates. The length of the delay of effective antimicrobial therapy was defined as the interval between the time the blood culture samples were obtained and the time effective antibiotics were administered. Nosocomially acquired infection was defined as the following: infection that occurred 148 h after hospital admission; infection that occurred !48 h after admission to hospital in patients who had been hospitalized within the 2 weeks prior to admission; or infection that occurred 148 h after hospital admission in patients who had been transferred from an outside hospital or nursing home [18]. Nosocomial bloodstream infections (and other nosocomial infections) were defined according to the criteria proposed by the Centers for Disease Control and Prevention [19]. Neutropenia was defined as an absolute neutrophil count of !500 cells/mm3. Septic shock was defined as sepsis associated with evidence of organ hypoperfusion and either a systolic blood pressure of !90 or 130 mm Hg less than the baseline value or a requirement for the use of vasopressor to maintain blood pressure [20]. Statistical analysis. The x2 test, Fishers exact test, or linear-by-linear association were used to compare categorical variables, as needed. To determine independent risk factors for mortality, a multiple logistic regression model was used to control for the effects of confounding variables. The results of logistic regression analyses were reported as adjusted ORs with 95% CIs. All P values were 2-tailed, and P ! .05 was considered to indicate statistical significance. The SPSS for Windows, version 10.0 (SPSS), software package was used for this analysis. Demographic and clinical characteristics. Data obtained from a total of 136 patients with P. aeruginosa bacteremia were analyzed. Of these patients, 66.2% were men, and the median age for all patients was 55 (range, 1585) years. The percentage of P. aeruginosa infections among all bloodstream infections diagnosed during the study period was 3.8%. Demographic data, underlying diseases, and risk factors for infection are shown in table 1. The most common underlying disease was solid tumor (58 [42.6%] of 136) and the most common primary site of infection, excluding patients for whom the primary site of infection was unknown (42 [30.9%] of 136), was the pancreaticobiliary tract (32 [23.5%] of 136); 28.7% of the patients had neutropenia; and 78.7% of the infections were nosocomial (table 1). Of 29 patients with community-acquired bloodstream infection, 15 (51.7%) had a solid tumor and 6 (20.7%) had a hematologic malignancy. Of 21 patients with a solid tumor or hematologic malignancy, 11 (52.4%) were febrile neutropenic patients. Of 32 patients with pancreaticobiliary tract infection, 23 (71.9%) had a transhepatic biliary drainage device and 6 (18.8%) had undergone endoscopic retrograde cholangiopancreatography (ERCP) within 72 h prior to the onset of Pseudomonas bacteremia. However, 3 of the 32 patients with pancreaticobiliary tract infection had no drainage devices and had not undergone ERCP. On the basis of antimicrobial susceptibility, the date of bacteremia, and the wards of acquisition of organisms, there was no evidence of clonal spread. Clinical outcomes and risk factors for mortality. The 30day mortality rate among all patients was 39% (53 of 136 patients). Among nonneutropenic patients, the mortality rate was 39.2% (38 of 97 patients), and, among neutropenic patients, it was 38.5% (15 of 39). Among the febrile neutropenic patients, the 30-day mortality rate was 15.8% among leukemia patients (3 of 19 patients) and 60% among nonleukemic patients (12 of 20). Forty-three patients received monotherapy and 93 patients received combination therapy. There was no significant difference between the mortality rate among patients receiving monotherapy and the rate among those receiving combination therapy (34.9% vs. 40.9%; P p .51). The distribution of antipseudomonal drugs used as definitive antimicrobial therapy in this study population is as follows: piperacillin, 21.3% of patients; ceftazidime, 34.6%; ciprofloxacin, 18.4%; and imipenem, 8.8%. The 30-day mortality rate among the patients with pancreaticobiliary tract infection was 22.2% (7 of 32 patients), which was relatively low. Of these 7 patients, 24% of those in the bTable 1. Demographic and clinical characteristics of patients with Pseudomonas aeruginosa bacteremia. Soft-tissue Catheter-related 55 (15 85) NOTE. Values are reported as no. (%) of patients unless otherwise indicated. a The site of infection was either documented or presumed on the basis of clinical findings. lactam therapy group (6 of 25) and 14.3% of those in the quinolone therapy group (1 of 7) died. There was no significant difference in the mortality rates of these 2 groups (P p 1.00). By univariate analysis, variables significantly associated with mortality included receipt of ineffective definitive antimicrobial therapy, receipt of ineffective empirical antimicrobial therapy, presentation with septic shock, receipt of ICU care, having pneumonia, and having an increasing APACHE II score (all P ! .05). No significant difference was observed in the mortalities associated with community-acquired infections and nosocomial infections (P p .897). Neutropenia was not associated with a higher mortality (P p .938) (table 2). Multivariate analysis using a logistic regression model demonstrated that the independent risk factors for 30-day mortality were: presentation with septic shock (OR, 45.37; 95% CI, 10.19 201.93; P ! .001), having pneumonia (OR, 11.43; 95% CI, 2.60 50.19; P p .001), receipt of ineffective definitive antimicrobial therapy (OR, 11.68; 95% CI, 2.5154.38; P p .002), receipt of ineffective empirical antimicrobial therapy (OR, 4.61; 95% CI, 1.1818.09; P p .028), and having an increasing APACHE II score (1-point increments; OR, 1.31; 95% CI, 1.151.50; P ! .001) (table 3). Influence of delayed effective antimicrobial therapy on mortality. To evaluate the influence of delayed effective antimicrobial therapy on mortality, data from 123 of 136 patients (excluding 13 patients who received inappropriate definitive antimicrobial therapy) were analyzed. The mean duration ( SD) of the delay in effective antimicrobial therapy was 3.5 1.28 days. The 30-day mortality rate in the delayed effective treatment group was 43.4% (33 of 76 patients), whereas that in the effective empirical treatment group was 27.7% (13 of 47). The former group tended to have a higher mortality rate than the latter group (P p .079). Before performing a subgroup analysis, we excluded a patient Table 2. Thirty-day mortality rate among 136 patients with Pseudomonas aeruginosa bacteremia. Effective Ineffective Effective Immunosuppressive treatmentb Yes Yes No. of deaths/ no. of patients (%) 32/108 (29.6) 21/28a (75) 13/47 (27.7) 40/89 (44.9) 11/29 (37.9) 42/107 (39.3) 38/97 (39.2) 15/39 (38.5) 25/103 (24.3) 28/33 (84.8) 43/122 (35.2) 10/14 (71.4) 36/114 (31.6) 17/22 (77.3) 13/51 (25.5) 30/71 (42.3) 10/14 (71.4) OR (95% CI) 7.13 (2.7618.42) 2.14 (1.004.58) 1.06 (0.452.46) 0.97 (0.452.08) 17.47 (6.0950.07) 4.59 (1.3615.52) 7.36 (2.5221.53) 3.40 (0.8114.25) 1.81 (0.814.03) a This group includes 13 patients who received inadequate definitive antibiotics and 15 patients who received ineffective empirical antibiotics and died before the pathogen was identified. b Excluding use of corticosteroids. Table 3. Independent risk factors for mortality for 136 patients with Pseudomonas aeruginosa bacteremia. DISCUSSION Ineffective definitive antibiotic treatment Ineffective empirical antibiotic treatment Presentation with septic shock Pneumonia Increasing APACHE II scorea OR (95% CI) 11.68 (2.5154.38) 4.61 (1.1818.09) 45.37 (10.19201.93) 11.43 (2.6050.19) 1.31 (1.151.50) NOTE. Multivariate analysis using logistic regression model. a Per 1 point increase in score. who had been treated with inappropriate definitive antibiotics from the group of 39 neutropenic patients. Of the 38 patients who received appropriate definitive antimicrobial therapy, 26 (68.4%) had received appropriate initial empirical antimicrobial therapy against P. aeruginosa and 12 (31.6%) had received inappropriate initial empirical antimicrobial therapy. Of 26 patients who received appropriate initial empirical antimicrobial therapy, 7 (26.9%) died, and, of 12 patients who received inappropriate initial empirical antimicrobial therapy, 7 (58.3%) died (P p .081) (table 4). Of the 97 nonneutropenic patients, 12 patients who had been treated with inappropriate definitive antibiotics were excluded. Of the 85 nonneutropenic patients with appropriate definitive antimicrobial therapy, 21 (24.7%) had received appropriate initial empirical antimicrobial therapy against P. aeruginosa and 64 (75.3%) had received inappropriate initial empirical antimicrobial therapy. Of the 21 patients who had received appropriate initial empirical antimicrobial therapy, 6 (28.6%) died, and, of the 64 patients who had received inappropriate initial empirical antimicrobial therapy, 26 (40.6%) died (P p .323) (table 4). No significant difference in mortality was found between the delayed therapy and nondelayed therapy groups among patients who had pancreaticobiliary tract infection (5 [21.7%] of 23 patients vs. 1 [25%] of 4 patients; P p 1.00) or among those who had soft-tissue infection (3 [50%] of 6 vs. 3 [60%] of 5; P p 1.00) (table 4). The 30-day mortality rates, stratified according to the duration of ineffective antimicrobial therapy, are presented in figure 1. A trend toward higher mortality with increasing length of delay was demonstrated (P p .020, using linear-by-linear association). The percentage of patients with delayed initiation of effective therapy whose therapy was delayed because the organism was resistant to the antipseudomonal drug initially administered was 10.1%. Our study shows that the overall mortality rate of patients infected with Pseudomonas bacteremia was 39%. No significant differences in mortality were evident between neutropenic and nonneutropenic patients. However, among the febrile neutropenic patients, the 30-day mortality rate in patients without leukemia was found to be higher than that in patients with leukemia. Previous studies have demonstrated that the presence of severe underlying disease, pneumonia, septic shock, neutropenia, and surgery are associated with a poor prognosis in cases of infection with P. aeruginosa bacteremia [2, 3, 911]. In the present study, delay in starting effective antimicrobial therapy and inadequate definitive antibiotics were also associated with a poor prognosis. However, subgroup analysis showed that a delay in starting effective antimicrobial therapy was not a significant cause of adverse outcome in nonneutropenic patients. To evaluate the influence of delayed effective antimicrobial therapy on mortality, we analyzed 123 of 136 patients, excluding those that received inappropriate definitive antimicrobial therapy. The delayed treatment group showed a trend toward higher mortality than the effective empirical antimicrobial therapy group, although this difference was not statistically significant (43.4% vs. 27.7%; P p .079). Vidal et al. [10] found no relationship between the adequacy of empirical antimicrobial therapy and mortality. However, in their institute, the length of delay in starting effective antimicrobial therapy was 13 days. They suggested that, if the delay was greater than that observed in their study, the administration of ineffective empirical antibiotics might be associated with a greater risk of death. In the present study, the mean duration of delay in starting effective antimicrobial therapy was 3.5 days, and this longer delay period may have adversely affected clinical outcome. Indeed, a trend toward higher mortality with increasing length of delay was demonstrated in our study. In the report by Fluckiger et al. [21], patients for whom an infectious diseases service was provided received appropriate treatment more often and experienced significantly fewer complications than those for whom one was not provided. Our study demonstrates that, among neutropenic patients with Pseudomonas bacteremia, the mortality rate is higher among those treated with ineffective empirical antibiotics than among those treated with effective antibiotics (7 [26.9%] of 26 vs. 7 [58.3%] of 12; P p .081). Vidal et al. [10] also suggested that mortality among neutropenic patients increases if empirical antibiotics are inactive in vitro against P. aeruginosa. High mortality was found among patients with cases of pneumonia, regardless of the adequacy of empirical antibiotics. P. aeruginosa pneumonia is a fulminant disease and difficult to treat [22, 23], and it may be reasonable to propose that the empirical anti Patient group Neutropenic Non-neutropenic All patients 46/123 (37.4) 14/38 (36.8) 32/85 (37.6) NOTE. Thirteen of the 136 patients in our study group were excluded from this analysis because they received inadequate definitive antimicrobial therapy. Deaths, n/N (%), by antibiotic regimen received Effective empirical antibiotic regimen 13/47 (27.7) Delayed effective antibiotic regimen 33/76 (43.4) 7/26 (26.9) 6/21 (28.6) 7/12 (58.3) 26/64 (40.6) biotic regimen for nosocomial pneumonia be used for cases of P. aeruginosa infection. In the present study, the pancreaticobiliary tract was one of the most common primary sites of Pseudomonas infection. Twenty-three (71.9%) of 32 patients with pancreaticobiliary tract infection caused by P. aeruginosa had a transhepatic biliary drainage device and 6 (18.8%) of 32 had undergone ERCP within the previous 72 h. These findings are consistent with previous studies, which reported that ERCP and transhepatic biliary drainage devices were associated with Pseudomonas infection [2426]. However, no significant mortality differences were found between patients with pancreaticobiliary tract infection who were in the effective empirical antimicrobial therapy group and those in the delayed treatment group. Our data suggest that, if definitive antimicrobial therapy is appropriate, delay in receiving effective antimicrobial therapy might not lead to adverse outcome in patients with pancreaticobiliary tract infection caused by P. aeruginosa. In this study, we demonstrated that delay in receiving appropriate antipseudomonal therapy had an adverse influence on clinical outcome in patients with bloodstream infection caused by P. aeruginosa. Therefore, we suggest that antipseudomonal antibiotics should be considered for the empirical antibiotic regimen, especially if P. aeruginosa infection is prevalent. However, empirical antibiotics for bloodstream infections should be recommended on the basis of the distribution of pathogens in the institution where the regimen is administered. We could not define the degree of prevalence of P. aeruginosa that should trigger a change in the empiric antibiotic treatment. Also, using these results to help derive recommendations for empiric use of antipseudomonal therapy requires knowledge of the likelihood that P. aeruginosa bacteremia is a cause of a particular infection syndrome. Furthermore, the effect of a delay in administering effective antimicrobial therapy might depend on the severity of the underlying diseases and comorbid conditions of the patients. In conclusion, receiving inappropriate antimicrobial therapy, experiencing septic shock, having pneumonia, and having a severe underlying disease were the independent risk factors for mortality. Delay in receiving effective antimicrobial therapy for P. aeruginosa bacteremia tended to be associated with higher mortality, and the mortality rate was higher with an increase in the length of the delay in receiving antimicrobial therapy. It is warranted that the delay of effective antimicrobial therapy should be prevented in cases of bloodstream infection caused by P. aeruginosa. References


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Cheol-In Kang, Sung-Han Kim, Hong-Bin Kim, Sang-Won Park, Young-Ju Choe, Myoung-don Oh, Eui-Chong Kim, Kang-Won Choe. Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Influence of Delayed Receipt of Effective Antimicrobial Therapy on Clinical Outcome, Clinical Infectious Diseases, 2003, 745-751, DOI: 10.1086/377200