Abstract
Infections due to multidrug-resistant (MDR) Pseudomonas aeruginosa are increasing. The aim of our study was to evaluate the influences of appropriate empirical antibiotic therapy and multidrug resistance on mortality in patients with bacteremia due to P. aeruginosa (PAB). Episodes of PAB were prospectively registered from 2000 to 2008. MDR was considered when the strain was resistant to ≥3 antipseudomonal antibiotics. Univariate and multivariate analyses were performed. A total of 709 episodes of PAB were studied. MDR PAB (n = 127 [17.9%]) was more frequently nosocomial and associated with longer hospitalization, bladder catheter use, steroid and antibiotic therapy, receipt of inappropriate empirical antibiotic therapy, and a higher mortality. Factors independently associated with mortality were age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002 to 1.033), shock (OR, 6.6; 95% CI, 4 to 10.8), cirrhosis (OR, 3.3; 95% CI, 1.4 to 7.6), intermediate-risk sources (OR, 2.5; 95% CI, 1.4 to 4.3) or high-risk sources (OR, 7.3; 95% CI, 4.1 to 12.9), and inappropriate empirical therapy (OR, 2.1; 95% CI, 1.3 to 3.5). To analyze the interaction between empirical therapy and MDR, a variable combining both was introduced in the multivariate analysis. Inappropriate therapy was significantly associated with higher mortality regardless of the susceptibility pattern, and there was a trend toward higher mortality in patients receiving appropriate therapy for MDR than in those appropriately treated for non-MDR strains (OR, 2.2; 95% CI, 0.9 to 5.4). In 47.9% of MDR PAB episodes, appropriate therapy consisted of monotherapy with amikacin. In conclusion, MDR PAB is associated with a higher mortality than non-MDR PAB. This may be related to a higher rate of inappropriate empirical therapy and probably also to amikacin as frequently the only appropriate empirical therapy given to patients with MDR PAB.
INTRODUCTION
Pseudomonas aeruginosa is one of the leading causes of nosocomial bloodstream infections and the third most frequent cause of Gram-negative infections in the United States (31). This pathogen causes severe infections, especially in immunocompromised hosts, and it is associated with a high mortality rate (29). In recent years, the number of multidrug-resistant (MDR) strains has increased, and this reduces the probability of administering an appropriate empirical treatment (19). In critically ill patients with septic shock, every hour of delay in the administration of appropriate antibiotic therapy has been associated with a cumulative increase in the risk of death (11–15). Other observations have also supported the importance of appropriate empirical therapy in patients with bacteremia in general (26) or due to particular pathogens, such as methicillin-resistant Staphylococcus aureus (22) or Escherichia coli (21). For Pseudomonas aeruginosa bacteremia (PAB), previous studies found that inappropriate empirical therapy was a risk factor for mortality when considering all patients (2, 9) or for a subset of patients with more severe infection (8, 27). However, the influence of multidrug resistance on the probability of receiving appropriate empirical therapy was not evaluated. Some authors have described a higher mortality rate among patients with MDR strains (1, 7, 8, 10, 16, 25, 28), but these patients more frequently received incorrect empirical therapy and had more severe underlying diseases and longer hospital stays than patients infected by susceptible Pseudomonas aeruginosa strains (24). Therefore, the individual influence of each one of these variables on the mortality of PAB is still not well defined.
The aim of our study was to determine the influence of appropriate empirical therapy and other important factors, particularly MDR, on the mortality of 709 consecutive patients with P. aeruginosa bacteremia.
MATERIALS AND METHODS
Study design.
The study was conducted in an 850-bed university center that provides specialized and broad medical, surgical, and intensive care for an urban population of 500,000 people. Since 1991, our unit has been prospectively identifying and monitoring all patients with bacteremia admitted to our hospital. The present report refers to all patients with bacteremia due to P. aeruginosa from January 2000 to December 2008. The Ethics Committee board of our institution approved the study.
Data collection and definition. (i) Assessed clinical variables.
Factors potentially associated with mortality were prospectively gathered from all patients by clinical investigators and retrospectively analyzed. Clinical and microbiological variables were age, gender, comorbidities, prognosis of the underlying disease (according to a modification of the McCabe and Jackson criteria) (20), treatment with antibiotics or steroids in the previous month, recent hospitalization (within the last month), surgery and other invasive procedures, origin of infection (community, nosocomial, or health care related), source of bacteremia, shock on presentation, antimicrobial susceptibility pattern, empirical antibiotic treatment, appropriateness of empirical therapy, and 30-day mortality.
(ii) Definitions.
MDR was considered when the strain was resistant to ≥3 antipseudomonal antibiotics (ciprofloxacin, ceftazidime, piperacillin-tazobactam, meropenem, and amikacin) (6). Appropriate empirical therapy was considered when the patient received at least one in vitro active antimicrobial agent within 24 h after blood cultures were obtained and before susceptibility results were available and if the dosage and route of administration were in accordance with the current medical standards. Specific dosages of antibiotics were not recorded. However, local guidelines during the study period recommended the administration of aminoglycosides in a single daily dose of 5 to 7 mg/kg of body weight for gentamicin and tobramycin and 15 to 20 mg/kg for amikacin in patients with normal renal function. Sources of infection were grouped according to their mortality risk as follows: (i) low risk (<15%), urinary tract, vascular catheter, skin and soft tissue, biliary tract, and bone and joint; (ii) intermediate risk (15 to 30%), unknown, abdominal, and other infections (pacemaker infection, endocarditis, and otolaryngology infections); (iii) high risk (>30%), respiratory.
Microbiological procedures.
Antimicrobial susceptibility testing was performed by using a microdilution system (Phoenix system [Becton, Dickinson, Franklin Lakes, NJ] or Etest [AB Biodisk, Solna, Sweden]). Current Clinical and Laboratory Standards Institute (CLSI) breakpoints for each year were used to define susceptibility or resistance to these antimicrobial agents. The antibiotics tested were piperacillin-tazobactam, ceftazidime, cefepime, imipenem, meropenem, ciprofloxacin, gentamicin, tobramycin, amikacin, and colistin. For the purpose of analysis, intermediate susceptibility was considered resistant.
Statistical analysis.
Data from different groups of patients were compared using chi-square or Fisher's exact tests for categorical variables and the Student t test or Mann-Whitney U test for continuous variables. Patient's characteristics or exposures with a P value of ≤0.20 in the univariate analysis were subjected to further selection by using a forward stepwise nonconditional logistic procedure, and the criteria for variables to step in and out were a P value of 0.10 and 0.10, respectively. A two-tailed P value of <0.05 was regarded as significant. To evaluate model calibration, the Hosmer-Lemeshow (H-L) test for goodness of fit was applied. Due to the fact that inappropriate empirical therapy was more frequent in MDR PAB, a new variable combining empirical antibiotic therapy and MDR was created to better define the effect of the appropriateness of empirical treatment on mortality. This composite variable was included in the multivariate analysis with four categories, as follows: appropriate therapy and non-MDR (reference category), appropriate therapy and MDR, inappropriate therapy and non-MDR, and inappropriate therapy and MDR. The analysis was carried out using SPSS software (version 17.0; SPSS, Inc., Chicago, IL).
RESULTS
From January 2000 to December 2008, a total of 709 consecutive episodes of Pseudomonas aeruginosa bacteremia were identified. The mean age (± standard deviation [SD]) of the entire cohort was 61.84 ± 16 years (median, 64.68; range, 17 to 102; interquartile range [IQR], 51.99 to 73.60), 66.7% were males, for 71% the infection source was nosocomial, and the 30-day mortality was 19.9% (141 of 709). The resistance rates to ceftazidime, piperacillin-tazobactam, meropenem, ciprofloxacin, and amikacin were 15.6% (111/709), 15.2% (108/709), 14% (99/709), 23.5% (167/709), and 0.4% (3/709), respectively. All isolates were susceptible to colistin, and the multidrug resistance rate, according to the definition stated in Materials and Methods, was 17.9% (127/709).
Clinical characteristic of patients with MDR and non-MDR PAB are shown in Table 1. In comparison with non-MDR PAB, MDR PAB episodes were more frequently hospital acquired (85% versus 68%; P < 0.0001) and were positively associated with a longer hospital stay (31.83 ± 30 days versus 16.38 ± 18 days; P < 0.0001), bladder catheterization (53.5% versus 37.5%; P < 0.0001), prior corticosteroid therapy (41.7% versus 33.8%; P = 0.03), prior antibiotic treatment (85.8% versus 53.4%; P < 0.0001), receipt of inappropriate empirical antibiotic therapy (62.2% versus 27%; P < 0.0001), and a higher 30-day mortality rate (32.3% versus 17.2%; P < 0.0001). The specific sources of PAB, the prevalence of MDR for each source, and the 30-day mortality are summarized in Table 2.
Table 1.
Clinical characteristics of patients with MDR or non-MDR P. aeruginosa bacteremia
| Characteristic | No. (%)a of patients with characteristic and: |
P value | |
|---|---|---|---|
| Non-MDR PAB (n = 582) | MDR PAB (n = 127) | ||
| Mean (SD) age (yrs) | 62.17 (16) | 60.30 (17) | 0.24 |
| Male gender | 379 (65.1) | 94 (74) | 0.06 |
| Acquisition | |||
| Community | 118 (20.3) | 1 (0.8) | |
| Nosocomial | 396 (68) | 108 (85) | <0.0001 |
| Health care related | 66 (11.3) | 18 (14.2) | |
| An ultimate/final fatal underlying disease | 305 (52.4) | 73 (57.5) | 0.58 |
| Mean (SD) days to death after admission | 16.38 (18) | 31.83 (30) | <0.0001 |
| Hematological cancer | 79 (13.6) | 16 (12.6) | 0.89 |
| Solid organ cancer | 103 (17.7) | 18 (14.2) | 0.36 |
| Solid organ transplant | 60 (10.3) | 20 (15.7) | 0.09 |
| Neutropenia (<500 cells) | 71 (12.2) | 17 (13.4) | 0.44 |
| COPDb | 70 (12) | 16 (12.6) | 0.88 |
| Chronic renal failure | 56 (9.6) | 17 (13.4) | 0.2 |
| Hemodialysis | 28 (4.8) | 6 (4.7) | 1 |
| Diabetes mellitus | 104 (17.9) | 21 (16.5) | 0.8 |
| Liver cirrhosis | 30 (5.2) | 10 (7.9) | 0.29 |
| HIV infection | 19 (3.3) | 8 (6.3) | 0.12 |
| Prior antibiotic therapy | 311 (53.4) | 109 (85.8) | <0.0001 |
| Prior steroid therapy | 197 (33.8) | 53 (41.7) | 0.03 |
| Bladder catheter | 218 (37.5) | 68 (53.5) | <0.0001 |
| Mechanical ventilation | 81 (13.9) | 21 (16.5) | 0.49 |
| Septic shock | 109 (18.7) | 31 (24.4) | 0.25 |
| Mortality risk groupc | |||
| Low risk | 291 (50) | 74 (58.3) | |
| Intermediate risk | 183 (31.4) | 28 (22) | 0.09 |
| High risk | 108 (18.6) | 25 (19.7) | |
| Inappropriate empirical antibiotic | 157 (27) | 79 (62.2) | <0.0001 |
| 30-day mortality | 100 (17.2) | 41 (32.3) | <0.0001 |
Values in parentheses are the percentage of patients with the indicated characteristic, with the exception of mean age and mean time to death after hospital admission (for which the SD are reported).
COPD, chronic obstructive pulmonary disease.
See the text for descriptions of risk groups and infection types.
Table 2.
Distribution of P. aeruginosa bacteremia sources, 30-day mortality rates, and prevalence of multidrug resistance
| Bacteremia source or original site of infection | na (%) | No. (%) of patients with MDR PAB (n = 127) | No. (%) of patients who died within 30 days of admission |
||
|---|---|---|---|---|---|
| Overall (n = 141) | Non-MDR PAB (n = 582) | MDR PAB (n = 127) | |||
| Vascular catheter | 200 (28.2) | 44 (34.6) | 19 (13.5) | 8 (1.4) | 11 (8.7) |
| Unknown | 164 (23.1) | 18 (14.2) | 32 (22.7) | 25 (4.3) | 7 (5.5) |
| Respiratory | 133 (18.8) | 25 (19.7) | 64 (45.4) | 48 (8.2) | 16 (12.6) |
| Urinary tract | 93 (13.1) | 20 (15.7) | 7 (5) | 6 (1) | 1 (0.8) |
| Biliary tract | 47 (6.6) | 6 (4.7) | 6 (4.3) | 3 (0.5) | 3 (2.4) |
| Abdominal | 22 (3.1) | 5 (3.9) | 6 (4.3) | 4 (0.7) | 2 (1.6) |
| Skin and soft tissue | 22 (3.1) | 4 (3.1) | 2 (1.4) | 2 (0.3) | 0 (0) |
| Otherb | 25 (3.5) | 5 (3.9) | 5 (3.5) | 4 (0.7) | 1 (0.8) |
| Bone and joint | 3 (0.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
The total number of study subjects was 709.
Other sources included pacemaker infection, endocarditis, and otolaryngology infection.
A total of 141 (19.9%) patients with PAB died. Factors associated with 30-day mortality in the univariate analysis included an ultimately or rapidly fatal underlying disease (P < 0.0001), liver cirrhosis (P = 0.02), MDR PAB (P < 0.0001), mechanical ventilation (P < 0.0001), septic shock (P < 0.0001), a high-risk source (P < 0.0001), and receiving inappropriate empirical antibiotic therapy (P = 0.001) (Table 3). In comparison with patients with non-MDR PAB who received appropriate empirical therapy, mortality was higher in those with non-MDR PAB who received inappropriate empirical therapy (33/157 [21%] versus 67/425 [15.8%]; P = 0.11), in those with MDR PAB receiving inappropriate therapy (31/79 [39.2%]; P < 0.0001), and in those with MDR PAB receiving appropriate therapy (10/48 [20.8%]; P = 0.36).
Table 3.
Univariate analysis results for the association of clinical, microbiological, and therapeutic characteristics with 30-day mortality
| Characteristic | No. (%)a of patients with characteristic who: |
P value | |
|---|---|---|---|
| Died (n = 141) | Survived (n = 568) | ||
| Mean (SD) age (yrs) | 63.98 (14) | 61.28 (16) | 0.08 |
| Male gender | 94 (66.7) | 376 (66.2) | 0.92 |
| Acquisition | |||
| Community | 21 (14.9) | 98 (17.2) | |
| Nosocomial | 108 (76.6) | 392 (69) | 0.17 |
| Health care related | 11 (7.8) | 73 (12.8) | |
| An ultimate/final fatal underlying disease | 97 (68.8) | 277 (48.8) | <0.0001 |
| Mean (SD) days after admission | 21.88 (23) | 18.59 (21) | 0.14 |
| Hematological cancer | 17 (12.1) | 76 (13.4) | 0.78 |
| Solid organ cancer | 31 (22) | 89 (15.7) | 0.1 |
| Solid organ transplant | 17 (12.1) | 63 (11.1) | 0.77 |
| Neutropenia (<500 cells) | 23 (16.3) | 64 (11.3) | 0.15 |
| COPDb | 20 (14.2) | 66 (11.6) | 0.47 |
| Chronic renal failure | 12 (8.5) | 61 (10.7) | 0.54 |
| Hemodialysis | 4 (2.8) | 30 (5.3) | 0.27 |
| Diabetes mellitus | 24 (17) | 100 (17.6) | 0.9 |
| Liver cirrhosis | 14 (9.9) | 26 (4.6) | 0.02 |
| HIV infection | 5 (3.5) | 22 (3.9) | 1 |
| Prior steroid therapy | 60 (42.6) | 188 (33.1) | 0.07 |
| Bladder catheter | 62 (44) | 220 (38.7) | 0.35 |
| MDR-PAB | 41 (29.1) | 86 (15.1) | <0.0001 |
| Mechanical ventilation | 35 (24.8) | 66 (11.6) | <0.0001 |
| Septic shock | 72 (51.1) | 68 (12) | <0.0001 |
| Mortality risk groupc | |||
| Low risk | 34 (24.1) | 331 (58.3) | |
| Intermediate risk | 43 (30.5) | 168 (29.6) | <0.0001 |
| High risk | 64 (45.4) | 69 (12.1) | |
| Persistent bacteremia | 16 (11.3) | 79 (13.9) | 0.6 |
| Inappropriate empirical antibiotic | 65 (46.1) | 176 (31) | 0.001 |
Values in parentheses are the percentage of patients with the indicated characteristic, with the exception of mean age and mean time to death after hospital admission (for which the SD are reported).
COPD, chronic obstructive pulmonary disease.
See the text for descriptions of risk groups and infection types.
The best multivariate model predicting 30-day mortality is shown in Table 4. Factors independently associated with 30-day mortality were age (P = 0.022), septic shock (P < 0.0001), liver cirrhosis (P = 0.005), an intermediate-risk (P = 0.002) or high-risk (P < 0.0001) source of infection, and, with use of appropriate empirical therapy in non-MDR PAB as the reference group, receiving inappropriate therapy for non-MDR PAB (OR, 2.18; 95% confidence interval [CI], 1.215 to 3.899; P = 0.009) or receiving inappropriate therapy for MDR PAB (OR, 4.09; 95% CI, 2.156 to 7.778; P < 0.0001). A nonsignificant trend toward higher mortality in patients with MDR PAB who received appropriate therapy was also observed (P = 0.072). In order to evaluate the quality of empirical therapy, the specific antibiotics administered for MDR PAB were reviewed. The most frequent empirical therapy was monotherapy with amikacin (47.9%), followed by amikacin plus colistin (18.8%), monotherapy with a carbapenem (14.6%), a carbapenem plus amikacin (8.3%), and piperacillin-tazobactam plus amikacin (4.2%).
Table 4.
Multivariate analysis of risk factors associated with 30-day mortality in P. aeruginosa bacteremia
| Factor | OR (95% CI) | P value |
|---|---|---|
| Age | 1.02 (1.002–1.033) | 0.022 |
| Septic shock | 6.58 (4.022–10.767) | <0.0001 |
| Liver cirrhosis | 3.30 (1.423–7.649) | 0.005 |
| Risk level of infection source | ||
| Low (<15%) | (Used as reference) | |
| Intermediate (15–30%) | 2.47 (1.410–4.326) | 0.002 |
| High (>30%) | 7.27 (4.092–12.928) | <0.0001 |
| Empirical antibiotic therapy | ||
| Non-MDR with appropriate agent | (Used as reference) | |
| Non-MDR with inappropriate agent | 2.18 (1.215–3.899) | 0.009 |
| MDR and inappropriate agent | 4.09 (2.156–7.778) | <0.0001 |
| MDR and appropriate agent | 2.25 (0.930–5.436) | 0.072 |
DISCUSSION
The 30-day mortality rate for PAB was 19.9%, and this was significantly higher when the infecting strain was MDR (17.2% versus 32.3%; P = 0.0001). Similar to previous published experiences (2, 8, 9, 13, 26, 27), the analysis of our patients showed an association between mortality and increasing age, patient's comorbidity (liver cirrhosis), shock on presentation, the source of infection (respiratory, unknown, and abdominal sources), and the appropriateness of empirical antibiotic therapy. Among these factors (besides perhaps an earlier and systematic goal-directed approach to maintain tissue perfusion in patients with septic shock), the only factor that could have been improved at the moment of bacteremia clinical presentation was the percentage of patients receiving appropriate empirical therapy. The worldwide increase of MDR in Pseudomonas spp. is directly impacting the proportion of patients adequately treated from the first presentation. Indeed, in our series, inappropriate empirical therapy was significantly more frequent in MDR PAB than in non-MDR PAB (62.2% versus 27%; P = 0.0001).
In general, resistant pathogens are more frequently isolated in patients with poor medical conditions (comorbidity, nosocomial acquisition, previous antimicrobial therapy, prolonged hospitalization), making it difficult to analyze the influence of empirical therapy on the outcome of resistant pathogens. Some authors have identified resistance to ceftazidime, carbapenems, or MDR as risk factors for mortality (1, 7, 16, 24, 25, 28). In contrast, Combes et al. (3) evaluated the impact of piperacillin resistance on the outcomes of P. aeruginosa ventilator-associated pneumonia in patients who received appropriate empirical antibiotics, and they found that piperacillin resistance was not associated with higher mortality. These results suggest the importance of adjusting for appropriate empirical antibiotic to clarify the influence of resistance on mortality. The present large series of PAB with an MDR prevalence of 17.9% allowed us to perform the analysis of the influence of both MDR and appropriateness of empirical therapy on the mortality of PAB. Since there was an interaction between MDR and receiving inappropriate empirical therapy, a variable combining both was included in the logistic regression analysis. Compared with appropriate therapy in non-MDR episodes, inappropriate therapy in non-MDR PAB (OR, 2.18; 95% CI, 1.215 to 3.899; P = 0.009) and inappropriate therapy in MDR PAB (OR, 4.09; 95% CI, 2.156 to 7.778; P < 0.0001) were associated with higher mortality. However, the observed nonsignificant trend toward higher mortality in patients with MD PAB who received appropriate therapy suggests an intrinsic influence of MDR on prognosis. This cannot be entirely discarded, since some virulence traits, such as the secretion of type III exotoxins by P. aeruginosa, have been independently associated with poor prognosis in patients with bacteremia, and this trait is, in turn, more prevalent in strains resistant to ciprofloxacin, cefepime, and gentamicin (5). An alternative explanation for that trend may lie in the fact that, in our center, MDR P. aeruginosa is in general only susceptible to amikacin and colistin. Therefore, in the present study appropriate empirical therapy for many cases of MDR PAB (47.9%) consisted of monotherapy with amikacin. According to previous clinical experiences, single-aminoglycoside therapy may be a suboptimal treatment (18, 23, 30), except for urinary tract infections. Although every effort should be made to administer aminoglycosides in a manner directed to achieve an optimal ratio of the maximal drug concentration in the serum versus the MIC (as a rule, in a high single daily dose) (4, 17), it is not clear whether this approach can overcome the apparent suboptimal efficacy of aminoglycosides as single agents and, certainly, the risk of nephrotoxicity is still of concern.
The present study has some limitations. First, the potential influences of different antibiotics or of combination therapies were not evaluated. Second, MIC values and specific dosages of antibiotics were not recorded; hence, we cannot evaluate the influence of pharmacokinetics-pharmacodynamics parameters. Lastly, despite use of multivariate analysis, inadequate control for confounding by comorbid illness cannot be completely discarded. However, this is the largest series of PAB with a high prevalence of MDR that has demonstrated the importance of appropriate empirical therapy.
In conclusion, the mortality for P. aeruginosa infection and the prevalence of MDR strains were high. MDR PAB had a higher 30-day mortality than non-MDR PAB, and according to our analysis this was due to a higher rate of inappropriate empirical antibiotic therapy and because in almost 50% of MDR PAB episodes appropriate empirical therapy consisted of monotherapy with amikacin. These findings strengthen the needs for revision of the empirical regimens for patients at risk of MDR PAB and of developing new antipseudomonal antibiotics.
ACKNOWLEDGMENT
We declare no conflicts of interest.
Footnotes
Published ahead of print 2 July 2012
REFERENCES
- 1. Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y. 2006. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob. Agents Chemother. 50:43–48 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Cheong HS, et al. 2008. Inappropriate initial antimicrobial therapy as a risk factor for mortality in patients with community-onset Pseudomonas aeruginosa bacteraemia. Eur. J. Clin. Microbiol. Infect. Dis. 27:1219–1225 [DOI] [PubMed] [Google Scholar]
- 3. Combes A, et al. 2006. Impact of piperacillin resistance on the outcome of Pseudomonas ventilator-associated pneumonia. Intensive Care Med. 32:1970–1978 [DOI] [PubMed] [Google Scholar]
- 4. Drusano GL, et al. 2007. Back to the future: using aminoglycosides again and how to dose them optimally. Clin. Infect. Dis. 45:753–760 [DOI] [PubMed] [Google Scholar]
- 5. El-Solh AA, Hattemer A, Hauser AR, Alhajhusain A, Vora H. 2012. Clinical outcomes of type III Pseudomonas aeruginosa bacteremia. Crit. Care Med. 40:1157–1163 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Falagas ME, Karageorgopoulos DE. 2008. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. Clin. Infect. Dis. 46:1121–1122 [DOI] [PubMed] [Google Scholar]
- 7. Joo EJ, et al. 2011. Risk factors for mortality in patients with Pseudomonas aeruginosa bacteremia: clinical impact of antimicrobial resistance on outcome. Microb. Drug Resist. 17:305–312 [DOI] [PubMed] [Google Scholar]
- 8. Joo EJ, et al. 2011. Impact of inappropriate empiric antimicrobial therapy on outcome in Pseudomonas aeruginosa bacteraemia: a stratified analysis according to sites of infection. Infection 39:309–318 [DOI] [PubMed] [Google Scholar]
- 9. Kang CI, et al. 2003. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin. Infect. Dis. 37:745–751 [DOI] [PubMed] [Google Scholar]
- 10. Kang CI, et al. 2005. Risk factors for antimicrobial resistance and influence of resistance on mortality in patients with bloodstream infection caused by Pseudomonas aeruginosa. Microb. Drug Resist. 11:68–74 [DOI] [PubMed] [Google Scholar]
- 11. Kumar A. 2010. Early antimicrobial therapy in severe sepsis and septic shock. Curr. Infect. Dis. Rep. 12:336–344 [DOI] [PubMed] [Google Scholar]
- 12. Kumar A, et al. 2009. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 136:1237–1248 [DOI] [PubMed] [Google Scholar]
- 13. Kumar A, et al. 2006. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 34:1589–1596 [DOI] [PubMed] [Google Scholar]
- 14. Kumar A, Safdar N, Kethireddy S, Chateau D. 2010. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit. Care Med. 38:1651–1664 [DOI] [PubMed] [Google Scholar]
- 15. Kumar A, et al. 2010. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit. Care Med. 38:1773–1785 [DOI] [PubMed] [Google Scholar]
- 16. Lautenbach E, et al. 2010. Imipenem resistance in Pseudomonas aeruginosa: emergence, epidemiology, and impact on clinical and economic outcomes. Infect. Control Hosp. Epidemiol. 31:47–53 [DOI] [PubMed] [Google Scholar]
- 17. Layeux B, Taccone FS, Fagnoul D, Vincent JL, Jacobs F. 2010. Amikacin monotherapy for sepsis caused by panresistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 54:4939–4941 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Leibovici L, Vidal L, Paul M. 2009. Aminoglycoside drugs in clinical practice: an evidence-based approach. J. Antimicrob. Chemother. 63:246–251 [DOI] [PubMed] [Google Scholar]
- 19. Lipovy B, et al. 2010. Prevalence and resistance of Pseudomonas aeruginosa in severely burned patients: a 10-year retrospective study. Acta Chir. Plast. 52:39–43 [PubMed] [Google Scholar]
- 20. McCabe W. 1962. Gram-negative bacteremia. I. Etiology and ecology. Arch. Intern. Med. 10:847–855 [Google Scholar]
- 21. Ortega M, et al. 2009. Analysis of 4758 Escherichia coli bacteraemia episodes: predictive factors for isolation of an antibiotic-resistant strain and their impact on the outcome. J. Antimicrob. Chemother. 63:568–574 [DOI] [PubMed] [Google Scholar]
- 22. Paul M, et al. 2010. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J. Antimicrob. Chemother. 65:2658–2665 [DOI] [PubMed] [Google Scholar]
- 23. Paul M, Leibovici L. 2005. Combination antibiotic therapy for Pseudomonas aeruginosa bacteraemia. Lancet Infect. Dis. 5:192–193 [DOI] [PubMed] [Google Scholar]
- 24. Pena C, et al. 2012. Prospective multicenter study of the impact of carbapenem resistance on mortality in Pseudomonas aeruginosa bloodstream infections. Antimicrob. Agents Chemother. 56:1265–1272 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Raymond DP, et al. 2003. Impact of antibiotic-resistant Gram-negative bacilli infections on outcome in hospitalized patients. Crit. Care Med. 31:1035–1041 [DOI] [PubMed] [Google Scholar]
- 26. Retamar P, et al. 2012. Impact of inadequate empirical therapy on the mortality of patients with bloodstream infections: a propensity score-based analysis. Antimicrob. Agents Chemother. 56:472–478 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Schechner V, et al. 2011. Pseudomonas aeruginosa bacteremia upon hospital admission: risk factors for mortality and influence of inadequate empirical antimicrobial therapy. Diagn. Microbiol. Infect. Dis. 71:38–45 [DOI] [PubMed] [Google Scholar]
- 28. Tam VH, et al. 2010. Impact of multidrug-resistant Pseudomonas aeruginosa bacteremia on patient outcomes. Antimicrob. Agents Chemother. 54:3717–3722 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Vidal F, et al. 1996. Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphasis on the influence of antibiotic treatment: analysis of 189 episodes. Arch. Intern. Med. 156:2121–2126 [PubMed] [Google Scholar]
- 30. Vidal L, et al. 2007. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J. Antimicrob. Chemother. 60:247–257 [DOI] [PubMed] [Google Scholar]
- 31. Wisplinghoff H, et al. 2004. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin. Infect. Dis. 39:309–317 [DOI] [PubMed] [Google Scholar]