Impact of Pseudomonas aeruginosa bacteraemia in a tertiary hospital: Mortality and prognostic factors

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Original article

Impact of Pseudomonas aeruginosa bacteraemia in a tertiary hospital: Mortality and prognostic factors夽 Alejandro Callejas-Díaz a,b,∗ , Cristina Fernández-Pérez c , Antonio Ramos-Martínez a,b,d , a,b ˜ ˜ a,d Elena Múnez-Rubio , Isabel Sánchez-Romero e , Juan Antonio Vargas Núnez a

Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain Unidad de Enfermedades Infecciosas, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain c Servicio de Medicina Preventiva, Hospital Clínico Universitario San Carlos, Madrid, Spain d Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain e Servicio de Microbiología, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain b

a r t i c l e

i n f o

Article history: Received 29 January 2018 Accepted 26 April 2018 Available online xxx Keywords: Pseudomonas aeruginosa Bacteraemia Nosocomial infection Bacterial resistance Mortality

a b s t r a c t Background and objectives: Pseudomonas aeruginosa bacteraemia is associated with a very high mortality, conditioned by comorbidity, source, severity of the episode and lack of adequate treatment. The aim of the study is to know the mortality and prognostic factors of bacteraemia by P. aeruginosa in our hospital. Patients and methods: We conducted a retrospective study of P. aeruginosa bacteraemia detected between 2009 and 2014. Epidemiological, clinical and microbiological characteristics were described. A risk factor analysis for mortality was performed. Results: We analysed 110 episodes of bacteraemia, which was more frequent in men of advanced age and with a history of hospitalisation, comorbidity and immunosuppression. Most of the bacteraemias were secondary (mainly of respiratory or urinary source) and led to a significant clinical deterioration. The presence of antibiotic resistance was very high, with 27.3% of multiresistant strains. Empirical treatment was adequate in 60.0% and 92.3% for definite treatment. Overall mortality was 37.3% and attributable mortality was 29.1%. The most important prognostic factors were Charlson index ≥3, history of haematologic malignancy, neutropenia and previous use of corticosteroids, source of bacteraemia, Pitt index ≥4, renal insufficiency, adequate definite treatment, empiric treatment with piperacillin/tazobactam in severe episodes and focus control. Conclusion: P. aeruginosa bacteraemia is associated with a very high mortality, possibly more related to previous comorbidity and severity of the episode than to the treatment chosen. However, the main goal in management remains to optimise treatment, including focus control. ˜ S.L.U. All rights reserved. © 2018 Elsevier Espana,

Impacto de la bacteriemia por Pseudomonas aeruginosa en un hospital de tercer nivel: mortalidad y factores pronósticos r e s u m e n Palabras clave: Pseudomonas aeruginosa Bacteriemia Infecciones nosocomiales Resistencias bacterianas Mortalidad

Antecedentes y objetivo: La bacteriemia por Pseudomonas aeruginosa se asocia a una mortalidad muy elevada, condicionada por la comorbilidad, el origen y la gravedad del episodio y la ausencia de un tratamiento adecuado. El objetivo del estudio es conocer la mortalidad y los factores pronósticos de la bacteriemia por P. aeruginosa en nuestro hospital. Pacientes y métodos: Se realizó un estudio retrospectivo de las bacteriemias por P. aeruginosa detectadas entre 2009 y 2014. Se calculó la incidencia y se describieron las características epidemiológicas, clínicas y microbiológicas, la mortalidad y sus factores pronósticos.

夽 Please cite this article as: Callejas-Díaz A, Fernández-Pérez C, Ramos-Martínez A, Múnez-Rubio ˜ ˜ E, Sánchez-Romero I, Vargas Núnez JA. Impacto de la bacteriemia por Pseudomonas aeruginosa en un hospital de tercer nivel: mortalidad y factores pronósticos. Med Clin (Barc). 2018. https://doi.org/10.1016/j.medcli.2018.04.020 ∗ Corresponding author. E-mail address: [email protected] (A. Callejas-Díaz). ˜ S.L.U. All rights reserved. 2387-0206/© 2018 Elsevier Espana,

MEDCLE-4524; No. of Pages 7

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Resultados: Se analizaron 110 episodios de bacteriemia por P. aeruginosa, frecuentemente observadas con antecedentes de hospitalización, comorbilidad e inmunodepresión. La mayoría fue de origen respiratorio o urinario. La presencia de resistencias fue muy elevada. El tratamiento empírico fue adecuado en el 60,0%, y el dirigido, en el 92,3%. La mortalidad global fue del 37,3%, y la atribuible, del 29,1%. Los factores pronósticos más importantes fueron el índice Charlson ≥3, los antecedentes de neoplasia hematológica, neutropenia y uso de corticoides, el origen, el índice de Pitt ≥4, la insuficiencia renal, el tratamiento dirigido adecuado, el tratamiento empírico con piperacilina/tazobactam en pacientes graves y el control del foco. Conclusiones: La bacteriemia por P. aeruginosa se asocia a una mortalidad muy elevada, posiblemente más relacionada con las condiciones previas del paciente y la gravedad del episodio que con el tratamiento elegido. No obstante, el principal objetivo en el manejo sigue siendo optimizar el tratamiento, incluyendo el control del foco. ˜ S.L.U. Todos los derechos reservados. © 2018 Elsevier Espana,

Introduction Pseudomonas aeruginosa is a gram-negative bacillus, ubiquitous in the environment, that can produce a wide-variety of infections in humans. It is usually closely associated with hospitalisation, intensive care units (ICU), the presence of comorbidity and immunosuppression and the use of invasive devices and previous antibiotherapy.1 Its main characteristics are its intrinsic pattern of susceptibility to antimicrobials and its ability to develop resistances. It is frequently isolated in significantly complex clinical processes, has a prolonged stay and high consumption of resources. In Europe, the prevalence of P. aeruginosa bacteraemia (PAB) is 6.1%,2 very similar to that of Spain, which is at 5.9%, the fourth most frequent microorganism after Escherichia coli, Staphylococcus aureus and Coagulase negative Staphylococcus.3 PAB is associated with a very high mortality, around 30%,4–13 frequently conditioned by patients’ baseline status, the origin of the bacteraemia, the severity of the episode and the absence of adequate empirical treatment (ET). Objectives The main objective of this study was to understand the impact of PAB in a third level hospital. In order to do this, we studied the mortality episodes from PAB and prognostic factors associated with it, while taking into account the overall mortality, attributable mortality and the mortality rate at 6 months, with a special emphasis on the importance of treatment, use of combination therapy and the differences between antibiotics. Patients and methods A retrospective study was carried out with a cohort that consisted of the patients who had presented an episode of PAB at the Puerta de Hierro Majadahonda University Hospital during the January 1, 2009 and December 31, 2014 period. Patients were not excluded by age. Isolates of P. aeruginosa were separated into blood culture sample vials in which different biological fluids blood were inoculated. The processing of the blood cultures was carried out in ® the BACTEC automated system (Becton Dickinson), the microorganism identification and susceptibility study was carried out with ® the broth microdilution method, using the MicroScan (Beckman ® Coulter) and/or Wider (Soria Melguizo) automated systems, and using the cut-off points recommend by the Clinical Laboratory Standards Institute. Epidemiological and clinical data were collected, as well as those regarding all patients’ treatment and evolution. Exposure to bacteraemia risk factors during the 30 days before the episode was explored: hospitalisations, admissions to ICU, major surgery

and use of invasive devices, chemotherapy, radiotherapy, exposure to corticosteroids, immunosuppressants and antibiotics, among others. Comorbidity was quantified with the Charlson index. Immunosuppression was defined by the presence of diabetes mellitus, neoplasms, neutropaenia, transplants of any type or use of chemotherapy, radiotherapy, corticosteroids or immunosuppressants. Nosocomial bacteraemia was considered nosocomial if it occurred within the first 48 h after admission or if the patient had been hospitalised at any time during the 2 weeks prior to the event. In addition, it was considered associated with healthcare settings if the patient had received health care in a health facility during the 30 days prior to the event or had been hospitalised 90 days prior to the event. The severity of the episodes was quantified with the Pitt index. Strains of isolated P. aeruginosa were classified as multiresistant if they belonged to either of Magiorakos et al.’s multidrug-resistant (MDR) or extensively drugresistant (XDR) categories.14 MDR is defined as non-susceptibility to at least one agent in three or more antimicrobial categories that act against P. aeruginosa, and XDR as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories. ET was defined as treatment that begins during the period that ranges between clinical suspicion of bacteraemia or the extraction of blood cultures and the moment in which the isolation susceptibility in blood culture is known. Targeted therapy (TT) was considered to be treatment administered after knowing said results. Treatment was classified as adequate if at least one active antibiotic was started in the first 24 h after onset of clinical symptoms or blood cultures were obtained. The use of aminoglycosides as monotherapy was not considered adequate, except in a urinary focus. The incidence rate was calculated and patients’ demographic, epidemiological and clinical characteristics, the treatment used and its evolution were described. The association of the qualitative variables with the outcome variables (mortality and attributable mortality) was analysed using the Chi-square test or Fisher’s exact test; the quantitative variables were evaluated using the Student’s t-test or Mood’s median test when the variable did not follow a normal distribution. A stratification was carried out to evaluate the possible effect modifications or interactions with the treatment variables according to comorbidity, the primary focus and the severity of the bacteraemia. A Poisson regression model was adjusted to evaluate the trends. Logistic regression models were adjusted in order to evaluate the factors associated with the events (mortality and attributable mortality). A Cox model was adjusted to estimate the effect of the variables on mortality at 6 months (180 days). The variables included in the model were selected by relevant biological criteria and/or significance (p < 0.05) in the univariate analysis, discriminating variables as they were prior to or post bacteraemia events.

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Table 1 Baseline characteristics of patients with Pseudomonas aeruginosa bacteraemia (110 cases). Variable Sex Female Male

n = 110 38 72

Table 2 Classification of Pseudomonas aeruginosa bacteraemia episodes (110 cases) by place of acquisition, source of origin and severity.

%

Variable

n = 110

%

34.5 65.5

According to place of acquisition Nosocomial Associated with health care Community

67 28 15

60.9 25.5 13.6

According to origin Primary Secondary Respiratory Urinal Biliary Abdominal (non-biliary) Catheter-related bacteraemia Skin and soft parts Vascular

24 81 25 25 14 11 5 5 1

21.8 73.6 22.7 22.7 12.7 10.0 4.6 4.6 0.9

According to severity Pitt index ≤ 1 (non-severe episode) Pitt index 2–3 (severe) Pitt index ≥ 4 (very severe)

42 31 37

38.2 28.2 33.6

Age (years)a Female Male Service Internal Medicine Intensive care unit Other medical services

25 21 50

22.7 19.1 45.5

Hospitalisation in the previous month Contact with health care centres within the previous 90 days Admission to the ICU within the previous month Use of invasive devices within the previous month Surgery within the previous month

67 65 23 75 25

60.9 59.1 20.9 68.2 22.7

Charlson Index Absence of comorbidity (0) Comorbidity low (1–2) Comorbidity high (≥3)

9 35 66

8.2 31.8 60.0

Immunosuppression Glucocorticoids Solid neoplasia Neutrophils (103 /mm3 ) Diabetes mellitus Immunosuppressants Solid organ transplant Chemotherapy within the previous month Severe neutropaenia (<0.5 × 103 /mm3 ) Haematological neoplasia Transplantation of haematopoietic stem cells Radiotherapy within the previous month

65 40 31 30 30 28 19 18 17 15 6 2

59.1 36.4 28.2 27.3 27.3 25.5 17.3 16.4 15.5 13.6 5.5 1.8

Use of antibiotics Act against P. aeruginosa Does not act against P. aeruginosa

72 48 24

65.5 43.6 21.8

a

3

67.3 (15.4) 69.5 (14.6) 66.1 (15.8)

Expressed in mean (SD).

Results

Table 3 Susceptibility pattern of Pseudomonas aeruginosa strains causing bacteraemia (110 cases). Antibiotic

n = 110 Colistin Piperacillin/tazobactam Amikacin Ceftazidime Tobramycin Imipenem Meropenem Cefepima Gentamicin Aztreonam Ciprofloxacin

107 103 97 91 88 87 87 83 81 71 69

60% 50%

In total, 110 episodes of bacteraemia were analysed, with an annual incidence of 73.3 cases per 100,000 discharges per year, showing a growing trend that was not statistically significant. The baseline characteristics of all patients are presented in Table 1. It was more frequent in males (72 patients, 65.5%) and in patients older than 55 (86 patients, 78.2%), with an age range ranging from 27 to 96. All patients were admitted as a consequence of the bacteraemia. This was most frequent in Internal Medicine and ICU. The majority of patients who suffered from PAB presented certain risk factors known to favour the development of the bacteraemia; the most frequent of these were: previous use of invasive devices and antibiotics (75 and 72 patients, 68.2 and 65.5%, respectively), prior hospitalisation (67 patients, 60.9%), comorbidity (Charlson ≥3 in 66 patients, 60.0%), immunosuppression (65 patients, 59.1%) and prior contact with healthcare centres (65 patients, 59.1%). There were 95 patients (86.4%) who had had at least one infection in the previous month, and P. aeruginosa was isolated in 52 of those patients (54.7%). The majority of bacteraemia was secondary (81 cases, 73.6%), with respiratory and urinary origin being the most frequent (Table 2). Bacteraemia associated with central venous catheter (CVC) and those of respiratory origin occurred more frequently in patients admitted to the ICU. Furthermore, those of respiratory origin, were associated more with the presence of immunosuppression, haematological neoplasms and the use of corticosteroids. P. aeruginosa was the only microorganism isolated in 90 blood

Susceptible

42.9%

Resistant %

n = 110

%

99 94 88 83 80 79 79 75 74 65 63

1 7 13 19 22 23 23 27 28 39 41

1 6 12 17 20 21 21 25 26 35 37

47.6% 40.9% 31.3%

40% 30%

17.6%

20%

15.0%

10% 0% 2009

2010

2011

2012

2013

2014

Figure 1. Percentage of multiresistant strains (MDR or XDR) per year.

cultures (81.8%), while 20 bacteraemia were polymicrobial (18.2%), with isolation of two microorganisms in 18 of them and three microorganisms in the other two. At their onset, bacteraemia episodes were severe in at least 68 patients (61.8%), defined by a Pitt index of ≥2 (Table 2). Most of the strains were resistant to some of the antibiotics evaluated, with colistin and piperacillin/tazobactam (P/T) being the most susceptible (Table 3). Imipenem resistance and P/T showed an upward trend, although not statistically significant (incidence rate ratio [IRR] 1.03, 95% confidence interval [95% CI] 0.84 to 1.27 for imipenem, and IRR 1.18; 95% CI 0.80–1.75 for P/T). Only eight strains (7.3%) were susceptible to all antibiotics evaluated, while 30 (27.3%) were MDR and six (5.5%) XDR strains, with a statistically significant downward trend throughout the years of study (Fig. 1). There were 105 patients (95.5%) who received ET at the onset of the bacteraemia episode. The most commonly used antibiotics were carbapenems, P/T and fluoroquinolones. There were 49 patients (44.5%) receiving monotherapy and 56 (50.9%) who

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Table 4 Overall and attributable mortality of patients with Pseudomonas aeruginosa bacteraemia (110 cases) Univariate analysis. Variable

Overall mortality n/N

Sex Female Male Age (years)a Deceased Not deceased Charlson Index ≤2 3–4 ≥5 Immunosuppression Yes No Haematological neoplasia Yes No Glucocorticoids Yes No Scope Community ACS Nosocomial Focus Primary Associated with CVC Abdominal Biliary Skin and soft parts Respiratory Urinal Pitt index ≤1 2–3 ≥4 Neutrophils (103 /mm3 ) ≤3.2 3.3–11.5 ≥11.6 Multiresistance Not multi-resistant Multiresistant Adequate ET Yes No Adequate TT Yes No Focus control Yes No

%

p

Attributable mortality RR (95% CI)

n/N

%

0.629 13/38 28/72

34.2 38.9

p

RR (95% CI) 0.981

0.88 (0.52–1.49)

11/38 21/72

28.9 29.2

0.308

0.99 (0.54–1.83) 0.049

69.2 (15.1) 66.1 (15.6)

71.75 (13.5) 65.42 (15.9) 0.001

9/44 11/31 21/35

20.5 35.5 60.0

29/65 12/45

44.6 26.7

10/15 31/95

66.7 32.6

22/40 19/70

55.0 27.1

6/15 10/28 25/67

40.0 35.7 37.3

10/24 1/5 6/11 4/14 1/5 15/25 3/25

41.7 20.0 54.5 28.6 20.0 60.0 12.0

6/42 9/31 26/37

14.3 29.0 70.3

21/36 12/37 8/37

58.3 32.4 21.6

23/74 18/36

31.1 50.0

26/66 15/44

39.4 34.1

22/84 19/26

26.2 73.1

5/22 36/83

18.5 43.4

0.001 1 1.73 (0.82–3.68) 2.93 (1.54–5.58)

6/44 8/31 18/35

13.6 25.8 51.4

1.67 (0.96–2.92)

24/65 8/45

36.9 17.8

2.04 (1.29–3.24)

9/15 23/95

60.0 24.2

2.03 (1.26–3.26)

16/40 16/70

40.0 22.9

1 0.89 (0.40–1.98) 0.93 (0.47–1.87)

5/15 10/28 17/67

33.3 35.7 25.4

3.47 (1.09–11.1) 1.67 (0.21–12.9) 4.55 (1.38–15.0) 2.38 (0.62–9.2) 1.67 (0.21–12.9) 5.00 (1.65–15.2) 1

8/24 0/5 4/11 3/14 1/5 15/25 2/25

33.3 0.0 36.4 21.4 20.0 56.0 8.0

1 2.03 (0.81–5.11) 4.92 (2.28–10.6)

3/42 5/31 24/37

7.1 16.1 64.9

1 0.56 (0.32–0.95) 0.37 (0.19–0.73)

16/36 11/37 5/37

44.4 29.7 13.5

0.62 (0.39–0.99)

20/74 12/36

27.0 33.3

1.16 (0.70–1.92)

21/66 11/44

31.8 25.0

0.36 (0.23–0.55)

13/84 19/26

15.5 73.1

0.43 (0.19–0.98)

3/27 29/83

11.1 34.9

1 1.89 (0.73–4.91) 3.77 (1.68–8.48) 0.030 2.08 (1.03–4.20)

0.056

0.011

0.011

0.004

2.48 (1.44–4.28) 0.047

0.962

1.75 (1.01–3.11) 0.560

0.010

1 1.07 (0.45–2.56) 0.76 (0.33–1.74) 0.004

<0.001

4.17 (0.98–17.7) Indeterminate 4.55 (0.97–21.3) 2.68 (0.51–14.2) 2.50 (0.28–22.6) 7.00 (1.77–27.7) 1 <0.001

0.004

1 2.26 (0.58–8.75) 9.08 (2.98–27.7) 0.014

0.049

1 0.67 (0.36–1.24) 0.30 (0.12–0.74) 0.494

0.573

0.81 (0.45–1.47) 0.441

<0.001

1.27 (0.68–2.37) <0.001

0.020

0.21 (0.12–0.37) 0.018 0.32 (0.32–0.96)

a Expressed in mean. RR: relative risk.

received combination therapy, with a 78.2% coverage against P. aeruginosa (86 patients). In 66 patients (60.0%) the ET used was adequate. In 40.0% it was inadequate, almost always due to the presence of resistance in the antibiogram. There were 91 patients (82.7%) who received TT AND IT WAS adequate in 92.3% of those (84 patients, 76.4% of the total). The main reason for not receiving adequate TT was the early withdrawal of antibiotics due to the presence of a fulminant evolution (18 patients, 16.4%). Control of the septic focus was carried out in 28 patients (25.5%), with the most frequent foci being biliary (10), abdominal (8), urinary (7) and CVC (3). A total of 79 patients (71.8%) developed severe sepsis or septic shock, 92.4% within the first 48 h (73 patients). There were 34 patients (30.9%) admitted to the ICU, 34 (30.9%) who required vasoactive support, 14 (12.7%) invasive mechanical ventilation (IMV) and seven (6.4%) renal replacement therapy. Bacteraemia secondary to respiratory

focus were admitted to the ICU and required vasoactive support and IMV more frequently. Overall mortality was 37.3% (41 patients), with 61.0% of deaths within the first week (25 patients, 22.7% of all patients) and 85.4% within the first month (35 patients, 31.8% of the total patients). The attributable mortality was 29.1% (32 patients, 78.1% of all deaths), almost exclusively secondary to septic shock with multiorgan failure and within the first week in 71.9% of the cases (23 patients). The cumulative probability of survival was 77.3% at 7 days, 68.2% at 28 days and 50.0% at 180 days, with a median survival of 162 days. There were multiple variables associated with mortality in the univariate analysis, which are shown in Table 4. The prognostic factors that showed an independent effect on mortality can be seen in Table 5. In all, there were five prognostic factors independently associated with all mortality variables: Charlson index ≥5,

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Table 5 Independent prognostic factors of overall and attributable mortality and mortality rate of patients with Pseudomonas aeruginosa bacteraemia (110 cases). Baseline variables

Charlson index ≥5 Haematological neoplasia Urinary origin Respiratory origin Corticosteroids

Overall mortality p

5.51 (2.00–15.17) 3.10 (1.32–11.78) 0.17 (0.04–0.67) − 2.99 (1.15–7.75)

0.001 0.046 0.011

Evolution variables

OR

16.08 (3.51–73.68) 4.01 (1.19–13.48) 0.20 (0.05–0.83) 0.17 (0.03–0.94) 0.15 (0.02–0.99) −

Mortality rate

p

5.56 (1.82–17.01) 3.75 (1.10–14.14) 0.20 (0.04–0.92) 2.91 (1.08–8.65) −

0.024

Overall mortality OR

Pitt index ≥4 Neutrophils ≤3200 Adequate TT Focus control Empirical P/T with Pitt ≥4 Creatinine ≥1.8 mg/dl

Attributable mortality

OR

HR

0.003 0.041 0.043 0.045

3.52 (1.85–6.73) 2.95 (1.58–5.50) 0.34 (0.14–0.80) − −

Attributable mortality p

<0.001 0.025 0.027 0.042 0.049

OR 11.39 (3.45–37.58) − 0.12 (0.03–0.45) 0.16 (0.03–0.91) − −

p <0.001 0.02 0.039

p <0.001 0.001 0.014

Mortality rate HR 3.08 (1.60–5.94) 1.97 (1.10–3.53) 0.25 (0.13–0.48) − − 2.05 (1.10–3.83)

p 0.001 0.023 <0.001

0.025

OR: odds ratio; HR: hazard ratio.

the presence of haematological malignancies, urinary origin (protective factor), the Pitt index ≥4 and the adequateTT (protective factor). The empirical use of P/T showed a statistically significant interaction in the analysis stratified by severity of global mortality, so we decided to include it in the multivariate model, showing an independent protective effect on it (Table 5). Discussion The epidemiological characteristics of PAB found in our study were very similar to those that have been previously published; previous contact with the health system and the presence of immunosuppression were especially frequent.5,8,10,12,15–18 This reflects the complexity of the study centre population, which is a reference for oncohematological and transplant patients of all types. Previous use of antibiotics is one of the most prevalent risk factors for PAB in our sample, especially those that act against P. aeruginosa, this has already been described previously.1,15,19 Resistance to beta-lactams varies greatly from one group to another. In our sample, P/T was the beta-lactam that had the highest percentage of susceptible strains (94%), with a non-significant upward trend, again coinciding with previously published studies.17,20 The global figure for resistance to carbapenems was very similar to those of the rest of Spain (19.3–21.7%)21,22 ; we did not find any differences over time for this in our study, although in others it seems to be increasing.4,5,20–23 The prevalence of MDR strains is approximately 30%,6,9,17,22–24 somewhat higher than in our sample. In addition, the percentage of multiresistant strains showed a statistically significant downward trend, possibly conditioned by changes in the hospital’s policy on antibiotic use. In our population, overall mortality was 37.3%, while the mortality directly attributable to bacteraemia was 29.1%. The vast majority of publications focus on the hospital population, whose mortality is around 20–51.2%.4–13,16–18,21,25 Mortality was higher during the first days after bacteraemia onset, as noted by other studies.5,6,12,18,22 However, it remained very high in the medium term, as only 50% of patients survived the first 6 months, something difficult to contrast as there are not many references of medium to long term forecasts.26 The Charlson index has been previously implicated in the mortality of PAB10,16,17,24,26 and was – within the conditions prior to bacteraemia group – the main independent prognostic factor in the three mortality modalities studied. The same occurred for the history of haematological neoplasms group, whose mortality was higher than in patients without neoplasms or with solid organ neoplasms and when bacteraemia is associated with a respiratory focus.26,27 In addition, it is closely

related to the presence of two other factors that also showed a significant impact on mortality: neutropaenia and previous use of corticosteroids. Neutropaenia is traditionally a risk factor both for the development of PAB and for the mortality associated with it, especially severe and persistent neutropaenia.12,15,16 Conversely, despite previous use of steroids being a well-established risk factor for P. aeruginosa infection,1 its role in mortality has been documented as incidental.9,26 The urinary origin of bacteraemia turned out to be an independent protective factor in the three mortality variables, contrary to what was observed with the respiratory focus in attributable mortality. This observation has often been described5,8,9,11,12,16,17,21 and could be explained by the differences in the concentration of antibiotic in the different infectious foci and the ease of its control. In addition, the respiratory origin is usually closely related to other prognostic factors such as the presence of haematological neoplasms, previous use of corticosteroids and the IMV,4 although the latter did not show an independent effect on mortality. The Pitt index reflects the severity and prognosis of episodes of bacteraemia and has been validated in several studies on sepsis and P. aeruginosa,4,8,11,12,21,26 becoming one of the main prognostic factors. In our study it was indisputably the parameter that had the greatest effect on overall and attributable mortality in the multivariate analysis, while its significance was somewhat lower in the mortality rate at 6 months. This is consistent with the nature of PAB itself, whose impact on mortality is much more noticeable at the beginning of the event.5,6,12,18,22 One of the factors that seemed to influence mortality in the medium to long term was the presence of renal failure, which has also been previously implicated in mortality.17 The use of adequate ET is the most important prognostic factor in light of what has been published in a wide variety of studies.8–13,16,23,28 In our case, this association could not be established and, in fact, mortality was somewhat higher in patients who received adequate ET, albeit this was not statistically significant. This could be because more severe patients tend to receive greater antibiotic coverage, which could have been demonstrated in the stratified analysis if the sample size had been greater. It should be noted that there are few studies that obtained simi˜ et al.,6 in their prospective study with a lar results.5–7,18,25 Pena larger sample, failed to demonstrate the expected impact of adequate ET, despite including an adjustment for severity and focus. Schechner et al.8 observed that adequate ET only improves prognosis in the presence of severe sepsis or septic shock. Chamot et al.28 noted that the mortality occurring during the first few days after onset does not depend on whether the treatment was adequate or

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not. However, they did observe a mortality benefit occurring after the first few days. For the authors, this suggests that early mortality depends more on the patient’s clinical status at that moment than on the treatment they receive. In our sample, the analysis performed excluded patients who had a fulminant course in the first few days, and it was seen that, in the remaining subgroup, the use of adequate ET had a lower mortality than the inadequate ET, although this was not statistically significant. Hattemer et al.5 observed that 50% of the patients who received inadequate ET had a urinary origin that could explain the favourable evolution. In our study, half the patients with inadequate ET also had a urinary or biliary origin of the bacteraemia, whereas the origin was respiratory in only three. However, in the stratified analysis, no interaction was identified between the ET used and the focus of origin, once more this is probably related to the sample size. Another factor that could explain the absence of association is that, for methodological reasons, ET was considered adequate when it was started within the first 24 h from bacteraemia onset or obtaining blood cultures. A delay in the initiation of antibiotics is associated with an increase in mortality11 and it is more than probable that the threshold used was too wide a margin. Regardless of the adequacy of the treatment, no relationship has been established between any specific antibiotic and mortality to date. However, in our study P/T presented a protective effect on mortality in the multivariate analysis, something that was not observed with carbapenems. This benefit in survival, together with the low probability of resistance that it presents, could place P/T as a first-line ET for patients with suspected PAB in our context. However, this study was not designed for that purpose and it should be noted that there could be factors affecting both the probability of using carbapenems and mortality that have not been studied. This study and the majority of others have shown that combination therapy does not seem to have any benefit over monotherapy when the P. aeruginosa strain involved is adequately covered.4,6,12,24,29 In contrast to what was observed with ET, the use of adequate TT WAS able to establish itself as an independent prognostic factor in the three mortality variables studied. In this case, our data agree with other publications,11,28 which are much scarcer than those that focus on ET. Finally, the role that controlling the infectious focus plays is worth mentioning, as it is one of the main objectives in clinical practice, despite not usually being included in studies into PAB.30 In our study, when it was possible, an adequate control of the focus showed a protective effect on overall and attributable mortality, although we must note that the majority were patients with bacteraemia of biliary or urinary origins or associated with CVC, which often present better prognosis in any case. There are several limitations to this study. The first is the sample size, which was sufficient to obtain conclusions but whose statistical power decreases the probability of being able to confirm the real effect of certain variables and limits the possibilities of stratification. Second, the observational and retrospective nature of the study may introduce multiple biases. Finally, the sample is quite heterogeneous, so it may not be possible to extrapolate results to all patients and this could compromise the analysis of subgroups. Funding Nil. Conflict of interest None declared. References 1. Thuong M, Arvaniti K, Ruimy R, de la Salmoniere P, Scanvic-Hameg A, Lucet JC, et al. Epidemiology of Pseudomonas aeruginosa and risk factors for carriage acquisition in an intensive care unit. J Hosp Infect. 2003;53:274–82.

2. European Centre for Disease Prevention and Control. Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals 2011-2012. Available from: https://ecdc.europa.eu/en/publications-data/point-prevalence-surveyhealthcare-associated-infections-and-antimicrobial-use-0 [accessed 19.12.17]. ˜ de Medicina Preventiva, Salud Pública e Higiene. European 3. Sociedad Espanola Centre for Disease Prevention and Control. Estudio de Prevalencia de las Infec˜ Informe Global EPINE-EPPS 2015. Available ciones Nosocomiales en Espana: from: http://hws.vhebron.net/epine/ [accessed 19.12.17]. 4. Kim YJ, Jun YH, Kim YR, Park KG, Park YJ, Kang JY, et al. Risk factors for mortality in patients with Pseudomonas aeruginosa bacteremia; retrospective study of impact of combination antimicrobial therapy. BMC Infect Dis. 2014;14:161, http://dx.doi.org/10.1186/1471-2334-14-161. 5. Hattemer A, Hauser A, Diaz M, Scheetz M, Shah N, Allen JP, et al. 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Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC. Clinical features and outcome of patients with community-acquired Pseudomonas aeruginosa bacteraemia. Clin Microbiol Infect. 2005;11:415–8, http://dx.doi.org/ 10.1111/j.1469-0691.2005.01102.x. 19. Micek S, Johnson MT, Reichley R, Kollef MH. An institutional perspective on the impact of recent antibiotic exposure on length of stay and hospital costs for patients with gram-negative sepsis. BMC Infect Dis. 2012;12:56, http://dx.doi.org/10.1186/1471-2334-12-56. 20. European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2014. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015. Available from: https://ecdc.europa.eu/en/publications-data/antimicrobial-resistancesurveillance-europe-2014 [accessed 19.12.17]. ˜ C, Gavalda L, Tubau F, Manzur A, Dominguez MA, et al. Influ21. 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