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. 2020 Oct 11;5(3):130–138. doi: 10.3138/jammi-2020-0003

Pseudomonas aeruginosa infection in intensive care: Epidemiology, outcomes, and antimicrobial susceptibilities

Brittany E Kula 1, Darren Hudson 2, Wendy I Sligl 2,3,✉
PMCID: PMC9608728  PMID: 36341317

Abstract

Background

Pseudomonas aeruginosa (PA) infection in the intensive care unit (ICU) contributes to substantial mortality. In this study, we describe the epidemiology, antimicrobial susceptibilities, and outcomes of ICU patients with pseudomonal infection.

Methods

ICU patients with PA were identified and classified as colonized or infected. Infected patients were reviewed for source, patient characteristics, antimicrobial susceptibilities, appropriateness of empiric antimicrobial therapy, and 30-day mortality. Independent predictors of mortality were identified using multivariable logistic regression.

Results

One hundred forty (71%) patients with PA were infected. Mean patient age was 55 (SD 18) years; 62% were male. Admission categories included medical (71%), surgical (20%), and trauma or neurological (9%). Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 19 (SD 10). One hundred twenty-six (90%) patients were mechanically ventilated, 102 (73%) required vasopressors, and 27 (19%) received renal replacement; 32 (23%) died within 30 days. Infection was nosocomial in 101 (72%) cases. Sources were respiratory (66%), skin–soft tissue (11%), urinary (10%), blood (5%), surgical (5%), gastrointestinal (2%), or unknown (1%). Twenty (14%) isolates were multi-drug resistant; 6 (4%) were extensively drug resistant. Empiric antimicrobial therapy was effective in 97 (69%) cases. Liver disease (adjusted OR [aOR] 6.2, 95% CI 1.5 to 25.7; p = 0.01), malignancy (aOR 5.0, 95% CI 1.5 to 17.3; p = 0.01), and higher APACHE II score (aOR 1.1, 95% CI 1.0 to 1.1; p = 0.02) were independently associated with 30-day mortality.

Conclusions

PA infection in ICU is most commonly respiratory and associated with substantial mortality. Existing malignancy, liver disease, and higher APACHE II score were independently associated with mortality.

Keywords: antimicrobial resistance, pneumonia, Pseudomonas aeruginosa, sepsis

Pseudomonas aeruginosa (PA) is a non-fermenting Gram-negative bacillus that frequently causes nosocomial infections, particularly in the intensive care unit (ICU). Although it is a ubiquitous environmental organism, it is an important pathogen in the setting of impaired host defence (1). For this reason, PA is one of the most commonly isolated nosocomial pathogens—for example, in ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP)—and it is responsible for as many as 24% of ICU respiratory infections (2–4). Other recognized sites of infection include wounds, blood, genitourinary tract, surgical sites, burns, and central venous catheters (5).

PA is known to have multiple intrinsic and extrinsic mechanisms of antimicrobial resistance that result in unpredictable patterns of antimicrobial susceptibility (6,7). These mechanisms include upregulation of efflux pumps, insertion of porins, production of beta-lactamases, and target site alteration (8). Resistance is an increasing problem, and it has been independently associated with higher in-hospital mortality, prolonged hospital length of stay, and higher costs (9–18). Increasing resistance also poses a clinical challenge in terms of both empiric and definitive antibiotic selection. This is especially so among critically ill patients because the prevalence of resistance is almost two-fold higher in this population compared with non-ICU patients (9). For these reasons, the World Health Organization has deemed PA a critical priority for ongoing research and antimicrobial development (19).

The epidemiological characteristics of critically ill patients with pseudomonal VAP or HAP have previously been described in the literature; however, Canadian-specific data are lacking (11,20,21). PA VAP or HAP has been associated with as high as 43% mortality in the ICU population and prolonged ICU length of stay (20). The rate of inadequate empiric antimicrobial therapy has been reported to be as much as 56% when PA is identified as the causative organism (20). However, the characteristics of ICU patients with non-pneumonial PA infection have been less well described.

The objectives of this study were to describe the epidemiology, antimicrobial susceptibilities, and outcomes among critically ill patients with all types of pseudomonal infection. We hypothesized that resistance rates would not be greater than those described in the literature, that fluoroquinolone resistance would be more common than carbapenem resistance, and that we would have few (if any) pan-resistant isolates. We also postulated that ineffective empiric antimicrobial therapy would be associated with worse outcomes.

Methods

The Research Ethics Board at the University of Alberta approved the study and waived the need for informed consent (study no. Pro00072482). STROBE guidelines for reporting of observational studies were followed (22).

This retrospective observational cohort study was conducted at the University of Alberta Hospital, an 885-bed academic quaternary care hospital in Edmonton, Alberta. It is a level-one trauma centre with a referral area of more than 2 million people. It is also the largest solid organ transplant centre in Western Canada. The general systems ICU (GSICU) has 32 beds that service general medical, surgical, trauma, and solid organ transplant patients, with more than 1,500 admissions per year. This unit offers standard invasive hemodynamic monitoring and support, mechanical ventilation, and renal replacement therapy.

Adult patients (aged ≥ 18 y) who had a clinical isolate of PA while admitted to the GSICU at the University of Alberta from January 1, 2013, to December 31, 2016, were identified via the Public Health Laboratory microbiology database. For each unique patient, the paper and electronic ICU charts were reviewed for evidence of infection. Patients were classified as having PA infection if the intensivist specifically outlined this in the medical chart or prescribed directed anti-pseudomonal antimicrobial therapy when the isolate became available. Only patients treated for active infection were included for further analysis.

Socio-demographic data included age and sex. Comorbidity data included cystic fibrosis, chronic kidney disease requiring intermittent hemodialysis or peritoneal dialysis, structural lung diseases, diabetes treated with insulin or oral hypoglycemics, heart failure, malignancy, chronic liver disease, coronary artery disease, neuromuscular diseases, alcohol use disorder, smoking history, immunosuppression, and neutropenia. Structural lung disease included chronic obstructive pulmonary disease (COPD), lung resection, bronchiectasis, or malignancy. Smoking was deemed significant if patients were active users at admission or had a past history of 20 years or more. Immunosuppression included all patients who received biologics within 90 days of admission, who had received 20 mg or more of prednisone (or equivalent) daily for 1 month, or had a known immunodeficiency syndrome or active immunosuppression post-transplant.

Admission diagnosis category was recorded as medical, surgical, or trauma or neurological. Goals of care at the time of admission were also recorded. Goals of care communicate code status and are classified as R1 (full code), R2 (no cardiopulmonary resuscitation [CPR]), or R3 (no CPR, no intubation).

Disease severity was captured with the Acute Physiology and Chronic Health Evaluation (APACHE) II score at ICU admission (23). Organ failure and supportive requirements were also recorded, including duration of mechanical ventilation, vasopressor days, renal replacement therapy, and acute kidney injury. Acute kidney injury was defined as new-start dialysis via any modality.

PA-related variables included specimen site, community acquired or nosocomial (culture collected at least 48 hr after hospital admission), antimicrobial resistance, and appropriateness of empiric therapy (based on antimicrobial susceptibilities). According to international consensus definitions, PA was classified as multi-drug resistant (MDR) if not susceptible to at least one agent in three or more anti-pseudomonal antimicrobial categories, extensively drug resistant (XDR) if susceptible to at least one agent in two or fewer antimicrobial categories, or pan-drug resistant (PDR) if resistant to all available antimicrobials (24). Susceptibility to fluoroquinolones and carbapenems was also specifically recorded. Infection site was classified as respiratory, skin or soft tissue, urinary, blood, surgical, or gastrointestinal.

The primary outcome was 30-day mortality from ICU admission. Secondary outcomes included ICU and in-hospital mortality and health services utilization (hospital and ICU lengths of stay, receipt of organ support).

In cases in which a patient was admitted to the ICU more than once over the study period, only the first admission in which the patient was considered infected was included.

Demographic characteristics were reported as means with standard deviations (SD) or as medians with interquartile range (IQR) for continuous variables. Categorical variables were expressed as numbers and percentages. Characteristics of patients who died versus survived were compared using t tests or Mann–Whitney U tests, depending on their distributions, for continuous variables. The chi-square test or Fisher exact test was used for categorical variables.

All p values were two-tailed, with statistical significance defined as p < 0.05. Univariate logistic regression analyses were performed to identify associations with mortality. Multivariable logistic regression was performed to identify factors independently associated with mortality. Variables were selected for multivariable logistic regression modelling on the basis of univariate analyses (p ≤ 0.10) and overall clinical significance. C-statistics were reported as a measure of the model’s goodness of fit.

All statistical analyses were performed using IBM SPSS Statistics, Version 25.0 (IBM Corp., Armonk, NY).

Results

Over the study period, 196 patients had PA isolated from a clinical specimen while admitted to the GSICU. Of these, 187 had a single ICU admission, and only 131 of these were considered infected. Fifty-six (30%) were considered colonized. Eight patients were admitted on two separate occasions over the study period, and 1 patient had three admissions. All of these patients were considered infected on at least one ICU admission, and only the first admission when the patient was actively treated for PA infection was included. In total, 140 unique patients were included in the analysis; 7 had incomplete data (missing APACHE II scores only) but were still included in the analysis. On the basis of 43,786 patient-days over the study period, the infection rate was 3.2 per 1,000 patient days.

Baseline characteristics of the cohort are shown in Table 1. The mean patient age was 55 (SD 18) years, and 87 (62%) were male. The majority of admissions were medical (71%) followed by surgical (20%) and trauma or neurological (9%). Smoking history (39%), lung disease (35%), and diabetes (24%) were the most common medical comorbidities.

Table 1:

Baseline characteristics and univariate analysis for 30-day mortality

Variable No. (%)*
All patients; n = 140 Alive; n = 108 (77) Dead; n = 32 (23) p-value for χ2
Age, y, mean (SD) 55 (18) 54 (18) 59 (18) 0.18
Male sex 87 (62) 63 (58) 24 (75) 0.088
Admission class
Medical 100 (71) 74 (69) 26 (81)
Surgical 28 (20) 24 (22) 4 (13)
Trauma or neurological 12 (9) 10 (9) 2 (6)
Comorbidity†
Diabetes 33 (24) 26 (24) 7 (22) 0.80
Heart failure 12 (9) 8 (7) 4 (13) 0.37
Coronary artery disease 28 (20) 21 (19) 7 (22) 0.76
Liver disease 16 (11) 9 (8) 7 (22) 0.034
Neuromuscular 18 (13) 16 (15) 2 (6) 0.20
Chronic kidney disease 25 (18) 16 (15) 9 (28) 0.08
Malignancy 20 (14) 9 (8) 11 (34) 0.001
Structural lung disease 49 (35) 39 (36) 10 (31) 0.61
Cystic fibrosis 5 (4) 4 (4) 1 (3) 0.87
Immunosuppressed 34 (24) 24 (22) 10 (31) 0.30
Smoking history 54 (39) 42 (39) 12 (38) 0.89
Alcohol abuse 18 (13) 12 (11) 6 (19) 0.26
Long term care facility 7 (5) 5 (5) 2 (6) 0.71
Goals of care 0.019
R1 (full code) 95 (68) 79 (73) 16 (50)
R2 (no CPR) 40 (29) 27 (25) 13 (41)
R3 (no CPR, no intubation) 5 (4) 2 (2) 3 (9)
Sources of PA 0.15
Respiratory 93 (66) 76 (70) 17 (53)
Skin or soft tissue 15 (11) 10 (9) 5 (16)
Urinary 14 (10) 12 (11) 2 (6)
Blood 7 (5) 4 (4) 3 (9)
Surgical 7 (5) 4 (4) 3 (9)
Gastrointestinal 3 (2) 1 (1) 2 (6)
Unknown 1 (1) 1 (1) 0
Sensitivities of PA 0.79
Sensitive 114 (81) 88 (81) 26 (81)
Multi-drug resistant 20 (14) 16 (15) 4 (13)
Extensively drug resistant 6 (4) 4 (4) 2 (6)
Pan-drug resistant 0 n/a n/a
Appropriate empirical antibiotics 97 (69) 74 (69) 23 (72) 0.72
Nosocomial infection 101 (72) 82 (76) 19 (59) 0.06
Organ dysfunction†
Invasive mechanical ventilation 126 (90) 97 (90) 29 (91) 0.89
Vasopressor support 102 (73) 75 (69) 27 (84) 0.095
Renal replacement therapy 29 (21) 20 (19) 9 (28) 0.24
APACHE II score, mean (SD)‡ 19 (14) 18 (17) 25 (78) 0.001
Acute kidney injury 113 (81) 90 (83) 23 (72) 0.15
ICU stay, median (IQR), d 13 (5–27)
Death in hospital 49 (35)
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Notes: Bold indicates statistical significance. Percentages may not total 100 because of rounding.

* Unless otherwise indicated

† Patients could have more than one comorbidity or organ dysfunction.

‡Missing data

CPR = Cardiopulmonary resuscitation; PA = Pseudomonas aeruginosa; n/a = Not applicable; APACHE II = Acute Physiology and Chronic Health Evaluation; ICU = Intensive care unit; IQR = Interquartile range

The average APACHE II score at ICU admission was 19 (range 1–53, SD 10) compared with an average APACHE II score of 21 for all admissions over the same time period. One hundred twenty-six patients (90%) required invasive ventilation for a mean of 13 (SD 17) days, 102 (73%) required vasopressor support for a mean of 4 (SD 6) days, and 29 (21%) patients required new initiation of renal replacement therapy. The median ICU length of stay was 13 (IQR 5–27) days. Specimens were most commonly isolated from respiratory sources (66%) followed by skin or soft tissue (11%), urinary (10%), blood (5%), surgical (5%), and gastrointestinal (2%). One hundred one (72%) infections were nosocomial. The incidence of antimicrobial-susceptible specimens was 114 (81%); MDR specimens, 20 (14%); and XDR specimens, 6 (4%); there were no pan-resistant specimens (Figure 1). Thirty-four (24%) isolates were resistant to fluoroquinolones, 43 (31%) isolates were resistant to at least one carbapenem, and 35 (25%) were resistant to both imipenem and meropenem (Figure 2). Adequate empiric antimicrobial therapy was prescribed in 97 (69%) of cases.

Figure 1:

Figure 1:

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Isolate susceptibilities

MDR = Multi-drug resistant; XDR = Extensively drug resistant; PDR = Pan-drug resistant

Figure 2:

Figure 2:

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Resistance to fluoroquinolones and carbapenems

Overall, 32 patients (23%) died within 30 days of ICU admission, and 49 (35%) died in hospital. On univariate analysis, male sex (p = 0.008), liver disease (p = 0.034), active malignancy (p = 0.001), limitations in support based on code status (p = 0.019), nosocomial infection (p = 0.06), vasopressor support (p = 0.095), and APACHE II score (p = 0.001) differed between survivors and non-survivors. Of note, inadequate empiric antimicrobial therapy and antimicrobial resistance were not significantly different between survivors and non-survivors.

On multivariable analysis, liver disease (OR 6.2, 95% CI 1.5 to 25.7), malignancy (OR 5.0, 95% CI 1.5 to 17.3), and higher APACHE II scores (OR 1.1, 95% CI 1.0 to 1.1) were independently associated with higher 30-day mortality (Table 2). The C-statistic was 0.81, indicating a strong model.

Table 2:

Multivariable analysis for 30-day mortality

Variable Adjusted odds ratio 95% CI p-value
Male sex 1.5 0.56 to 4.23 0.40
Active malignancy 5.0 1.47 to 17.31 0.01
Chronic kidney disease 2.2 0.71 to 6.94 0.17
Liver disease 6.2 1.51 to 25.70 0.01
Goals of care 2.0 0.72 to 5.33 0.19
Nosocomial infection 0.4 0.14 to 1.15 0.09
Vasopressor support 1.6 0.46 to 5.25 0.48
APACHE II score 1.1 1.01 to 1.13 0.02
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Notes: Bold indicates statistical significance

APACHE II = Acute Physiology and Chronic Health Evaluation

Discussion

In this study, we describe the epidemiology and outcomes of critically ill patients with PA infection. Unlike previously published data, our 30-day mortality rate of 23% was lower than that anticipated for PA infection or gram-negative sepsis in an ICU population (20,25,26). However, our mean APACHE II score corresponds to a similar predicted mortality rate of 24% (non-surgical) (23). Previous local studies investigating gram-negative sepsis demonstrated a 30-day mortality rate of 35% but an average APACHE II score of 25 (25). This may also be secondary to an overrepresentation of colonized patients among our cohort, as a result of reliance on the intensivists’ clinical diagnosis rather than on strict laboratory, imaging, and clinical criteria. Our overall in-hospital mortality, however, was substantially higher at 35%.

The majority (66%) of PA isolates were from the respiratory tract, previously described as the most common site of ICU-acquired infection (27). Aside from nosocomial acquisition, previous studies identify risk factors for PA pneumonia as a history of COPD or other structural lung disease (28), solid cancer (29), previous antimicrobial exposure (29), and prior colonization with PA. In our population, structural lung disease was present in 49 (35%) cases, cystic fibrosis in 5 (4%) cases, and malignancy in 20 (14%) cases.

The most common non-pulmonary sites of infection in our cohort included skin or soft tissue in 15 (11%) cases, urinary tract in 14 (10%) cases, blood in 7 (5%) cases, and gastrointestinal tract in 7 (5%) cases. This distribution is consistent with a previous single-centre study that investigated carbapenem-resistant PA in critically ill people (5), but otherwise source percentages are seldomly described.

It is not surprising that the majority of cases were hospital acquired (72%). With regard to resistance, MDR isolates were relatively common (14%), but XDR was rare (6%). The incidence of MDR is in keeping with current North American estimates (17,30). Although most isolates were relatively susceptible, 34 (24%) were resistant to fluoroquinolones, and 35 (25%) were resistant to all carbapenems. It is concerning that appropriate empiric antimicrobial therapy was prescribed in only 69% of cases. Ineffective antimicrobial therapy in PA infection has been associated with higher mortality (20,31). Our present data did not demonstrate a correlation between mortality and ineffective empiric antimicrobial therapy; however, our study may have been underpowered to do so. Aggressive empiric therapy followed by de-escalation is in line with the Surviving Sepsis Campaign (32). Despite the lack of mortality signal in the present study, the lack of adequate empiric therapy does highlight the importance of maintaining a high clinical suspicion for PA, initiating antimicrobial therapy based on local susceptibility patterns, and tailoring therapy based on susceptibility results (33). Previous studies have suggested that all-cause mortality in patients with pseudomonal infection may be associated with prolonged ICU lengths of stay and subsequent complications (34,35) rather than being specifically infection related.

Pre-existing liver disease and active malignancy were both independently associated with mortality. In the literature, these two conditions have previously been associated with development of MDR PA infection (26,36) and with increased mortality (17,36). Previous studies have also identified chronic kidney disease (11) as a risk factor for mortality in PA infection, but our analysis did not demonstrate this. Again, this may be due to our relatively small sample size.

Despite its strengths, our study has several limitations. First, it is observational and retrospective; however, mortality data were available for all patients. Second, given the single-centre design, our data have limited generalizability. Third, we may have inadvertently included some patients colonized with PA rather than truly infected given our inability to apply strict clinical, radiographic, or biochemical criteria for infection. This could potentially have resulted in lower mortality rates. Fourth, we included only the first admission for each individual patient, which may downplay the importance of recurrent infection. Finally, our sample size was relatively small given a relatively low rate of pseudomonal infection over the 4 years of data collection.

Conclusion

PA is a common cause of infection in critically ill patients and may be challenging to treat given increasing resistance. The most common source of PA in our cohort of critically ill patients was the respiratory tract. Antimicrobial resistance was fairly low, with 14% MDR and 6% XDR isolates, but fluoroquinolone and carbapenem resistance was relatively high (24% and 25%, respectively). Only 69% of patients received adequate empiric antimicrobial therapy. Severity of critical illness (APACHE II score), chronic liver disease, and active malignancy were independently associated with 30-day mortality.

Funding:

No funding was received for this article.

Disclosures:

The authors have nothing to declare.

Informed Consent:

Informed consent was obtained from the patients.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A.

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