Baseline characteristics of the study population
Of the 3,465 screened patients, 461 patients were enrolled for analysis and classified into three group as follows: low-PA (n = 171), moderate-PA (n = 149), and high-PA (n = 141) groups (Fig. 1). The baseline characteristics are shown in Table 1. No significant differences were observed among the three groups in terms of demographic characteristics, admission category, and illness severity parameters. Almost half of the patients were admitted to the ICU for reasons such as respiratory failure, pneumonia, and septic shock. The most common comorbid condition was malignancy. Patients in the high-PA group were more likely to have respiratory disease (P < 0.01). The details of respiratory disease were as follows: chronic obstructive pulmonary disease, 42%; interstitial lung disease, 31.8%; bronchial asthma, 21.6%; and bronchiectasis, 12.5%. Laboratory findings at ICU admission showed that patients in the high-PA group had significantly higher mean blood glucose levels and more hyperglycemia than other groups (P < 0.01).
Clinical features and outcomes
The clinical features at the time-point when the peak density of PA was detected are presented in Table 2. The number of ETA performed after ICU admission until peak density of PA was detected was 2 (range 1–2) in the low-density group, 2 (1–3) in the moderate-density group, and 2 (1–4) in the high-density group, thus increasing with increased PA density. The frequency of VA-LRTI was less than 50% in the low-PA group, whereas it was about 80% in the moderate- and high-PA group. VAT accounted for about 70‒80% of VA-LRTI in each group, and the frequency of VAP tended to be higher in the high-PA group (P < 0.01). SOFA scores did not differ significantly among the three groups, whereas the CPIS tended to increase as the PA density increased. Levels of systemic inflammation markers, including white blood cell (WBC) count and C-reactive protein (CRP), were also higher in the high-PA group than in the other groups (P < 0.01). The CRP level in the moderate-density group was lower than that in the other two groups. Chest X-rays showed that pulmonary infiltrate lesions were more diffuse in the high-PA group.
In the ETA analysis, the number of neutrophil cells increased as the PA density increased (P < 0.01). Regarding pathogenic bacteria besides PA, counts of Stenotrophomonas maltophilia were slightly lower in the high-PA group. VFDs at 28 days and ICU mortality were worse in the higher density groups.
After adjustment by multivariate analysis, the high-PA group still had significantly worse clinical outcomes than the low-PA group (VFDs, adjusted coefficient B ‒1.94, 95% confidence interval [CI] ‒3.28 to ‒0.61, P < 0.01; ICU mortality, odds ratio [OR] 2.78, 95% CI 1.02‒7.58, P = 0.047), whereas the moderate-PA group did not differ significantly from the low-PA group.
Risk factors for a high density of P. aeruginosa in the airway
Table 3 presents risk factors associated with high-PA in univariate and multivariate analyses. Univariate logistic regression analysis revealed that longer duration (> 28 days) of MV, hyperglycemia, and use of non-antipseudomonal cephalosporins during the ICU stay were all significantly associated with high-PA in MV patients. Patients with commensal colonizers during their ICU stay had a lower risk of having high-PA. The main microorganisms among commensal colonizers were Candida spp. (34.1%), α-Streptococcus spp. (29.7%), and coagulase-negative staphylococci (14.3%). Marginal associations were observed for respiratory disease, low serum albumin levels at ICU admission, and use of antifungal antibiotics during the ICU stay.
Multivariate logistic regression analysis confirmed that independent risk factors for high-PA were longer duration (> 28 days) of MV (OR 3.07, 95% CI 1.35‒6.97, P < 0.01), use of non-antipseudomonal cephalosporins (OR 2.17, 95% CI 1.35‒3.49, P < 0.01), hyperglycemia (OR 2.01, 95% CI 1.26‒3.22, P < 0.01) during ICU stay, and respiratory diseases (OR 1.9, 95% CI 1.12‒3.23, P = 0.018). Isolation of commensal colonizers was independently associated with a lower risk of high-PA (OR 0.43, 95% CI 0.26‒0.73, P < 0.01).
Antibiotic therapy and outcomes
VFDs and ICU mortality in patients without VA-LRTI were similar in all groups, with median values of 20‒26 days and 4‒13%, respectively. Association of antibiotic therapy with outcomes in patients with VA-LRTI are shown in Table 4. In patients with VAT, VFDs in low- and moderate-PA groups did not vary significantly with appropriateness for antibiotic therapy. On the other hand, in the high-PA group, the number of VFDs in patients who received inappropriate antibiotic therapy (IAAT) was markedly lower than in those who received AAT. Patients with VAP had shorter VFDs, particularly in the moderate- and high-PA groups. ICU mortality tended to be decreased in VAP patients in the low- and moderate-PA groups who received AAT, as compared to those who did not (0‒16.7% vs. 45.5‒46.2%). Patients with high-PA VAP had a very high mortality rate, even with AAT (41.7%). We performed separate propensity score matching for VAT patients within each density group (Table 4, right panel). After matching, although not statistically significant due to the small numbers, AAT was also associated with an improvement in VFDs, but only in the high-PA group (median 0 vs. 17 days, P = 0.06), and not in the low- and moderate-PA groups. Kaplan–Meier analyses among matched patients showed that weaning from MV was almost identical between AAT and IAAT in both the low- and moderate-PA groups, while, in the high-PA group, a lower and later incidence of weaning success were observed with IAAT as compared to with AAT (Fig. 2).