# Characteristics of Pseudomonas aeruginosa infection in intensive care unit before (2007–2010) and after (2011–2014) the beginning of an antimicrobial stewardship program

Alessio Strazzulla, Vladimir Adrien, Segla Robert Houngnandan, Sandra Devatine, Ouerdia Bahmed, Sarra Abroug, Sarra Hamrouni, Mehran Monchi, Sylvain Diamantis

► To cite this version:

Alessio Strazzulla, Vladimir Adrien, Segla Robert Houngnandan, Sandra Devatine, Ouerdia Bahmed, et al.. Characteristics of Pseudomonas aeruginosa infection in intensive care unit before (2007–2010) and after (2011–2014) the beginning of an antimicrobial stewardship program. Antimicrobial Stewardship & Healthcare Epidemiology, 2024, 4 (1), pp.e60. 10.1017/ash.2024.53 . hal-05219662

HAL Id: hal-05219662

https://hal.science/hal-05219662v1

Submitted on 22 Aug 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Original Article

Characteristics of *Pseudomonas aeruginosa* infection in intensive care unit before (2007–2010) and after (2011–2014) the beginning of an antimicrobial stewardship program

Alessio Strazzulla MD<fnref n="1" /> ID, Vladimir Adrien MD²,³ ID, Segla Robert Houngnandan MD<fnref n="1" />, Sandra Devatine MD², Ouerdia Bahmed MD<fnref n="1" />, Sarra Abroug MD<fnref n="1" />, Sarra Hamrouni MD<fnref n="1" />, Mehran Monchi MD⁴ ID and Sylvain Diamantis MD<fnref n="1" />,²,⁵

Abstract

Objectives: To investigate the factors associated with *Pseudomonas aeruginosa* isolates in intensive care unit (ICU) before and after an antimicrobial stewardship program.

Materials: Monocentric retrospective cohort study. Patients admitted to the ICU in 2007–2014 were included. Characteristics of *P. aeruginosa* patients were compared to overall ICU population. Clinical and microbiological characteristics of *P. aeruginosa* patients before (2007–2010) and after (2011–2014) the beginning of the AMP were compared.

Results: Overall, 5,263 patients were admitted to the ICU, 274/5,263 (5%) had a *P. aeruginosa* isolate during their staying. In 2011–2014, the percentage *P. aeruginosa* isolates reduced (7% vs 4%, P ≤ .0001). Patients with *P. aeruginosa* had higher rates of in-hospital death (43% vs 20%, P < .0001) than overall ICU population. In 2011–2014, rates of multidrug-resistant (11% vs 2%, P = .0020), fluoroquinolone-resistant (35% vs 12%, P < .0001), and ceftazidime-resistant (23% vs 8%, P = .0009) *P. aeruginosa* reduced. Treatments by fluoroquinolones (36% vs 4%, P ≤ .0001), carbapenems (27% vs 9%, P = .0002), and third-generation cephalosporins (49% vs 12%, P ≤ .0001) before *P. aeruginosa* isolation reduced while piperacillin (0% vs 13%, P < .0001) and trimethoprim-sulfamethoxazole (8% vs 26%, P = .0023) increased. Endotracheal intubation reduced in 2011–2014 (61% vs 35%, P < .0001). Fluoroquinolone-resistance was higher in patients who received endotracheal intubation (29% vs 17%, P = .0197). Previous treatment by fluoroquinolones (OR = 2.94, P = .0020) and study period (2007–2010) (OR = 2.07, P = .0462) were the factors associated with fluoroquinolone-resistance at the multivariate analysis.

Conclusions: Antibiotic susceptibility in *P. aeruginosa* isolates was restored after the reduction of endotracheal intubation, fluoroquinolones, carbapenems, and third-generation cephalosporins and the increased use of molecules with a low ecological footprint, as piperacillin and trimethoprim-sulfamethoxazole.

(Received 14 August 2023; accepted 15 March 2024)

Introduction

*Pseudomonas aeruginosa* can be responsible of life-threatening diseases, as a consequence of urinary, bone, respiratory, abdominal, and disseminated infections.<fnref n="1" /> It colonizes human body, being part of the human microbiota (especially in the respiratory tract), and it can also be acquired from exogenous sources.² Patients hospitalized in intensive care unit (ICU) are at risk of contamination. Potential exogenous sources are tap-water and fomites while patient-to-patient transmission is possible but it

can be limited by standard precautions.³ Antibiotic pressure is the most relevant factor for *P. aeruginosa* acquisition in ICU.⁴

At each antibiotic treatment, germs of the human microbiota are exposed to sub-lethal levels of antibiotics. This event enhances the selection of antibiotic resistance genes, which often are host in transferable plasmids.⁵ Otherwise, the antibiotic pressure can trigger chromosomal mutations and transfer of resistance determinants, as is typical for *P. aeruginosa*.⁶ Because of the risk of antibiotic resistance, the use of broad-spectrum molecules is currently discouraged as antibiotic prophylaxis and treatment.⁷ The benefits in terms of antimicrobial susceptibility resulting from the reduced consumption of broad-spectrum molecules in ICU was largely demonstrated for gram-negative bacilli.⁸ However, the results of antimicrobial stewardship programs (ASPs) in ICU concerning *P. aeruginosa* are often deceiving with no significant reduction of antimicrobial resistance rates.⁹⁻¹¹

<footnote n="1">¹Internal and General Medicine Unit, Groupe Hospitalier Sud Ile de France, Melun, France, ²Infectious Diseases Unit, Groupe Hospitalier Sud Ile de France, Melun, France, ³Department of Infectious and Tropical Diseases, Avicenne Hospital, AP-HP, Université Sorbonne Paris Nord, Bobigny, France, ⁴Intensive Care Unit, Groupe Hospitalier Sud Ile de France, Melun, France and ⁵EA 7380 Dynamic, Université Paris Est Créteil, EnvA, USC ANSES, Créteil, France</footnote>

<footnote>**Corresponding author:** Alessio Strazzulla; Email: alessio.strazzulla@ghsif.fr

**Cite this article:** Strazzulla A, Adrien V, Houngnandan SR, et al. Characteristics of *Pseudomonas aeruginosa* infection in intensive care unit before (2007–2010) and after (2011–2014) the beginning of an antimicrobial stewardship program. *Antimicrob Steward Healthc Epidemiol* 2024. doi: 10.1017/ash.2024.53</footnote>
At the end of 2010, an ASP started at the ICU of the Melun General Hospital, a 350-bed tertiary care hospital in the Ile-de-France region in France, its ICU accounting for a total of 24 beds. The main objective of the ASP was to restrain the consumption of broad-spectrum molecules (carbapenems, fluoroquinolones (FLQ), and third-generation cephalosporins (3-GC)). This objective was fully achieved. Indeed, a reduction of 50%–85% in the consumption of carbapenems, FLQ, and 3-GC was observed in the following 4-year period (from 2011 to 2014) when compared to the previous one (from 2007 to 2010). Contemporarily, a reduction of AmpC hyperproducing group 3 Enterobacteriaceae, FLQ resistant, and ceftazidime resistant *P. aeruginosa* was observed.¹²

This study pursues the previous one through a *P. aeruginosa* targeted analysis. It investigates the factors associated with isolation of *P. aeruginosa* from ICU patients before and after the beginning of the ASP, with a special focus on the risk of antibiotic-resistance and the benefits produced by the ASP in terms of antibiotic susceptibility recovering.

## Materials and methods

A monocentric retrospective cohort study was conducted at Melun General Hospital, a 350 tertiary bed hospital in Melun (France). Patients were hospitalized in ICU, accounting for 24 beds. All adult patients admitted to the ICU presenting *P. aeruginosa* isolates during their hospitalization in ICU from January the 1st, 2007 to December 31st, 2014 were included. Two timeframes were analyzed: (1) before the beginning of the ASP (2007–2010); (2) after the beginning of the ASP (2011–2014).

The previous study by Abbara *et al* already evaluated the susceptibility of all *P. aeruginosa* isolated from any site in patients hospitalized in ICU during the same study period. It focused on resistance to single molecules and did not explored the factors associated with *P. aeruginosa* isolation.¹² For this study, we revised all ICU patient's files and selected patients with *P. aeruginosa* isolation from any site during ICU stay and up to 7 days after ICU discharge to explore the possible late impact of ICU stay on *P. aeruginosa* selection. We included all *P. aeruginosa* isolates, both infections and colonizations, while in the previous study only isolates of clinical significance were included. We also added analysis about multidrug resistant (MDR) *P. aeruginosa*. The characteristics of patients with *P. aeruginosa* isolation were compared to ICU population and an analysis before/after intervention was performed.

The study was conducted in accordance with Declaration of Helsinki and national and institutional standards.¹³

Data were obtained through the revision of patients' files which were collected in software used in daily clinical practice (Sillage v17 and CGM Lab channel 1.20.33686). Microbiological identifications and susceptibility tests were performed according to recommendations of the European committee on antimicrobial susceptibility testing.¹⁴ The following outcomes were considered: (1) acquisition MDR bacteria; (2) length of ICU stay; (3) length of hospital stay; (4) in-ICU death; and (5) in-hospital death.

Fisher's exact test (qualitative variables) and Student's t-test (quantitative variables) were applied for the univariate analysis. At first, characteristics of *P. aeruginosa* patients were compared to overall ICU population. Then, clinical and microbiological characteristics of *P. aeruginosa* patients before (2007–2010) and after (2011–2014) the beginning of the AMP were compared. Analysis according to the origin of the infection (community acquired vs hospital acquired) was also performed. Logistic

regression analysis was performed for multivariate analysis. For the multivariate analysis of risk factors of FLQ resistance the parameters included in the analysis were chosen according to univariate analysis results ($P \le .0001$). For the analysis of the risk of MDR *P. aeruginosa* only the exposition to any class of antibiotics was considered. Statistical significance was set at $P < .050$.

## Results

Overall, 5,263 patients were admitted to the ICU during the study period (2007–2014), 274/5263 (5%) having at least a *P. aeruginosa* isolate during hospitalization in ICU and up to 7 days after ICU discharge. The percentage of patients with *P. aeruginosa* isolates reduced significantly before and after the ASP (7% in 2007–2010 vs 4% in 2011–2014, $P \le .0001$). Patients with *P. aeruginosa* had longer hospital stays and higher rates of in-hospital and in-ICU death ($P < .0001$) than overall ICU population. They received endotracheal intubation more frequently than patients without *P. aeruginosa* isolates ($P < .0001$). Table 1 resumes characteristics of the study population.

In 2011–2014, rates of multidrug-resistant, fluoroquinolone-resistant, and ceftazidime-resistant *P. aeruginosa* reduced significantly ($P = .0020$, $P < .0001$ and $P = .0009$, respectively). Rates of antibiotic treatments by FLQ, carbapenems, and 3-GC before *P. aeruginosa* isolation reduced significantly in 2011–2014 ($P \le .0002$). Simultaneously, use of piperacillin (without tazobactam) and trimethoprim-sulfamethoxazole (TMP-SMX) increased ($P < .0001$ and $P = .0023$, respectively). *P. aeruginosa* patients received endotracheal intubation and mechanical ventilation less frequently in 2011–2014 than 2007–2010. Also, the length of hospital and ICU stay decreased during the same period ($P < 0.0001$ and $P = 0.08$, respectively). Table 2 shows characteristics of the population with *P. aeruginosa* isolates.

Patients with hospital acquired *P. aeruginosa* had higher rates of endotracheal intubation ($P < .0001$), central venous catheter ($P = .0316$), and previous FLQ treatment ($P = .0059$) than patients with community acquired *P. aeruginosa*. Sepsis was more frequent ($P = .0063$) among patient with community acquired *P. aeruginosa* than patients with hospital acquired *P. aeruginosa* (Table 3).

The univariate analysis showed that patients who received endotracheal intubation had higher rates of fluoroquinolone resistant *P. aeruginosa* isolation ($P = .0197$; Table 4). At the multivariate analysis, the factors associated with fluoroquinolone-resistance were study period (2007–2010) and previous treatment by fluoroquinolones ($P = 0.0020$ and $P = 0.0462$, respectively), as shown in Table 5. No previous use of any class of antibiotics was associated with the risk of MDR *P. aeruginosa* (Table 6).

## Discussion

This study showed that the frequency of *P. aeruginosa* infection in ICU reduced after the beginning of an ASP, principally based on saving of broad-spectrum antibiotics. The antimicrobial susceptibility of *P. aeruginosa* recovered after the reduction of 3-GC and fluoroquinolone consumption and the increased prescription of alternative “old” molecules, such as piperacillin and trimethoprim-sulfamethoxazole. Endotracheal intubation was associated with FLQ resistance.

Although ASP are strongly recommended, reducing antibiotic consumption in ICU is extremely difficult because patients' uncertain diagnosis and compromised hemodynamic state push prescribers keeping long-course broad-spectrum antibiotic
<table><caption>**Table 1.** Characteristics of the population</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Pseudomonas aeruginosa</th><th rowspan="2">P value</th></tr><tr><th>No<br>n = 4,989</th><th>Yes<br>n = 274</th></tr></thead><tbody><tr><td>Median age, years [min-max]</td><td>65 [51-78]</td><td>73 [58-81]</td><td>&lt;.0001</td></tr><tr><td>Male gender, n [%]</td><td>2,929 [57]</td><td>180 [64]</td><td>&lt;.0001</td></tr><tr><td>SAPS-II at ICU admission, mean [%]</td><td>39.7 [25.4]</td><td>48.8 [18.8]</td><td>.59</td></tr><tr><td>Fluid resuscitation, n [%]</td><td>1004 [20]</td><td>63 [23]</td><td>.14</td></tr><tr><td>Renal replacement therapy, n [%]</td><td>390 [8]</td><td>44 [16]</td><td>&lt;.0001</td></tr><tr><td>Vasopressors, n [%]</td><td>1590 [32]</td><td>172 [63]</td><td>&lt;.0001</td></tr><tr><td>Central venal catheter, n [%]</td><td>2169 [43]</td><td>215 [78]</td><td>&lt;.0001</td></tr><tr><td>Endotracheal intubation, n [%]</td><td>887 [18]</td><td>130 [47]</td><td>&lt;.0001</td></tr><tr><td>MV with PEEP ≤ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≤ 60%, n [%]</td><td>1293 [26]</td><td>147 [54]</td><td>&lt;.0001</td></tr><tr><td>MV with PEEP ≥ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≥ 60%, n [%]</td><td>1202 [24]</td><td>140 [51]</td><td>&lt;.0001</td></tr><tr><td>MV with PEEP ≥ 6 and FiO<sub>2</sub> ≥ 60% cmH<sub>2</sub>O and ventral decubitus, n [%]</td><td>80 [1.6]</td><td>10 [4]</td><td>.0182</td></tr><tr><td>ICU length of stay, days, mean [SD]</td><td>3.2 [6.1]</td><td>9.1 [16.9]</td><td>&lt;.0001</td></tr><tr><td>Hospital length of stay, days, mean [SD]</td><td>15.2 [19.1]</td><td>41.3 [40.4]</td><td>&lt;.0001</td></tr><tr><td>In-ICU death, n [%]</td><td>840 [17]</td><td>102 [37]</td><td>&lt;.0001</td></tr><tr><td>In-hospital death, n [%]</td><td>995 [20]</td><td>118 [43]</td><td>&lt;.0001</td></tr></tbody></table>

Note. CI, confidence interval; ICU, intensive care unit; FiO2, fraction of inspired oxygen; MV, mechanical ventilation; PEEP, positive end-expiratory pressure; RR, related ratio; SAPS-II, simplified acute physiology score-II; SD, standard deviation.

treatments. A consequence of this attitude is an increased risk of *P. aeruginosa* infection which occurs almost exclusively in patients who received a previous antibiotic treatment.¹⁵ In fact, broad-spectrum antibiotics interact with the environment and facilitate *P. aeruginosa* acquisition.⁴ Our ASP succeeded in reducing both *P. aeruginosa* antibiotic resistance and infection incidence. One of the key of this success was the increased use of molecules with low ecological footprint to treat infections others than *P. aeruginosa*.

The use of FLQ as empirical treatment for *P. aeruginosa* is inadvisable because of the risk of treatment failure and the increased mortality due to the development of antibiotic resistance.¹⁶ Indeed, *P. aeruginosa* has many mechanisms of resistance, frequently based on *GyrA*, *ParC*, and *MexR* enzymes.¹⁷ In ICU setting, an important virulence and resistance factor is biofilm which contributes reducing susceptibility to antimicrobial molecules and host-immune factors.¹⁸ This effect disappears when bacteria are deprived of the capacity of producing the extracellular matrix made by polysaccharides, proteins, and metabolites.¹⁹ As a consequence, biofilm reduces antibiotic efficacy by several mechanisms: reduction of antibiotic penetration, microenvironment modifications, and increased inflammatory response.²⁰ FLQ activity is largely limited by biofilm production.²¹ In ICU, the main sources of biofilm producing *P. aeruginosa* are invasive devices.⁴ Moreover, endotracheal intubation is the most relevant determinant of *P. aeruginosa* acquisition and ventilator-associated pneumonia (VAP).²² The restriction of endotracheal intubation was adopted in our ICU to reduce respiratory infection rate. It was obtained through new standard of care, such as protocol-based sedation, favoring noninvasive ventilation over invasive ventilation whenever possible, and improved ventilation weaning process in mechanical ventilation. No change in devices and patient admission policy was adopted during the study period. Results of this study are in line with other studies which showed that

restriction of endotracheal intubation was associated with reduction of mortality and MDR bacterial infection.²³,²⁴ This study showed that previous FLQ treatment was associated with FLQ resistance in *P. aeruginosa* strains afterward isolated. It also showed that patients who received endotracheal intubation had higher rates of FLQ resistance. We can hypothesize that the reduction of endotracheal intubation observed from 2011 to 2014 could have contributed in reducing rates of FLQ resistant *P. aeruginosa*. This study advocates against the use of FLQ in intubated patients because of the increased risk of FLQ resistance in *P. aeruginosa* strains.

FLQ are frequently prescribed for atypical pneumonia and intracellular bacterial infections but their collateral damages in term of selection of MDR bacterial impose their limitation as empirical antibiotic treatment. For this reason, our ASP suggested macrolides as alternative molecules.¹² Indeed, macrolides can be preferred to FLQ in many situations. At first, macrolides are not inferior to FLQ for the treatment of *Legionella* pneumonia.²⁵ Second, the treatment of severe community acquired pneumonia with beta-lactam plus macrolides resulted more effective than treatment with FLQ alone in reducing mortality and length of hospitalization in ICU.²⁶ Third, because of their immunomodulatory effects, macrolides are an interesting alternative for the treatment of low respiratory tract infections in patients affected by chronic respiratory diseases.²⁷ In this study, macrolides contributed to reduce FLQ prescriptions.

Piperacillin is a broad-spectrum beta-lactam. It is active against gram-positive bacteria and it shows high activity against gram-negative bacilli, both aerobic and anaerobic (*Klebsiella pneumoniae*, *Serratia marcescens*, and *P. aeruginosa*).²⁸ It is hydrolyzed by beta-lactamases (as TEM-1) and, therefore, it is almost always administrated in association with tazobactam, a beta-lactamase inhibitor which successfully restores the activity of piperacillin
<table><caption>**Table 2.** Characteristics of patients with *Pseudomonas aeruginosa* isolates</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="3">Pseudomonas aeruginosa</th><th rowspan="2">P value</th></tr><tr><th>Overall<br>n = 274</th><th>2007-2010<br>n = 132</th><th>2011-2014<br>n = 142</th></tr></thead><tbody><tr><td><strong>Patients' biological parameters and medical history</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Median age, years [min-max]</td><td>72.5 [58-81]</td><td>75 [60.5-82]</td><td>70 [59-78.5]</td><td>.02</td></tr><tr><td>Male gender, n [%]</td><td>177 [65]</td><td>77 [57]</td><td>100 [70]</td><td>.02</td></tr><tr><td>Chronic obstructive pulmonary disease, n [%]</td><td>89 [32]</td><td>49 [37]</td><td>40 [28]</td><td>.07</td></tr><tr><td>Alcohol addiction, n [%]</td><td>43 [16]</td><td>26 [20]</td><td>17 [12]</td><td>.06</td></tr><tr><td>Diabetes, n [%]</td><td>59 [22]</td><td>32 [24]</td><td>27 [19]</td><td>.18</td></tr><tr><td>Immunodepression, n [%]</td><td>24 [9]</td><td>4 [3]</td><td>20 [14]</td><td>.0007</td></tr><tr><td>Traumatic brain injury, n [%]</td><td>16 [5.8]</td><td>9 [7]</td><td>7 [5]</td><td>.34</td></tr><tr><td>Wounds, n [%]</td><td>82 [30]</td><td>36 [27]</td><td>46 [32]</td><td>.21</td></tr><tr><td><strong>Hospital stay in ICU</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>SAPS-II at ICU admission, mean [SD]</td><td>48.7 [19.8]</td><td>48.6 [20.7]</td><td>48.8 [18.9]</td><td>.93</td></tr><tr><td>Fluid resuscitation, n [%]</td><td>63 [23]</td><td>10 [8]</td><td>53 [37]</td><td>&lt;.0001</td></tr><tr><td>Renal replacement therapy, n [%]</td><td>44 [16]</td><td>7 [5]</td><td>37 [26]</td><td>&lt;.0001</td></tr><tr><td>Vasopressors, n [%]</td><td>172 [63]</td><td>94 [71]</td><td>78 [55]</td><td>.0042</td></tr><tr><td>Central venal catheter, n [%]</td><td>215 [78]</td><td>118 [89]</td><td>97 [68]</td><td>&lt;.0001</td></tr><tr><td>Continued noninvasive ventilation, n [%]</td><td>10 [4]</td><td>2 [2]</td><td>8 [6]</td><td>.07</td></tr><tr><td>Endotracheal intubation, n [%]</td><td>130 [47]</td><td>80 [61]</td><td>50 [35]</td><td>&lt;.0001</td></tr><tr><td>MV with PEEP ≤ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≤ 60%, n [%]</td><td>147 [54]</td><td>96 [73]</td><td>51 [36]</td><td>&lt;.0001</td></tr><tr><td>MV with PEEP ≥ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≥ 60%, n [%]</td><td>140 [51]</td><td>68 [52]</td><td>72 [51]</td><td>.49</td></tr><tr><td>MV with PEEP ≥ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≥ 60% and ventral decubitus, n [%]</td><td>10 [4]</td><td>1 [1]</td><td>9 [6.3]</td><td>.0132</td></tr><tr><td>Length of invasive mechanical ventilation, days, mean [SD]</td><td>22.5 [24.3]</td><td>29.7 [29.8]</td><td>15.9 [14.8]</td><td>&lt;.0001</td></tr><tr><td>Length of intratracheal intubation, days, mean [SD]</td><td>14.5 [13.2]</td><td>16.6 [13.3]</td><td>12.5 [12.8]</td><td>.0168</td></tr><tr><td><strong>Previous antibiotic treatments</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Antibiotic treatment before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>247 [90]</td><td>122 [92]</td><td>125 [88]</td><td>.22</td></tr><tr><td>Amoxicillin/clavulanic acid before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>68 [25]</td><td>38 [29]</td><td>30 [21]</td><td>.14</td></tr><tr><td>Piperacillin before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>18 [7]</td><td>0 [0]</td><td>18 [13]</td><td>&lt;.0001</td></tr><tr><td>Piperacillin/tazobactam before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>104 [38]</td><td>44 [33]</td><td>60 [42]</td><td>.13</td></tr><tr><td>Ceftriaxone/cefotaxime before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>53 [19]</td><td>39 [30]</td><td>14 [10]</td><td>&lt;.0001</td></tr><tr><td>Ceftazidime before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>29 [11]</td><td>26 [20]</td><td>3 [2]</td><td>&lt;.0001</td></tr><tr><td>Cefepime before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>3 [1]</td><td>1 [1]</td><td>1 [1]</td><td>NA</td></tr><tr><td>Carbapenem before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>48 [18]</td><td>35 [27]</td><td>13 [9]</td><td>.0002</td></tr><tr><td>Aminoglycoside before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>123 [45]</td><td>57 [51]</td><td>56 [39]</td><td>.06</td></tr><tr><td>Glycopeptide before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>50 [18]</td><td>40 [30]</td><td>10 [7]</td><td>&lt;.0001</td></tr><tr><td>Fluoroquinolone before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>54 [20]</td><td>48 [36]</td><td>6 [4]</td><td>&lt;.0001</td></tr><tr><td>Macrolide/lincosamide before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>38 [14]</td><td>9 [7]</td><td>29 [20]</td><td>.0011</td></tr><tr><td>Trimethoprim/sulfamethoxazole before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>47 [17]</td><td>10 [8]</td><td>37 [26]</td><td>.0023</td></tr><tr><td>Tetracyclines before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>2 [1]</td><td>1 [1]</td><td>1 [1]</td><td>NA</td></tr><tr><td>Colistin before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>17 [6]</td><td>15 [11]</td><td>2 [1]</td><td>.0006</td></tr><tr><td>Other molecules* before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>26 [9]</td><td>10 [8]</td><td>16 [11]</td><td>.30</td></tr><tr><td><strong>Risk factors of MDR <i>Pseudomonas aeruginosa</i></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Antibiotic therapy &lt;6 mo, n [%]</td><td>93 [34]</td><td>45 [34]</td><td>48 [34]</td><td>.53</td></tr><tr><td>Hospitalization &lt;6 mo, n [%]</td><td>123 [45]</td><td>63 [48]</td><td>60 [42]</td><td>.22</td></tr><tr><td>Other infection than <i>Pseudomonas aeruginosa</i>, n [%]</td><td>188 [69]</td><td>96 [73]</td><td>92 [65]</td><td>.1</td></tr></tbody></table>

(Continued)
<table><caption>**Table 2.** (Continued)</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="3">Pseudomonas aeruginosa</th><th rowspan="2">P value</th></tr><tr><th>Overall<br>n = 274</th><th>2007-2010<br>n = 132</th><th>2011-2014<br>n = 142</th></tr></thead><tbody><tr><td>Previous Pseudomonas aeruginosa infection, n [%]</td><td>22 [8]</td><td>9 [7]</td><td>13 [9]</td><td>.31</td></tr><tr><td colspan="5"><strong>Characteristics of Pseudomonas aeruginosa isolates</strong></td></tr><tr><td>Δ date of ICU admission - date of Pseudomonas aeruginosa isolation, mean [SD]</td><td>10 [30]</td><td>13 [35]</td><td>8 [23]</td><td>.1618</td></tr><tr><td>Pseudomonas aeruginosa isolation &gt; day 7 of stay in ICU, n [%]</td><td>84 [31]</td><td>39 [30]</td><td>45 [42]</td><td>.67</td></tr><tr><td>Pseudomonas aeruginosa colonization, n [%]</td><td>95 [35%]</td><td>39 [30%]</td><td>56 [39%]</td><td>.055</td></tr><tr><td>Pseudomonas aeruginosa infection, n [%]</td><td>179 [65%]</td><td>93 [70%]</td><td>86 [61%]</td><td>.055</td></tr><tr><td>Pseudomonas aeruginosa in respiratory tract, n [%]</td><td>120 [44]</td><td>58 [44]</td><td>62 [44]</td><td>.45</td></tr><tr><td>Pseudomonas aeruginosa in bloodstream, n [%]</td><td>13 [5]</td><td>6 [5]</td><td>7 [5]</td><td>.86</td></tr><tr><td>Pseudomonas aeruginosa in urine, n [%]</td><td>36 [13]</td><td>16 [12]</td><td>20 [14]</td><td>.53</td></tr><tr><td>Pseudomonas aeruginosa in other sites**, n [%]</td><td>24 [9]</td><td>12 [9]</td><td>12 [9]</td><td>.56</td></tr><tr><td>Pseudomonas aeruginosa VAP, n [%]</td><td>92 [34]</td><td>44 [33]</td><td>48 [34]</td><td>.52</td></tr><tr><td>Pseudomonas aeruginosa sepsis, n [%]</td><td>24 [10]</td><td>12 [9]</td><td>12 [8.5]</td><td>.51</td></tr><tr><td>Ceftazidime resistant Pseudomonas aeruginosa, n [%]</td><td>41 [15]</td><td>30 [23]</td><td>11 [8]</td><td>.0009</td></tr><tr><td>Ceftazidime resistant Pseudomonas aeruginosa &gt; day 7 of stay, n [%]</td><td>8 [3]</td><td>7 [5]</td><td>1 [1]</td><td>.93</td></tr><tr><td>Imipenem resistant Pseudomonas aeruginosa, n [%]</td><td>37 [14]</td><td>21 [16]</td><td>16 [11]</td><td>.26</td></tr><tr><td>Imipenem resistant Pseudomonas aeruginosa &gt; day 7 of stay, n [%]</td><td>9 [3]</td><td>5 [4]</td><td>4 [3]</td><td>.28</td></tr><tr><td>Fluoroquinolone resistant Pseudomonas aeruginosa, n [%]</td><td>63 [23]</td><td>46 [35]</td><td>17 [12]</td><td>&lt;.0001</td></tr><tr><td>Fluoroquinolone resistant Pseudomonas aeruginosa &gt; day 7 of stay, n [%]</td><td>5 [14]</td><td>10 [8]</td><td>4 [3]</td><td>.91</td></tr><tr><td>MDR Pseudomonas aeruginosa, n [%]</td><td>18 [7]</td><td>15 [11]</td><td>3 [2]</td><td>.0020</td></tr><tr><td>MDR Pseudomonas aeruginosa &gt; day 7 of stay, n [%]</td><td>4 [1]</td><td>3 [2]</td><td>1 [1]</td><td>.61</td></tr><tr><td colspan="5"><strong>Outcomes</strong></td></tr><tr><td>Overall MDR bacteria, n [%]</td><td>74 [27]</td><td>43 [33]</td><td>31 [22]</td><td>.03</td></tr><tr><td>Hospital acquired MDR bacteria, n [%]</td><td>37 [14]</td><td>22 [17]</td><td>15 [11]</td><td>.1</td></tr><tr><td>ICU length of stay (days), mean [SD]</td><td>9.1 [16.9]</td><td>11 [20.3]</td><td>7.4 [12.7]</td><td>.08</td></tr><tr><td>Hospital length of stay (days), mean [SD]</td><td>41.3 [40.4]</td><td>53 [50.7]</td><td>30.3 [22.9]</td><td>&lt;.0001</td></tr><tr><td>In-ICU death, n [%]</td><td>102 [37]</td><td>47 [36]</td><td>55 [39]</td><td>.34</td></tr><tr><td>In-hospital death, n [%]</td><td>118 [43]</td><td>53 [40]</td><td>65 [46]</td><td>.21</td></tr></tbody></table>

Note. *including: linezolid, fosfomycin, daptomycin, rifampicin; **including: purulent lesions, cutaneous biopsies, vascular catheter, bone biopsies, coprocultures and peritoneal fluids; CI, confidence interval; ICU, intensive care unit; FIO₂, fraction of inspired oxygen; MDR, multidrug resistant; MV, mechanical ventilation; NA, not applicable; PEEP, positive end-expiratory pressure; RR, related ratio; SAPS-II, simplified acute physiology score-II; SD, standard deviation; VAP, ventilator associated pneumonia.

against many beta-lactamases.²⁹ However, *P. aeruginosa* may rapidly develop resistance to tazobactam by the production of extended spectrum beta-lactamases and AmpC beta-lactamases.³⁰ The use of piperacillin “alone” without the adding of tazobactam for documented infection caused by gram-negative bacteria was adopted in our ICU with the rationale of sparing tazobactam and, therefore, reducing the antimicrobial selective pressure on targeted pathogens, bacteria of the human microbiota and invasive device’s contaminants. Results of this study suggest that this strategy could have contributed in reducing rates of MDR and ceftazidime resistant *P. aeruginosa* strains. Further studies are needed to confirm this hypothesis.

TMP-SMX represents an alternative to FLQ and beta-lactams for the treatment of infection by gram-negative (*Enterobacteriaceae*) and gram-positive (*Staphylococcus aureus*) bacteria, although it is not active against *P. aeruginosa*. In France, it is currently the first choice for treatment of documented urinary infection according to French national recommendations.³¹ In our establishment, TMP-SFX is

successfully used for the treatment of VAP by bacteria other than *P. aeruginosa*.³² According to our ASP, TMP-SMX was preferred to FLQ and beta-lactams whenever the antimicrobial susceptibility test confirmed the sensibility to TMP-SMX. Aim of this choice was to reduce antibiotic “collateral damages” and in particular the selection of MDR bacteria. The reduction of *P. aeruginosa*'s resistance rates to FLQ and beta-lactams was likely influenced by the reduced consumption of broad-spectrum molecules (FLQ and 3-GC) and their replacement by molecules with a lower ecological footprint, such as TMP-SMX and piperacillin.

Results of this study were limited by its retrospective design. Indeed, a loss of data was expected and direct comparison between molecules were not possible. Also, a longer period analysis was necessary to confirm the positive results of the ASP. Because of the study design, the number of variables was limited and many factors potentially associated with *P. aeruginosa* isolation were not investigated. Notwithstanding, results of this study are encouraging and justify the pursue of exploration by further studies. In particular,
<table><caption>**Table 3.** Characteristics of patients with *Pseudomonas aeruginosa* isolates</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="3">Pseudomonas aeruginosa</th><th rowspan="2">P value</th></tr><tr><th>Overall<br>n = 274</th><th>Nosocomial<br>n = 213</th><th>Community acquired<br>n = 61</th></tr></thead><tbody><tr><td colspan="5"><strong>Patients' biological parameters and medical history</strong></td></tr><tr><td>Median age, years [min-max]</td><td>72.5 [58-81]</td><td>72 [15-92]</td><td>74 [33-91]</td><td>.02</td></tr><tr><td>Male gender, n [%]</td><td>180 [64]</td><td>137 [65]</td><td>40 [66]</td><td>.49</td></tr><tr><td>Chronic obstructive pulmonary disease, n [%]</td><td>89 [32]</td><td>69 [33]</td><td>20 [33]</td><td>.53</td></tr><tr><td>Alcohol addiction, n [%]</td><td>43 [16]</td><td>36 [17]</td><td>7 [12]</td><td>.21</td></tr><tr><td>Diabetes, n [%]</td><td>59 [22]</td><td>50 [24]</td><td>9 [15]</td><td>.10</td></tr><tr><td>Traumatic brain injury, n [%]</td><td>16 [5.8]</td><td>14 [7]</td><td>2 [13]</td><td>.26</td></tr><tr><td>Wounds, n [%]</td><td>82 [30]</td><td>64 [30]</td><td>18 [29]</td><td>.53</td></tr><tr><td colspan="5"><strong>Hospital stay in ICU</strong></td></tr><tr><td>SAPS-II at ICU admission, mean [SD]</td><td>48.7 [19.8]</td><td>47.7 [18.6]</td><td>51.9 [23.1]</td><td>.10</td></tr><tr><td>Fluid resuscitation, n [%]</td><td>63 [23]</td><td>42 [20]</td><td>21 [34]</td><td>.0146</td></tr><tr><td>Renal replacement therapy, n [%]</td><td>44 [16]</td><td>33 [16]</td><td>11 [18]</td><td>.38</td></tr><tr><td>Vasopressors, n [%]</td><td>172 [63]</td><td>138 [65]</td><td>34 [56]</td><td>.13</td></tr><tr><td>Central venal catheter, n [%]</td><td>215 [78]</td><td>173 [81]</td><td>42 [68]</td><td>.0316</td></tr><tr><td>Continued non-invasive ventilation, n [%]</td><td>10 [4]</td><td>8 [4]</td><td>2 [3]</td><td>.61</td></tr><tr><td>Endotracheal intubation, n [%]</td><td>130 [47]</td><td>117 [55]</td><td>13 [21]</td><td>&lt;.0001</td></tr><tr><td>MV with PEEP ≤ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≤ 60%, n [%]</td><td>147 [54]</td><td>125 [59]</td><td>22 [36]</td><td>.0014</td></tr><tr><td>MV with PEEP ≥ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≥ 60%, n [%]</td><td>140 [51]</td><td>11 [52]</td><td>29 [48]</td><td>.31</td></tr><tr><td>MV with PEEP ≥ 6 cmH<sub>2</sub>O and FiO<sub>2</sub> ≥ 60% and ventral decubitus, n [%]</td><td>10 [4]</td><td>10 [5]</td><td>0 [0.0]</td><td>.07</td></tr><tr><td>Length of invasive mechanical ventilation, days, mean [SD]</td><td>22.5 [24.3]</td><td>25.4 [24.1]</td><td>12.3 [21.8]</td><td>.0002</td></tr><tr><td>Length of intratracheal intubation, days, mean [SD]</td><td>14.5 [13.2]</td><td>16.2 [12.2]</td><td>8.1 [14.3]</td><td>&lt;.0001</td></tr><tr><td colspan="5"><strong>Previous antibiotic treatments</strong></td></tr><tr><td>Antibiotic treatment before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>247 [90]</td><td>196 [92]</td><td>51 [84]</td><td>.04</td></tr><tr><td>Amoxicillin/clavulanic acid before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>68 [25]</td><td>57 [27]</td><td>11 [18]</td><td>.10</td></tr><tr><td>Piperacillin before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>18 [7]</td><td>16 [8]</td><td>2 [3]</td><td>.19</td></tr><tr><td>Piperacillin/tazobactam before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>104 [38]</td><td>80 [38]</td><td>24 [39]</td><td>.45</td></tr><tr><td>Ceftriaxone/cefotaxime before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>53 [19]</td><td>45 [21]</td><td>8 [13]</td><td>.11</td></tr><tr><td>Ceftazidime before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>29 [11]</td><td>25 [12]</td><td>4 [7]</td><td>.18</td></tr><tr><td>Cefepime before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>3 [1]</td><td>3 [1]</td><td>0 [0]</td><td>.46</td></tr><tr><td>Carbapenem before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>48 [18]</td><td>41 [19]</td><td>7 [11]</td><td>.11</td></tr><tr><td>Aminoglycoside before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>123 [45]</td><td>98 [46]</td><td>25 [39]</td><td>.28</td></tr><tr><td>Glycopeptide before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>50 [18]</td><td>39 [18]</td><td>11 [18]</td><td>.55</td></tr><tr><td>Fluoroquinolone before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>54 [20]</td><td>49 [23]</td><td>5 [8]</td><td>.0059</td></tr><tr><td>Macrolide/lincosamide before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>38 [14]</td><td>30 [14]</td><td>8 [13]</td><td>.52</td></tr><tr><td>Trimethoprim/sulfamethoxazole before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>47 [17]</td><td>39 [18]</td><td>8 [13]</td><td>.23</td></tr><tr><td>Tetracyclines before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>2 [1]</td><td>2 [1]</td><td>0 [0]</td><td>.60</td></tr><tr><td>Colistin before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>17 [6]</td><td>14 [7]</td><td>3 [5]</td><td>.77</td></tr><tr><td>Other molecules* before <i>Pseudomonas aeruginosa</i>, n [%]</td><td>26 [9]</td><td>23 [11]</td><td>3 [5]</td><td>.12</td></tr><tr><td colspan="5"><strong>Risk factors of MDR <i>Pseudomonas aeruginosa</i></strong></td></tr><tr><td>Antibiotic therapy &lt; 6 mo, n [%]</td><td>93 [34]</td><td>69 [32]</td><td>24 [39]</td><td>.19</td></tr><tr><td>Hospitalization &lt; 6 mo, n [%]</td><td>123 [45]</td><td>86 [40]</td><td>37 [61]</td><td>.0040</td></tr><tr><td>Other infection than <i>Pseudomonas aeruginosa</i>, n [%]</td><td>188 [69]</td><td>163 [76]</td><td>25 [40]</td><td>&lt;.0001</td></tr><tr><td>Previous <i>Pseudomonas aeruginosa</i> infection, n [%]</td><td>22 [8]</td><td>13 [6]</td><td>9 [15]</td><td>.0324</td></tr></tbody></table>

(Continued)
<table><caption>**Table 3.** (Continued)</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="3">Pseudomonas aeruginosa</th><th rowspan="2">P value</th></tr><tr><th>Overall<br>n = 274</th><th>Nosocomial<br>n = 213</th><th>Community acquired<br>n = 61</th></tr></thead><tbody><tr><td colspan="5"><strong>Characteristics of Pseudomonas aeruginosa isolates</strong></td></tr><tr><td>Pseudomonas aeruginosa colonization, n [%]</td><td>95 [35%]</td><td>75 [35%]</td><td>20 [33%]</td><td>.42</td></tr><tr><td>Pseudomonas aeruginosa infection, n [%]</td><td>179 [65%]</td><td>138 [64%]</td><td>41 [67%]</td><td>.42</td></tr><tr><td>Pseudomonas aeruginosa in respiratory tract, n [%]</td><td>146 [53]</td><td>99 [47]</td><td>21 [35]</td><td>.05</td></tr><tr><td>Pseudomonas aeruginosa in urine, n [%]</td><td>36 [13]</td><td>27 [13]</td><td>9 [15]</td><td>.40</td></tr><tr><td>Pseudomonas aeruginosa in other sites**, n [%]</td><td>24 [9]</td><td>13 [6]</td><td>11 [18]</td><td>.0062</td></tr><tr><td>Pseudomonas aeruginosa sepsis, n [%]</td><td>24 [10]</td><td>13 [6]</td><td>11 [18]</td><td>.0063</td></tr><tr><td>Ceftazidime resistant Pseudomonas aeruginosa, n [%]</td><td>41 [15]</td><td>32 [15]</td><td>9 [15]</td><td>.57</td></tr><tr><td>Imipenem resistant Pseudomonas aeruginosa, n [%]</td><td>37 [14]</td><td>33 [15]</td><td>4 [7]</td><td>.0497</td></tr><tr><td>Fluoroquinolone resistant Pseudomonas aeruginosa, n [%]</td><td>63 [23]</td><td>54 [25]</td><td>9 [15]</td><td>.06</td></tr><tr><td>MDR Pseudomonas aeruginosa, n [%]</td><td>18 [7]</td><td>16 [8]</td><td>2 [3]</td><td>.19</td></tr><tr><td colspan="5"><strong>Outcomes</strong></td></tr><tr><td>Overall MDR bacteria, n [%]</td><td>74 [27]</td><td>61 [29]</td><td>13 [22]</td><td>.18</td></tr><tr><td>ICU length of stay (days), mean [SD]</td><td>9.1 [16.9]</td><td>10.4 [18.0]</td><td>4.4 [10.7]</td><td>.032</td></tr><tr><td>Hospital length of stay (days), mean [SD]</td><td>41.3 [40.4]</td><td>46.3 [40.3]</td><td>23.6 [35.6]</td><td>.0001</td></tr><tr><td>In-ICU death, n [%]</td><td>102 [37]</td><td>76 [36]</td><td>26 [42]</td><td>.20</td></tr><tr><td>In-hospital death, n [%]</td><td>118 [43]</td><td>89 [42]</td><td>29 [48]</td><td>.25</td></tr></tbody></table>

Note. *including linezolid, fosfomycin, daptomycin, rifampicin; **including purulent lesions, cutaneous biopsies, vascular catheter, bone biopsies, coprocultures and peritoneal fluids; CI, confidence interval; ICU, intensive care unit; FiO2, fraction of inspired oxygen; MDR, multidrug resistant; MV, mechanical ventilation; NA, not applicable; PEEP, positive end-expiratory pressure; RR, related ratio; SAPS-II, simplified acute physiology score-II; SD, standard deviation; VAP, ventilator associated pneumonia.

<table><caption>**Table 4.** Resistance to fluoroquinolones among *Pseudomonas aeruginosa* isolates from patients receiving endotracheal intubation</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="3">Endotracheal intubation</th></tr><tr><th>Yes</th><th>No</th><th>P value</th></tr></thead><tbody><tr><td><strong>Overall (n = 274)</strong></td><td></td><td></td><td></td></tr><tr><td>Fluoroquinolone resistant isolates, n [%]</td><td>38 [29]</td><td>25 [17]</td><td>.0197</td></tr><tr><td>Fluoroquinolone resistant isolates in patients treated by fluoroquinolones, n [%]</td><td>18 [46]</td><td>5 [20]</td><td>.0273</td></tr><tr><td><strong>Respiratory samples (n = 146)</strong></td><td></td><td></td><td></td></tr><tr><td>Fluoroquinolone resistant isolates, n [%]</td><td>26 [35]</td><td>14 [24]</td><td>.0259</td></tr><tr><td>Fluoroquinolone resistant isolates in patients treated by fluoroquinolones, n [%]</td><td>12 [54]</td><td>3 [21]</td><td>.0495</td></tr></tbody></table>

<table><caption>**Table 5.** Multivariate analysis of factors associated with fluoroquinolone resistance in *Pseudomonas aeruginosa* isolates</caption><thead><tr><th>Characteristics</th><th>OR (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Length of endotracheal intubation, days</td><td>1.39 (0.6–3.2)</td><td>.44</td></tr><tr><td>Length of invasive mechanical ventilation</td><td>0.60 (0.3–1.4)</td><td>.23</td></tr><tr><td>Continued non-invasive ventilation</td><td>1.30 (0.2–6.7)</td><td>.76</td></tr><tr><td>Previous fluoroquinolone treatment</td><td>2.07 (1.0–4.2)</td><td>.0462</td></tr><tr><td>Study period (2007–2010 vs 2011–2014)</td><td>2.94 (1.5–5.8)</td><td>.0020</td></tr></tbody></table>

<table><caption>**Table 6.** Multivariate analysis of factors associated with presence of multi drug resistant *Pseudomonas aeruginosa* isolates</caption><thead><tr><th>Characteristics</th><th>OR (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Previous aminoglycoside</td><td>1.82 (0.6–5.1)</td><td>.26</td></tr><tr><td>Previous cephalosporin</td><td>0.78 (0.2–2.5)</td><td>.68</td></tr><tr><td>Previous carbapenem</td><td>1.17 (0.3–3.9)</td><td>.80</td></tr><tr><td>Previous tetracycline</td><td>0.0001 (NA)</td><td>.98</td></tr><tr><td>Previous fluoroquinolone</td><td>2.13 (0.7–6.9)</td><td>.20</td></tr><tr><td>Previous macrolide</td><td>1.63 (0.4–6.2)</td><td>.47</td></tr><tr><td>Previous penicillin</td><td>0.40 (0.1–1.2)</td><td>.09</td></tr><tr><td>Previous Trimethoprim/sulfamethoxazole</td><td>0.31 (0.03–2.4)</td><td>.27</td></tr></tbody></table>

Note. NA, not applicable.

factors associated with *P. aeruginosa* isolates occurring in patients hospitalized in non-ICU units needs to be explored. Also, risk factors of *P. aeruginosa* VAP need to be investigated. A direct comparison between different molecules necessitates to be performed.

## Conclusions

The antibiotic stewardship program implemented in our institution achieved in reducing rates of antibiotic resistance in *P. aeruginosa* isolates obtained from ICU patients. Among the factors investigated by this study, the decreasing consumption of
3-GC and FLQ and the increased use of TMP-SMX and piperacillin contributed in achieving this result. Also, the decreasing use of endotracheal intubation was observed and likely participate in reducing rates of *P. aeruginosa* isolation. Further studies are needed to verify the effectiveness of this strategy in other settings.

**Acknowledgments.** None.

**Author contribution.** AS drafted the work; VA gave substantial contribution in data acquisition, RH revised the draft, SD contributed in interpretation of data; OB contributed in interpretation of data; SA contributed in interpretation of data; SH contributed in interpretation of data; MM gave substantial contributions to conception or design of the work; SD gave.

**Financial support.** This study did not receive any funding from public or private entities.

**Competing interests.** All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## References

1. Pop-Vicas A, Opal SM. The clinical impact of multidrug-resistant gram-negative bacilli in the management of septic shock. *Virulence* 2014;5:206–12. doi: 10.4161/viru.26210.

2. Bertrand X, Thouverez M, Talon D, et al. Endemicity, molecular diversity and colonisation routes of Pseudomonas aeruginosa in intensive care units. *Intens Care Med* 2001;27:1263–8. doi: 10.1007/s001340100979.

3. Rogues AM, Boulestreau H, Lasheras A, et al. Contribution of tap water to patient colonisation with Pseudomonas aeruginosa in a medical intensive care unit. *J Hosp Infect* 2007;67:72–78. doi: 10.1016/j.jhin.2007.06.019.

4. Boyer A, Doussau A, Thiébault R, et al. Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients’ environment. *Crit Care* 2011;15:R55. doi: 10.1186/cc10026.

5. Gullberg E, Albrecht LM, Karlsson C, Sandegren L, Andersson DI. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals. *mBio* 2014;5:e01918–14. doi: 10.1128/mBio.01918-14.

6. Oliver A, Mulet X, López-Causapé C, Juan C. The increasing threat of Pseudomonas aeruginosa high-risk clones. *Drug Resist Updat* 2015; 21:22–41:59. doi: 10.1016/j.drup.2015.08.002.

7. Ioannou P, Karakonstantis S, Schouten J, et al. Indications for medical antibiotic prophylaxis and potential targets for antimicrobial stewardship intervention: a narrative review. *Clin Microbiol Infect* 2022;28:362–370. doi: 10.1016/j.cmi.2021.10.001.

8. Onorato L, Macera M, Calò F, et al. The effect of an antimicrobial stewardship programme in two intensive care units of a teaching hospital: an interrupted time series analysis. *Clin Microbiol Infect* 2020;26: 782.e1–782.e6. doi: 10.1016/j.cmi.2019.10.021.

9. Abbara S, Domenech de Cellès M, Batista R, et al. Variable impact of an antimicrobial stewardship programme in three intensive care units: time-series analysis of 2012–2017 surveillance data. *J Hosp Infect* 2020;104: 150–157. doi: 10.1016/j.jhin.2019.10.002.

10. Taggart LR, Leung E, Muller MP, Matukas LM, Daneman N. Differential outcome of an antimicrobial stewardship audit and feedback program in two intensive care units: a controlled interrupted time series study. *BMC Infect Dis* 2015;15:480. doi: 10.1186/s12879-015-1223-2.

11. Slain D, Sarwari AR, Petros KO, et al. Impact of a multimodal antimicrobial stewardship program on Pseudomonas aeruginosa susceptibility and antimicrobial use in the intensive care unit setting. *Crit Care Res Pract* 2011;2011:416426. doi: 10.1155/2011/416426.

12. Abbara S, Pitsch A, Jochmans S, et al. Impact of a multimodal strategy combining a new standard of care and restriction of carbapenems, fluoroquinolones and cephalosporins on antibiotic consumption and resistance of Pseudomonas aeruginosa in a French intensive care unit. *Int J Antimicrob Agents* 2019;53:416–422. doi: 10.1016/j.ijantimicag.2018.12.001.

13. Deplanque D., Sénéchal-Cohen S., Lemaire F. French Jarde's law and European regulation on drug trials: harmonization and implementation of new rules. *Thérapie* 2017;72:73–80. doi: 10.1016/j.therap.2016.12.006.

14. European committee on antimicrobial susceptibility testing: Guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance; Version 2.0 July 2017. https://www.eucast.org/resistance_mechanisms. Published 2017. Accessed March 15, 2023.

15. Pickens CI, Wunderink RG. Principles and Practice of Antibiotic Stewardship in the ICU. *Chest* 2019;156:163–171. doi: 10.1016/j.chest.2019.01.013.

16. Nguyen LH, Hsu DI, Ganapathy V, Shriner K, Wong-Beringer A. Reducing empirical use of fluoroquinolones for Pseudomonas aeruginosa infections improves outcome. *J Antimicrob Chemother* 2008;61:714–20. doi: 10.1093/jac/dkm510.

17. Nguyen KV, Nguyen TV, Nguyen HTT, Le DV. Mutations in the gyrA, parC, and mexR genes provide functional insights into the fluoroquinolone resistant *Pseudomonas aeruginosa* isolated in Vietnam. *Infect Drug Resist* 2018;11:275–282. doi: 10.2147/IDR.S147581.

18. Das T, Sehar S, Manefield M. The roles of extracellular DNA in the structural integrity of extracellular polymeric substance and bacterial biofilm development. *Environ Microbiol Rep* 2013;5:778–86. doi: 10.1111/1758-2229.12085.

19. Walters MC, Frank R, Amandine B, Franklin MJ, Stewart PS. Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin. *Antimicrob Agents Chemother* 2003;47:317–23. doi: 10.1128/AAC.47.1.317-323.2003.

20. Pang Z, Raudonis R, Glick BR, Lin TJ, Cheng Z. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. *Biotechnol Adv* 2019;37:177–192. doi: 10.1016/j.biotechadv.2018.11.013.

21. Cepas V, López Y, Muñoz E, et al. Relationship between biofilm formation and antimicrobial resistance in gram-negative bacteria. *Microb Drug Resist* 2019;25:72–79.

22. Coppadoro A, Bellani G, Foti G. Non-pharmacological interventions to prevent ventilator-associated pneumonia: a literature review. *Respir Care* 2019;64:1586–1595. doi: 10.4187/respcare.07127.

23. Villemure-Poliquin N, Costerousse O, Lessard Bonaventure P, et al. Tracheostomy versus prolonged intubation in moderate to severe traumatic brain injury: a multicentre retrospective cohort study. *Can J Anaesth* 2023;70:1516–1526. doi: 10.1007/s12630-023-02539-7.

24. Wang S, Li J, Dai J, et al. Establishment and validation of models for the risk of multi-drug resistant bacteria infection and prognosis in elderly patients with pulmonary infection: a multicenter retrospective study. *Infect Drug Resist* 2023;16:6549–6566. doi: 10.2147/IDR.S422564.

25. Jasper AS, Musuua JS, Tischendorf JS, et al. Are fluoroquinolones or macrolides better for treating legionella pneumonia? A systematic review and meta-analysis. *Clin Infect Dis* 2021;72:1979–1989. doi: 10.1093/cid/ciaa441.

26. Ito A, Ishida T, Tachibana H, et al. Usefulness of β-lactam and macrolide combination therapy for treating community-acquired pneumonia patients hospitalized in the intensive care unit: Propensity score analysis of a prospective cohort study. *J Infect Chemother* 2021;27:1447–1453. doi: 10.1016/j.jiac.2021.06.003.

27. Pollock J, Chalmers JD. The immunomodulatory effects of macrolide antibiotics in respiratory disease. *Pulm Pharmacol Ther* 2021;71:102095. doi: 10.1016/j.pupt.2021.102095.

28. Drusano GL, Schimpff SC, Hewitt WL. The acylampicillins: mezlocillin, piperacillin, and azlocillin. *Rev Infect Dis* 1984;6:13–32.
29. Bryson HM, Brogden RN. Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. *Drugs* 1994;47:506-35. doi: 10.2165/00003495-199447030-00008.

30. Karaiskos I, Giamarellou H. Carbapenem-sparing strategies for ESBL producers: when and how. *Antibiotics* (Basel) 2020;9:61. doi: 10.3390/antibiotics9020061.

31. Société de Réanimation de langue Français, Haute Autorité de Santé, Societe de Pathologie Infectieuse de langue Français. Antibiothérapie des infections

à entérobactéries et à Pseudomonas aeruginosa chez l'adulte: place des
carbapénèmes et de leurs alternatives (FRENCH). https://www.
infectiologie.com/fr/recommandations.html. Published 2023. Accessed
April 16, 2023.

32. Strazzulla A, Postorino MC, Youbong T, et al. Trimethoprim-sulfamethox-
azole as de-escalation in ventilator-associated pneumonia: a cohort study
subanalysis. *Eur J Clin Microbiol Infect Dis* 2021;40:1511-1516. doi: 10.
1007/s10096-021-04184-8.