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 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. ^{Reference Pickens and Wunderink15} In fact, broad-spectrum antibiotics interact with the environment and facilitate P. aeruginosa acquisition. ^{Reference Boyer, Doussau and Thiébault4} 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. ^{Reference Nguyen, Hsu, Ganapathy, Shriner and Wong-Beringer16} Indeed, P. aeruginosa has many mechanisms of resistance, frequently based on GyrA, ParC, and MexR enzymes. ^{Reference Nguyen, Nguyen, Nguyen and Le17} In ICU setting, an important virulence and resistance factor is biofilm which contributes reducing susceptibility to antimicrobial molecules and host-immune factors. ^{Reference Das, Sehar and Manefield18} This effect disappears when bacteria are deprived of the capacity of producing the extracellular matrix made by polysaccharides, proteins, and metabolites. ^{Reference Walters, Frank, Amandine, Franklin and Stewart19} As a consequence, biofilm reduces antibiotic efficacy by several mechanisms: reduction of antibiotic penetration, microenvironment modifications, and increased inflammatory response. ^{Reference Pang, Raudonis, Glick, Lin and Cheng20} FLQ activity is largely limited by biofilm production. ^{Reference Cepas, López and Muñoz21} In ICU, the main sources of biofilm producing P. aeruginosa are invasive devices. ^{Reference Boyer, Doussau and Thiébault4} Moreover, endotracheal intubation is the most relevant determinant of P. aeruginosa acquisition and ventilator-associated pneumonia (VAP). ^{Reference Coppadoro, Bellani and Foti22} 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. ^{Reference Villemure-Poliquin, Costerousse and Lessard Bonaventure23,Reference Wang, Li and Dai24} 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. ^{Reference Abbara, Pitsch and Jochmans12} Indeed, macrolides can be preferred to FLQ in many situations. At first, macrolides are not inferior to FLQ for the treatment of Legionella pneumonia. ^{Reference Jasper, Musuuza and Tischendorf25} 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. ^{Reference Ito, Ishida and Tachibana26} 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. ^{Reference Pollock and Chalmers27} 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). ^{Reference Drusano, Schimpff and Hewitt28} 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 against many beta-lactamases. ^{Reference Bryson and Brogden29} However, P. aeruginosa may rapidly develop resistance to tazobactam by the production of extended spectrum beta-lactamases and AmpC beta-lactamases. ^{Reference Karaiskos and Giamarellou30} 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. ^{Reference Strazzulla, Postorino and Youbong32} 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, 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.