Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy.

The rise of antimicrobial resistance has led to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused by Pseudomonas aeruginosa relies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that depletion of alveolar macrophages (AM) shortens the survival of mice without boosting the P. aeruginosa load in the lungs. Unexpectedly, upon bacteriophage treatment, pulmonary levels of P. aeruginosa were significantly lower in AM-depleted than in immunocompetent mice. To explore potential mechanisms underlying the benefit of AM-depletion in treated mice, we developed a mathematical model of phage, bacteria, and innate immune system dynamics. Simulations from the model fitted to data suggest that AM reduce bacteriophage density in the lungs. We experimentally confirmed that the in vivo decay of bacteriophage is faster in immunocompetent compared to AM-depleted animals. These findings demonstrate the involvement of feedback between bacteriophage, bacteria, and the immune system in shaping the outcomes of phage therapy in clinical settings.

Opioid Reduced Anesthesia in Major Oncologic Cervicofacial Surgery: A Retrospective Study.

Opioid sparing is one of the new challenges in anesthesia and perioperative medicine. Opioid reduced anesthesia (ORA) is part of this approach, and it consists of a multimodal analgesia-associating non-opioid analgesic regional anesthesia to reduce intraoperative opioid requirements. Major cervicofacial oncologic surgery could specifically benefit from ORA, since it is known to generate intense and prolonged postoperative pain, with a high risk of pulmonary complications. METHODS: This is a retrospective case-controlled study of 172 patients with major cervicofacial oncologic surgery. Group ORA (dexmedetomidine and lidocaine), n = 86, was compared to patients treated with standard opioid based anesthesia, Group control, n = 86. The main endpoint was to study perioperative opioid consumption and postoperative pain scores, and the secondary endpoint was to observe opioid related side effects. RESULTS: The ORA group received 6.2 ± 3.1 mg morphine titration at the end of surgery, while the control group received 10.1 ± 3.7 mg p < 0.0001; there was no significant difference in post-operative analgesia requirements and pain scores between the groups. Intraoperatively, the ORA protocol yielded bradycardia in 4 persons, while in the control group, only 2 persons had bradycardia necessitating intervention, p < 0.05. Postoperatively, episodes of hypoxemia (50%) and the need for additional pressure-assisted ventilation (6%), was significantly different in the ORA group than in the control group (70% and 19%), p < 0.05. There was no difference between the two groups for the incidence of nausea and vomiting, ileus, or postoperative delirium. DISCUSSION: ORA was not associated with a decrease in postoperative pain and opioid requirement, but possibly reduced the incidence of hypoxemia and the use of additional pressure-assisted ventilation, although we cannot rule out confounding factors. The possible benefits of ORA remain to be demonstrated by prospective studies.