Development of Novel Immunoprophylactic Agents against Multidrug-Resistant Gram-Negative Bacterial Infections.

The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.

Ultra-fast-track anesthesia in off-pump coronary artery bypass grafting: a prospective audit comparing opioid-based anesthesia vs thoracic epidural-based anesthesia.

PURPOSE: To examine the feasibility of immediate extubation after off-pump coronary artery bypass grafting (OPCAB) using opioid based analgesia or high thoracic epidural analgesia (TEA) and compare postoperative analgesia with continuous TEA vs patient-controlled analgesia (PCA). METHODS: One hundred consecutive patients undergoing OPCAB were included in this prospective audit. After induction of anesthesia using fentanyl 2 to 5 microg.kg(-1), propofol 1 to 2 mg.kg(-1) and endotracheal intubation facilitated by rocuronium, anesthesia was maintained using sevoflurane titrated according to bispectral index monitoring. Perioperative analgesia was provided by TEA (n = 63) at the T3/T4 interspace or T4/T5 interspace using bupivacaine 0.125% 8 to 14 mL.hr(-1) and repetitive boluses of bupivacaine 0.25% during surgery. In patients who were fully anticoagulated or refused TEA, perioperative analgesia was achieved by i.v. fentanyl boluses (up to 15 microg.kg(-1)) and remifentanil 0.1 to 0.2 microg.kg(-1).min(-1), followed by morphine PCA after surgery (n = 37). Maintenance of body temperature was achieved by a heated operating room and forced-air warming blankets. RESULTS: Ninety-five patients were extubated within 25 min after surgery (PCA, n = 33; TEA, n = 62). Five patients were not extubated immediately because their core temperature was lower than 35 degrees C. One patient was re-intubated because of agitation (TEA group); one was re-intubated because of severe pain and morphine-induced respiratory depression (PCA group). Pain scores were low after surgery, with pain scores in the TEA group being significantly lower immediately, at six hours, 24 hr and 48 hr after surgery (P < 0.05). CONCLUSION: Immediate extubation is possible after OPCAB using either opioid-based analgesia or TEA. TEA provides significantly lower pain scores after surgery in comparison to morphine PCA.

Falsely increased bispectral index values in a series of patients undergoing cardiac surgery using forced-air-warming therapy of the head.

IMPLICATIONS: Falsely increased bispectral index (BIS) values of >70 occur during forced-warm-air therapy in patients undergoing cardiac surgery. When forced-warm-air therapy for the head is used (as in ultra-fast-tracking cardiac patients), BIS interpretation needs careful examination. Falsely increased BIS values can easily be recognized when the warm-air flow is stopped. Within 2-3 min, BIS returns to a much lower, "true" value.