Impact of combining vancomycin with piperacillin/tazobactam or with meropenem on vancomycin-induced nephrotoxicity.

Vancomycin (VAN) is a broad-spectrum antibiotic against Gram-positive cocci used empirically with other broad-spectrum antibiotics, such as piperacillin/tazobactam (TZP), cefepime, or meropenem (MEM). Conflicting literature on the rates of acute kidney injury (AKI) of VAN with TZP is reported, and studies on AKI rate with MEM are limited. This study aimed to evaluate AKI rates in patients receiving VAN with either TZP or MEM. This was a retrospective cohort study of patients received either VAN-TZP or VAN-MEM for ≥ 72 h. Patients with a baseline serum creatinine (SCr) of ≥ 1.5 mg/dL were excluded. The primary outcome was rate of AKI as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. SCr was recorded at baseline and 3-5 days post antibiotics initiation. 158 patients were included, 77 in the VAN-TZP group versus 81 in the VAN-MEM group. While the percentage of patients meeting AKI definition was numerically higher in the VAN-MEM group, the difference was not significant (10.4% vs. 21%; P = 0.07). As such, change in SCr was not significantly different between the two groups (- 7.4 vs. - 6.1%; P = 0.7). In-hospital mortality was higher in the VAN-MEM group (23.4% vs. 39.5%; P = 0.03) possibly because the majority of this group's patients were critically ill. This study showed that combining MEM with VAN did not offer the benefit of a lower rate of AKI compared with a combination with TZP. Therefore, patients with no risk factors for infections resistant to TZP can continue to receive TZP with VAN without risking AKI development.

Antidepressant-like and anxiolytic-like effects following activation of the µ-δ opioid receptor heteromer in the nucleus accumbens.

Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The µ-δ OR heteromer represents a unique signaling complex with distinct properties compared with µ- and δ-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the µ-δ heteromer, we devised a strategy to selectively antagonize the function of the µ-δOR complex using a specific interfering peptide derived from the δOR distal carboxyl tail, a sequence implicated in µ-δOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of δ-agonists at the µ-δ heteromer, with no effect on µ- or δ-OR homomers, and a dissociation of the µ-δOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the δ-agonist UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512's antidepressant-like and anxiolytic-like actions were abolished by pretreatment with either µOR or δOR antagonists. Overall, these findings demonstrate that the µ-δ heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders.

Agonists at the δ-opioid receptor modify the binding of µ-receptor agonists to the µ-δ receptor hetero-oligomer.

BACKGROUND AND PURPOSE: µ- and δ-opioid receptors form heteromeric complexes with unique ligand binding and G protein-coupling profiles linked to G protein α z-subunit (Gα(z) ) activation. However, the mechanism of action of agonists and their regulation of the µ-δ receptor heteromer are not well understood. EXPERIMENTAL APPROACH: Competition radioligand binding, cell surface receptor internalization in intact cells, confocal microscopy and receptor immunofluorescence techniques were employed to study the regulation of the µ-δ receptor heteromer in heterologous cells with and without agonist exposure. KEY RESULTS: Gα(z) enhanced affinity of some agonists at µ-δ receptor heteromers, independent of agonist chemical structure. δ-Opioid agonists displaced µ-agonist binding with high affinity from µ-δ heteromers, but not µ receptor homomers, suggestive of δ-agonists occupying a novel µ-receptor ligand binding pocket within the heteromers. Also, δ-agonists induced internalization of µ-opioid receptors in cells co-expressing µ- and δ-receptors, but not those expressing µ-receptors alone, indicative of µ-δ heteromer internalization. This dose-dependent, Pertussis toxin-resistant and clathrin- and dynamin-dependent effect required agonist occupancy of both µ- and δ-opioid receptors. In contrast to µ-receptor homomers, agonist-induced internalization of µ-δ heteromers persisted following chronic morphine exposure. CONCLUSIONS AND IMPLICATIONS: The µ-δ receptor heteromer may contain a novel δ-agonist-detected, high-affinity, µ-receptor ligand binding pocket and is regulated differently from the µ-receptor homomer following chronic morphine exposure. Occupancy of both µ- and δ-receptor binding pockets is required for δ-agonist-induced endocytosis of µ-δ receptor heteromers. δ-Opioid agonists target µ-δ receptor heteromers, and thus have a broader pharmacological specificity than previously identified.