In patients with renal impairment (n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.

Background: This risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined. Objectives: To quantify the dose-AKI relationships of VAN alone and in combination with TZP or imipenem-cilastatin/relebactam (IMP-C/REL). Methods: Ten to twelve week old male C57BL/6J mice (Charles River Laboratory) were dosed with study drug regimens in three stages. Stage 1 consisted of a VAN dose-ranging design (0-600 mg/kg/day) over a 7-day period to identify the VAN monotherapy dose-AKI relationship in the murine model. Stage 2 evaluated the approximate VAN dose eliciting 50% AKI response in Stage 1 in combination with the highest human equivalent doses (HED) used in pre-clinical murine models (2.5 g/kg/day of TZP, 320 mg/kg/day of IMP-C/REL). Stage 3 tested these combinations with fractionated doses of TZP or IMP-C/REL administered at 6- and 12-hour intervals. In these studies, AKI was defined both by biomarkers (serum creatinine [SCr], blood urea nitrogen [BUN]) and histopathological assessment by a treatment-blinded pathologist. Results: VAN doses of 300 to 500 mg/kg/day reproducibly led to development of AKI within 4 days of dosing. Mice treated with VAN alone had a near doubling of their baseline SCr and BUN compared to control, IMP-C/REL alone, or TZP alone. Both VAN+IMP-C/REL and VAN+TZP had significantly (p<0.05) lower SCr and BUN values compared to VAN alone when dosed once daily. This nephroprotective effect was retained with VAN+IMP-C/REL, but not VAN+TZP, when IMP-C/REL and TZP were administered every 6 hours. Biomarker results were concordant with histopathologic findings. Conclusions: The VAN dose-AKI relationship can be attenuated with single daily HEDs of TZP or IMP-C/REL in mice. IMP-C/REL, but not TZP, retained a nephroprotective effect compared to VAN monotherapy when administered as fractionated doses.

Fluoroquinolones form drug-topoisomerase-DNA complexes that rapidly block transcription and replication. Crystallographic and biochemical studies show that quinolone binding involves a water/metal-ion bridge between the quinolone C3-C4 keto-acid and amino acids in helix-4 of the target proteins, GyrA (gyrase) and ParC (topoisomerase IV). A recent cross-linking study revealed a second drug-binding mode in which the other end of the quinolone, the C7 ring system, interacts with GyrA. We report that addition of a dinitrophenyl (DNP) moiety to the C7 end of ciprofloxacin (Cip-DNP) reduced protection due to resistance substitutions in Escherichia coli GyrA helix-4, consistent with the existence of a second drug-binding mode not evident in X-ray structures of drug-topoisomerase-DNA complexes. Several other C7 aryl fluoroquinolones behaved in a similar manner with particular GyrA mutants. Treatment of E. coli cultures with Cip-DNP selectively enriched an uncommon variant, GyrA-A119E, a change that may impede binding of the dinitrophenyl group at or near the GyrA-GyrA interface. Collectively the data support the existence of a secondary quinolone-binding mode in which the quinolone C7 ring system interacts with GyrA; the data also identify C7 aryl derivatives as a new way to obtain fluoroquinolones that overcome existing GyrA-mediated quinolone resistance.

SUMMARY1. In cats anaesthetized with chloralose the release of vasopressin in response to nicotine injections was examined. This release was measured by assaying the hormone in samples of venous blood.2. Nicotine injections were given by three different routes, namely intravertebral, intracarotid and intravenous. The first two represent close arterial routes to the medulla and to the hypothalamus, respectively, the effects of which could be compared to those following intravenous, i.e. systemic, administration.3. Nicotine was found to increase vasopressin secretion by all three routes of administration. The potency of intracarotid injections was found to be no greater than that of intravenous injections, in sharp contrast to intravertebral injections, which were 4-5 times more potent.4. In terms of vascular effects, intracarotid and intravenous injections of nicotine were found to increase blood pressure, whereas intravertebral injections of low doses of nicotine were always followed by a fall in blood pressure. Higher doses of intravertebral nicotine produce mixed results, pressor or depressor, in different animals.5. The vasodepressor effect of intravertebral nicotine was part of a cardiovascular response which included a lowering of total peripheral resistance and of stroke work, whereas the cardiac output, the heart rate and the stroke volume remained essentially unchanged. 6. These results clearly indicate that a medullary area, which has been previously described, is the most sensitive site for the vasopressin releasing action of nicotine and that systemic administration of the drug induces vasopressin secretion by virtue of its action on the medulla, rather than directly on the supraoptic nucleus. 298 E. M. CASTRO DE SOUZA AND M. ROCHA E SILVA 7. The results also indicate that the vasodepressor effect which follows the application of nicotine on the medulla is chiefly due to vasodilator effects on systemic blood vessels, with practically no action on cardiac function. The significance of these results is discussed.

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