BackgroundVancomycin (VCM) treatment outcomes depend on the characteristics of the patient, and it is well known that hypoalbuminemia is a risk factor for poor treatment outcomes, as reported in a previous study. However, the reason that severe hypoalbuminemia has an influence on the treatment outcome of VCM remains unknown.ObjectiveTo elucidate the association between severe hypoalbuminemia and VCM treatment outcomes, we examined pharmacokinetic/pharmacodynamic (PK/PD) parameters in elderly patients with severe hypoalbuminemia.MethodsWe conducted a retrospective observational study of 94 patients with methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia who had been treated with VCM between January 2006 and December 2012. The 94 patients were divided into severe hypoalbuminemia and non-severe hypoalbuminemia groups. The PK/PD parameters and treatment outcomes of VCM were compared between the two groups.ResultsThe half-life of VCM in the severe hypoalbuminemia group was significantly longer than in the non-severe hypoalbuminemia group (33.2 + 5.4 vs 24.9 + 1.6; P = 0.049). Area under the concentration curve (AUC)/minimum inhibitory concentration (MIC) values of 250–450 and >450 μg × h/mL were significantly associated with 28-day mortality in the severe hypoalbuminemia group (P < 0.001), whereas AUC/MIC values of <250 μg × h/mL were not associated. We also detected a significant difference in the increased percentage of nephrotoxicity in the severe hypoalbuminemia group (6 of 23 patients [26%]) compared with the non-severe hypoalbuminemia group (6 of 71 patients [8%]; P < 0.001).ConclusionThese findings indicate that severe hypoalbuminemia influences the half-life of VCM and treatment outcomes in elderly patients (≥75 years of age). To establish a more effective and safer treatment protocol, the issue of malnutrition in elderly patients needs to be addressed and improved.

We previously characterized LNCaP-E9, a low-androgen-sensitive LNCaP cell subline. LNCaP-E9 cells exhibit lower expression of androgen-regulated genes, including prostate-specific antigen (PSA), FK506 binding protein 5 (FKBP5), and prostatic acid phosphatase (PAcP), compared with LNCaP cells after treatment with the synthetic androgen R1881, confirming that the cells have low sensitivity to androgens. To understand the mechanism underlying low androgen sensitivity of LNCaP-E9 cells, we examined the activities of the Akt, p44/ 42, and p38 mitogen-activated protein kinase signaling pathways, all of which are known to be linked to androgen receptor signaling. We found that the phosphorylation of Akt at Ser473 was markedly lower in LNCaP-E9 cells than in LNCaP cells. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase inhibitor LY294002 resulted in reduction of PSA expression in LNCaP cells. Conversely, activation of Akt by serum starvation led to the induction of PSA expression in LNCaP-E9 cells. These results suggest that the impaired Akt phosphorylation in LNCaP-E9 cells is associated with low androgen sensitivity.

The androgen-independent LNCaP (AIDL) cell line was generated by maintaining prostate cancer LNCaP cells in a hormone-deprived medium. Notably, synthetic androgen R1881-related gene response is attenuated in AIDL cells as compared to the parental LNCaP cells. The aim of this study was to clarify the mechanisms underlying androgen sensitivity in AIDL cells. We first examined the expression of androgen receptor (AR) and its co-regulators. However, no significant difference in mRNA expression was found between LNCaP and AIDL cells. Remarkably, AR protein levels were induced by R1881 and DHT in LNCaP cells, but not in AIDL cells. We next performed the cDNA sequencing to detect mutations in the AR gene. The T877A mutation was detected both in LNCaP and AIDL cells. Furthermore, AIDL cells harbored a missense substitution (TGG → TGT) in the AR gene, which caused a point mutation at codon 741 (W741C). Double T877A and W741C AR mutants have been previously reported to exhibit reduced androgen sensitivity. Hence, the low-androgen-sensitive responses of AIDL cells may be explained, at least in part, by AR gene mutations.

The methods of administering the chemical antibiotic agent TAZ/PIPC were investigated through PK/PD analysis, in order to promote an improved efficacy of the drug. The subjects were patients with suspected bacteremia who received rapid (30 -60 min, n = 24) and extended (4 hr, n = 33) administrations of TAZ/PIPC. The clinical outcomes in the two groups were analyzed and compared to evaluate the ef cacy of the two methods of administration. An analysis of WBC, CRP, and body temperature on the 7 -9th day of administration revealed no signi cant difference between the two groups in terms of the decrease in each parameter. However, 67 of the patients with a SIRS score 3 in the extended administration (n = 18) group showed improvement in at least two of the three parameters, compared to only 33 of those in the rapid administration group (n = 12). Thus, there was a marginally higher rate of improvement in the extended administration group (P = 0.073) than in the rapid administration group. Similarly, among the patients with a SIRS score ≥ 3, CRP improved signi cantly in the extended administration group on the 7 -9th day of administration (P = 0.0042). These results suggest that extended administration of TAZ/PIPC may improve clinical outcomes more effectively than rapid administration in patients with severe bacteremia.