Prescribing Ceftolozane/Tazobactam for Pediatric Patients: Current Status and Future Implications.

Antibiotics are arguably the greatest medical development of the 20th century but these precious resources are being threatened by the continued rise in infections caused by multidrug-resistant bacteria. There is concern that we are on the precipice of a 'post-antibiotic era'. The situation is exacerbated by a stagnation in the pharmaceutical industry in developing new antibiotics, particularly those with activity against some of the most resistant Gram-negative organisms because of significant economic, scientific, and regulatory barriers. One of the products of recent initiatives to reinvigorate the antibiotic pipeline is the agent ceftolozane/tazobactam. Ceftolozane/tazobactam was approved in December 2014 by the US Food and Drug Administration for the treatment of complicated urinary tract infections and complicated intra-abdominal infections for patients 18 years of age and older. The safety and effectiveness of ceftolozane/tazobactam in pediatric patients has not been established in clinical studies. However, with the rise of highly drug-resistant Gram-negative organisms in children and the current climate of ongoing, multiple, and simultaneous antibiotic shortages--particularly of broad-spectrum antibiotics, the potential off-label role of ceftolozane/tazobactam for children needs to be explored while pediatric studies are ongoing. The objective of this opinion piece is to discuss what is currently known about ceftolozane/tazobactam and its potential implications for use in the pediatric population.

Influence of polyunsaturated fatty acids on urologic inflammation.

PURPOSE: Studies demonstrate that polyunsaturated fatty acids, fish oils, and alpha-linoleic acid are beneficial anti-inflammatory agents, which suppress inflammatory mediators and their activity. METHODS: This review focuses on the effects of omega-3 fatty acids (O-3FAs) on three primary urologic organs (bladder, kidney, and prostate) and associated conditions such as urolithiasis, kidney transplantation, interstitial cystitis/bladder pain syndrome, bladder cancer, prostate cancer (CaP), and chronic prostatitis/chronic pelvic pain syndrome. RESULTS: The following themes emerged: the potential influence of O-3FA in suppressing urologic inflammation; the supportive role of O-3FA in therapeutic interventions; pro-inflammatory mechanisms of omega-6 fatty acids (O-6FAs) associated with disease progression; and the importance of the optimal ratio of O-6FAs/O-3FAs. CONCLUSIONS: The need for further research on the role of PUFAs in suppressing urological inflammation precipitated.

p38 MAPK plays a role in IL-4 synthesis in jacalin plus CD28-stimulated CD4+ T cells--II.

We have previously shown that jacalin, a CD4+ T cell lectin, induces phosphorylation of intracellular events, moderate levels of interleukin (IL)-2 secretion. We have also shown that in the presence of CD28 costimulation, jacalin induces IL-4 secretion. In the present study, we showed that stimulation of normal CD4+ T cells with jacalin plus CD28 cross-linking (CD28XL) resulted in phosphorylation of signal transducer and activator of transcription (STAT)-6 and expression of Bcl-2 and Bcl-xL, which were inhibited significantly when cells were cultured in the presence of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. We further generated jacalin-induced CD4+ T cell blasts, examined the effects of CD28XL, and observed enhanced up-regulation of p38 and activation of STAT-6, Bcl-2, and Bcl-xL. Engagement of CD28 alone induced a marked degree of phosphorylation of p38 MAPK and IL-4 secretion in memory T cells (jacalin blasts), whereas in naïve T cells, jacalin plus CD28XL was required to induce these molecules. Incubation of cells with p38 inhibitor prior to CD28XL resulted in down-modulation of all these molecules. Further treatment with IL-4 has not reversed this trend. Our studies imply that p38 MAPK may play an important role in induction of these molecules and a putative role in protecting cells from undergoing apoptosis.

The lectin jacalin plus costimulation with anti-CD28 antibody induces phosphorylation of p38 MAPK and IL-4 synthesis-I.

Costimulatory signals play an important role in the development of T helper cell type 1 (Th1) or Th2 type. Little is known about jacalin plus CD28-mediated signaling and cytokine secretion. In the present study, we analyzed the intracellular signaling events following stimulation of CD4+ T cells with jacalin plus CD28 cross-linking (CD28XL) with anti-CD28 antibody. Our results indicate enhanced phosphorylation of Tec and linker for activation of T cells when compared with stimulation with jacalin alone or CD28XL alone. Stimulation with jacalin or CD28XL appears to be insufficient to induce interleukin (IL)-4 secretion; however, CD28XL followed by stimulation with jacalin resulted in enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and increased secretion of IL-4. However, compared with stimulation with phorbol 12-myristate 13-acetate plus ionomycin, jacalin plus CD28XL resulted in decreased levels of tumor necrosis factor alpha secretion. Addition of p38 inhibitor, SB203580, inhibited p38 phosphorylation and IL-4 secretion. These data suggest that jacalin stimulation alone appears to be insufficient for Th2 development, and addition of CD28 costimulation induced Th2 generation. We propose that jacalin plus CD28XL induces Th2 differentiation via activation of p38 MAPK.

IgD-receptor (IgD-R) cross-linking partially protects murine T cells from dexamethasone-induced apoptosis.

Based on our previous findings that immunoglobulin D (IgD) receptor (IgD-R) cross-linking with oligomeric IgD (IgD-R-xL) led to T cell activation, we examined the effect of IgD-R-xL on the expression of Fas antigen and apoptosis induction. In splenic T cells, IgD-R-xL followed by dexamethasone (dex) treatment resulted in a decreased percentage of Fas-positive cells as well as a decreased mean fluorescence intensity (P<0.05) when compared with cells treated with dex alone. There are significant differences in annexin-fluorescein isothiocyanate (FITC) and phosphatidylinositol (PI) staining between samples treated with dex alone and IgD-R-xL followed by dex-treated samples (P<0.05), suggesting a protective role for IgD-R-xL. No significant differences are seen in Fas antigen expression, annexin-FITC staining, and/or PI staining in murine T hybridoma (7C5) cells cultured under similar conditions (P<0.07). We hypothesize that ligation of IgD-R may predispose antigen-specific T lymphocytes for survival during primary immune responses when IgD-positive B cells serve as antigen-presenting cells.

The lectin jacalin induces phosphorylation of ERK and JNK in CD4+ T cells.

The CD4 molecule plays an essential role in mediating the transduction of intracellular signals by functioning as a coreceptor for the complex T cell receptor/CD3 and also acts as the primary receptor for human immunodeficiency virus (HIV). Several authors have shown evidence that jacalin, a plant lectin, binds to CD4 and inhibits in vitro HIV infection. We analyzed jacalin-induced intracellular signaling events in CD4(+) T cells and have shown that cell activation resulted in tyrosine phosphorylation of intracellular substrates p56(lck), p59(fyn), ZAP-70, p95 (vav), phospholipase C-gamma1, and ras activation, as assessed by conversion of ras guanosine 5'-diphosphate to ras guanosine 5'-triphosphate. We further examined extracellular regulated kinase (ERK) and c-jun NH(2)-terminal kinase (JNK) phosphorylation following stimulation with jacalin. The data indicate that the kinetics of JNK phosphorylation is delayed. Optimum phosphorylation of ERK2 was observed by 10 min, and that of JNK was observed by 30 min. Pretreatment with gp120 followed by stimulation with jacalin resulted in marked inhibition of all of the aforementioned intracellular events. The data presented here provide insight into the intracellular signaling events associated with the CD4 molecule-jacalin-gp120 interactions and HIV-induced CD4(+) T cell anergy. Jacalin may be used as a possible tool for the study of CD4-mediated signal transduction and HIV-impaired CD4(+) T cell activation.