Chemical Stability of Ceftolozane/Tazobactam in Polyvinylchloride Bags and Elastomeric Pumps.

BACKGROUND: Elastomeric pumps are often used to administer intravenous antibiotics in the outpatient setting, but effective infusion requires that the drug remain stable in solution throughout the procedure. OBJECTIVE: To determine the chemical stability of ceftolozane/tazobactam when reconstituted and stored over an extended time in the AccuFlo (EMED Technologies, El Dorado Hills, California) and I-Flow Homepump Eclipse (Halyard, Alpharetta, Georgia) elastomeric pumps compared with the results of the label-supporting studies in polyvinylchloride (PVC) bags. METHODS: Two ceftolozane/tazobactam dosages were tested for the elastomeric pump studies: 1500 mg (1 g ceftolozane/0.5 g tazobactam) and 150 mg (100 mg ceftolozane/50 mg tazobactam). The solution hold time was evaluated for 10 days at 5°C (±3°C) (tolerance ±3 hours) and for 1 day (24 hours) at ambient room temperature (tolerance ±3 hours). Results of a previously conducted label-supporting PVC intravenous bag study were used as a comparator. RESULTS: At each time point, the visual appearance of all pump and PVC bag solutions remained clear and free of visible particulates, and subvisible particulate matter did not differ significantly between the initial time point and at 10 days. No notable changes in pH in any of the pump or PVC solutions occurred throughout the study. Recovery of ceftolozane and tazobactam was greater than 93% and 94%, respectively, for all samples (elastomeric pump and PVC bag) at 10 days. CONCLUSIONS: Ceftolozane/tazobactam remains physically and chemically stable for at least 7 days, as indicated on the US label, when reconstituted, diluted, and stored in the AccuFlo and I-Flow Homepump Eclipse elastomeric pumps and in PVC intravenous bags.

Caryophyllenes from a fungal culture of Chrysosporium pilosum.

Four new caryophyllene derivatives, Sch 725432 (1), Sch 601253 (2), Sch 601254 (3), and Sch 725434 (4), were isolated from the fungal fermentation broth of Chrysosporium pilosum by reversed-phase HPLC purification. The structure elucidation of trioxygenated caryophyllenes 1-4 was accomplished on the basis of spectroscopic data interpretation. Sch 725434 (4) possesses a dihydrofuran-3-one ring, forming a tricyclic ring skeleton, which represents an unprecedented ring skeleton for the caryophyllene-type of sesquiterpenes. Compounds 1-4 were evaluated for their antifungal activity.

Sch 213766, a novel chemokine receptor CCR-5 inhibitor from Chaetomium globosum.

A novel fungal secondary metabolite, Sch 213766 was isolated from the fungal fermentation broth of Chaetomium globosum as the chemokine receptor CCR-5 inhibitor and shown to be the methyl ester of the previously described tetramic acid Sch 210972 on the basis of UV, MS and NMR spectral data analyses. Sch213766 exhibited an IC(50) value of 8.6 muM in the CCR-5 receptor in vitro binding assay.

Chemokine receptor CCR-5 inhibitors produced by Chaetomium globosum.

Two novel chemokine receptor CCR-5 inhibitors, Sch 210971 (1) and Sch 210972 (2), were isolated from the fungal fermentation broth of Chaetomium globosum by normal- and reversed-phase HPLC purifications. The structure determination of 1 and 2 was accomplished on the basis of UV, MS, and NMR spectral data analyses including COSY, NOESY, HMQC, and HMBC experiments. The structure and relative configuration of 2 were determined unequivocally by X-ray crystallographic analysis. The major component 2 demonstrated a potent inhibitory activity of IC(50) = 79 nM in the CCR-5 receptor in vitro binding assay.

A new 5-alkenylresorcinol sch 725681 from Aspergillus sp.

A new 5-alkenylresorcinol Sch725681 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 16 and 64 microg/ml, respectively.

A new hydrogenated azaphilone Sch 725680 from Aspergillus sp.

A new hydrogenated azaphilone Sch725680 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was achieved based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 64 microg/ml, respectively.

Structure elucidation of Sch 725674 from Aspergillus sp.

A new macrolide Sch725674 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 32 microg/ml, respectively.

New antibiotic Sch 725424 and its dehydration product Sch 725428 from Kitasatospora sp.

A new microbial metabolite Sch 725424 (1) was isolated from the culture of Kitasatospora sp. The structure elucidation of 1 was accomplished based on NMR spectroscopic analyses as well as extensive structure elucidation of its dehydration product Sch 725428 (2). Compound 1 showed inhibitory activity against Staphylococcus aureus with MIC values 1-2 microg/ml, and also displayed weak antifungal activity against Saccharomyces cerevisiae (PM503) with an MIC 32 microg/ml.

Two novel antibiotics, Sch 419558 and Sch 419559, produced by Pseudomonas fluorescens: effect on activity by overexpression of RpoE.

Two new secondary metabolites designated as Sch 419558 (1) and Sch 419559 (2), were isolated from the fermentation broth of Pseudomonas fluorescens. Structure elucidation of 1 and 2 was accomplished by spectroscopic data analyses including MS and NMR experiments. Both compounds were identified as lipopeptides containing valine and threonine linked with 1-amino-1-hydroxy-heptadec-9-en-2-one or 1-amino-1-hydroxy-pentadecan-2-one carbon chains, respectively. Characterization of the amino acids was further confirmed by amino acid analysis. Compounds 1 and 2 exhibited antibacterial activity against a sensitized E. coli strain with minimum inhibitory concentration of 0.3 and 0.6 microg/mL, respectively. Overexpression of RpoE in the E. coli strain increased the MIC over 60-fold for compounds 1 and 2.

Use of red-shifted dyes in a fluorescence polarization AKT kinase assay for detection of biological activity in natural product extracts.

Kinases are an important therapeutic target for drug discovery, and many cancer chemotherapeutic agents have been derived from natural product sources. Natural product samples, however, have the likelihood of assay interference, particularly at elevated test concentrations. The authors developed a competitive fluorescence polarization (FP) assay using red-shifted fluorophores for the AKT kinase and demonstrated utility for testing concentrated natural product extracts. A set of 7 actinomycetes cultures containing indolocarbazoles, known nonselective kinase inhibitors, and a control set of 22 nonproducing indolocarbazole cultures were evaluated. Using red-shifted dyes (Cy3B or Cy5), the authors identified active samples with minimal interference up to the extract concentrations that are 3 times nonextracted culture levels. In contrast, a significant number of interferences were observed using either a fluorescein competitive FP assay or a [33P]ATP Flashplate assay. This work demonstrates that one can screen natural product extracts at high concentrations successfully using FP technology with red-shifted dyes.

Isolation and structure elucidation of Sch 642305, a novel bacterial DNA primase inhibitor produced by Penicillium verrucosum.

A novel primase inhibitor, Sch 642305 (1), was isolated from the fermentation broth of the fungal culture Penicillium verrucosum. The structure of 1 was elucidated on the basis of MS and NMR spectroscopic data as a new and unusual bicyclic 10-membered macrolide. The absolute configuration of the asymmetric centers was determined by X-ray crystallographic analysis of the p-bromobenzoate derivative (3). Compound 1 exhibited inhibitory activity against bacterial DNA primase enzyme with an EC(50) of 70 microM.

Isolation and characterization of two new antifungal antibiotics from a basidiomycete.

Two novel antibiotics, Sch 484129 (1) and Sch 484130 (2), were isolated from the fermentation broth of a fungal culture, which was identified as a Basidiomycete. The new antibiotics were obtained by ethyl acetate extraction followed by reversed phase HPLC purification. Structure elucidation of 1 and 2 was accomplished by spectroscopic data analyses. Derivatizations of the major component 1 were performed in order to provide definitive structural information. Both components were identified as glycolipids and displayed antifungal activity against Saccharomyces and Aspergillus strains.