PubMed · 10088396
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T Haruta. 1999. [Pneumococcal meningitis].. https://pubmed.ncbi.nlm.nih.gov/10088396/
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Increased drug resistance in Staphylcocci and Enterococci to currently available antibiotics has significantly limited therapeutic options. Recently, a novel carbapenem antibiotic (Compound A) with a releasable side chain adjacent to the carbapenem was investigated to combat methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci. The major advantage of Compound A over existing antibiotics can be attributed to the fact that cleavage of the side chain upon beta-lactam ring opening retained anti-bacterial activity while expelling the immunodominant epitope of the presumed beta-lactam hapten. In this work, LC/MS methods were developed to identify degradates of Compound A in an aqueous matrix utilized in assessing product safety and supporting analytical method and formulation development. A total of eight significant degradates were observed in this Compound A sample by LC/MS(n) and other techniques. Detailed structural analysis of degradates based upon LC/MS(n) data and other supporting results will be described in this work. Proposed molecular structures were confirmed by synthesis and use of authentic standards for several degradates. Degradates 1 and 4 were identified as degradates formed through the reversal of Michael reaction from Degradate 3 that is apparently formed by hydrolysis. Degradates 2 and 8 were found to be Hofmann elimination degradates. Degradates 5 and 6 are believed to be formed through dimerization of two parent molecules followed by the reversal of Michael reaction. Finally, Degradate 7 is attributed to a displacement reaction. Potential degradation pathways based upon these preliminary studies will also be discussed.
A series of tricyclic pyrrolizidinone carboxylic acids harboring an angular methano group were synthesized as mimics of carbapenems and carbapenams. A key reaction involved a novel intramolecular cyclopropanation mediated by a trimethylstannylmethyl group and an adjacent iminium ion. Enolate chemistry on a tricyclic lactam ring unit allowed the introduction of various substituents. Further elaboration afforded tricyclic pyrrolidinone carboxylic acids, which were found to be inactive as inhibitors against a panel of bacterial strains. However, the antibacterial activity of ceftazidine was enhanced in the presence of the tricyclic analogues.
Reversed-phase high-performance liquid chromatography (RP-HPLC) assays using ultraviolet (UV) absorbance detection have been developed for the determination of a new carbapenem antibiotic I in human plasma and urine. A column-switching technique is employed in the HPLC methods to perform on-line extraction and separation for each sample. Each plasma sample is thawed, centrifuged, stabilized, and then injected onto an in-line reversed-phase extraction column using a methanol (8%)/phosphate buffer, pH 6.5. After 3 min, the analytes are back-flushed off the extraction column with a mixture of acetonitrile (5.5%) and methanol (10%)/phosphate buffer (pH 6.5) for 3 min onto a BDS Hypersil 3 microm C18 (100 x 4.6 mm i.d.) analytical column. The sample preparation and HPLC conditions for the urine assay are similar to the plasma assay, except that a CN extraction column is used. Both assays are specific with respect to endogenous material and the major metabolite II, and both are linear over the concentration range of 0.25-50, and 2-200 microg/ml, respectively. The assays were successfully applied to a clinical dose-ranging study. One limitation of the on-line extraction method is that the extraction column needs to be replaced regularly every 100-150 plasma samples and every 200-300 urine samples. Subsequently, the urine method was modified to an ion-pair HPLC assay for the simultaneous determination of both the antibiotic I and its metabolite II.