ABSTRACT
A systematic approach toward building activity against methicillin-resistant staphylococci into the cephalosporin class of beta-lactam antibiotics is described. Initial work focused on finding the optimal linkage between the cephem nucleus and a biphenyl pharmacophore, which established that a thio linkage afforded potent activity in vitro. Efforts to optimize this activity by altering substitution on the pharmacophore afforded iodophenylthio analog MC-02,002, which although highly potent against MRSA, was also highly bound to serum proteins. Further work to decrease serum protein binding showed that replacement of the iodo substituent by the positively-charged isothiouronium group afforded potent activity and reduced serum binding, but insufficient aqueous solubility. Solubility was enhanced by incorporation of a second positively-charged group into the 7-acyl substituent. Such derivatives (MC-02,171 and MC-02,306) lacked sufficient stability to staphylococcal beta-lactamase enzymes. The second positive charge was incorporated into the cephem 3-substituent in order to utilize the beta-lactamase-stable aminothiazolyl(oximino)acetyl class of 7-substituents. These efforts culminated with the discovery of bis(isothiouroniummethyl)phenylthio analog MC-02,331, whose profile is acceptable with respect to potency against MRSA, serum binding, aqueous solubility, and beta-lactamase stability.
Subject(s)
Bacterial Proteins , Cephalosporins/chemistry , Hexosyltransferases , Lactams/chemistry , Peptidyl Transferases , Staphylococcus aureus/drug effects , Animals , Carrier Proteins/metabolism , Cephalosporins/metabolism , Cephalosporins/pharmacology , Humans , Lactams/metabolism , Lactams/pharmacology , Male , Methicillin Resistance , Mice , Microbial Sensitivity Tests , Muramoylpentapeptide Carboxypeptidase/metabolism , Penicillin-Binding Proteins , Structure-Activity RelationshipABSTRACT
We performed a prospective randomized controlled trial to assess the efficacy of a chlorhexidine dressing in reducing the microbial flora at the insertion site of epidural catheters. These catheters were used for acute pain management and were dressed either by a standardized method or with a CHX/urethane sponge composite. Microbial colonization of the catheter developed in 9 of 31 controls (29.0%) and 1 of 26 (3.8%) catheters with the CHX dressing (P less than 0.05%). The CHX dressing caused no adverse effects. The data suggest that delivery of antiseptic to the catheter wound site reduces catheter colonization with a possible reduction in the risk of epidural catheter-related infection.
Subject(s)
Analgesia, Epidural/instrumentation , Catheters, Indwelling , Chlorhexidine/therapeutic use , Infection Control , Pain, Postoperative/prevention & control , Bandages , Chlorhexidine/administration & dosage , Chlorhexidine/pharmacokinetics , Humans , In Vitro Techniques , Infections/etiology , Prospective StudiesSubject(s)
Cardiac Pacing, Artificial , Computer Systems , Humans , North America , Societies, Medical , SoftwareABSTRACT
Air embolism and static pressure errors have been attributed to continuous infusion systems. Experiments show that the primary source of air bubbles in such a system is the drip chamber. A drip chamber that minimizes this problem was tested and is recommended. Pressure errors due to the flush system are shown to be clinically insignificant. Fast flushing through a central arterial catheter is shown to be a minimal hazard.
