Antibacterial agents that inhibit two-component signal transduction systems.

A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA::Spo0F two-component signal transduction system in vitro. Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase::response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy.

The future of general surgery characterized by general surgical chief residents.

The future of any specialty in medicine depends in large part on the career choices of its trainees. We obtained data from General Surgery Chief Residents who finished their training in 1990 and compared their attitudes to a similar survey conducted by us in 1985. According to those responses, residents in general surgery continue to choose fellowship training at a time when they no longer perceive an oversupply of general surgeons. This has broad implications for the future of general surgery as a specialty that requires significant change in the structure of our residency programs.

Patency of a small vessel prosthesis bonded to tissue plasminogen activator and iloprost.

To test the thrombosis resistance of a vascular prosthesis coated with antithrombogenic agents, we evaluated a small vessel prosthesis of expanded polytetrafluoroethylene (ePTFE) implanted in the rat aorta and removed 1 week following surgery. Control grafts consisted of 1 mm internal diameter ePTFE. Experimental grafts consisted of 1 mm internal diameter ePTFE noncovalently bonded to tissue plasminogen activator (tPA) and iloprost using the surfactant tridodecylmethylammonium chloride. After 1 week the grafts were harvested, patency was determined, and histologic specimens were prepared for electron microscopy. Six of 10 control grafts were thrombosed, whereas 9 of 10 tPA-iloprost-bonded grafts were patent (p < 0.03). Of concern, there was an unexpectedly high mortality rate in the tPA-iloprost group compared to the control group among animals that died before completion of the study. Evaluation of the safety of these drugs must, therefore, be an early component of future experiments. Nevertheless, these studies indicate that a small vessel prosthesis bonded to tPA and iloprost may ameliorate some of the complications associated with early graft failure.

Prevention of vascular prosthetic infection with an antibiotic-bonded Dacron graft.

Surfactant-mediated antibiotic bonding was used in an animal model of aortic prosthetic infection. Control grafts, control plus parenteral oxacillin, and oxacillin-bonded Dacron grafts were challenged by local inoculation with Staphylococcus aureus. Ninety percent of controls, 80% of parenteral antibiotic recipients, and only 30% of antibiotic-bonded Dacron grafts became infected (p less than 0.01, p less than 0.03). Antibiotic-bonded grafts were also superior in terms of suture line cultures and patency. In separate experiments in a subcutaneous pouch model, antibiotic bonding significantly improved the median infective dose of Dacron over that of controls and Dacron soaked in cephalosporin. These studies demonstrate that antibiotic-bonded Dacron implants are highly resistant to infection. A multicenter clinical trial is planned.

The influence of debt, moonlighting, practice, oversupply and gender on career development of residents in university and independent training programs.

A survey of chief residents in general surgery was conducted to evaluate debt and moonlighting, planned practice characteristics, the influence of oversupply and gender. Debt and moonlighting were closely related. The latter also correlated statistically with the perceived oversupply of general surgeons. Most residents planned to practice in a suburban area, in a community or university affiliated hospital with some teaching responsibilities. General surgeons were those more likely to choose a rural area, a community hospital and no teaching responsibilities. Subspecialists were those more likely to choose an urban area, a university hospital and a complete teaching environment. Two-thirds of residents thought there was an oversupply of general surgeons. They were more likely to take fellowships, especially those in transplantation, vascular, trauma, oncologic and colorectal surgery. Women represented less than 10 per cent of chief residents. They differed from men in the types of fellowships chosen, moonlighting activity and interest in teaching.

Infection-resistant continuous peritoneal dialysis catheters.

The techniques of bonding of anionic antibiotics by treatment with cationic surfactants were applied to continuous ambulatory peritoneal dialysis (CAPD) catheters. The elution of 14C-penicillin from tridodecylmethylammonium chloride (TDMAC) treated silicone elastomer catheters in dialysis solution was biphasic, with 95% dissociated from the catheter by 48 h. Forty percent of the TDMAC left the catheter surface during the initial 2 days. The ability of the surfactant TDMAC to bind antibiotics after incubation in dialysis solution correlated directly with the amount of surfactant remaining. Rats with intraperitoneal dialysis catheters were inoculated with exit site and intraluminal bacterial challenges. Intraperitoneal catheter tips treated with TDMAC-penicillin were rendered more resistant to colonization after exit site and intraluminal bacterial challenges.

Career development of residents in university and independent training programs: the influence of special training fellowships, type of practice, specialization, and research.

General surgical chief residents in all approved training programs were surveyed to evaluate the influence of fellowships, specialization, and research. Respondents represented 76% of programs and 60% of residents. Most chief residents plan to take post-residency fellowships. This is most common among those from university training programs and residents planning an academic career. Vascular surgery and cardiothoracic surgery represent half of all fellowships. Sixty-two percent of residents plan to enter private practice compared with 28% who plan to join a medical school faculty. More than one third of university trainees plan an academic career. More than 90% plan fellowships. The practice of general surgery alone or combined with a specialty was more common among trainees from independent training programs. Practice of a subspecialty was more common among university trainees. More than 80% of residents did research during training. Research leading to publication was more common among university trainees planning academic careers and least common among future general surgeons. This survey suggests that general surgery is predominant among residents in independent training programs who then enter private practice. University programs produce subspecialists who are predominant among future academic surgeons. This trend has vital implications for the future of academic general surgery.

Prevention of catheter sepsis by antibiotic bonding.

The techniques of antibiotic bonding were applied to the problem of hyperalimentation catheter sepsis. Pretreatment with tridodecylmethylammonium chloride (TDMAC) increased the bonding of 14C-penicillin to polyethylene catheter segments from 3.1 to 212 micrograms/cm and to silicone elastomer catheter segments from 0.09 to 181 micrograms/cm. The elution of the bound ligands from silicone elastomer catheter segments in the presence of plasma was studied. At 2 weeks more than 60% of the bound TDMAC remained adherent to the catheter. The elution of the bonded penicillin from the silicone elastomer catheters was biphasic, initially 95% dissociated after 48 hours of incubation. A bioassay revealed that the dissociated penicillin was bacteriocidal. Polyethylene catheters were placed in the jugular vein of rats and positioned in the right atrium. The catheters were tunneled posteriorly, exited between the forelimb shoulder girdles, and connected to a swivel mechanism. The exit site was inoculated before closure with 1 X 10(8) Staphylococcus aureus. Five days after insertion the catheters were removed via sterile thoracotomy and the tips cultured. Untreated control catheters, catheters treated by antibiotic soaking, and catheters pretreated with TDMAC all had high rates of catheter colonization (60% to 80)%. TDMAC-penicillin-bonded catheters did not become colonized. This difference was significant (p less than 0.005). Antibiotic bonding may prove effective in preventing hyperalimentation catheter sepsis.

The application of antibiotic bonding to the treatment of established vascular prosthetic infection.

We used surfactant-mediated antibiotic bonding to treat established vascular prosthetic infections in an animal model. The infrarenal aorta of dogs was replaced with a polytef (PTFE) graft locally contaminated with Staphylococcus aureus. Infected grafts were then replaced with control polytef or polytef bonded with benzylkonium chloride and penicillin G tagged with radioactive carbon, or polytef bonded with tridodecylmethylammonium chloride and penicillin G tagged with radioactive carbon. Both types of antibiotic-bonded grafts had significantly fewer infections than control grafts did. The labeled penicillin G remained bound to both groups of antibiotic-bonded grafts for at least three weeks. In a second group of studies, surfactant-treated polytef adsorbed parenterally administered labeled penicillin G in highly significant concentrations compared with control grafts. These studies suggest the possibility that human vascular prosthetic infection may be treated with an antibiotic-bonded graft.

Stability of antibiotics bound to polytetrafluoroethylene with cationic surfactants.

This study evaluated the effect of prolonged storage and sterilization on the noncovalent bonding of penicillin to polytetrafluoroethylene grafts. The surfactant tridodecylmethylammonium chloride was unaffected by prolonged storage or sterilization, and its ability to bind penicillin remained constant for as long as 3 months. Steam or ethylene oxide sterilization markedly diminished the antibacterial activity of bound penicillin. However, the antibacterial properties of penicillin remained constant for up to 12 weeks when the grafts were stored at either 4 degrees C or room temperature. Thus, the bonding process appears to increase the stability of the antibiotic, and the data presented suggest that vascular prostheses can be treated with a surfactant, sterilized, and stored for at least 3 months. Grafts can then be treated with an antibiotic in the operating room, washed, and implanted.