When Old Ways No Longer Work: Antibiotics and Drug Development

Abstract

Richard I. Shader, MD Like many others during their years in medical school, I rarely had the time or the money to go to the movies. A memorable exception for me came when my pharmacology professor recommended that we see Death of a Scoundrel. He was a movie buff and did so at a time when we were learning about the mechanism of action of penicillin (PCN). What I recall about the movie is that George Sanders starred as a suave grifter who used stolen money to invest in a company that manufactured PCN. Not surprisingly, he made a very large profit. Sanders learned about PCN from a ship’s physician who was removing a bullet from a shooting victim. The year was 1957, and PCN was still king – a miracle drug. Plasmids, penicillinases (including β-lactamases), and resistance were just being taught. Two years later in 1959, Edward Abraham reported that his derivative of cephalosporin C (cephaloram) was also effective against Staphylococcus aureus (Staph) strains. Cephaloram and the soon to be developed newer cephalosporins all contained a β-lactam ring, just like PCN. Not surprisingly, β-lactamases caused resistance to these early antibiotics. Today, none of these early agents is effective against resistant Staph. This is a good example of the old ways no longer working. The old ways may no longer work (or be the best approach) for many reasons, including, but not limited to, technological advances, evolution, tolerance, new discoveries, fads going out of style, and, in the above example, the development of adaptation or resistance. Another example in the medical care realm is the change in treatment for peptic ulcers. I remember well the limited success with Sippy diets (scheduled intake of milk and cream, farina, and eggs) and anticholinergic antispasmodics. Today we know about Helicobacter pylori (first known in the 1950s as Campylobacter pylori), and, instead we use appropriate antibiotics (eg, erythromycin), proton pump inhibitors (eg, omeprazole), and bismuth. Some examples outside of the medical field are the replacement of the mimeograph by today’s laser printers, the disappearance of large Sunday newspaper advertisement sections because of the Internet and ads on social media, the reduction in the volume of snail mail because of e-mail, the replacement of print journals by online versions, and the scarcity of long-playing records in the wake of iTunes and MP3 players. And what young person has a land line anymore? Remember the children’s phone? I am sure readers could fill many pages with pet examples. In this issue of Clinical Therapeutics, two of our Topic Editors are addressing how old ways are being replaced in their specialties. Dr. Susan Hadley brings us papers that discuss dealing with bacterial resistance by using combinations of drugs including daptomycin, vancomycin, piperacillin-tazobactam, and a new-generation cephalosporin, ceftaroline fosamil (Teflaro, Cerexa) that is active against resistant Staph. Dr. Kenneth Kaitin and his chosen contributors address how the conduct of clinical trials, indeed the landscape of drug development, is being altered by precompetitive alliances, strategic outsourcing, improvements in site development and support, quality management, and greater attention to safety. This is Dr. Kaitin’s first themed contribution as Topic Editor for Drugs and Biologics. The Drugs and Biologics area focuses on topics related to the discovery, development, regulation, and use of drugs and biological products and particularly on clinical trial designs, ethics review, regulatory initiatives and impact, industry performance, partnerships, financing, outsourcing, and global development issues. We welcome future submissions for this focus area. Finally, here is an old way that is making a comeback in Clinical Therapeutics: an emphasis on the importance of the chemical structures of medicinal compounds that are encountered in the clinic or the laboratory. Most courses in pharmacology these days are shorter than in the past and are streamlined to be more practical. Fewer drugs are covered, and often only one or two examples of a class may be discussed in any detail. Chemical