Antibiotics represent a miracle of science that has saved innumerable lives. The use of antibiotics is however a two-edged sword. Antibiotics may also do harm and also, by their very nature, their use carries the elements of their own inevitable obsolescence. In December 1940, Albert Alexander a 43-year-old Oxfordshire Constable, developed a severe facial infection after having scratched his face while pruning rosebushes. This led to a severe facial infection and to his hospitalization at the Radcliffe Infirmary in Oxford. The infection progressed despite administration of sulfur pyridine until on February 12th, 1941, he became the first patient to receive parental penicillin for treatment of an infection. On that date, he was given under the supervision of 30-year-old Dr. Charles Fletcher 160 milligrams intravenously followed by 100 milligrams every three hours. He had observable improvement after having received a total of only 800 milligrams over the 24 hours. Alexander had been chosen after a not thoroughly encouraging experience in a single patient in a single-dose phase one trial. As Fletcher told a story in 1984, Florey explained that although penicillin had been found to be entirely harmless to leukocytes, tissue cultures and a wide variety of laboratory animals, he did not want to risk giving the first injection to a healthy volunteer in case of some unique adverse reaction in man. So, he asked me to find a patient with some inevitably fatal disorder who might be willing to help. There were no ethical committees in those days that had to be consulted. So, I looked around the wards and found the pleasant 50-year-old woman with disseminated breast cancer who had not long to live. I explained to her that I wanted to try a new medicine that could be of value to many people and asked if she would agree to a test injection of it. This she readily did. An injection of a 100 milligrams was administered via an antecubital vein on January 17th, 1981 and was followed several hours later by a rigor and fever. This experience resulted in further purification of the preparation with removal of pyrogens before its next administration to a human. While Albert Alexander had demonstrated continued dramatic improvement with continued penicillin administration, after five days and approximately 4.4 grams of treatment however, the entire supply of available penicillin had been exhausted. The limited supply was the result of the difficulties in production which was originally done in covered bedpans but these became unobtainable in England during the war. They were supplanted by 700 flat bottom stackable ceramic vessels tended around the clock by Penicillin girls but the production problem remained. The exhaustion of the penicillin supply for Constable Alexander occurred in fact, despite re-administration to him of penicillin recovered from his urine, which Fletcher transported by bicycle to the Dan Laboratory each morning. The infection resumed its inexorable progression, Constable Alexander died on the Ides of March, 1941. Once the problem of mass production was eventually solved, penicillin use became widespread. In his December 11th, 1985, Nobel lecture, Alexander Fleming warned of the danger of bacteria becoming resistant to penicillin as the result of its misuse. In fact, antibiotic resistance occurs with or without misuse is a result of the selective pressure exerted on the bacterial ecology by its administration. The emergence of resistance may be rapid or slow but it does appear to be inevitable. Among the infections for which penicillin proved to be lifesaving was pneumonia caused by Streptococcus pneumoniae. The emergence of resistance to this organism to penicillin was relatively slow to appear. Thus, it was not until 1967 after two decades of penicillin use that investigators reported the first clinical pneumococcal islet resistant to this antibiotic. The resistant islet was recovered from a patient with hypergammaglobulinemia and chronic bronchiectasis who had received multiple courses of antibiotics over her 25 years. While there were only sporadic reports of resistance over the next decade, the emergence of multiple cases in South Africa and other locations of penicillin-resistant and in some cases, multidrug-resistant pneumococcal disease was a harbinger of the global diminishing efficacy of penicillin in the treatment of infection due to this pathogen. Staphylococcus aureus took a different path. Penicillin resistance emerged in the 1940's and became pandemic in hospitals in the early 1950's. Currently, 90 percent of both hospital and community strains are penicillin-resistant. The introduction of the semi-synthetic penicillin methicillin was followed within a year by evidence of resistance which is now pandemic in both hospitals and the community. Penicillin resistance and Neisseria gonorrheae can result from a variety of mechanisms, including mutational and by horizontal gene transmission. In each of the above instances, the widespread use of antibiotics exerted the selective pressure that led to the emergence of resistance. In each horizontal gene transfer played a critical role. Penicillin resistance in the pneumococcus is the consequence of acquisition of genetic material from commensal alpha hemolytic streptococci resulting in mosaicism in the gene encoding a penicillin-binding protein, the enzyme target of the antibiotic. Gradual accumulation of changes in the gene is associated with progressively increased amounts of penicillin required to inhibit the organism. In contrast, in Stephylococcus aureus, penicillin resistance is due to the acquisition of a plasmid containing a complete gene encoding a penicillinase, an all or nothing phenomenon. Resistance to Methicillin similarly is the result of the horizontal acquisition of a gene cassette. These explain this slow gradual appearance of penicillin resistance in Streptococcus pneumoniae and its rapid abrupt acquisition in Staphylococcus aureus. In contrast to these examples of horizontal acquisition of resistance genes, resistance may also occur by additional mechanisms, including up-regulation of e-flux genes and genetic mutations within the target organism. A remarkable example of the latter was the result of the selective pressure exerted after the introduction of ciprofloxacin into clinical practice. At one institution, high-level resistance to ciprofloxacin and staphorious resulting from chromosomal mutations increased from 0 to 79 percent in the first year after its use. These mechanisms described also enhanced the possibility of multidrug resistance. Mechanisms such as these driven by the selective pressure exerted by antibiotic use, have led to the widespread emergence of resistance in a broad variety of organisms. In addition to the examples just discussed, we are dealing with Vancomycin resistant enterococcus, extended spectrum beta-lactamase producing enterobacteriaceae, carbapenemase-producing Klebsiella, multidrug-resistant Acinetobacter Pseudomonas, as well as others. Antifungal and antiviral resistance is also becoming more prevalent. Clinicians are thus caught between Scylla and Charybdis. On the one hand, withholding antibiotics when they are truly indicated may lead to the death of an individual, while promiscuous use of antibiotics accelerates their path through irrelevance because of the emergence of resistance. Every antibiotic use has a potential public health consequence. The goals of antimicrobial stewardship are the optimisation of patient outcomes while limiting adverse effects on the bacterial ecology. In this course, we will present a comprehensive approach to optimal antimicrobial use.
