Antimicrobials and the emergence of disease-specific therapies
Sir Alexander Fleming’s discovery of the anti-microbial activity of penicillin in 1928 is often considered the first disease-specific therapy (5). In actual fact, this seminal observation did not translate into changes in care until well after the widespread use of another antimicrobial drug, sulfanilamide. The scientific community initially responded with little enthusiasm for “mould juice”, and given challenges associated with producing the antimicrobial in large quantities, Fleming had initially considered penicillin to be most useful as a potential surface cleaner or as an agent to help isolate bacteria in culture (6). At the same time, in the early 1930s, Dr. Gerhard Domagk, a German physician, was exploring the use of various chemical agents to combat bacterial infections. In this work, he found that the sulphonamide groups in azo dyes offered potential as antimicrobial agents, notably the compound Prontosil™. Famously, the first human to benefit from his landmark advance was his own daughter. When six year old Hildegard developed a serious Strep infection, and amputation of her arm was being considered, he treated her with Prontosil™ and she quickly recovered,.. In 1935, he published his work demonstrating that mice infected with Streptococci survived when administered a single dose of a synthetic azo dye (7). His work led to the introduction of Prontosil™ to the market shortly thereafter. Tréfouël and Tréfouël and colleagues at the Pasteur Institute subsequently determined that the active agent in Prontosil™ was the sulphonamide sulfanilamide (8).
The impact of the introduction of specific and effective medical therapy on health care –specifically child health care - and medical culture was substantial and permanent. As described by Lewis Thomas, the role of the physician up to the early 20th Century had been primarily to provide supportive care to suffering patients, including providing explanations to support diagnosis and suggest outcome, with cure being reserved (in certain and limited cases) to surgeons (9). Prior to the 1940’s, for most patients with infection, medical management includes watchful waiting and symptom management until the infection resolved or the patient succumbed. The establishment of effective antimicrobial therapy was a paradigm-changing event, comparable today to curing all cancer, or reversing now-irreversible neurologic injury (9). As effective antimicrobial therapy became available, the mortality rate from meningitis fell from 95% to 5%. Similarly, death from pneumonia or bacterial skin infection – previously common – became rare. In parallel, the pharmaceutical industry formalized itself, and came to recognize the significant potential associated with disease-specific cures, which launched a focused search for other new molecular entities (1,5). The Therapeutic Revolution that followed these fundamental discoveries first led to a wave of new treatments based on innovative small molecules and subsequently led to the revolution in biological and gene-based therapies.
For children, this focus on disease-specific therapy has been profound for some disorders. While the first and arguably largest impact was with infectious diseases, advances in the understanding of the fundamentals of paediatric drug therapy, including paediatric pharmacokinetics and the role of therapeutic drug monitoring – led to substantial changes in the management of other common and serious disorders in childhood. Childhood cancer, which had a nearly universally fatal outcome less than a century ago, now boasts cure rates, for some of the commonest cancers, of 80 to 90% in large part due to highly effective therapy (10). Paediatricians and other child health care providers have proven adroit at applying medications developed for adult indications into paediatric practice, often very shortly after the drug in question entered the market.