Biology’s Armaments Race

As World War II raged in Europe in 1941, the British medical journal “Lancet” described a discovery of historic importance. “A 43-year old policeman in Oxford, England,” the article reported, “was admitted to the hospital in early October of 1940, with disseminated Staphylococcus aureus and Streptococcus pyogenes infection. His disease began as a sore at the corner of his mouth. He failed all local drainage therapy ... When the penicillin was begun on February 12, 1941, the infection had already spread to involve most of his face, both orbits, his lungs, and his right arm (with osteomyelitis). Between February 12-17, 4.4 grams of penicillin were administered. This caused dramatic improvement. Infection of the face and arm disappeared, and the policeman’s fever subsided. His white blood cell count fell from 20,000 at the start of the therapy to 8,400 at the end.” “Treatment had to be discontinued,” the report went on, “because the supply of penicillin was exhausted. The patient relapsed and died of overwhelming staphylococcal infection on March 15, 1941.” Within a year or so penicillin was recognized as a miracle drug. Mass production, stimulated by wartime demand, guaranteed supply. The era of antibiotics had begun. In little more than two decades the number of antibacterial agents added to the arsenal of antibiotics increased rapidly. The names are familiar: streptomycin, chloramphenicol, tetracycline, erythromycin, methicillin, vancomycin, rifampin, cephalosporins, gentamicin. All were products of microbes living in the soil, amidst which the newly born anti-infective industry found its most resourceful allies. Together, these powerfully toxic agents had activities that appeared to cover the entire range of human pathogens. It is important to realize how radically these agents changed the eons old battle between Man and disease-causing Microbes. In the pre-penicillin era, an infectious disease was the private matter of the patient: his or her immune system confronted the virulent factors of the invading microbial pathogen alone. Introduction of penicillin and other powerful antibacterial agents changed this scenario to a kind of surrogate warfare. The invading bacterium was confronted not by the host but by toxic chemicals, the arsenal of antibacterial agents that could kill the invaders through highly selective mechanisms, targeted at critical points in the metabolism of microbes essential for their survival. At first glance the power of these agents appeared limitless. Indeed, so victorious did science seem that the US surgeon general was prompted to declare in 1970 that “we can close the books on infectious diseases.” Unfortunately, subsequent events shattered his optimistic forecast. Within 5-6 years of the introduction of penicillin into therapy physicians began to report cases in which infections by Staphylococcus aureus – the bacterium that infected the British police officer in 1941 – could no longer be cured by penicillin. The incidence of penicillin resistant staphylococci increased rapidly. By the early 1950s the miracle drug penicillin was useless against most staphylococcus isolates. The microbial world was fighting back against antibiotics. To overcome the penicillinase resistance mechanism, scientists at Beecham Laboratories redesigned the penicillin molecule, leading to the introduction of a new compound, methicillin, in 1957. But within a year, reports of methicillin-resistant staphylococcus aureus (MRSA) began to appear. By the mid-1970s MRSA strains had invaded Europe, the US, Australia, and East Asia, bearing a new mechanism of resistance that neutralized not only penicillin and methicillin, but all the so-called β- lactam antibiotics - the most effective and abundant group of anti-microbial agents developed by the pharmaceutical industry. Even more alarming was the appearance of multi-drug resistant strains. The first MRSA isolates identified in blood stream infections of patients in the UK in 1960 were already resistant to penicillin, streptomycin, tetracycline and - often - to erythromycin as well, i.e., they carried resistance traits against each of the major classes of antibiotics that have been used in therapy before the introduction of methicillin. The situation was not unique to staphylococci but involved several major human pathogens. The early victories of the antibiotic era were being transformed into the frustrations of an arms race: each new anti-microbial weapon seemed to be followed sooner or later by the emergence of a matching bacterial resistance mechanism. Hospital microbiology laboratories routinely testing the susceptibility of disease-causing microbes against panels of the most powerful 12-15 antibiotics. A bacterium susceptible to the power of one or more of these is assigned the mark S, a resistant bacterium receives the mark R. Isolates preserved from the pre-penicillin era had the letter S written next to all these agents. Over time, clinical microbiology charts began to fill with Rs next to once useful therapeutic agents – indicating that they had lost their power, that the particular bacterial strain was multiresistant. The accumulation of these Rs on clinical chart in hospital labs all over the world is an ominous reminder of the shrinking arsenal of antibiotics. The change in the “balance of power” between antibiotics and the counter-weapons produced by the bacteria is most apparent in the case of Staphylococcus aureus – currently a frequent cause of infections in hospitals . The strain that ultimately caused the fatality of the British police officer of 1941 would have had S written next to not only penicillin, but each of the antibiotics we now have available. Looking at the clinical susceptibility profiles of staphylococcal strains most frequently isolated from patients hospitalized in year 2000 in the USA, Europe and Latin America, one finds the letter R written next to most of the available antibiotics – therapy is often reduced to a single surviving antibacterial agent called vancomycin. The therapy of that British police officer failed in 1945 because the supply of penicillin ran out. Is it possible that, some time soon, patients will die not because a bottle is empty, but because the antibiotic arsenal has lost its potence against the widely spread multi-drug resistant strains? Is it possible that we are losing the antibacterial armaments race? This question is not from the realm of science fiction – it is a matter of reality. How do bacteria become resistant to antibiotics? What are the biological reservoirs from which they acquire their resistance mechanisms? Are there lessons we should learn from the first antibiotic era in order to prevent the loss of miracle drugs that have saved so many lives? These questions must be answered if humanity is to continue to fend off the scourge of disease.