Vaccines, antisepsis and the first antimicrobial drugs

Ehrlich’s founding insight was chemical rather than medical: if a dye can bind one tissue and not another, then a chemical can in principle bind one kind of cell and not another. He expressed this as a search for substances with a high affinity for the parasite and a low affinity for host tissue, and the metaphor he used was a magic bullet that strikes the intended target and nothing else. The practical measure of that idea is the chemotherapy index, the ratio between the largest dose the patient tolerates and the smallest dose that cures, so that a wide index means the drug is safe to use with a margin and a narrow one means the prescriber must watch the patient closely and measure the concentration in the blood. Arsphenamine had a narrow index: it was an arsenic compound that damaged the liver, the skin and the nervous system, and it had to be given intravenously by a trained operator, which is exactly why it was eventually replaced by penicillin for syphilis.

Penicillin has an extraordinarily wide index, and the reason is structural. Penicillin belongs to the beta-lactam family; it attaches to enzymes called penicillin-binding proteins and blocks the transpeptidase reaction that cross-links the peptidoglycan of the bacterial cell wall. Because the wall is under osmotic pressure, the bacterium cannot hold its shape while it grows and it bursts. Human cells have no peptidoglycan and no transpeptidase, so the drug has no target in the patient and can be given in very large doses. This is the logic that every antimicrobial shares: a target must exist in the microbe and must be absent from, or different in, the host. It explains whole families of practice.

Antibiotics that block bacterial ribosomes are less selective because human cells also have ribosomes, so the difference is one of detail and the therapeutic margin narrows; drugs that block folate synthesis exploit a pathway humans take from the diet rather than build; and antiseptics such as alcohol or chlorhexidine have no selectivity at all, which is why they are used on surfaces and intact skin and not swallowed. For a nurse the rule translates into three habits: give the concentration that was tested rather than half of it; watch for the organ that the particular drug is known to touch, such as kidneys or liver; and remember that a broad-spectrum antibiotic also suppresses the patient’s normal flora, which is a form of harm that selective toxicity does not prevent.

The gap between Fleming’s observation in 1928 and penicillin on a ward is a story about solubility, stability and scale, and it begins with chemistry. Penicillin is an acid that is unstable in the presence of water, heat and acid, so it cannot simply be boiled, concentrated or dried like many laboratory chemicals; it loses its activity while it is being purified by ordinary methods. Howard Florey and Ernst Chain began work at Oxford in the late 1930s on natural antibacterial substances, and they had to solve that problem before they could test the substance in an animal. The key technique came from Norman Heatley, who exploited the fact that penicillin is more soluble in an organic solvent such as amyl acetate when the solution is acid, and more soluble in water when it is neutral. By shifting the acidity back and forth he moved the penicillin into amyl acetate, discarded the water with its impurities, then moved it back into a small volume of water, obtaining a concentrated and much purer product without destroying it.

With that material they showed in 1940 that penicillin protected mice from an otherwise fatal streptococcal infection, and in 1941 they treated a policeman with a severe infection; he improved dramatically, but their whole supply ran out and he died when the drug could not be continued, which is itself a lesson about the difference between a dose and a cure. Production then became an industrial problem that Britain, under bombing and blockade, could not solve alone. The Oxford team took the process to the United States in 1941, where the Northern Regional Research Laboratory in Peoria found that adding corn steep liquor to the culture medium increased the yield many times over, and a worldwide search for better strains produced a high-yielding mould from a melon that became the ancestor of industrial production.

By 1944 there was enough penicillin for the Allied casualties of the Normandy landings, and the price of a dose fell from a figure no patient could pay to a few dollars within a few years. Penicillin is a small molecule of about 334 daltons, which is one reason it reaches most tissues and fluids easily and is excreted rapidly by the kidneys, needing frequent dosing. The modern species used industrially is Penicillium chrysogenum, not the Penicillium notatum of the original plate. The lesson to carry into nursing is that a discovery in a dish becomes a medicine only when someone solves purification, stability, dosing and manufacture, and that the same is true today of every new antimicrobial: the interesting biology is only the first chapter.

Vaccination works by exploiting a property that no drug possesses: the immune system learns. When the body meets an antigen for the first time it produces a slow, small response, but it also keeps a memory of that antigen in long-lived lymphocytes. On a second encounter the response is faster, larger and more specific, and antibodies are produced in quantity before the microbe can multiply to a harmful level. A vaccine supplies that first meeting safely. It may contain a live but weakened organism, a killed organism, a purified protein, a toxoid or, in the newest designs, only the genetic instructions for one antigen. What matters is that the preparation reaches the immune system without causing the disease, which is why vaccination is sometimes described as training rather than treatment. Jenner’s cowpox material worked because vaccinia virus is closely related to variola virus: the antibodies and lymphocytes raised against the harmless relative recognised the dangerous one as well.

This is called cross-protection, and it depends on the two antigens being similar, not identical. It is important to be honest about the limits of the original discovery: neither Jenner nor Pasteur knew what an antibody was. Immunology only explained vaccination in the twentieth century, and the word vaccine, from vacca, cow, was applied by Pasteur to unrelated preparations made from chicken cholera and rabies because they followed the same empirical pattern. Smallpox itself is the only human disease that has been eradicated, and the campaign that achieved it was built on two practical advantages. The first is that vaccinia could be produced in large amounts by infecting calves or, later, cultured cells, then purified and freeze-dried with glycerinated lymph so that it stayed potent in the heat of tropical countries.

The second is that smallpox has no animal reservoir and no carrier state, so there was nowhere for the virus to hide once human cases were eliminated. The strategy was ring vaccination: find every case, isolate it, and vaccinate all the contacts around it, which was more efficient than trying to vaccinate whole populations. The World Health Organization declared eradication in 1980. Nursing sits at the centre of that story, because every vaccination programme depends on someone who can explain the schedule, manage the cold chain, record the dose correctly and answer a hesitant parent with evidence rather than pressure. Modern concerns about vaccine safety, and the refusal that followed the false association between the MMR vaccine and autism, are the reason that teaching remains part of the job.