The Early Emergence of Antibiotic Resistance

The development of resistance to the antibiotics is a phenomenon of great theoretic interest to a bacteriologist, and it may some day become a matter of major concern to the clinician.

This is the opening line in C. Phillip Miller's paper on the development of resistance to antibiotics, which he published in 1947. Penicillin had only just been in production for five years. It was saving countless lives. It was emerging as a miracle drug. But even in this relatively optimistic era, a number of scientists were getting a taste of things to come.

Alexander Fleming, the discoverer of penicillin, was well aware that it does not kill all bacteria. Whilst it was effective against bacteria like Staphylococcus aureus, he found that E. coli (it was called B.coli at this stage in history) was not killed by penicillin. These bacteria appeared to be naturally resistant to penicillin. The question of what caused this resistance in some species of bacteria was taken up ten years later, by Edward Abraham and Ernest Chain. In 1940 they took cultures of E.coli and then broke them down into a mush. They filtered penicillin through this mush, and then tested whether it still killed Staphylococcus aureus. It turned out that the penicillin no longer worked, and they inferred that E.coli had some form of enzyme that broke down penicillin.

But this paper only talked about E.coli’s natural ability to break down penicillin. Surely this wouldn’t be a problem. This just means that penicillin won’t be useful against infections caused by E.coli. It’s not as if it would ever be a problem for fighting bacteria which they knew to be sensitive to penicillin, like Staphylococcus aureus ? Right ?

In 1942** it became clear that Staphylococcus aureus could become resistant to penicillin. Charles Rammelkamp and Thelma Maxon were trying out penicillin therapy for human infections. They noticed that penicillin therapy was not always effective for treating patients infected with Staphylococcus aureus.  Some of the Staphylococcus isolated from these patients were now resistant to penicillin.

They then took some strains of Staphylococcus aureus that they knew could be killed by penicillin. The exposed these bacteria to increasing concentrations of penicillin, and over the course of 50 days they managed to dramatically increase the resistance of these bacteria to penicillin. The reason this had not been spotted before was because it had taken so long to develop. In the years after, similar methods were used to show that other bacteria could also develop resistance to penicillin.

By the time Alexander Fleming gave his Nobel Prize lecture in 1945, he was very much aware of the threat that antibiotic resistance posed. At the end of his lecture, he issued a warning about the perils of underdosing penicillin, and how it could eventually lead to the proliferation of penicillin resistance.

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.

In this speech, he also proposed his solution to this problem. He observed that since penicillin wasn’t toxic, there was no such thing as an overdose.

C. Phillip Miller’s paper further expands on this theory. He compared the development of resistance to Penicillin and Streptomycin.  Other works had shown that antibiotic resistance had developed when low doses of penicillin were used to treat animal infection. Miller however disputed that this was relevant to the human situation, as penicillin was usually given in high doses to produce a “margin of safety”. He said that most bacteria develop resistance so slowly that infections are brought under control before a detectable degree of resistance has begun to build up. In his work, he noted how comparatively slowly organisms developed resistance to penicillin, and thus predicted the rise in Streptomycin resistant strains of bacteria, but not penicillin resistant strains. At this point in time, penicillin resistance could be dismissed as a rare event.

By 1957, the emergence of Staphylococcus aureus strain 52/42B/81, which possessed resistance to penicillin, streptomycin and tetracyclines, put paid to the idea that the threat from antibiotic resistance was only theoretical. When we talk about the emergence of antibiotic resistant strains, it must be remembered that they have been around for nearly as long as antibiotics themselves, and even the earliest pioneers could foresee the danger they presented.

References

Miller C.P. (1947). Development of Bacterial Resistance to Antibiotics, The Journal of the American Medical Association, 135 (12) 749. DOI: 10.1001/jama.1947.02890120003002

Abraham E.P. & Chain E. (1940). An Enzyme from Bacteria able to Destroy Penicillin, Nature, 146 (3713) 837-837. DOI: 10.1038/146837a0

Rammelkamp C. (1942). Resistance of Staphylococcus aureus to the Action of Penicillin, Proceedings of the Society for Experimental biology and Medicine, DOI: 10.3181/00379727-51-13986

Alexander Fleming's Nobel Prize Lecture (1945)
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.html

Finland M. (1979). Emergence of antibiotic resistance in hospitals, 1935-1975, Reviews of infectious diseases, PMID: 45521

Footnotes

*They called resistant bacteria “antibiotic-fast”, for linguistic reasons that are unclear to me.

** The earliest paper that I could find which demonstrates penicillin resistance was from 1942. In the paper the authors say that penicillin resistance had been described before in 1941, and then cites those papers…. incorrectly. The first paper cited only looked at resistant to sulphonamide antibiotics. The second paper they cite was by howard florey, and in that paper there is no reference to either resistant (or “fast” as the term would be) Staphylococcus aureus. So somewhere out there there may be a paper in 1941 that shows the development of antibiotic resistance in Staphylococcus aureus, but it has been expunged from the record for completely unknown reasons.