Staphylococcus aureus and penicillin


Staphylococcus aureus is a disease-causing bacterium that looks like a purple grape under a microscope and yellow or golden when grown into colonies, hence why it’s known as ‘Golden Staph’. Since its’ discovery in the late 1800s, it has been recognised as a danger to humans and livestock.

Antibiotic treatment against bacteria have been such a stalwart part of our lives that it is hard to comprehend that it’s been less than one hundred years since antibiotics were first identified and introduced as a treatment. One of the first antibiotics discovered, penicillin, has been used to treat S. aureus and is one of the investigational agents in the SNAP trial. Interestingly, we may have never found out about penicillin and other antibiotics without S. aureus.


Staphylococcus aureus before the discovery of penicillin

Prior to the antibiotic era, infections from bacteria were the scourge of clinicians. S. aureus infections were frequently discussed in the newspapers, with one article entitled ‘The Yellow Peril’¹. Treatment options were limited, with heavily toxic chemicals such as arsenic and mercury the often used². Some reports suggested that S. aureus mortality rates were over 80%³.  

Most research dedicated at the time was heavily focused on the development of a vaccine. Although no vaccine for Staphylococcus aureus has been approved for commercial use to date, little were we to know that this research would be instrumental in finding the drug that would revolutionise treatment against bacterial infections.


Penicillin: the wonder drug

In 1928, the Scottish scientist Alexander Fleming was investigating the possibility of a vaccine against Staphylococcus aureus⁴, when a culture became contaminated with mould. The mould was found to stop the growth of the bacteria on the plate. Purification of the chemical agent eluded Fleming and so the unknown agent was distributed to many laboratories in the hopes that the research would be continued⁵. In 1939, a team from Oxford University, led by Australian Howard Florey, German-born British man Ernst Chain, and Englishmen Norman Heatley and Edward Abraham, successfully purified the penicillin and determined its’ clinical effectiveness. However, World War II commitments would prevent development of upscaled production in England⁵. 

In 1941, Florey and Heatley smeared the penicillin onto their jackets, so as to not have the vial lost, and travelled to Peoria, Illinois USA. In collaboration with the Americans Charles Thom and Andrew Jackson Moyer, the multinational team managed to upscale the production of the antibiotic⁵. By 1945 the Nobel prize for medicine was awarded to Fleming, Florey, and Chain for the identification of penicillin and the approach to treating bacterial infections had been forever changed⁵.


Staphylococcus aureus fights back

“But I would like to sound one note of warning… It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body”⁶.

Even from the outset of the penicillin discovery, Fleming noted that S. aureus could develop resistance towards the wonder drug. Later studies identified that Staphylococcus aureus had obtained an enzyme that would break down the penicillin before it could act. Worryingly, it was also found that this enzyme could be passed between individual bacteria allowing the resistance to spread. By the 1960s it was believed that over 80% of all S. aureus were resistant to penicillin and so penicillin was abandoned as the antibiotic of choice to treat this bacterium⁷. Instead, synthetic penicillins such as flucloxacillin, nafcillin and oxacillin, and cefazolin, have become the usual treatment for most S. aureus.


The case to bring back penicillin in the fight

“Penicillin is to all intents and purposes non-poisonous so there is no need to worry about giving an overdose and poisoning the patient”⁶. 

Somewhat surprisingly, the rate of S. aureus strains sensitive to penicillin has recently risen. In fact, in some hospitals, penicillin sensitive S. aureus is now more common than the notorious methicillin resistant S. aureus (MRSA). Therefore, the question of whether we should be using good old penicillin to treat penicillin sensitive S. aureus has once again become relevant. SNAP will test this hypothesis by randomly assigning patients with penicillin sensitive S. aureus bloodstream infections to either penicillin or flucloxacillin.

1          Harrison, W. in Watchman (Sydney, NSW : 1902 - 1926)    8 (Sydney, NSW, 1909).
2          Landecker, H. Antimicrobials before antibiotics: war, peace, and disinfectants. Palgrave Communications 5, 45, doi:10.1057/s41599-019-0251-8 (2019).
3          Skinner, D. & Keefer, C.S. Significance of bacteremia caused by Staphylococcus aureus: a study of one hundred and twenty-two cases and a review of the literature concerned with experimental infection in animals. Archives of Internal Medicine 68, 851-875, doi:10.1001/archinte.1941.00200110003001 (1941).
4          Hare, R. The scientific activities of Alexander Fleming, other than the discovery of penicillin. Med Hist 27, 347-372, doi:10.1017/s0025727300043386 (1983).
5          Gaynes, R. The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use. Emerging Infectious Diseases 23, 849-853, doi:10.3201/eid2305.161556 (2017).
6          Fleming, A. in Nobel Lecture    (1945).
7          Chambers, H. F. & Deleo, F. R. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature reviews. Microbiology 7, 629-641,doi:10.1038/nrmicro2200 (2009).