Antibiotics

 

by John Aitken

We are at the dawning of a new era in the use of antibiotics.

For some 20 years there have been attempts to use antibiotics in the treatment of Crohn’s disease. Although most trials have delivered mixed results, this direction has been reinforced by the association of Mycobacterium avium ssp paratuberculosis (MAP) with Crohn’s disease.

The main principle of judicious and effective antibiotic usage has been the targeting of the suspected pathogen with a therapy that is both specific and directed.  This has been a difficult job, as there has been, up to now, no protocol that will ensure the reliable isolation of the pathogen from the patient. The model that is used for new compounds against MAP-associated organisms is directly related to the proven therapies for tuberculosis, and this has been a wise model to follow.

Tuberculosis therapy, since the discovery of streptomycin in the 1940’s, has been a case of trials and errors. The development of effective interventions has paralleled other advances in antibiotic therapies. The first lesson learned from the use of streptomycin in tuberculosis was the rapid development of resistance to that antibiotic by Mycobacterium tuberculosis (MTB). Fortunately for us, once streptomycin was discovered, the race was on for similar antibiotics active against MTB. The subsequent research was not without controversy and surprises.

In the 1970’s, solidly based on clinical trials, therapy for MTB promised an end to the disease. Therapy relied on a mix of at least three antibiotics, each shown by the laboratory to be effective against the pathogen. This approach, called “triple therapy”, was akin to a directed attack on MTB from three sides at once. Cure was expected and recurrence was rare, but the patient was still monitored for decades to ensure that reactivation did not happen.

When I started work on MTB in the hospital laboratory in the 1970’s, I was often told that I was wasting my time, as the war against MTB was won. And when I reviewed figures, it seemed that this was so. Every year we were seeing fewer cases than the year before, and the majority of these cases were reactivations.

Then something happened to change the balance. A combination of public health developments combined to form the perfect storm, and resistance to first line treatments became more common. HIV, inadequate treatments, cessation of therapy prematurely, association with IV drug users, and spill over from the third world all contributed to produce multidrug resistant tuberculosis (MRTB). MTB, the old “Captain of the Men of Death” had reinvented itself to become resistant to most available antibiotics, and medicine is holding on by a fingernail against the weight of evolution and natural selection.

History is a powerful teacher. In the treatment of emerging mycobacterial diseases, these lessons have been well learned. The use of antibiotics in the treatment of Crohn’s disease has been long in development for several reasons.

Most trials on antibiotics have used the form of MAP that is found in cattle, or isolates from patients that required up to 2 years in artificial conditions for growth to be seen on agar plates. These forms of MAP are very far removed from the form MAP probably takes in the human body. In the absence of reliable culture methods, researchers have developed antibiotic therapies based on educated guesses, followed by clinical trials.

As Pasteur observed, “Chance favours the prepared mind”, so the design of new therapies has been a synthesis of old ideas and new observations. Yet there is still the problem that the form of Mycobacterium species linked with Crohn’s disease is not easily seen and cultured in the form postulated to exist in patients. This form is thought to have a depleted cell wall (“L form”) and reliable growth is extremely difficult.

This barrier to progress has been the quest of the group I work with for 10 years, and our research has made promising discoveries in this area. We are now working on the next phase: the testing of patient isolates against promising antibiotics. This aspect of our research is close to validation against isolated “L forms” from Crohn’s disease patients.

The surprising thing is that we are following a well-marked pathway. This is simply orthodox bacteriology.  There is nothing remarkable about the route to be followed; every medical microbiology laboratory follows the same steps. The suspected pathogen is rapidly isolated from the patient and then tested against the range of antibiotics available for treatment. There is a good reason for this “menu.”

The clinician requires an assurance, if one is available, that the projected therapy can be optimized. As in the case of MTB, any triple therapy will work best when the formulation is optimized; to put it simply, when the engine is firing on all cylinders.

The pharmaceutical industry, in partnership with innovative ideas from clinicians, has done breathtakingly  well in the discovery of new interventions for treatment of Mycobacterial-associated infections, and mostly without practical input from the microbiologists. The challenge is now out there, and it is time to make worthwhile contributions from the microbiology laboratory bench. Physicians and the pharmaceutical industry require reliable methods to monitor therapy, and our group has risen to the challenge.

[Readers who want an excellent book on the battle against tuberculosis can do no better than to read  The Forgotten Plague: How the Battle Against Tuberculosis was Won – and Lost, by Frank Ryan M.D. It is a rollicking read that exposes both human weakness and human ingenuity in medicine and drug discovery. The story of the discovery of streptomycin is also well told in a 2 part article in the American Journal of Respiratory Disease, authored by Julius H. Comroe, Jr. The story can be accessed via the 2 part article linked below or from a medical library. 

Pay Dirt: The Story of Streptomycin