Sir John Crofton, TB combination therapy pioneer - a long and admirable life

Denise Gellene in the New York Times is reporting this morning that Scottish physician, Sir John Crofton, passed away on 3 November at age 97.

Crofton is best known for implementing a combination drug regimen to treat tuberculosis, the insidious lung infection with Mycobacterium tuberculosis which decimated the US early last century and still kills 2 million a year worldwide. The concept of using drug combinations to increase individual drug potency and slow the emergence of resistance is now a mainstay of therapeutic approaches for cancer, HIV, and other infectious diseases.

Gellene reports that Crofton first investigated streptomycin for TB shortly after the drug's discovery and isolation at Rutgers by Selman Waksman and his then-graduate student, Albert Schatz. Waksman was sole winner of the 1952 Nobel Prize in Physiology or Medicine, with the oversight of Schatz ranked by Scientific American among the top 10 Nobel snubs.

Crofton's original 1950 letter to the British Medical Journal on use of intermittent doses of streptomycin can be seen in this PDF.

Incidentally, the revered German physician, Robert Koch, was awarded the 1905 Nobel Prize in Physiology or Medicine for the discovery of M. tuberculosis. His medical microbiology criteria, known as Koch's Postulates, became the rubric for establishing causation of an infectious agent.

Streptomycin was in short supply after World War II and Crofton had the idea to use subtherapeutic amounts of it together with another drug, 4-aminosalicylic acid (or para-amino, of course, which led to its abbreviation, PAS). In 1951-52, Crofton added isoniazid to the regimen, a compound synthesized first in 1912 but later recognized for activity against the mycobacterium.
Gellene writes:

The third drug was the charm. Through careful monitoring, he devised a regimen that called for starting patients on all three drugs and then stopping streptomycin, which can cause hearing loss, after several months. For more than a decade, until it was replaced by a cocktail of newer and more powerful drugs, Sir John's three-drug regimen was the standard treatment for tuberculosis.

"The treatment principles he developed are the ones we are using today," said Dr. Mario C. Raviglione, director of the World Health Organization's Stop TB department. "They are the model for cancer and for H.I.V. His legacy is quite significant."

Sir John was knighted in 1977, the year he retired from the University of Edinburgh. In the mid-1990s, as an adviser to W.H.O., he helped write the organization's tuberculosis treatment guidelines.

A more detailed and colorful (colourful, in this case) biography of Sir John Crofton by Tam Dalyell appeared on 5 November in the UK Independent.