The antibiotic known by the names Septrin, Bactrim, Septra, co-trimoxazole, and many others, is among the most commercially successful drugs ever - prescribed to millions of people each year. But, as BRIAN DEER reports, it has been linked to a hidden toll of deaths and injuries.
When Justine Gibbs died after taking Septrin, her mother Susanne's reaction was to blame herself. Maybe if they had gone to the hospital more quickly, she agonised, something might have been done to save her daughter's life. Possibly, she speculated, there was a genetic weakness at work, passed down through the family, with herself as the link. Or perhaps, she even debated, her loss was a divine punishment for some past parental misdeed.
In the weeks that followed Justine's death, in August 1988, there did not seem to be anybody else at whom Susanne could point the finger. Her daughter was just 18 years old and had been prescribed a course of Septrin antibacterial tablets for cystitis, a common and usually trivial urinary tract infection. The doctor's decision was in proper accord with medical books and the guidelines of the drug's maker, the Wellcome Foundation.
Justine's health collapsed from an allergic reaction within days of taking the tablets; but in the health service's response there was nothing to complain about. The family lived in West Sussex, which boasts some of the world's finest medical facilities: it seemed that everyone at the hospital was impeccably professional. Even as Susanne was roused by nurses at five one morning to witness the conclusion, nobody with a job to do appeared to miss a beat.
According to the death certificate, Justine died from a combination of Lyell and Stevens-Johnson syndromes - rare conditions which were accepted at an inquest as the effects of an ingredient of Septrin. For a week, as most of her relatives and friends were kept at bay, every part of her body, both external and internal, began to blister and seemingly burn. Her skin, in particular, decayed and fell away.
In shock after her daughter's death and with nobody visible to accuse, Susanne went home and turned anger into guilt. "One of my problems is that I try and analyse too much," she says now of the five years of torment that have followed. "The whys, wheres and whats. What if this? Or what if that?"
Two weeks ago, however, her attitude began to change. Susanne saw a report in The Sunday Times in which Septrin was revealed as a synthetic antibiotic which experts say has exposed people all over the world to potentially life-threatening risks. In search of some long-sought explanation, she called the newspaper and, perhaps, began the process through which she would eventually find closure.
Septrin (which is also marketed by the company Hoffman-La Roche as Bactrim, and in unbranded generic versions as "co-trimoxazole") has been one of the most successful medicines ever, grossing more than $5 billion for its manufacturers. Around 3m prescriptions are written each year in Britain and up to 100m courses are taken around the world.
The Sunday Times reported how a mass of scientific research links the drugs with what could be thousands of deaths and injuries world-wide - including rare blood disorders and syndromes like the ones from which Justine suffered. Moreover, we pointed out that Septrin is in fact two antibacterials. One is a relatively safe and effective compound called trimethoprim. The other is a sulphur-based chemical called sulphamethoxazole, which has long been known to cause a wide spectrum of side-effects.
This sulphur chemical has not only been shown to be responsible for deaths such as Justine's, but (apart from some unusual illnesses, such as an Aids-related pneumonia) it has also never been proven to have a clinical basis for inclusion in Septrin. After confirming the facts with seven professors in this area of medicine and exhaustively reviewing research, we found that in nearly every condition for which Septrin is used, trimethoprim alone was as good.
Susanne's was one of dozens of phone calls and letters The Sunday Times received complaining about deaths and injuries. Readers said that for the first time they could make sense of events which they previously did not know were linked to wider problems with the drug. Some asked about their legal rights, while others wanted to be put in touch with those afflicted like themselves.
Among the most serious was the case of a 31-year-old man who died 12 months ago from one of the same horrific syndromes that afflicted Justine. He had taken Bactrim for a urinary tract infection. "We want to get answers to a lot of questions," his father-in-law wrote. "He was in the prime of his life, with a young family."
Others said they only narrowly escaped with their lives and now appear to suffer from chronic disabilities. One man, aged 44, was admitted to hospital in January with liver failure after being prescribed Septrin for what felt like earache. He lapsed into a coma and, after emergency surgery, can now walk only with difficulty.
Although specific side-effects were not suggested in the Sunday Times reports, a number of readers complained of hard-to-define conditions that sounded similar to each other. "I seem to be very vulnerable to infections, "one man wrote of his experiences after Septrin. "This, it appears, is due to my natural defence mechanism being weakened."
Most have not consulted solicitors, previously believing that they were merely unlucky in suffering from rare side-effects. With a medicine in such widespread use, there are bound to be adverse reactions and family doctors have often regarded any risks from the drug to be outweighed by its benefits.
Arguments about acceptable risks, however, do not easily come into play in the case of this drug. Research over more than two decades shows that in Septrin's main uses - urinary tract infections and bronchitis - there is no advantage at all from the inclusion of the sulphamethoxazole element.
The lack of any demonstrable advantage of Septrin, the combination drug, over its safer component trimethoprim has been exhaustively discussed in medical literature - but largely ignored by doctors. The British Medical Journal carried papers in 1969, 1972 and 1978, as did the research journal Chemotherapy in 1973. So did the Annals of Clinical Research in 1974, the Journal of Clinical Pathology (1974 and 1981) and The Lancet (1980 and 1982).
One research team was led by Sir William Asscher, now dean of the medical school at London's St George's hospital, author of the book Urinary Tract Infection and, until the beginning of last year chairman of the government's Committee on the Safety of Medicines. "The fact is that trimethoprim alone, by most of us in the trade, was regarded as the treatment of choice," he said last week. "Years and years ago I changed to trimethoprim alone."
Trimethoprim alone would probably have spared Justine's life, but government agencies have failed to act against the widespread use of the combination. In response to our reports, the Medicines Control Agency issued a bland statement: "Co-trimoxazole is an effective antibiotic that has been widely used in the UK and world-wide for many years. Its safety profile is well-known and documented."
This safety profile, however, is legitimate cause for disquiet. In 1985 it was acknowledged by the Committee on the Safety of Medicines to include 1.42 deaths for every million prescriptions issued - nearly eight times the figure for ampicillin, a rival antibiotic. Moreover, research carried out for the committee and published in the British Medical Journal in 1977 found serious underreporting of fatalities. Out of 13 Septrin/Bactrim-related deaths identified by researchers (all of which involved rare blood disorders), only one had been formally recorded.
The impact of such research is often overshadowed in journals by drug promotion campaigns - distracting doctors's attentions from the details found in texts. In magazines during the 1970s and early 1980s, Septrin was one of the most extensively advertised products, often emphasising young women with urinary tract infections as the most likely patients to benefit.
One popular ad featured a blonde-haired young woman, not far from Justine's age, in a light brown dress, standing over a table in a beige and pink room. She was bathed in sunlight, arranging tulips in a vase. "Septrin assurance," said the headline. The small print didn't say it could kill you.
But if Septrin and Bactrim found success through marketing rather than medicine, explanations of their origins are no less odd. Despite some test tube evidence of a theoretical "synergy" between trimethoprim and sulphamethoxazole, the two antibacterials are really quite separate and were once potential commercial rivals, piggybacked together in an ambitious promotional plan.
Trimethoprim had been invented by Wellcome in its United States laboratories at Tuckahoe, just outside New York City, and patented in 1957. But just five months previously, a Japanese firm, Shionogi, had registered sulphamethoxazole for exactly the same purposes, and licensed its use to the pharmaceutical super-giant Hoffman-La Roche. The headquarters of Roche were at Nutley, New Jersey, just across the Hudson River from Wellcome.
Roche was concerned about the potential threat posed by the Wellcome rival, and the shotgun marriage that followed involved mixing five parts of the bigger company's drug with one part of that from the smaller. The resulting pill was unusually large and hard to swallow, but the claim that the two chemicals had a complimentary effect provided a scientific-sounding notion for promoting the mixture, and captured the imagination of doctors in a world-wide advertising campaign.
In the 1960s, Wellcome lacked the marketing and production muscle needed to launch a blockbuster antibiotic, and Roche was also under pressure to collaborate. Roche dominated the sulphur-based drugs market, which was already being undermined by resistant strains of bacteria and by public anxiety about sometimes fatal side-effects. Moreover, emerging environmental concerns were creating a glut of sulphur, much of which was recovered as waste from oil refineries, chemical plants and metal smelters.
The companies' solution to the dilemma was Septrin (marketed in the US as Septra), from Wellcome, and Bactrim from Roche, with a deal in which Wellcome agreed not to market strongly in the US and Roche agreed not to market strongly in Britain. Both have become established as among the most commercially successful pharmaceutical products ever.
The vast market is of great export benefit to the British-based Wellcome and the Swiss-owned Roche, but even to those without specialist knowledge there might seem to be something amiss. "Sulphur burns," says Susanne. "So it always seemed a bit strange to me that you would have that in a medicine."
Hers is perhaps a naive view, but Susanne has been stronger on questions than answers about the reasons for Justine's death. For the past five years, she has voraciously hunted for any information that might fill the gap in her understanding.
Wellcome points out that prescribing medicines is the responsibility of physicians, and says that following the Sunday Times stories it too had received calls - from doctors and nurses concerned about the paper's "unbalanced and alarmist" reports. Roche said that serious and occasionally fatal reactions had been associated with Bactrim, but that these were rare and that doctors continued to use the product where the expected benefits outweighed the very small risk.
One consequence of that very small risk now casts a shadow across Susanne's life: she continues to visualise what happened during the days when her daughter was dying. "I still don't know anybody who has actually had to see what I had to see for that week," she says of secrets which she still keeps from her family. "I haven't actually told them. Possibly that was one of the reasons why nothing went any further."
[The length of this report varies slightly between Sunday Times print editions]