Third in a series on
Bactrim - Septra -Septrin side-effects
THE
PILL THAT KILLED
The
Sunday Times (London) March 20 1994
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."
Copyright,
Brian Deer. All rights reserved. No portion of this
article on Septrin, Bactrim, Septra, Sulfatrim,
Cotrim, co-trimoxazole, Septran side-effects may be
copied, retransmitted, reposted, duplicated or
otherwise used without the express written approval
of the author. Responses, information and other
feedback are appreciated - via Brian Deer's homepage.
