David Mack/Science Photo Library
Escherichia coli strains were initially sensitive to ciprofloxacin |
Celebrating its 21st birthday this month is a broad-spectrum antibiotic
that, when launched, was recognised as a “quantum- leap” forward
from its decades-old grandparent nalidixic acid.
At launch, its indications
included urinary and respiratory infections, pseudomonas infection in
cystic fibrosis and gonorrhoea. In its twilight years, it was back in
the headlines as the only treatment to combat a terrorist attack with
anthrax. Its name is ciprofloxacin (Ciproxin).
“‘Cipro’ was 100–1,000 times more active than
nalidixic acid against enterobacteraemia and systemic infections, and
it was the first
oral drug for pseudomonas infection. There was even enthusiasm that it
could inhibit meticillin resistant Staphylococcus aureus (MRSA)
and some early cures were achieved.
“But mutational resistance was very
easy in
MRSA and, within a couple of years, the prevalent strains were no longer
susceptible,” recalls David Livermore, director
of the Antibiotic Resistance Monitoring and Reference Laboratory at the
Health Protection
Agency’s Centre for Infections, London.
Ciprofloxacin is a member of the 4-quinolone group of antibiotics, which
work by inhibiting the topoisomerase enzymes that break, supercoil and
reseal strands of DNA so that it can be packed into cells. Specifically,
they inhibit bacterial DNA gyrase (topoisomerase II), which leads to
the disruption and breakdown of bacterial DNA, and failure of replication
and transcription.
A significant perceived advantage of the quinolones over other groups
of antibiotics, at the time of ciprofloxacin’s launch, was that
they were thought not to be susceptible to resistance mechanisms associated
with plasmid transfer.
It was predicted that resistance could only arise through an extremely
unlikely combination of bacterial mutations.1 How
wrong such optimists were.
Early quinolones developed in the 1960s were poorly absorbed and had
low tissue levels, with only moderate activity against a limited range
of gram-negative bacilli, and their use was restricted mainly to urinary
tract infections. Ciprofloxacin was the first of a new generation of
quinolones to be launched in the UK that were active, not only against
a broader range of gram-negative organisms, including Escherichia
coli,
klebsiella and salmonella, but also some gram-positive staphylococci
and, marginally, streptococci.
“It was excellent for urinary infections in general. In addition,
by the 1990s, one tablet of cipro was standard treatment for gonorrhoea.
The
sexually transmitted disease physicians liked it because they could watch
the patient taking it and know that they had been treated,” Dr
Livermore explains.
Ciprofloxacin was also promoted for chest infections although, as Dr
Livermore points out, it never had good activity against Streptococcus
pneumoniae — the most important cause of community-acquired pneumonia — and
was more useful in hospital pneumonia which is likely to be caused by
gram-negative organisms.
Effective against the E coli strains that cause traveller’s diarrhoea,
ciprofloxacin also became the antibiotic of choice to pack with the sunscreen
for exotic holidays, although, from the public health viewpoint, this
was not something to be encouraged. Resistance
As with so many antibiotics, ciprofloxacin’s success has also proved
to be its Achilles heel. A rapid rise in resistance, particularly over
the past decade, has drastically curtailed its value in treatment of
many serious infections.
In 1987, when ciprofloxacin was launched, the dangers of resistance were
widely recognised. But there was an expectation that ciprofloxacin would
be relatively immune and that pharmaceutical research would stay a step
or two ahead of the bacteria, so there would always be something else
in the cupboard for patients with really hard-to-treat infections.
Instead, the number of new classes of antibiotics developed has fallen
from 11 in the first 30 years of the antibiotic era to just two new classes
in the past 30 years. Whereas 16 new antibacterial agents were registered
in the four years before the launch of ciprofloxacin, this was down to
just seven between 1998 and 2002.
By the middle of the 1990s, there was significant resistance to ciprofloxacin
among Neisseria gonorrhoeae isolates in patients in the Far East and
the strains responsible soon spread to Europe and the US. Today, about
25 per cent of infected patients in the UK have strains resistant to
ciprofloxacin.
“Ironically, it was a case of guidelines being counterproductive. STD
physicians were treating 75–80 per cent of gonorrhoea patients
with cipro, so when resistance emerged it spread rapidly because there
was no firebreak. In the late 90s, we could perhaps have rotated it with
cefixime and spectinomycin, and avoided the subsequent problems,” Dr
Livermore believes.
“Resistance to ciprofloxacin in gonorrhoea is still increasing, even though
the drug is hardly used as treatment now, which suggests that the resistant
strains are very tough organisms or that other selective factors remain
in play,” he adds.
Different factors have undermined ciprofloxacin’s usefulness against
other pathogens and types of infection. Ciprofloxacin’s close relation,
enrofloxacin, was granted a veterinary licence which resulted in it being
used for metaphylaxis — mass treatment of herds to eliminate or
minimise an expected outbreak of disease.
As a result, resistant E coli and salmonella have been selected
in animals and poultry that enter the human food chain, and cross resistance
among
quinolones means that these
are resistant to ciprofloxacin as well as to
enrofloxacin.
“Whereas ciprofloxacin was a quantum leap from nalidixic acid, no one
has achieved a further quantum leap in quinolone development, so cross
resistance remains a problem with the successors to cipro,” Dr
Livermore explains.
Ofloxacin — the racemic mixture of the biologically active enantiomer
levofloxacin — was launched at about the same time as ciprofloxacin,
with a similar spectrum of activity. Levofloxacin, later launched by
itself, has the advantage of greater activity against pneumococci that
ciprofloxacin, as does moxifloxacin, which is also useful in anaerobic
infection but is not active against pseudomonas.
Other quinolones, including grepafloxacin and trovafloxacin, have fallen
foul of toxicity problems either after launch or during clinical trials.
However, none of these
analogues overcomes the types of resistance seen in E coli, salmonella,
MRSA or N
gonorrhoeae.
Warnings
Ciprofloxacin, though generally well tolerated, has been associated
with peripheral neuropathy and tendon rupture and, in 2004, the US Food
and Drug Administration approved additional warnings about these effects
for both ciprofloxacin and moxifloxacin. A warning about the risk of
pseudomembranous colitis was added to the intravenous and long acting
forms of ciprofloxacin.
In the UK, all quinolones carry a warning about the risk of tendon
rupture within 48 hours of use and are contraindicated in people with
a history
of tendon disorders related to quinolone use.
In its long life, ciprofloxacin has been prescribed for more than 340
million people worldwide, not to mention those who have bought it over
the counter in less regulated markets.
In 2001, with patent expiry looming across major markets, ciprofloxacin
was given an unexpected new lease of life after letters containing anthrax
spores were delivered to senate offices and media outlets in the US in
the wake of the “9/11” attacks. Licensed in the US for use
after exposure to inhalational anthrax only 12 months previously, ciprofloxacin
was soon being stockpiled by governments around the world.
Ciprofloxacin manufacturer, Bayer, rapidly scaled up production to meet
demand and the renewed profitability of the trusty antibiotic helped
to offset problems the company was having after the loss of its cholesterol-lowering
drug, cerivastatin.
The feared anthrax epidemic never materialised and ciprofloxacin, now
widely available in generic formulations, went back to treating mainly
urinary tract and respiratory infections. So what has been its lasting
legacy?
Dr Livermore points out that in general practice, ciprofloxacin was always
competing against beta-lactam antibiotics, which are more appropriate
treatment for most chest infections, while trimethoprim tended to be
the treatment of choice for urinary tract infections in the UK.
Ciprofloxacin
also became a particular target of British government pressure to reduce
unnecessary antibiotic prescribing in general practice. “We certainly
underestimated how quickly resistance would occur, particularly in E
coli and N gonorrhoeae, and our optimism for cipro in MRSA
was clearly misplaced,” he says.
Imipenem, the first of the carbapenems, which was launched at around
the same time as cipro, achieved greater longevity because it was less
widely used, owing to its higher cost.
But, as Dr Livermore points out, the growing resistance to ciprofloxacin
and cephalosporins in klebsiella, enterobacter and bacteremic E coli infection
is now driving wider use of carbapenems,2 with
the same predictable consequences:
“Cipro was oral, convenient to use and cheap. It’s
still useful, but its benefits have been eroded because it was used recklessly.
Looking at what we are doing now with antibiotic use, I’m not sure
that we’ve really learnt our lesson from cipro. History has a way
of repeating itself.”
References
1. Smith JT. Frequency and expression of mutational resistance to the
4-quinolone antibacterials. Scandinavian Journal of Infectious Diseases
1986;49(suppl):115–23.
2. Livermore D. The zeitgeist of resistance. Journal of Antimicrobial
Chemotherapy 2007;60 (suppl 1):i59–i61. |
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Pharmaceutical Journal