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Ciprofloxacin — not invincible

David Mack/Science Photo Library

Escherichia coli strains

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.

Citation: The Pharmaceutical Journal URI: 10006032

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