a case of placement over policy?

We know the history. First a photographer goes sick, then he is diagnosed with inhalation anthrax. Just before he dies a second man is found with the same disease. They both work in the same offices. One victim is suspicious — two is confirmation. This outbreak was deliberate. With the dust of the World Trade Center still settling in New York, it's time to panic. In such situations events are difficult to control. Tom Brokaw is the anchorman at NBC Nightly News, a station that had received anthrax, which had already infected a colleague with the skin version of the disease. With millions tuned in for information he held a jar of tablets and announced 'In Cipro we trust'. The effect was dramatic. US stocks of the antibiotic all but vanished as people rushed to get a prescription so that they could hold their own stockpile, or start taking it 'just in case' they had come into contact. "None of his science writers got to him ahead of time and said hey look Tom, don't over-use this," said Stuart Levy, President of the Boston-based Alliance for the Prudent Use of Antibiotics (APUA), who is one of the growing band of health experts who are anxious that the dash for this drug may have long-term consequences. Created and marketed by Bayer, Cipro is one of the fluoroquinolone class of antibiotics. It operates by antagonising DNA gyrase, an enzyme that bacteria need to separate interlocking DNA during replication. But bacteria have two ways of resisting this drug. They can mutate the enzyme so that the antibiotic is less effective, or increase production of an efflux pump that drives fluoroquinolones out of the cell. "Both mechanisms of resistance come from mutations within the bacteria," explained Levy. Fortunately for us they cannot use plasmids to pass the traits from one bacterium to another. But, Levy is quick to point out that this leaves no room for complacency. "The chance of building up resistance within a population is diminished, but remember resistance in methicillin resistant Staphylococcus aureus is not passed either and we certainly have a problem with MRSA — we can not breathe easily and say that things won't happen." Indeed a few cases of clinical infections that are resistant to the drug have been reported. "The existence of Cipro in large amounts is only going to increase their numbers," Levy warns. Of greater concern is that resistance to Cipro would also increase cross-resistance to all other quinolones, risking the effectiveness of this entire class of antibiotics. The use of Cipro is all the more surprising for two reasons. To start with, it has an appreciable level of side-effects. According to the FDA Cipro label, adverse events that were "considered likely to be drug related" occurred in 7.3% of patients treated and an additional 9.2% were "possibly related". A further 3% had adverse events that were "remotely related" to the therapy. "With thousands taking [Cipro] we are not talking small numbers of people who are coming back to the doctor because they have other problems related to the medication — you can see an escalation of medical costs just on the basis of handling the side effects," comments Levy. The second reason for surprise in the extent of the clamour to obtain Cipro is that the strain of anthrax is highly susceptible to many antibiotics including penicillin and doxycycline. Intriguingly one of the first people exposed to inhaled anthrax in Florida may have survived because he was taking penicillin to treat an existing respiratory infection. Indeed, almost two months after the initial cases — on 2 November 2001 — the US Centers for Disease Control issued a recommendation that penicillin should be used to treat anthrax in asymptomatic pregnant women. This follows hard on the heels of a change in policy recommending that doxycycline rather than Cipro should be the drug of first choice in prophylaxis, preserving Cipro for treatment. "We now have a double experiment, because we are now going to use doxycycline as well, and resistance to doxycycline is mainly due to pumps or changes in the target which are both due to genes that can be transferred. So here we can see rapid exchange," says Levy. "It is a real experiment that we are going to witness on a scale that nobody could have foreseen". "What is concerning to me is the fact that households have taken [Cipro] on their own to stockpile it and so as new fears come along, and the flu season begins, I am afraid that people are going to start popping these pills," he says. Looking back it is interesting to see why Cipro rose to such heights. It turns out that it is the only drug in the US with anthrax specifically on its label. All other antibiotics need to be used on a named patient basis for anthrax treatment. But the indication for anthrax was only added in 2000, thirteen years after the drug won its US licence. Other countries, such as the UK, still have no drug bearing a licensed indication for anthrax, although not surprisingly the queue is starting to form — Johnson & Johnson are seeking approval for their quinolone, Levaquin and Bristol-Myers Squibb for Tequin. In the war to be nicest, both companies are offering their products free for use against anthrax. At a press briefing in New York on 30 October 2001, Bradley Perkins — a leading epidemiologist at the CDC — and anthrax experts stressed that policy decisions needed to balance risks of infection, adverse effects and the potential of generating resistance. He also pointed out that once there is wide-spread prophylactic use of antibiotics there is no way of discovering the real numbers of people who have become infected with the disease. With new cases of anthrax exposure becoming an almost daily occurrence, one thing is clear. The scale of this experiment with antibiotics is huge and growing. For an in depth description of the fundamental biology and basis of toxicity of five of the organisms most likely to be used as bioweapons, click through to: Anatomy and actions of microscopic agents of terror

a case of placement over policy?

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