Hidden anthrax risks

The prospect of an all-out bioterrorism assault is causing panic in America. Whether the anthrax spores found in the mailrooms of public offices in the US are the work of Osama Bin-Laden and his Al Qaida network, or a homegrown lone bioterrorist, the potential public health implications are severe — and not just because of the direct threat of anthrax infections.

Around 2,000 cases of naturally occurring anthrax are diagnosed around the world every year, mostly in people working closely with animals. It is caused by the Gram positive bacterium Bacillus anthracis, which can lie dormant in spores for decades awaiting the right conditions to reactivate and cause infection. Cutaneous anthrax, in which sores develop after spores enter a cut in the skin, is easily treated with antibiotics in its early stages, and used to be a common occupational hazard among people handling animals and their products, such as wool. Gastrointestinal anthrax is extremely rare, fatal in maybe half of the patients infected, and results from the ingestion of spores.

But pulmonary anthrax, caused by the inhalation of spores is, in 90% of cases, lethal once the infection takes hold. The inhaled spores are transported through the lymphatic system to the lymph nodes, where the bacteria germinate. Their release, a few days to a couple of months later, results initially in flu-like symptoms, but soon the body is overwhelmed by the disease, usually resulting in death. However, this can be prevented by antibiotic treatment as soon as possible after exposure to the spores.

degree of luck

The human LD₅₀ by inhalation is only a few thousand spores, but creating an epidemic of pulmonary anthrax would require the deliberate release of huge quantities. The WHO estimates that if 50kg of spores were released from an aircraft over a town of 5m people, it would cause 250,000 infections. But manufacturing this quantity of anthrax spores would take several months and very large fermenters. And successful delivery of the agent would require a degree of luck. The Japanese Aum sect, which killed several commuters by releasing the nerve gas sarin on the Tokyo underground, is thought to have failed on a number of occasions to release anthrax in the city.

Anthrax is, in fact, far from an ideal biological weapon in battle, as vulnerable soldiers will have been vaccinated, and fight in protective suits. But the spores are long lived, and relatively straightforward to manufacture, with a fermentation broth merely needing to be lyophilised into a powder. The weapons grade spores involved in the US incidents would have been harder to produce, as they have been milled into an extremely fine form to enhance their inhalation properties.

Currently, only two antibiotics are approved by the FDA for use in the prevention of anthrax infection after exposure to spores — Bayer's fluoroquinolone ciprofloxacin (Cipro – see below) and the off-patent tetracycline doxycycline. The generic penicillin amoxicillin is also indicated for the treatment of the disease once it has developed. A full 60-day course of ciprofloxacin or doxycycline is needed to treat patients who have been exposed to the spores, as the antibiotics cannot treat the spores themselves, merely the bacteria once they have reactivated, and incubation takes time. Other fluoroquinolone antibiotics, such as levofloxacin and ofloxacin, may also be effective, but there is insufficient data on their efficacy to justify their indications being altered as yet. This may be reviewed if a mass outbreak of disease were to put pressure on the supplies of ciprofloxacin.

generic alternatives

The threat of infection has lured many frightened Americans into their local drug stores in search of the antibiotics they believe will save them. Sales of Bayer's Cipro soared by 27% in New York City after the anthrax scares there. Americans are also reported to be crossing the border into Mexico to snap up generic ciprofloxacin, where a pack of 36 tablets retails for US$55 (€62.18), compared with around US$170 (€192.18) in the US. A knock-on effect for the pharmaceutical industry is a substantial rise in prescriptions for anxiolytics being given to patients worried about the perceived threat of anthrax.

The US government has been stockpiling supplies of ciprofloxacin in case of a mass infection, and has made plans to ship the drugs wherever they are needed. The FDA has also banned private imports of ciprofloxacin in an attempt to curb the illegal sale of the drug over the internet. Several sites are reported to be selling fakes.

Yet widespread use of prophylactic antibiotics in people who have not been exposed to the spores is not the answer — and may, indeed, exacerbate the anthrax threat. Misuse of antibiotics is a public health problem in itself, as it can all too easily lead to pathogens mutating to create resistant strains. Even though few mutations have so far been reported in B. anthracis, if it were to occur then the threat from anthrax would become much greater. The antibiotics have no protective effect if taken before exposure, and widespread inappropriate use can only serve to reduce their effectiveness in the long term.

unlicensed antibiotics

Antibiotic resistance is a growing problem. Around 70% of the bacteria responsible for hospital-acquired infections are resistant to at least one of the commonly-used antibiotics, and there are some that are extremely difficult to treat with currently approved drugs. The only chance of curing infections caused by these microbes is with experimental unlicensed antibiotics, a strategy which has its own dangers. Strains of Staphylococcus aureus resistant to methicillin and other antibiotics are endemic in many hospitals, and their incidence is believed to be growing in the community. There are still some antibiotics that can treat drug resistant S. aureus, but strains with reduced susceptibility to the antibiotic last line of defence, vancomycin, have been reported recently in the US and Japan. Fully resistant strains would pose a huge public health problem.

Many organisms have developed strains that are resistant to one or more antibiotics, and the bacterium Salmonella typhimurium, resistant to ampicillin, streptomycin, tetracycline, chloramphenicol and sulpha drugs, is causing concern.

The major contributing factor in the development of resistant strains is the misuse of antibiotics — either because they are inappropriately prescribed (or taken without prescription) for conditions that are not bacterial in origin, or by the full course not being taken. This allows residual bacteria to remain alive, and having learned about the treatment agent, are more likely to be able to mutate to avoid its lethal effects.

Many pharmaceutical companies are now working on creating new antibacterial agents to plug the gaps in therapy that are being created as resistant organisms break through. Increased knowledge of the pathways by which resistance develops means new targets for antimicrobial drug therapy are being established.

It is never going to be possible to prevent resistant organisms developing, but with careful use of the antibiotics we already have, the pace of evolution should be able to be slowed down. We must hope that the anthrax scares do not lead to further ground being lost in the battle against antibiotic resistant bacteria.

Pharmacia offers anti- biotic to treat anthrax

Pharmacia has offered the US government a donation of its Cleocin HCI (clindamycin hydrochloride capsules) antibiotic both to treat diagnosed cases of anthrax and for prophylactic use, if necessary. While Cleocin is not currently approved by the FDA for use against anthrax, animal studies indicate that the drug is active against most strains of anthrax. Zyvox (linezolid injection, tablets and for oral suspension) and other Pharmacia antibiotics are in laboratory testing to determine efficacy against anthrax and other potential threatening agents. In addition, Pharmacia has said it will provide the departments of Defence and Health and Human Services with confidential access to its internal scientific information for potential antimicrobial and antiviral agents. Government scientists will be given access to Pharmacia's laboratories and ts production facilities.

Bayer increases ciprofloxacin supplies to the US government

Bayer Corporation has reached an agreement to supply up to 300 million tablets of Cipro to the US government. The deal is valued at US$95m (€107.4m). The company has also donated two million tablets of Cipro to the US Department of Health and Human Services (HHS) for emergency workers on the frontline of the fight against anthrax. A further two million tablets have been donated to postal workers who may have been exposed to anthrax but, so far, show no symptoms. Under the terms of the agreement, HHS will pay US$0.95 (€1.07) per tablet, for a total initial order of 100 million tablets to be supplied by the end of the year. This compares with a previously discounted price of US$1.77 (€2.00) per tablet paid by the federal government. Bayer is also to rotate the government's inventory to assure a continuously fresh supply of Cipro (fluoroquinolone ciprofloxacin). The US has an option to purchase an additional 200 million tablets.

Lilly responds to bioterrorism threat

Eli Lilly is to undertake several initiatives in response to the bioterrorism threats in the US. According to Sidney Taurel, Lilly president, chairman and ceo, the company has already begun to determine whether any of its antibiotics, including cephalosporins and macrolides, are effective in combating anthrax or other potential bioterrorism agents. Any antibiotics approved by the American government for that use will be provided at cost for victims of bioterrorism. The company is prepared to increase production to meet demand for its existing antibiotics, and, if requested, Lilly says it will convert its manufacturing capacity to augment the production of antibiotics made by other pharmaceutical companies. To address bioterrorism threats Lilly will make available specialised research facilities for government and/or industry-driven research and development into antibiotics and new anti-virals. Additionally, the company will make available, at its own expense, a selected group of Lilly scientists highly skilled in anti-bacterial and anti-viral research.

Roche Diagnostics releases rapid anthrax test

A DNA test that can identify the presence of anthrax in less than an hour is being made available by Roche Diagnostics. Developed by the Mayo Clinic, the test will be offered initially in the US to laboratories at no charge, although Roche plans to make it available globally. "This rapid identification will enable doctors to begin more timely treatment of patients who have been exposed to anthrax, and it will more quickly alleviate undue anxiety for people who haven't been exposed," said Dr Franklin R. Cockerill III, the Mayo Clinic microbiologist who led the development team. The test was developed using Roche's LightCycler instrument for polymerase chain reaction (PCR)-based assays. To make the test widely available, Roche significantly accelerated production of the reagents needed to run the assay on the LightCycler instrument; more than 20 geographically dispersed LightCycler-equipped laboratories in the US are able to conduct the test. Picture: Roche's LightCycler instrument for polymerase chain reaction on which the assay runs. Copyright F.Hoffman La Roche