7.2.1.1. Early treatment for animals

Following the first incident of anthrax in a herd, the remaining animals should be moved immediately from the field or area where the index case died, and regularly checked at least three times a day for two weeks for signs of illness (rapid breathing, elevated body temperature), or of submandibular or other oedema. Any animal showing these signs should be separated from the herd and given immediate treatment. Where such close observation and individual animal handling is difficult or not possible or likely to be stressful, the whole herd should be treated with long-acting antibiotic that provides at least 72-hours cover.

Clinical experience has frequently demonstrated that animals, especially cattle, will respond favourably to treatment even though apparently in the terminal stages of anthrax. Even if they go on to die (death in anthrax results from the effect of the toxin – section 7.1.1), the infecting load of B. anthracis will have been greatly reduced, if not entirely eliminated, thereby significantly reducing the chance of subsequent transmission from the carcass to other animals.

In certain countries, antibiotic treatment is not permitted and slaughter policies are in place (section 7.2.2.4).

7.2.1.2. Vaccination for animals

In endemic areas, or if there is concern that the outbreak may spread, the herd should be vaccinated (section 8.7). Further anthrax deaths can be expected to cease within 8 to 14 days of vaccination.

Decontamination of the site(s) where the index case or other case(s) died should be carried out (see section 8.3 and Annex 3). Subject to local regulations giving different instructions, herd quarantine can be lifted 21 days after the last death (see Annex 4).

Where animals are scheduled to be moved for local or international livestock and meat trade purposes, it is important to check whether there are local advisories in place specifying a withholding period following vaccination before which animals may be moved to other premises, or sent to slaughter. OIE standards are given in Annex 4.

More information on animal vaccines is given in section 8.6.2 and in Annex 5, section 2.

7.2.1.3. Treatment and vaccination in animals

Where the response to an outbreak consists of treatment first, followed by vaccination, it should be remembered that, in those animals that are treated, a suitable period of time should be allowed between the end of treatment and the start of vaccination, otherwise the treatment will prevent the live vaccine taking effect. The precise time lapse will depend on the antibiotic used but, in the absence of specific studies on the minimum withdrawal times before the vaccine can be administered, 8–12 days would appear logical for long-acting antibiotics. It should also not be forgotten that if the livestock are consuming feedstuffs containing antibiotics, or are being individually treated (e.g. intramammary antibiotics for mastitis), this is likely to render the vaccine ineffective (Lee et al., 1961; Webster, 1973).

Long intervals between outbreaks in a given area despite a lack of vaccination programmes are a notable feature in animal anthrax epidemiology (Fox et al., 1973, 1977). As implied in section 7.2.1.1, treatment alone can halt an outbreak and further cases may not occur on cessation of treatment.

7.2.2.1. Antimicrobial therapy in animals

The recommended procedure for treating animals showing clinical illness in which anthrax is thought to be the likely or possible cause is immediate intravenous administration of sodium benzylpenicillin as directed by the manufacturer’s instructions (usually in the range 12 000–22 000 units per kg of body weight) followed 6–8 hours later by intramuscular injection of long-acting benethamine penicillin (manufacturers’ instructions usually recommend a dose within the range of 6000–12 000 units per kg of body weight) or other appropriate preparation such as Clamoxyl® (15 mg/kg), a long–acting preparation of amoxycillin. If long-acting preparations are unavailable, procaine penicillin (the dose recommended by manufacturers is usually 6000–12 000 units/kg) can be used for intramuscular injection, but should be administered again after 24 and 48 hours.

Streptomycin acts synergically with penicillin (Lincoln et al., 1964) and penicillin/streptomycin mixtures are available commercially. Recommended doses of streptomycin to be administered together with penicillin intramuscularly are 5–10 mg per kg body weight in large animals and 25–100 mg per kg body weight in small animals.

Lincoln et al. (1964) noted in studies with rhesus monkeys that, for penicillin, the route of administration was important, with intramuscular injection being more effective than intravenous.

Veterinary experience in the United Kingdom is that, in contrast to advice frequently found in textbooks, treatment with tetracyclines may not be fully effective (Taylor, personal communication, 1997).

Attention should be paid to manufacturers’ recommendations regarding precautions and limitations of use of their antibiotics, including aspects relating to withdrawal periods after use in food animals.

Cost and availability are likely to be major considerations in the choice of treatment. For example, combined penicillin and streptomycin treatment can be expected to cost twice as much as penicillin alone.

7.2.2.2. Supportive therapy for animals

Symptomatic treatment may also be useful, and a range of possible agents is available. Supportive therapy with an agent such as flunixin (an analgesic with anti-inflammatory, antipyretic and anti- endotoxic properties) may be advantageous although it will add significantly to the cost of the therapy. As with steroids (section 7.3.1.10), it is, with current understanding of the pathogenesis of anthrax, difficult to see a scientific basis for efficacy with this type of therapeutic agent.

7.2.2.3. Hyperimmune serum therapy for animals

Hyperimmune serum has been used in the past for treating anthrax cases (Sterne, 1959) and it was generally considered that homologous sera (e.g. serum prepared in cattle for bovine use, etc.) were more effective than heterologous sera, although in rabbits equine antisera were twice as effective as bovine antisera (Spears, 1955). In Spears’s experiments, substantially increased time to death was a notable feature in animals that were not fully protected, indicating that serum therapy could only be regarded as supportive rather than a stand-alone action. This appeared to be understood in 1935 (Gochenour et al., 1935) when it was found that antiserum in combination with spore vaccine was more effective over time than antiserum alone.

Serum treatment of livestock is still practised in the Russian Federation at a rate of approximately 5 cases a year (Cherkasskiy, personal communication, 2002). The antiserum is produced in horses hyper-immunized with vaccine strain 55-VNIIVVM (see Annex 5, section 4.1). As far as could be ascertained, antiserum for this purpose is not produced or routinely used elsewhere for therapy against anthrax in animals.

The protective effect of immune serum administered therapeutically was demonstrated in monkeys (Henderson et al., 1956; Lincoln et al., 1964). These were challenged by the inhalation route and, in Henderson et al.’s experiments, once the effects of the immune serum wore off at about 20 days, the animals began to die of anthrax from continued uptake into the lymphatics of spores that still remained in the lungs. The possibility of relapse after the effect of this therapy has worn off was thereby illustrated. Lincoln et al. (1964), anticipating this outcome, administered the forerunner to the United States and United Kingdom human vaccines on day 8 and had no deaths. Lincoln et al. also found that intramuscular and intravenous administration of antiserum were equally effective.

7.2.2.4. Countries prohibiting treatment in livestock

It should be noted that treatment of animals is forbidden in some countries. Veterinary requirements in these countries are that, in a herd that has experienced a case of anthrax, other animals showing signs of illness must be killed without spilling of blood or exsanguinations, and the unopened carcass must be disposed of appropriately (section 8.3.2). It is understood that certain countries require the slaughter of the entire herd following a case of anthrax; this draconian approach is unnecessary and wasteful. Anthrax is not a chronic infection; if treated, animals will certainly recover. Killing sick animals instead of treating them is costly and alienates owners, even if compensated, and may leave them unwilling to report illness in their animals in the future. This is counterproductive.

7.2.2.5. Therapy in wildlife

While the use of antibiotics for controlling anthrax in wildlife is, generally speaking, unlikely to be feasible, it has reportedly been done with success in an outbreak in the United Republic of Tanzania where a single treatment of roan, sable antelope and kudu, 50 animals in total, by direct darting, appeared to arrest an outbreak (Jiwa, personal communication, 1995). In September 2002, a number of lions in the Etosha National Park (Namibia) were observed with severely swollen heads. Anthrax was confirmed in two of these but a third was captured and treated with a single dose of 15 ml (2250 mg) of procain benzylpenicillin (long acting) and lived (Jago, personal communication, 2006). The second lion that died was the mother of two cubs and was lactating heavily. The cubs were apparently healthy.

7.3.1.1. Mild uncomplicated cases

Penicillin G is still the drug of choice in the therapy of naturally-occurring anthrax in most parts of the world. In mild uncomplicated cases of cutaneous anthrax, the treatment usually recommended is intramuscular procaine penicillin, 500 to 600 mg (800 000 to 1 million units) every 12–24 hours for 3–7 days (procaine penicillin is frequently marketed in vials containing 800 000 units in developing countries). Intravenous antibiotic therapy is not recommended in mild cases. If the patient rejects intramuscular injection, penicillin V (500 mg taken orally every 6 hours) or amoxicillin (500 mg orally every 8 hours for 3–7 days) are acceptable alternatives. Cutaneous lesions usually become sterile within the first 24 hours of such regimens and the accompanying oedema usually subsides within 24 to 48 hours but, although early treatment will limit the size of the lesion, it will not alter the evolutionary stages it must go through (Gold, 1955; Kobuch et al., 1990).

7.3.1.2. Severe or potentially life-threatening cases

In patients exhibiting signs of systemic involvement, such as with inhalational or gastrointestinal anthrax, meningoencephalitis, sepsis, or cutaneous anthrax with extensive oedema, antibiotics should be given intravenously. Penicillin G is generally the first choice, 2400 mg (4 million units) every 4–6 hours by infusion (total daily dose should be 20–24 million units) until the patient’s symptoms resolve with the temperature returning to normal. At this point consideration may be given to switching to the intramuscular procaine penicillin regimen described in section 7.3.1.1. Also in severe cases, penicillin or another chosen antibiotic, e.g., ciprofloxacin, may be combined with another appropriate agent, preferably one that penetrates well to the central nervous system (CNS) (see also section 7.3.1.7). Penicillin G may be combined with clindamycin or clarithromycin in treating inhalational anthrax, or with an aminoglycoside (streptomycin is suggested) in gastrointestinal anthrax. The synergistic action of streptomycin when combined with penicillin has already been noted in relation to treatment of animals (section 7.2.2.1). In the USA, the most up-to-date recommendation for anthrax meningoencephalitis (Sejvar et al., 2005) is a fluoroquinolone (levofloxacin has also been shown to be effective in an animal model – Deziel et al., 2005) with two additional agents that penetrate well to the CSF (see section 7.3.1.9).

Use of more than one antibiotic is discussed further in section 7.3.1.6. Suggested doses are given in Table 5. As a general principle, in life-threatening infection with B. anthracis, low doses of antibiotics should not be used.

TABLE 5

Suggested antibiotic administration regimens for anthrax.

General measures for treatment of shock may be life-saving since death is caused, at least in part, by toxin-induced shock. Intubation, tracheotomy or ventilatory support may be required in the event of respiratory problems, for example in cases where compression on the neck from oedema is leading to danger of tracheal obstruction; once oedema is extensive it can be difficult to find the trachea at operation. Vasomotor support may be called for when there is haemodynamic instability. If administration of the appropriate volume of intravenous fluid fails to raise the systolic blood pressure above 90 mm Hg, a vasoactive drug such as dopamine or dobutamine can be given. Primary haematological, renal or liver function disorders are not generally seen.

7.3.1.3. Therapy in children

Penicillin is again the antibiotic of choice for treatment of anthrax in children. Generally the approach taken at least in Africa has been to give half-adult doses to children of less than 10 years of age (Martin, 1975; Turnbull, personal observations).

In mild uncomplicated paediatric cases of cutaneous anthrax, penicillin V should be given by the oral route at a dosage of 25–50 mg/kg/day in 3–4 doses, or amoxicillin according to the following formulae:

• weight > 20 kg, 500 mg orally every 8 hours for 3–7 days;
• weight < 20 kg, 40 mg/kg orally every 8 hours or intramuscular procaine penicillin (25 000 to 50 000 units/kg/day divided into 1–2 doses) for 3–7 days.

In severe or life-threatening cases, penicillin G should be administered intravenously in a dose of 300 000 to 400 000 units/kg/day for systemic anthrax and for cutaneous anthrax if (i) there are signs of systemic toxicity, (ii) the lesion(s) is/are located on the head and neck, and (iii) extensive oedema is present. As with adults (section 7.3.1.2), consideration should be given to combining the penicillin with rifampicin or vancomycin (Sejvar et al., 2005). Penicillin combined with streptomycin may be given in gastrointestinal anthrax, and penicillin combined with clindamycin or clarithromycin may be given in inhalation anthrax. Suggested doses are given in Table 5. As with severe cases in adults, once the patient’s temperature returns to normal, consideration may be given to switching to the regimen described for mild cases.

According to Sejvar et al. (2005), in view of the recognized potential of ciprofloxacin to cause arthropathy in children, the United States Working Group on Civilian Biodefense has recommended the use of ciprofloxacin in anthrax-related emergencies in children owing to the severity of the disease.

See section 7.3.1.7 for a discussion of alternatives to penicillin and section 7.3.2.1 for a discussion of postexposure prophylaxis.

7.3.1.4. Adequate doses of penicillin

The possibility that subinhibitory concentrations of penicillins may induce β-lactamase and the importance of using adequate doses of penicillin when this is chosen for treatment is covered in section 7.1.2. This needs to be appreciated in developing country situations, where there may be a temptation to economize.

7.3.1.5. Duration of treatment

The appropriate duration of treatment is a subject for debate. B. anthracis cannot be isolated from cutaneous lesions 24–48 hours after commencement of antibiotic therapy (Ellingson et al., 1946) and Kobuch et al. (1990) could see no advantage to continuing treatment of cutaneous anthrax beyond 4 days. A report from Ethiopia (Martin, 1975) records that 100 patients with cutaneous anthrax were treated with a single intramuscular dose of procaine penicillin, 600 000 units, and 99 of these were sent home with the invitation to return if complications occurred. Only 5 returned on account of further developments. Continuation of treatment for 7–14 days or longer has become standard, but frequently it is not appreciated that the lesions, or other toxin-related systemic damage, will continue to progress through their cycles of development and resolution regardless of the elimination of the infecting B. anthracis. Excessive antibiotic treatment may be wasteful and counterproductive, possibly giving rise to adverse side-effects. Supportive therapy becomes more important after the first few days. For guidance, it is suggested that the duration of antibiotic therapy in uncomplicated cutaneous anthrax be 3–7 days but, in the absence of clinical experience with short-course antibiotic therapy in systemic anthrax, therapy in cases of systemic anthrax should be continued for 10–14 days.

The same reasoning applies to treatment of alimentary tract cases; after the first 24 to 72 hours of antibiotic treatment, which can be expected to have eliminated viable anthrax bacilli, patient survival becomes dependent on supportive therapy while systemic damage caused by the toxin is overcome.

The topic of postexposure prophylaxis following substantial aerosol exposure in deliberate release events is covered in section 7.3.2.1.

7.3.1.6. Use of more than one antibiotic

The concept of using two antibiotics is not a new one. Forty years ago, Lincoln et al. (1964), following animal studies showing that penicillin together with streptomycin was more effective than either antibiotic alone, recommended that streptomycin should be administered together with penicillin in the treatment of septicaemic anthrax.

Recently, in the aftermath of the anthrax letter events in the USA in 2001, it was felt that the use of more than one antibiotic may have been life-saving in the 6 of 11 individuals who survived inhalational anthrax infection (Inglesby et al., 2002; Jernigan, 2001) and, while acknowledging that controlled studies to support a multidrug approach are not available, multidrug regimens were recommended for cases with signs of systemic involvement. As stated in section 7.1.2, it is certainly reasonable to add a second drug in cases showing signs of systemic involvement, utilizing two antibiotics to which B. anthracis is typically sensitive initially, with at least one of these able to penetrate well to the CNS. It may be appropriate to revert to one drug when progression of symptoms ceases, temperature returns to normal and the sensitivity profiles of any isolate have been established. Suggested antibiotic combinations for severe or life-threatening anthrax infections are given in section 7.3.1.2.

7.3.1.7. Alternatives to penicillin

In the event of allergy to penicillin, effective alternatives that are likely to be available in developing countries are tetracyclines and erythromycin (see also section 7.1.1). If ciprofloxacin or doxycycline are available, these are now accepted as best alternatives, although it needs to be remembered that doxycycline penetrates poorly to the CNS (see section 7.3.1.6). For uncomplicated cases, suggested doses are given in Table 5.

In severe, potentially life-threatening cases, ciprofloxacin or doxycycline (also see section 7.3.2.1) should be given intravenously, preferably together with another antibiotic having good CNS penetrability (see section 7.3.1.2) until the patient’s clinical condition permits switching to oral therapy. For adults, the recommended dose of intravenous ciprofloxacin is 400 mg every 12 hours and the recommended intravenous dose for doxycycline is 100 mg every 12 hours. The intravenous form of doxycycline is not available in some developing countries.

Ciprofloxacin and doxycycline are normally considered not ideal for children owing to their potential side-effects. Doxycycline is generally not recommended for use in children < 8 years old, owing to staining of teeth and the inhibition of bone growth associated with tetracyclines, and ciprofloxacin has been shown to cause cartilage toxicity in immature animals. However, as discussed in section 7.3.1.3, ciprofloxacin is recommended in anthrax-related emergencies in children owing to the severity of the disease.

The topic of prolonged postexposure prophylaxis for children following substantial aerosol exposure in a deliberate release event is covered in section 7.3.2.1.

7.3.1.8. Pregnancy

There are few reports of anthrax during pregnancy both in humans and animals. Kadanali et al. (2003) found only four human cases reported in the literature; three of these occurred before the availability of antibiotics and all three patients died. The fourth patient, in the Islamic Republic of Iran, went into labour within 48 hours after the appearance of the lesion; she died shortly after admission to hospital from massive oedema of head and neck, which interfered with her breathing. The neonate had no evidence of congenital infection and lived.

All the reports and Kadanali et al.’s own two (cutaneous anthrax) cases were in the last trimester of pregnancy. Kadanali et al. considered it advisable to use penicillin instead of more fetotoxic drugs, such as ciprofloxacin. Treatment was successful in both mothers, though both delivered preterm babies; neither of these showed any evidence of congenital infection. The authors concluded that anthrax during pregnancy could be successfully managed with penicillin, but preterm delivery could be a complication.

Sejvar et al. (2005) support the use of penicillin G (in combination with rifampicin or vancomycin) to treat naturally-occurring anthrax meningitis in pregnant women in endemic countries. As with children (section 7.3.1.3), while recognizing that ciprofloxacin has the potential to cause arthropathy in children, owing to the severity of anthrax meningitis, they state that ciprofloxacin should still be considered for pregnant women under such circumstances.

Published recommendations from the United States Centers for Disease Control and Prevention (CDC) following the anthrax letter events were generally careful to specify that the recommendations were for postexposure prophylaxis for prevention of inhalational anthrax after exposure to intentionally released anthrax spores, and specified the same regimen of ciprofloxacin or doxycycline for pregnant women under such circumstances as for non-pregnant ones (Anon., 2001c). For cutaneous anthrax, Carucci et al. (2002) similarly recommend the same doses of ciprofloxacin or doxycycline for pregnant and non-pregnant women, adding that ciprofloxacin is favoured over doxycycline. Carucci et al. do not state that this is related to bioterrorism, but their recommendation that duration of treatment should be 60 days indicates that it was.

Further discussion of prolonged postexposure prophylaxis for pregnant women and nursing mothers following substantial aerosol exposure in a deliberate release event is given in section 7.3.2.1.

7.3.1.9. Treatment of anthrax meningoencephalitis

Anthrax meningoencephalitis is a life-threatening infection, and mortality is very high. Currently, the first-choice treatment is penicillin G or a fluoroquinolone combined with rifampicin. These have the dual benefits of effective activity against B. anthracis and rapid penetration into the CSF. The intravenous form of rifampicin is not yet available in some developing countries. Another choice would be penicillin G or a fluoroquinolone in combination with vancomycin, but vancomycin is costly. For patients allergic to penicillin, a combination of a fluoroquinolone with two additional agents that penetrate well to the CSF, such as a β-lactam (penicillin, ampicillin or meropenem), rifampicin or vancomycin is recommended (Sejvar et al., 2005). A regime of vancomycin, 1 g intravenously every 12 hours, combined with rifampicin (600–1200 mg/day) for 10–14 days is another alternative.

Lessons from the few recorded instances of survival in cases of anthrax meningoencephalitis suggest that the doses of penicillin G should be 20–24 million units/day divided for intravenous administration every 2–4 hours, and a daily dose of rifampicin, 600–1200 mg/day (intravenous administration is suggested but it may also be given via an enteral tube).

The suggestion given in the third edition of these guidelines (1998) that penicillin may be replaced by chloramphenicol for patients who are hypersensitive to penicillin has now been withdrawn. Chloramphenicol has been stated to be a satisfactory alternative but, in early experimental studies, Lincoln et al. (1964) found that chloramphenicol was not effective in mice or monkeys. It is bacteriostatic rather than bactericidal against B. anthracis, and some strains may be resistant to it (Athamna et al., 2004). Furthermore, chloramphenicol has the potential for serious side-effects on bone marrow. In vivo data regarding its effectiveness in the treatment of severe anthrax infections is lacking, and there is a wide availability of more effective alternatives (Sejvar et al., 2005).

Doxycycline should not be used if meningitis is suspected because of its lack of adequate central nervous system penetration (Bell et al., 2002; Sejvar et al., 2005).

It should be stressed that the therapy failure rate is very high in cases of anthrax meningoencephalitis; in 47 cases covered by four reports (Levy et al., 1981; George et al., 1994; Lalitha et al., 1996; Kanungo et al., 2002), there were only two survivors. Delayed suspicion of the true cause of illness, with initial diagnoses ranging from cerebral malaria to subarachnoid haemorrhage, was considered by Kanungo et al. to be responsible in part for the high treatment failure rate.

Supportive therapy is very important in anthrax meningoencephalitis; respiratory support and anti-oedema therapy for the brain may be required. Essential supportive therapy includes the early institution of assisted respiration, fluid and electrolyte supplement and anticerebral oedema measures, such as 100 ml of 20% mannitol intravenously every 8 hours and hydrocortisone, 100 mg every 6 hours. Dexamethasone is generally suggested.

Useful references concerning anthrax meningoencephalitis are given in section 4.4.5.

7.3.1.10. Immuno- or otherwise compromised individuals

Although written with the deliberate release event in mind, recommended therapy for the immunocompromised individual was the same as that for immunocompetent persons in Anon. (2001c) and Carucci et al. (2002). Special consideration may be needed for patients with renal or hepatic insufficiency.

7.3.1.11. Corticosteroids

The swelling seen in an anthrax infection is caused by the action of oedema toxin, and inflammation is fairly minimal. As discussed in section 5.5.3, the EF component of the toxin is anti-inflammatory in nature. Theoretically, therefore, steroids should be of little value. In practice, some reports indicate that these have been administered with evidence of benefit, but others (Kobuch et al., 1990) have concluded that they were ineffective, discontinuing their use. In experimental studies on therapy in rhesus monkeys, Lincoln et al. (1964) concluded that hydrocortisone did not have a statistically significant effect on survival. In section 7.3.1.9, hydrocortisone is suggested as part of supportive treatment in the event of the very dangerous meningoencephalitic complication. In such situations, it is reasonable to give corticosteroids the benefit of the doubt on the basis that any help they may offer is welcome.

7.3.1.12. Surgery in gastrointestinal anthrax

It should be pointed out that some value a surgical approach to management of advanced intestinal anthrax (Binkley et al., 2002; Kanafani et al., 2003). Kanafani et al. propose that the management of cases of gastrointestinal anthrax should consist of:

• initiation of intensive intravenous antibiotic therapy as soon as diagnosis is made;
• in patients not improving with medical therapy, wide resection into seemingly healthy tissue with primary anastomosis;
• continuous drainage of the ascites, as fluid will continue to accumulate for several days after surgery;
• aggressive replacement of protein and electrolyte losses.

7.3.2.1. Reaction to bioterrorism

Fear resulting from increasing numbers of anthrax hoaxes, especially in the USA, and then the 2001 anthrax letter events, also in the USA, have led to recommended treatment schedules that would frequently not be possible in developing countries.

7.3.2.2. Treatment for naturally acquired anthrax in high-economy countries

The issue of treatment of occasional cases of naturally acquired anthrax that still occur periodically in developed countries has not been raised in the vast amount of recent literature resulting from the bioterrorist threats and events of recent years. Unless there is reason to believe that the infection represents possible exposure to substantial numbers of inhaled spores, it is suggested that simple regimens of limited duration be adhered to, but possibly utilizing two antibiotics to which B. anthracis is typically sensitive initially, reverting to one when progression of oedema ceases in the case of uncomplicated cutaneous anthrax, or when the temperature has returned to normal in systemic cases, and the sensitivity profiles of any isolate have been established (sections 7.3.1.5, 7.3.1.6).

7.3.2.3. Antibiotic prophylaxis in natural anthrax scenarios

Prolonged antibiotic prophylaxis is only a recommendation for persons known to have been, or strongly suspected of having been, exposed to very substantial doses of aerosolized spores in a deliberate release scenario. Antibiotics should not be administered in that way for other situations. Antibiotics should only be used for treatment, not prophylaxis, unless there is a real danger of a very substantial exposure having taken place. This is almost certainly not the case in any natural exposure scenario (as opposed to a human-made situation). Where sufficient fear of a substantial exposure in a natural situation exists (e.g. consumption of meat from a poorly cooked anthrax carcass), antibiotic prophylaxis may be considered but should only be of ± 10 day duration. In other suspected natural exposure situations, the relevant medical personnel should be notified, and the individual(s) concerned should report to them immediately for treatment should a spot/pimple/boil-like lesion develop, especially on exposed areas, or flulike symptoms appear.

Where possible exposure is anticipated, but has not yet happened (e.g. preparing to dispose of carcasses in an outbreak), use of proper personal protection methods (Annex 1, section 7.1.2) is the correct approach, not antibiotic prophylaxis. Again, however, the persons concerned should consult their medical practitioner without delay should any unusual lesion or flulike illness develop within 3 or 4 weeks of the exposure.

7.3.4.1. Novel immune and other therapies

Antibiotics are only effective against anthrax if administered early enough in the course of the infection (section 7.1.1). After a certain point, enough toxin has been formed to cause death of the host even if the antibiotic treatment has killed all the B. anthracis. Among other aftermaths of the 2001 anthrax letter events in the USA have been some intense efforts to develop therapies that will continue to be effective after antibiotics can offer no hope. Among the approaches being taken are therapies targeting:

• one or more of the points of interaction between the toxin components and the host cell, such as the host-cell receptors, or the receptors on PA63 for LF and EF (see 5.5.3 and Fig. 7);
• the toxin-induced events within the host cell;
• other virulence factor entities.

Probably among the most advanced in their development are humanized monoclonal antibodies targeting toxin-component interactions. For example, the toxin-neutralizing antibodies mentioned by Maynard et al. (2002), referred to in 7.3.4, operated by competing with the host-cell receptor for PA binding. Similarly, the Fab fragments developed by Wild et al. (2003) functioned by binding in a manner that inhibited the interaction of LF with PA. EluSys Therapeutics² reports on the Web the development of a heteropolymer system using two monoclonal antibodies chemically joined together; one binds to anthrax toxin and the other to red blood cells which then carry the bound toxin to the liver for destruction. Human Genome Sciences, Inc.³ also has a product well into its development stage based on human or humanized neutralizing anti-PA monoclonal antibodies. A non-immunologically based approach is illustrated in the report of Sarac et al. (2004) that furin inhibitor, hexa-D-arginine, might be an effective therapeutic agent by preventing cleavage of PA to its active form.

An example of therapy targeting toxin-induced events within the host cell is the observation by Shen et al. (2004) that adefovir diphosphate, a drug approved to treat chronic hepatitis B virus infection, inhibits the adenylyl cyclase activity of EF and thereby EF-induced cAMP accumulation (see section 5.5.3).

Illustrating other virulence factor entities are the reports of Gold et al. (2004) suggesting that interferon may have a benefit as an immunoadjuvant therapy and of Kozel et al. (2004) on their monoclonal antibodies to capsular antigen (sections 7.3.4). An intriguing suggestion for novel therapy was the proposed use of gamma phage lysin by Schuch et al. (2002) that lysed B. anthracis cells from without in in vitro tests, and protected mice against infection with a phage-sensitive B. cereus used as a simulant for B. anthracis. Success in this case for real anthrax treatment would depend on the lysin’s ability to penetrate the B. anthracis capsule in genuine anthrax infections. Direct phage therapy, an idea that has been considered from time to time in the past for anthrax, has to overcome the fact that the phage does not attack capsulated B. anthracis cells (section 6.3.1.5).⁴