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Problems associated with potential massive use of antimicrobial agents as prophylaxis or therapy of a bioterrorist attack

2002; Elsevier BV; Volume: 8; Issue: 8 Linguagem: Inglês

10.1046/j.1469-0691.2002.00495.x

1469-0691

Enrique Navas,

Antibiotic Resistance in Bacteria

In addition to the direct sanitary damage of a terrorist attack caused by biological weapons, the consequences of the massive stockpiling and consumption of antimicrobial agents in order to treat or prevent the disease under a potential epidemic due to pathogenic bacteria must also be considered. Bacillus anthracis, Francisella tularensis and Yersinia pestis are the bacteria most likely to be used as terrorist weapons. Tetracyclines, quinolones and aminoglycoside are the antibiotics of choice against these microorganisms. The recent terrorist attack with anthrax spores in the USA caused a substantial increase in the sales of ciprofloxacin, as thousands of citizens received antibiotic prophylaxis for either confirmed or suspected exposure to anthrax, and many others stockpiled antibiotic supplies at their homes under a panic scenario. The massive consumption of antimicrobial drugs may lead to the selection of antibiotic resistant strains, and to the appearance of undesirable side effects, such as anaphylaxis or teratogenesis.National health authorities must develop realistic protocols in order to detect, treat and prevent mass casualties caused by biological weapons. An antibiotic stockpile has to be planned and implemented, and home stockpiling of antibiotics must be strongly discouraged. In addition to the direct sanitary damage of a terrorist attack caused by biological weapons, the consequences of the massive stockpiling and consumption of antimicrobial agents in order to treat or prevent the disease under a potential epidemic due to pathogenic bacteria must also be considered. Bacillus anthracis, Francisella tularensis and Yersinia pestis are the bacteria most likely to be used as terrorist weapons. Tetracyclines, quinolones and aminoglycoside are the antibiotics of choice against these microorganisms. The recent terrorist attack with anthrax spores in the USA caused a substantial increase in the sales of ciprofloxacin, as thousands of citizens received antibiotic prophylaxis for either confirmed or suspected exposure to anthrax, and many others stockpiled antibiotic supplies at their homes under a panic scenario. The massive consumption of antimicrobial drugs may lead to the selection of antibiotic resistant strains, and to the appearance of undesirable side effects, such as anaphylaxis or teratogenesis. National health authorities must develop realistic protocols in order to detect, treat and prevent mass casualties caused by biological weapons. An antibiotic stockpile has to be planned and implemented, and home stockpiling of antibiotics must be strongly discouraged. Biological terrorism has unique characteristics that make it different from other kinds of war. The reaction of the population to conventional terrorist attacks (e.g. bombs) is unfortunately well known and, to some extent, predictable. Such attacks are readily detected by the authorities, and the injured receive immediate medical care. The consequences of a massive attack with a biological weapon may be dramatically different. The release of microorganisms or their toxins is silent, and detection of the epidemic is not possible until significant numbers of people with the disease are assisted at medical facilities; moreover, the affected patients may be far from the geographic location where the biological weapon has been used, and the agent may have been disseminated in different locations. As time passes, transmission of the agent may cause the appearance of secondary cases, confusing the situation even more. The initial consequences of the attack will depend on the infectivity, virulence, lethality and contagiousness of the infective agent. Infection control measures will be decisive in limiting the outbreak, and they begin with communication of the risks to the population in order to avoid panic reactions. Prompt implementation of quarantine precautions and administration of vaccines and antimicrobials to the exposed population are essential in avoiding further spread of the disease [1AnonBiological and chemical terrorism: strategic plan for preparedness and response. Recommendations of the CDC strategic planning workgroup.MMWR Morb Mortal Wkly Rep. 2000; 49: 1-14PubMed Google Scholar,2Barbera J Macintyre A Gostin L et al.Large-scale quarantine following biological terrorism in the United States: scientific examination, logistic and legal limits, and possible consequences.JAMA. 2001; 286: 2711-2717Crossref PubMed Scopus (152) Google Scholar]. In a theoretical situation, once the attack is detected, and a first estimation of the magnitude of the disease has been made, coordination of the public health resources is mandatory, and evaluation of the availability of hospitals and clinics, staff and pharmaceutical products is a basic step in the design of the emergency plan. In a conventional terrorist event, there is no doubt which people are injured by the weapons. In a bioterrorist attack, however, unaffected civilians may overwhelm the medical facilities because of panic, minor symptoms due to coincidental diseases, or fear that they are suffering from the disease. In this situation, massive personal stockpiling and consumption of antibiotics to prevent the disease may have incalculable consequences [3Inglesby TV Anthrax: a possible case history.Emerg Infect Dis. 1999; 5: 556-560Crossref PubMed Scopus (24) Google Scholar]. Among the potential biological weapons, category A agents are those most likely to cause mass casualties, because of their infectivity and virulence. This category includes three pathogenic bacteria that have the highest potential for use in large-scale bioterrorist attacks: Bacillus anthracis, Francisella tularensis and Yersinia pestis [4Khan AS Morse S Lillibridge S Public-health preparedness for biological terrorism in the USA.Lancet. 2000; 356: 1179-1182Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. The antibiotics of choice in the treatment and prevention of these agents, according to the Working Group on Civilian Biodefense, are summarized in Table 1 [5Inglesby TV Henderson DA Bartlett JG et al.Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense.JAMA. 1999; 281: 1735-1745Crossref PubMed Scopus (713) Google Scholar, 6Dennis DT Inglesby TV Henderson DA et al.Tularemia as a biological weapon: medical and public health management. Working Group on Civilian Biodefense.JAMA. 2001; 285: 2763-2773Crossref PubMed Scopus (1163) Google Scholar, 7Inglesby TV Dennis DT Henderson DA et al.Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense.JAMA. 2000; 283: 2281-2290Crossref PubMed Scopus (849) Google Scholar]. Doxycycline, fluoroquinolones and streptomycin are the antibiotics that must be considered in the prevention and treatment of these conditions. Other bacteria that could be used as weapons, such as Coxiella burnetti, Brucella spp., Burkholderia mallei, Vibrio cholerae, Salmonella spp., Shigella dysenteriae or Escherichia coli 0157:H7, are less likely to be disseminated widely, have less lethality, and are therefore placed in category B [4Khan AS Morse S Lillibridge S Public-health preparedness for biological terrorism in the USA.Lancet. 2000; 356: 1179-1182Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar].Table 1Recommendations for antimicrobial therapy following bioterrorist bacterial attacks (Working Group on Civilian Biodefense)TreatmentPost-exposure prophylaxisAnthraxCiprofloxacin for 60 daysCiprofloxacin for 60 daysPenicillin G for 60 daysAmoxicillin for 60 daysDoxycycline for 60 daysDoxycycline for 60 daysYersinia pestisStreptomycin for 10 daysDoxycycline for 7 daysGentamicin for 10 daysCiprofloxacin for 7 daysDoxycycline for 10 daysChloramphenicol for 7 daysChloramphenicol for 10 daysCiprofloxacin for 10 daysFrancisella tularensisStreptomycin for 10 daysDoxycycline for 14 daysGentamicin for 10 daysCiprofloxacin for 14 daysDoxycycline for 14-21 daysChloramphenicol for 14-21 daysCiprofloxacin for 10 days Open table in a new tab In the case of exposure to Bacillus anthracis spores, 60 days of an antibiotic regimen that includes either doxycycline or a quinolone is recommended. The delayed transformation of the inhaled spores to vegetative bacteria explains why the antibiotic regimen must be extended up to 60 days after exposure [5Inglesby TV Henderson DA Bartlett JG et al.Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense.JAMA. 1999; 281: 1735-1745Crossref PubMed Scopus (713) Google Scholar,8AnonInvestigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001.MMWR Morb Mortal Wkly Rep. 2001; 50: 889-893PubMed Google Scholar]. Recent experience in the USA was that no patient exposed to anthrax spores receiving antibiotic prophylaxis developed the disease [9AnonInvestigation of bioterrorism-related anthrax, 2001.MMWR Morb Mortal Wkly Rep. 2001; 50: 1008-1010PubMed Google Scholar]. Scientific evidence on the efficacy of antimicrobial prevention of tularemia and plagueisscarce. For tularemia, streptomycin is the most active antibiotic, and, to date, most authorities have recommended preemptive streptomycin (gentamicin can be used instead) as first choice after accidental laboratory exposure to this agent [10Cross JT Penn RL Francisella tularensis (tularemia).in: Mandell G Principles and practice of infectious diseases. Churchill Livingstone, Philadelphia, Pa2000: 2393-2402Google Scholar]. The aminoglycoside antibiotics have to be given parenterally, are ototoxic and nephrotoxic, and so seem to be unsuitable for mass prophylaxis. Although the efficacy of ciprofloxacin and doxycycline in humans for an aerosol challenge of F. tularensis is unknown, an experimental mouse model indicates that, when initiated early, they may be effective as post-exposure prophylaxis [11Russell P Eley SM Fulop MJ Bell DL Titball RW The efficacy of ciprofloxacin and doxycycline against experimental tularaemia.J Antimicrob Chemother. 1998; 41: 461-465Crossref PubMed Scopus (63) Google Scholar]. In the case of plague, streptomycin is the most active drug, and is the antibiotic of choice in the treatment of severe cases [12Smego RA Frean J Koornhof HJ Yersiniosis I Microbiological and clinicoepidemiological aspects of plague and non-plague Yersinia infections.Eur J Clin Microbiol Infect Dis. 1999; 18: 1-15Crossref PubMed Scopus (103) Google Scholar,13AnonPrevention of plague: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Morb Mortal Wkly Rep. 1996; 45: 1-15PubMed Google Scholar]. Doxycycline is preferred for prophylaxis, although ciprofloxacin, chloramphenicol and cotrimoxazole may also be effective [14Russell P Eley SM Green M et al.Efficacy of doxycycline and ciprofloxacin against experimental Yersinia pestis infection.J Antimicrob Chemother. 1998; 41: 301-305Crossref PubMed Scopus (51) Google Scholar,15Byrne WR Welkos SL Pitt ML et al.Antibiotic treatment of experimental pneumonic plague in mice.Antimicrob Agents Chemother. 1998; 42: 675-681Crossref PubMed Scopus (6) Google Scholar]. The required duration of prophylaxis against Y. pestis and F. tularensis is unknown; because they are not spore-forming bacteria, a short course (7-14 days) should be enough for most attacks. Pneumonic plague is capable of being transmitted by inhalation from person to person; in a situation in which an established epidemic makes human-to-human transmission possible, besides quarantine and barrier measures [16Nolte KB Safety precautions to limit exposure from plague-infected patients.JAMA. 2000; 284: 1648Crossref PubMed Scopus (19) Google Scholar], antimicrobial prophylaxis may well have to be prolonged. In summary, in order to be prepared for a potential bacterial attack due to any of these three species, governments should guarantee a sufficient supply of tetracyclines, quinolones and streptomycin. The authorities must, however, keep in mind that the threat of attack with antibiotic-resistant microorganisms may make this antibiotic choice completely useless; the recent isolation of a Y. pestis strain with plasmid-mediated multiresistance in Madagascar [17Guiyoule A Gerbaud G Buchrieser C et al.Transferable plasmid-mediated resistance to streptomycin in a clinical isolate of Yersinia pestis.Emerg Infect Dis. 2001; 7: 43-48Crossref PubMed Scopus (184) Google Scholar,18Galimand M Guiyoule A Gerbaud G et al.Multi-drug resistance in Yersinia pestis mediated by a transferable plasmid.N Engl J Med. 1997; 337: 677-680Crossref PubMed Scopus (365) Google Scholar] is worrisome, and introduction of resistance and virulence genes into these pathogenic bacteria through bioengineering may well be achieved by military or terrorist-allied laboratories. Public-health plans, in order to be prepared against the release of any of the previously mentioned microbiological weapons, must, of course, include an estimate of the types and quantities of vaccines and antibiotics that must be stockpiled by the health authorities. This is not, however, an easy task, as the dynamics of transmission of these diseases in an artificial setting caused by the intentional spread of the infectious agent through terrorist action may be very different from what we know about the biology of the microorganisms in the natural environment. In 1970, the World Health Organization estimated that the aerial release of 50kg of anthrax spores over a population area of five million people would harm 250 000, and that 100 000 people would be expected to die without treatment; 50kg of F. tularensis in a similar area would cause disease in 250 000, and 19 000 deaths, and 50kg of Y. pestis would cause 150 000 cases of pneumonic plague and 36000 deaths [19World Health OrganizationHealth aspects of chemical and biological weapons. WHO, Geneva1970Google Scholar]. Although the scientific basis of these estimates has not been clearly described in the literature, the assumption may not be unreasonable, as was shown by the consequences of the accidental leak of anthrax from a military facility in Sverdlovsk, in the former USSR [20Abramova FA Grinberg LM Yampolskaya OV Walker DH Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979.Proc Natl Acad Sci USA. 1993; 90: 2291-2294Crossref PubMed Scopus (338) Google Scholar]; this unintentional release of a non-specified quantity of Bacillus anthracis spores was responsible for at least 64 human deaths. How feasible it is to obtain large quantities of anthrax spores or other pathogens in some kind of dry powder suitable for massive aerosolization is something that only military researchers or bioterrorist scientists can determine. If the menace of an airborne massive attack with virulent F. tularensis, Y. pestis or Bacillus anthracis is real, the threatened governments should stockpile millions of doses of tetracyclines and fluoroquinolones. The list of potential biological agents is so large that it is impossible to keep large stocks of every vaccine, antiserum or antibacterial to off-set every agent that may be used in a biological attack. The pharmaceutical companies should also be queried about their capacity to manufacture the drugs upon demand. The recent US experience with the terrorist attacks using anthrax spores sent through the mail is particularly helpful as a guide on how to approach future bioterrorist events. As of 14 November, the Centers for Disease Control (CDC) reported 22 anthrax cases in several districts (Columbia, Florida, New Jersey, New York City) and five fatalities due to inhalation disease. Most cases occurred among persons with known or suspected contact with opened letters contaminated with Bacillus anthracis spores [9AnonInvestigation of bioterrorism-related anthrax, 2001.MMWR Morb Mortal Wkly Rep. 2001; 50: 1008-1010PubMed Google Scholar]. Approximately 32 000 people initiated antimicrobial prophylaxis following potential exposure to Bacillus anthracis at workplaces in the affected districts, and approximately 7500 specimens were sent for Bacillus anthracis testing [21AnonInvestigation of bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis.MMWR Morb Mortal Wkly Rep. 2001; 50: 973-976PubMed Google Scholar]. It is obvious that thousands of other citizens might have received antibiotic prophylaxis without the CDC's knowledge, and that many others might have stockpiled ciprofloxacin at home. The sales of ciprofloxacin in the USA increased by 12% during the period of the anthrax attack, in comparison with the preceding year. The possibility of a large-scale attack caused a patent dispute between the US and Canadian governments and Bayer, the manufacturer of ciprofloxacin. The US government authorities calculated a need for antibiotics for ten million persons. For a 60-day supply, Bayer's capacity to manufacture enough ciprofloxacin was clearly insufficient. Several generic companies received Food and Drug Administration (FDA) clearance under a special legal framework, the rule 28 USC 1498, so that they could be asked to manufacture the drug for the government without a license from Bayer. The link between antibiotic use and the development of resistance has been well known since the discovery of penicillin more than 50 years ago [22Levy SB The challenge of antibiotic resistance.Sci Am. 1998; 278: 46-53Crossref PubMed Scopus (587) Google Scholar]. Obviously, one of the dangers of the widespread use of antibiotics for the prevention or treatment of infections due to biological weapons is the selection and community spread of resistant bacteria. The use of antimicrobial agents in food animals for growth promotion is an excellent, although unfortunate, experimental model of selection of resistant strains, and explains the high rate of antimicrobial resistance in Salmonella and Campylobacter strains isolated from human sources [23Gorbach SL Antimicrobial use in animal feed;time to stop.N Engl J Med. 2001; 345: 1202-1203Crossref PubMed Scopus (139) Google Scholar]. In the case of the quinolones, resistance in E. coli has increased in many countries in the last decade, in close relation to the rising use of this antibiotic in the treatment of urinary tract infections and as prophylaxis in neutropenic and cirrhotic patients [24Carratala J Fernandez-Sevilla A Tubau F Dominguez MA Gudiol F Emergence of fluoroquinolone-resistant Escherichia coli in fecal flora of cancer patients receiving norfloxacin prophylaxis.Antimicrob Agents Chemother. 1996; 40: 503-505PubMed Google Scholar]. The use of trimethoprim-sulfamethoxazole in AIDS patients as prophylaxis against Pneumocystis carinii pneumonia has also been linked to the development of resistance; in a report from San Francisco General Hospital, resistance of E. coli isolated from HIV patients increased from 24% in 1988 to 74% in 1995 [25Martin JN Rose DA Hadley WK Perdreau-Remington F Lam PK Gerberding JL Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS era.J Infect Dis. 1999; 180: 1809-1818Crossref PubMed Scopus (103) Google Scholar]. In a scenario of indiscriminate use of fluoroquinolones, not only is the selection of resistant strains among Gram-negative bacteria worrisome, but also, the dissemination of quinolone-resistant Streptococcus pneumoniae in the community may compromise therapeutic options in the treatment of respiratory infections in areas with high endemicity of penicillin-resistant pneumococci. In the last 5 years, several publications from different countries have reported an increasing prevalence of fluoroquinolone resistance in S. pneumoniae, in parallel with prescriptions of this group of antibiotics [26Chen DK McGeer A de Azavedo JC Low DE Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network.N Engl J Med. 1999; 341: 233-239Crossref PubMed Scopus (1035) Google Scholar, 27Goldsmith CE Moore JE Murphy PG Ambler JE Increased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland.J Antimicrob Chemother. 1998; 41: 420-421Crossref PubMed Scopus (64) Google Scholar, 28Liñares J de la Campa AG Pallares R Fluoroquinolone resistance in Streptococcus pneumoniae.N Engl J Med. 1999; 341: 1546-1547PubMed Google Scholar]. In a survey of S. pneumoniae isolates collected during the year 2000 in Hong Kong, the prevalence of fluoroquinolone resistance (levofloxacin MIC ≥4 mg/L) was 13.3%. Fluoroquinolone resistance was associated with old age and chronic obstructive pulmonary disease, and a history of previous quinolone therapy was common among the people harboring resistant strains [29Peterson DE Sahm DF Fluoroquinolone resistance in Streptococcus pneumoniae.N Engl J Med. 1999; 341: 1547-1548PubMed Google Scholar]. In a recent Spanish survey, no strains of S. pneumoniae with an MIC for ciprofloxacin ≥4 mg/L were found among 125 pneumococcal strains isolated from children; on the contrary, 59 of 988 (6%) strains from adults were resistant. As children are seldom treated with fluoroquinolones, this finding suggests a link between fluoroquinolone consumption and development of resistance [30Garcia-Rey C Aquilar L Baquero F Influences of different factors on prevalence of ciprofloxacin resistance in Streptococcus pneumoniae in Spain.Antimicrob Agents Chemother. 2000; 44: 3481-3482Crossref PubMed Scopus (40) Google Scholar]. Undoubtedly, although the development of reduced susceptibility to fluoroquinolones in S. pneumoniae requires sequential mutations in the antibiotic target, massive consumption of fluoroquinolones as a result of a bioterrorist attack may definitely contribute to a significant increase in the prevalence of quinolone-resistant bacteria in the affected areas. The tetracyclines inhibit protein synthesis by reversible binding on the 30S ribosome. Efflux-based mechanisms are the principal means of resistance to the tetracyclines, and most frequently they are plasmid encoded. The tetracyclines are the drugs of choice for rickettsiae, chlamydiae, borreliae, and brucellae [31Smilack JD The tetracyclines.Mayo Clin Proc. 1999; 74: 727-729Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. Although antibiotic treatment may contribute to the selection and spread of tetracycline-resistant bacteria, at the present time few strains of Pneumococcus, Staphylococcus and Gram-negative bacilli are susceptible to the tetracyclines, and therefore they are not first-choice agents for the treatment of infections due to these microorganisms. The ecological effect of the use of doxycycline for mass prophylaxis may therefore not have long-term adverse therapeutic consequences. Personal stockpiling of antibiotics must always be discouraged, even in the face of a bioterrorist threat. If people accumulate antibiotics at home, and the anticipated exposure does not take place, it is probable that they will later misuse the stocked antibiotics for the treatment of other medical conditions, such as self-limited viral infections or uncomplicated bacterial infections. Antibiotic recommendations in a mass casualty setting must be carefully devised, in order to avoid agents with potential life-threatening secondary effects, such as severe hypersensitivity reactions or anaphylaxis, fulminant hepatitis, or exfoliative skin rash [32Neugut AI Ghatak AT Miller RL Anaphylaxis in the United States: an investigation into its epidemiology.Arch Intern Med. 2001; 161: 15-21Crossref PubMed Scopus (359) Google Scholar]. The teratogenic potential of the drugs must also be considered in this circumstance, as women of childbearing age may be treated in the first weeks of conception without knowledge of being pregnant. In any case, the therapeutic decisions must find a balance between the toxicity of the drugs against the benefits of preventive therapy for a potentially lethal infection. The toxicity profiles of the quinolones and of doxycycline are summarized in Table 2. The post-marketing studies of the newer quinolones (tema-floxacin, grepafloxacin, trovafloxacin) identified severe adverse effects such as anaphylactoid reactions, hemolytic anemia, QT-interval prolongation and liver necrosis [33Bertino Jr, J Fish D The safety profile of the fluoroquinolones.Clin Ther. 2000; 22: 798-817Abstract Full Text PDF PubMed Scopus (193) Google Scholar]. The older quinolones—ciprofloxacin, ofloxacin and levofloxacin—have not been associated with these adverse events, except for anecdotal anaphylactoid reactions due to ciprofloxacin reported in the literature [34Deamer RL Prichard JG Loman GJ Hypersensitivity and anaphylactoid reactions to ciprofloxacin.Ann Pharmacother. 1992; 26: 1081-1084Crossref PubMed Scopus (29) Google Scholar]. Fluoroquinolones are not recommended for women during pregnancy, lactation or for young children, because of concerns about teratogenesis and cartilage toxicity. Animal models using high doses of ciprofloxacin, and surveys of mothers exposed to ciprofloxacin during pregnancy, have not shown that ciprofloxacin causes maternal toxicity, embryotoxicity, or teratogenic effects. Quinolones have been reported to cause arthropathy in immature animals of various species [35Berkovitch M Pastuszak A Gazarian M Lewis M Koren G Safety of the new quinolones in pregnancy.Obstet Gynecol. 1994; 84: 535-538PubMed Google Scholar,36Loebstein R Addis A Ho E et al.Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study.Antimicrob Agents Chemother. 1998; 42: 1336-1339PubMed Google Scholar]. Fluoroquinolones have been used successfullyas second-line therapy in children with severe or multiresistant infections, although causing reversible arthropathy in some children with cystic fibrosis.Table 2Adverse effects attributed to fluoroquinolones and tetracyclinesFluoroquinolonesGastrointestinal (anorexia, nausea, bloating, abdominal pain)Central nervous system (dizziness, headache)Allergic and skin reactionsDiarrhea (including Clostridium difficile colitis)PhototoxicityArthropathy and tendinitisQTc prolongationLaboratory abnormalities (leukopenia, eosinophilia, elevated transaminases)DoxycyclineGastrointestinal intoleranceAllergic and skin reactionsPhotosensitivityCentral nervous system (dizziness, headache)Dental discolorationEsophageal ulcerationsDiarrhea (including Clostridium difficile colitisHepatotoxicityPancreatitisBenign intracranial hypertension Open table in a new tab Doxycycline is the preferred tetracycline, because of its activity, safety profile and pharma-cokinetic properties. Hypersensitivity reactions are rare, and photosensitivity is less frequent with doxycycline than with other tetracyclines. Liver toxicity has been described, especially in patients receiving intravenous tetracyclines; pregnant patients are particularly susceptible to liver disease. Doxycycline-induced liver disease is exceptional. Pancreatitis has also been linked to tetracycline treatment. Tetracyclines are also contraindicated in pregnant patients and in young children, because of dental staining, enamel hypoplasia, and inhibition of skeletal growth in the fetus. The Hungarian Congenital Abnormality Registry failed to detect any teratogenic risk in a case-control study of 32 804 pregnant women, 63 of them treated with doxycycline [37Czeizel AE Rockenbauer M Teratogenic study of doxycycline.Obstet Gynecol. 1997; 89: 524-528Crossref PubMed Scopus (74) Google Scholar]. Doxycycline undergoes less binding to calcium than do other tetracyclines, and may cause dental changes less frequently in children. Streptomycin and gentamicin are aminoglyco-side antibiotics that have to be administered par-enterally; theymaycause irreversible cochlear and vestibular damage. Hypersensitivity reactions are uncommon. In the context of a bioterrorist attack setting, they should be reserved for the therapy of patients with severe plague or tularemia. Oral agents are better choices for large-scale post-exposure prophylaxis. Biological terrorism should no longer be considered as a hypothetical danger; the threat is real, and public-health systems must be prepared for a rapid and efficacious response. In the case of bacterial biological weapons, B. anthracis, F. tularensis and Y. pestis are most likely to be implicated. Governments must endorse national plans for the detection, treatment and prevention of mass casualties due to these organisms. National stockpiles of doxycycline, fluoroquinolones and aminoglycosides are needed, and pharmaceutical manufacturers must be ready to produce sufficient quantitities of antimicrobials in the event of a massive bioterrorist attack. Personal stockpiling should be discouraged, in order to avoid misuse and shortage of antibiotics. The massive use of antimicrobials in this setting may eventually lead to an increase in the prevalence of resistant bacteria in the community. Recommendations and guidelines for the treatment and prevention of infections due to biological weapons must also take into account the cost, effectiveness and side-effects of the selected vaccines and antimicrobials.