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CDC Publishes Report on Meeting of Experts to Update Guidelines for Management of Anthrax

By Luciana Borio, M.D., and John G. Bartlett, M.D., April 14, 2008

A little over two years ago, on March 13-14, 2006, the Centers for Disease Control and Prevention (CDC), in collaboration with the Southeastern Center for Emerging Biologic Threats, convened approximately 40 subject matter experts for a meeting in Atlanta to “review research developments and clinical experience with anthrax prophylaxis and treatment and to make consensus recommendations for updating guidelines for PEP (postexposure prophylaxis), treatment, and clinical evaluation of patients with anthrax.”1

The journal Emerging Infectious Diseases recently published a conference report1 summarizing the meeting’s presentations, discussions, and consensus recommendations (the authors indicate that updated CDC guidelines are forthcoming). Summarized below are key findings regarding PEP, treatment, and screening of patients. The major changes discussed in the meeting related to the treatment of severe anthrax disease are: 1) the preference given to ciprofloxacin over doxycycline, as concomitant meningitis should be suspected in all patients and ciprofloxacin has better meningeal penetration; and 2) the emphasis on “early and aggressive” drainage of pleural effusions in all patients.

Postexposure Prophylaxis for Inhalation Anthrax

For PEP following presumed exposure to aerosolized B. anthracis, CDC currently recommends 60 days of oral antibiotics in combination with a 3-dose series of anthrax vaccine adsorbed (AVA) BioThrax (BioPort Corporation, Lansing, MI, USA), administered at time zero, 2 weeks, and 4 weeks.2 AVA is not currently approved by the FDA for PEP and would have to be administered under an Investigational New Drug (IND) protocol or an Emergency Use Authorization (EUA) in a declared emergency.

Choice of Antibiotic for PEP

Ciprofloxacin, doxycycline, and penicillin G procaine are FDA-approved for "inhalational anthrax (postexposure)" in all age groups,3 and meeting participants thought that ciprofloxacin and doxycycline were equivalent first-line antimicrobial agents for PEP, with similar safety, efficacy, and tolerability profiles.4,5

Levofloxacin is FDA-approved for "inhalational anthrax (postexposure)" in adults 18 years of age and older.6 However, because safety data on extended use (greater than 28 days) is limited, it should be reserved as a second-line agent for prophylaxis.

Antimicrobial resistance must be considered for the following reasons: variable β-lactam resistance, especially to the cephalosporins, has been identified among naturally occurring B. anthracis isolates;7-9 in  2001, isolates had both cephalosporinase and penicillinase enzymes;10 and resistance to a number of antimicrobial classes (eg, fluoroquinolones, tetracyclines) can be induced in vitro.11-14

Therefore, the EID report notes that “Penicillins should not be initially used for PEP of anthrax, due to concern for penicillin resistance, which has been found in naturally occurring isolates . . . Amoxicillin can be used for PEP once the B. anthracis strain has been proven penicillin susceptible, when other antimicrobial agents are not considered safe to use, such as for pediatric patients and for nursing or pregnant women. However, amoxicillin is not FDA-approved for this indication, and this use is considered ‘off-label.’”1

Duration of Prophylaxis Regimen

Meeting participants considered whether a shortened course of antimicrobial therapy plus a 3-dose AVA series would be effective. A study conducted at USAMRIID showed that all nonhuman primates challenged to a large dose of anthrax spores (approximately 1,600 LD50) that received a 14-day PEP course of ciprofloxacin combined with 3 AVA doses survived.15 However, the group opted to keep the current recommendation of a 60-day course of antimicrobial therapy combined with the 3-dose AVA series for the following reasons:

  • lack of well-defined serologic correlates of protection to demonstrate that AVA vaccination has conferred adequate protective immunity in a person receiving PEP

  • lack of human clinical trial data supporting a reduction in the duration of antimicrobial PEP

  • small number of study participants fail to seroconvert following vaccination with AVA (CDC, unpublished data).1

Screening Guidelines

Screening algorithms for inhalational anthrax (IA) are useful in identifying infected patients during an event, either in the setting of appropriate epidemiologic data or clinical presentation. However, clinicians should be cognizant of the limited specificity and sensitivity of current algorithms. Neither the original CDC guidelines16 nor the proposed Inova Fairfax guidelines17 would have detected the solitary 2006 IA case.18 It should also be noted that current guidelines are not applicable to pediatric patients.

Clinicians considering IA as a differential diagnosis should alert hospital microbiology staff of their suspicions and obtain blood cultures before initiating antimicrobial treatment.

Thoracic imaging is an important tool. Studies were abnormal in all 11 of the IA cases from 2001 (8/11 with widened mediastinum; 9/11 with pleural effusions; and 7/11 with pulmonary infiltrates). However, initial thoracic radiographs are not as sensitive as computerized tomography and might miss the classic findings associated with inhalational anthrax during earlier stages of disease.

Treatment

Severe Disease, including Inhalation and Gastrointestinal Anthrax, Anthrax Meningitis, and Bacteremia

The following revisions to CDC treatment protocols for IA and serious systemic illness from anthrax were recommended by meeting participants:

  • Clinical or subclinical meningitis in patients with IA is likely and should be suspected in all patients with inhalational or systemic anthrax. Although only 1 of the 11 IA case-patients in 2001 had confirmed meningitis, 4 others had symptoms suggesting meningeal involvement, which could not be ruled out as the cerebrospinal fluid was not examined.

    • Thus, for the treatment of severe anthrax disease, IV ciprofloxacin, or other fluoroquinolones with a similar spectrum of activity and central nervous system (CNS) penetration, are recommended over doxycycline as the primary antimicrobial agent (unless ciprofloxacin use is contraindicated). Central nervous system penetration of ciprofloxacin in the presence of meningeal inflammation is much higher than the poor CNS penetration of doxycycline.19

    • At least 1 or more additional antibiotics with adequate CNS penetration and expected in vitro activity against B. anthracis (eg, ampicillin or penicillin, meropenem, rifampin, or vancomycin) should be used in the treatment of systemic cases of anthrax regardless of clinical suspicion of meningeal involvement.

    • The use of corticosteroids as an adjunct to antibiotic therapy may be of benefit in the setting of anthrax meningitis,19 but there are no data from controlled clinical trials.

  • Clindamycin is recommended for inclusion in the therapeutic regimen because of its ability to inhibit protein synthesis, theoretically reducing exotoxin production.

  • Antibiotics should be continued for 60 days, with adjustment of the regimen based on the clinical course of the disease in the patient.10

  • Early and aggressive pleural fluid drainage is recommended for all patients with IA.

Bioterrorism-related Cutaneous Anthrax

  • For localized or uncomplicated cases, oral ciprofloxacin or doxycycline is recommended for initial treatment, and amoxicillin may be used to complete the regimen if the strain is susceptible.

  • Patients with cutaneous anthrax and signs of systemic involvement, extensive edema, or lesions of the head or neck should be treated with IV ciprofloxacin and additional antibiotics, as recommended for IA and severe disease. When clinically appropriate, patients could be switched to oral antibiotics to complete a 60-day course.

  • Participants thought that, given the concomitant risk of aerosol exposure in patients with bioterrorism-related cutaneous anthrax, those patients should receive a full 60-day course of PEP. However, this is a matter of debate since some thought that such a prolonged course is unnecessary given the protective immune response generated to cutaneous anthrax.

Immunotherapeutics

Human-derived anthrax immune globulin (AIG) was part of the successful treatment of the 2006 IA case-patient administered under an emergency IND protocol.18 Data were insufficient to develop general recommendations for its use. It should be considered for severely ill patients and for those who fail to improve with standard antimicrobial therapy; CDC will continue to offer AIG under emergency IND on a case-by-case basis.

Special Populations

Pregnant Women

  • Ciprofloxacin is recommended as the first-line oral antimicrobial agent for PEP or treatment of anthrax during pregnancy.20

  • Doxycycline should not be used for PEP or treatment during pregnancy except in the third trimester.

  • For susceptible isolates, transition to amoxicillin for PEP is recommended.

  • AVA should be included in the PEP protocol for pregnancy if there is strong evidence of risk for IA as the benefit is likely to outweigh risks of vaccination. According to the report, “Although the Department of Defense has published safety data on AVA during pregnancy, the statistical power of the study was limited.”21

Children

  • Treatment of BT-related anthrax in pediatric patients should be consistent with recommendations for adults (ie, ciprofloxacin preferred for severe disease, ciprofloxacin or doxycycline as the first-line oral antimicrobial agent for PEP, and amoxicillin as an alternative when the isolate involved is susceptible to penicillin).
  • However, anthrax vaccination cannot be recommended because safety and efficacy data are lacking.

Conclusions

  1. The major changes to the recommendations are the preferential use of ciprofloxacin over doxycycline in the treatment of severe anthrax disease in order to treat potential concomitant meningitis, and the emphasis on pleural effusion drainage.

  2. Further discussions on whether shortening the course of antibiotics if used along with vaccine in the postexposure prophylaxis of anthrax is warranted since supplies might be limited in a large-scale attack. The data generated by Vietri and colleagues in nonhuman primates15 is compelling. An epidemiologic study involving exposure to anthrax in the U.S. Capitol in 2001 revealed that anthrax spores primed antibody and cellular immune responses in a dose-dependent manner, which enhanced the response to vaccination.22 Together, these two studies suggest that in the event of a large-scale bioterrorism attack employing anthrax spores, an abbreviated postexposure regimen of antibiotics plus vaccination would be effective in preventing illness. If the vaccine supply is inadequate, then the longer course of antibiotics is appropriate.

  3. Continuing antibiotics for 60 days after cutaneous anthrax seems overcautious given the immune response generated, and such recommendation should be critically reviewed given growing evidence that prolonged and unnecessary administration of antibiotics is not without harm.23

References

  1. Stern EJ, Uhde KB, Shadomy SV, Messonnier N. Conference report on public health and clinical guidelines for anthrax [conference summary]. Emerg Infect Dis 2008;14. http://www.cdc.gov/eid/content/14/4/e1.htm. April 7, 2008.

  2. Centers for Disease Control and Prevention. Use of anthrax vaccine in response to terrorism: supplemental recommendations of the Advisory Committee on Immunization Practices. MMWR 2002;51:1024-6.

  3. Department of Health and Human Services. Food and Drug Administration. Prescription drug products: doxycycline and penicillin G procaine administration for inhalational anthrax (postexposure). Fed Register 2001;66(213)55679-82.

  4. Friedlander AM, Welkos SL, Pitt ML, et al. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis 1993;167:1239-43.

  5. Tierney BC, Martin SW, Franzke LH, et al. Serious adverse events among participants in the Centers for Disease Control and Prevention’s anthrax vaccine and antimicrobial availability program for persons at risk for bioterrorism-related inhalational anthrax. Clin Infect Dis 2003;37:905-11.

  6. Levaquin (Levofloxacin) [package insert]. Titusville, NJ: Ortho-McNeil Pharmaceutical; 2004.

  7. Doganay M, Aydin N. Antimicrobial susceptibility of Bacillus anthracis. Scand J Infect Dis 1991;23:333-5.

  8. Lightfoot N, Scott R, Turnbull B. Antimicrobial susceptibility of Bacillus anthracis. Salisbury Med Bull 1990;68 (Special Suppl):95-8.

  9. Turnbull PC, Sirianni NM, LeBron CI, et al. MICs of selected antibiotics for Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis, and Bacillus mycoides from a range of clinical and environmental sources as determined by the Etest. J Clin Microbiol 2004;42:3626-34.

  10. Centers for Disease Control and Prevention. Update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy. October 2001. MMWR 2001;50:909-19.

  11. Athamna A, Athamna M, Abu-Rashed N, et al. Selection of Bacillus anthracis isolates resistant to antibiotics. J Antimicrob Chemother 2004;54:424-8.

  12. Price LB, Vogler A, Pearson T, et al. In vitro selection and characterization of Bacillus anthracis mutants with high-level resistance to ciprofloxacin. Antimicrob Agents Chemother 2003;47:2362-5.

  13. Brook I, Elliott TB, Pryor HI, et al. In vitro resistance of Bacillus anthracis Sterne to doxycycline, macrolides and quinolones. Int J Antimicrob Agents 2001;18:559-62.

  14. Choe CH, Bouhaouala SS, Brook I, et al. In vitro development of resistance to ofloxacin and doxycycline in Bacillus anthracis Sterne. Antimicrob Agents Chemother 2000;44:1766.

  15. Vietri NJ, Purcell BK, Lawler JV, et al. Short-course postexposure antibiotic prophylaxis combined with vaccination protects against experimental inhalational anthrax. Proc Natl Acad Sci U S A 2006;103:7813-6.

  16. Centers for Disease Control and Prevention. Update: Investigation of bioterrorism-related anthrax and interim guidelines for clinical evaluation of persons with possible anthrax. MMWR 2001;50:941-8.

  17. Mayer TA, Morrison A, Bersoff-Matcha S, et al. Inhalational anthrax due to bioterrorism: would current Centers for Disease Control and Prevention guidelines have identified the 11 patients with inhalational anthrax from October through November 2001? Clin Infect Dis 2003;36:1275-83.

  18. Walsh JJ, Pesik N, Quinn CP, et al. A case of naturally acquired inhalation anthrax: clinical care and analyses of anti-protective antigen immunoglobulin G and lethal factor. Clin Infect Dis 2007;44:968-71.

  19. Sejvar JJ, Tenover FC, Stephens DS. Management of anthrax meningitis. Lancet Infect Dis 2005;5:287-95.

  20. American College of Obstetricians and Gynecologists. ACOG Committee on Obstetric Practice. ACOG committee opinion number 268, February 2002: management of asymptomatic pregnant or lactating women exposed to anthrax. Obstet Gynecol 2008;99:366-8.

  21. Wiesen AR, Littell CT. Relationship between prepregnancy anthrax vaccination and pregnancy and birth outcomes among US Army women. JAMA 2002;287:1556-60.

  22. Doolan DL, Freilich DA, Brice GT, et al. The US capitol bioterrorism anthrax exposures: clinical epidemiological and immunological characteristics. J Infect Dis 2007;195:174-84.

  23. Rice LB. The Maxwell Finland Lecture: for the duration-rational antibiotic administration in an era of antimicrobial resistance and clostridium difficile. Clin Infect Dis 2008;46:491-6.