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To the Editor: We wish to provide the following factual corrections in response to the article by Dr Inglesby and colleagues¹ about anthrax as a biological weapon.

First, Inglesby et al state that there are no US Food and Drug Administration (FDA)–approved postexposure antibiotic regimens following exposure to a Bacillus anthracis aerosol. In fact, on August 30, 2000, the FDA approved ciprofloxacin for use in inhalational anthrax (postexposure) for both adults and children. (Inhalational anthrax postexposure is also referred to as anthrax postexposure prophylaxis [PEP].)

Second, the FDA and its Anti-infectives Advisory Committee have stated that the risk-benefit assessment for use of ciprofloxacin for inhalational anthrax PEP is such that it is presently recommended for use in children.² The members of the agency believe clinicians should be informed that ciprofloxacin is approved by the FDA for pediatric use in inhalational anthrax PEP. Specifically, the ciprofloxacin label states:

Safety and effectiveness in pediatric patients and adolescents less than 18 years of age have not been established, except for use in inhalational anthrax (post-exposure). . . . For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate.³

Andrea Meyerhoff, MD,MSc,DTMH
Office of the Commissioner

Dianne Murphy, MD
Center for Drug Evaluation and Research
US Food and Drug Administration Rockville, Md

1. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-2252. FREE FULL TEXT 2. Food and Drug Administration, Center for Drug Evaluation and Research, Anti-Infective Drugs Advisory Committee meeting [transcript]. July 28, 2000; Parklawn Building, Rockville, Md. Available at: http://www.fda.gov/ohrms/dockets/AC/CDER00.htm. Accessed May 14, 2002. Accessibility verfied September 13, 2002. 3. Cipro (ciprofloxacin hydrochloride) tablets, Cipro oral suspension, and Cipro IV for intravenous infusion [package insert]. West Haven, Conn: Bayer Corp; 2002.

To the Editor: Dr Inglesby and colleagues¹ emphasize the importance of prompt and appropriate antimicrobial therapy for inhalational anthrax.

I was concerned, however, that the authors did not recommend loading doses of antibiotics. Without a loading dose, serum levels do not reach a steady state until after several doses of the drug have been administered. For compartments such as infected lymph nodes and the mediastinum, effective concentrations would be even more difficult to achieve. This may be a particular problem for doxycycline, which has a half-life of 18 hours.² A loading dose of twice the standard intermittent dose should carry no more likelihood of toxicity than a regular dose and may be appropriate for ciprofloxacin as well.

Alan D. Tice, MD
Department of Infectious Diseases
John A. Burns School of Medicine
University of Hawaii
Honolulu

1. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-2252. FREE FULL TEXT 2. Fabre J, Milek E, Kalfopoulos P, et al. The kinetics of tetracyclines in man: digestive absorption and serum concentrations. In: Doxycycline (Vibramycin): A Compendium of Clinical Evaluation. New York, NY: Pfizer Laboratories: 1973:13-18.

In Reply: We appreciate the clarifications from Drs Meyerhoff and Murphy. The accompanying corrections clarify the status of FDA approval for specific medication indications and adjust the Working Group's recommended doses for 3 drugs used in the treatment or postexposure prophylaxis of anthrax. Although these corrections do not substantively change any of the key Working Group recommendations, they are important enough to warrant specific notice.

Meyerhoff and Murphy emphasize that ciprofloxacin has been approved by the FDA for both children and adults for postexposure prophylaxis for inhalational anthrax. They also state that the FDA has not approved any therapy specifically for the treatment of inhalational anthrax while "penicillin G procaine and doxycycline are both approved by the FDA for the treatment of disease due to B anthracis, as well as for anthrax PEP. Ciprofloxacin is only approved for "inhalational anthrax (postexposure)" and is not approved by the FDA for the treatment of inhalational anthrax." At this time, then, clinicians have no options that have been approved by the FDA for the treatment of inhalational anthrax. In the absence of FDA approval for any specific treatment for inhalational anthrax, clinicians must rely on other sources of guidance regarding treatment recommendations for this disease process.

Dr Tice recommends consideration of a loading dose of doxycycline and ciprofloxacin in the treatment of inhalational anthrax. We do not believe there is sufficient evidence to support changing our recommendations to include these recommendations. Tetracyclines exhibit persistent time-dependent bactericidal effects; the time above minimum inhibitory concentration (MIC) predicts therapeutic outcome.¹ Fluoroquinolone antibiotics, on the other hand, exhibit persistent concentration-dependent killing with persistent effects; the ratio of the area under the curve to the MIC predicts therapeutic outcome.² These factors are more important clinically than steady state levels of these drugs. In addition, we are aware of no information that suggests improvement in clinical outcome using loading doses of these classes of antibiotics, and the therapeutic efficacy of the standard recommended dosing regimen for these antibiotics (the same regimens that appear in our consensus paper) have been demonstrated in numerous clinical settings. Until more data regarding improvement in clinical outcomes following the use of loading doses for these antimicrobials exists, we are reluctant to propose any changes in the guidelines.

Thomas Inglesby, MD; Tara O'Toole, MD,MPH
Johns Hopkins Center for Civilian Biodefense Strategies
Baltimore, Md

1. Craig W. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-10. ISI | PUBMED 2. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993;37:1073-10781. FREE FULL TEXT

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2002;288:1848-1849.

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