Central Nervous System Antimicrobial Exposure and Proposed Dosing for Anthrax Meningitis.

BACKGROUND: The high mortality of systemic anthrax is likely a consequence of the severe central nervous system inflammation that occurs in anthrax meningitis. Effective treatment of such infections requires, at a minimum, adequate cerebrospinal fluid (CSF) antimicrobial concentrations. METHODS: We reviewed English medical literature and regulatory documents to extract information on serum and CSF exposures for antimicrobials with in vitro activity against Bacillus anthracis. Using CSF pharmacokinetic exposures and in vitro B. anthracis susceptibility data, we used population pharmacokinetic modeling and Monte Carlo simulations to determine whether a specific antimicrobial dosage would likely achieve effective CSF antimicrobial activity in patients with normal to inflamed meninges (ie, an intact to markedly disrupted blood-brain barrier). RESULTS: The probability of microbiologic success at achievable antimicrobial dosages was high (≥95%) for ciprofloxacin, levofloxacin (500 mg every 12 hours), meropenem, imipenem/cilastatin, penicillin G, ampicillin, ampicillin/sulbactam, doxycycline, and minocycline; acceptable (90%-95%) for piperacillin/tazobactam and levofloxacin (750 mg every 24 hours); and low (<90%) for vancomycin, amikacin, clindamycin, and linezolid. CONCLUSIONS: Prompt empiric antimicrobial therapy of patients with suspected or confirmed anthrax meningitis may reduce the high morbidity and mortality. Our data support using several ß-lactam-, fluoroquinolone-, and tetracycline-class antimicrobials as first-line and alternative agents for treatment of patients with anthrax meningitis; all should achieve effective microbiologic exposures. Our data suggest antimicrobials that should not be relied on to treat suspected or documented anthrax meningitis. Furthermore, the protein synthesis inhibitors clindamycin and linezolid can decrease toxin production and may be useful components of combination therapy.

Cost-effectiveness comparison of response strategies to a large-scale anthrax attack on the chicago metropolitan area: impact of timing and surge capacity.

Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality. However, there is uncertainty about the optimal cost-effective response strategy based on timing of intervention, public health resources, and critical care facilities. We conducted a decision analytic study to compare response strategies to a theoretical large-scale anthrax attack on the Chicago metropolitan area beginning either Day 2 or Day 5 after the attack. These strategies correspond to the policy options set forth by the Anthrax Modeling Working Group for population-wide responses to a large-scale anthrax attack: (1) postattack antibiotic prophylaxis, (2) postattack antibiotic prophylaxis and vaccination, (3) preattack vaccination with postattack antibiotic prophylaxis, and (4) preattack vaccination with postattack antibiotic prophylaxis and vaccination. Outcomes were measured in costs, lives saved, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We estimated that postattack antibiotic prophylaxis of all 1,390,000 anthrax-exposed people beginning on Day 2 after attack would result in 205,835 infected victims, 35,049 fulminant victims, and 28,612 deaths. Only 6,437 (18.5%) of the fulminant victims could be saved with the existing critical care facilities in the Chicago metropolitan area. Mortality would increase to 69,136 if the response strategy began on Day 5. Including postattack vaccination with antibiotic prophylaxis of all exposed people reduces mortality and is cost-effective for both Day 2 (ICER=$182/QALY) and Day 5 (ICER=$1,088/QALY) response strategies. Increasing ICU bed availability significantly reduces mortality for all response strategies. We conclude that postattack antibiotic prophylaxis and vaccination of all exposed people is the optimal cost-effective response strategy for a large-scale anthrax attack. Our findings support the US government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack. Future policies should consider expanding critical care capacity to allow for the rescue of more victims.

The social context shaping bioweapons (non)proliferation.

This article explores the practices behind the creation and transfer of knowledge related to biological weapons (BW) in the former Soviet BW program and their implications for understanding bioweapons proliferation. Using in-depth interviews collected for an ongoing oral history project of the Soviet and U.S. bioweapons programs, this article shows that BW proliferation is a complex issue that involves thus far unrecognized social factors that can shape the production and proliferation of bioweapons knowledge. The article highlights (1) the local and personal character of bioweapons knowledge, specialized skills, and scientific know-how, which cannot be transferred easily from one person to another and from one location to another; (2) the importance of organization and management style in creating certain types of knowledge and skills and allowing or preventing the transfer of those skills to occur within and outside an organization; and (3) the differences that exist among various groups of former Soviet BW facilities in their ability to efficiently transfer bioweapons knowledge and laboratory skills. The article concludes with a discussion on the policy implications of these findings and provides guidance for constructing and implementing a more consistent and rigorous set of targeted nonproliferation interventions to address facility-specific "brain-drain" threats involving former bioweaponeers.

Pharmacokinetic-pharmacodynamic assessment of faropenem in a lethal murine Bacillus anthracis inhalation postexposure prophylaxis model.

There are few options for prophylaxis after exposure to Bacillus anthracis, especially in children and women of childbearing potential. Faropenem is a beta-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have in vitro activity against B. anthracis strains that variably express the bla1 beta-lactamase (MIC range,

Uncertainty and operational considerations in mass prophylaxis workforce planning.

BACKGROUND: The public health response to an influenza pandemic or other large-scale health emergency may include mass prophylaxis using multiple points of dispensing (PODs) to deliver countermeasures rapidly to affected populations. Computer models created to date to determine "optimal" staffing levels at PODs typically assume stable patient demand for service. The authors investigated POD function under dynamic and uncertain operational environments. METHODS: The authors constructed a Monte Carlo simulation model of mass prophylaxis (the Dynamic POD Simulator, or D-PODS) to assess the consequences of nonstationary patient arrival patterns on POD function under a variety of POD layouts and staffing plans. Compared are the performance of a standard POD layout under steady-state and variable patient arrival rates that may mimic real-life variation in patient demand. RESULTS: To achieve similar performance, PODs functioning under nonstationary patient arrival rates require higher staffing levels than would be predicted using the assumption of stationary arrival rates. Furthermore, PODs may develop severe bottlenecks unless staffing levels vary over time to meet changing patient arrival patterns. Efficient POD networks therefore require command and control systems capable of dynamically adjusting intra- and inter-POD staff levels to meet demand. In addition, under real-world operating conditions of heightened uncertainty, fewer large PODs will require a smaller total staff than many small PODs to achieve comparable performance. CONCLUSIONS: Modeling environments that capture the effects of fundamental uncertainties in public health disasters are essential for the realistic evaluation of response mechanisms and policies. D-PODS quantifies POD operational efficiency under more realistic conditions than have been modeled previously. The authors' experiments demonstrate that effective POD staffing plans must be responsive to variation and uncertainty in POD arrival patterns. These experiments highlight the need for command and control systems to be created to manage emergency response successfully.

An ounce of prevention is worth a pound of cure: improving communication to reduce mortality during bioterrorism responses.

OBJECTIVE: To identify communication needs and evaluate the effectiveness of alternative communication strategies for bioterrorism responses. METHODS: We provide a framework for evaluating communication needs during a bioterrorism response. Then, using a simulation model of a hypothetical response to anthrax bioterrorism in a large metropolitan area, we evaluate the costs and benefits of alternative strategies for communication during a response. RESULTS: Expected mortality increases significantly with increases in the time for attack detection and announcement; decreases in the rate at which exposed individuals seek and receive prophylaxis; increases in the number of unexposed people seeking prophylaxis; and increases in workload imbalances at dispensing centers. Thus, the timeliness, accuracy, and precision of communications about the mechanisms of exposure and instructions for obtaining prophylaxis and treatment are critical. Investment in strategies that improve adherence to prophylaxis is likely to be highly cost effective, even if the improvement in adherence is modest, and even if such strategies reduce the prophylaxis dispensing rate. CONCLUSIONS: Communication during the response to a bioterror attack must involve the right information delivered at the appropriate time in an effective manner from trusted sources. Because the response system for bioterror communication is only fully operationalized once an attack has occurred, tabletop planning and simulation exercises, and other up-front investments in the design of an effective communication strategy, are critical for effective response planning.

Use of an in vitro pharmacodynamic model to derive a linezolid regimen that optimizes bacterial kill and prevents emergence of resistance in Bacillus anthracis.

Simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for > or =700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthracis without resistance selection. Linezolid at < or =600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at > or =500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthracis was predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (C(max))/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg x h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg x h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracis and prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.

Pharmacokinetics-pharmacodynamics of gatifloxacin in a lethal murine Bacillus anthracis inhalation infection model.

We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC of the drug for the organism (AUC(0-24)/MIC ratio) was the PK-PD measure most predictive of survival (R(2) = 0.96). The 50% effective dose (ED(50)) and the ED(90) and ED(99) corresponded to AUC(0-24)/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED(99)). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

Responding to a small-scale bioterrorist anthrax attack: cost-effectiveness analysis comparing preattack vaccination with postattack antibiotic treatment and vaccination.

BACKGROUND: In 2001, a small-scale bioterrorism-related anthrax attack was perpetrated via the US mail. The optimal future response may require strategies different from those required in a large-scale attack. METHODS: We conducted a cost-effectiveness analysis using Monte Carlo simulation during a 10-year time frame from a societal perspective to determine the optimal response strategy for a small-scale anthrax attack perpetrated against US Postal Service distribution centers in a large metropolitan area. Three strategies were compared: preattack vaccination of all US distribution center postal workers, postattack antibiotic therapy followed by vaccination of exposed personnel, and postattack antibiotic therapy without vaccination of exposed personnel. Outcome measures were costs, quality-adjusted life-years, and incremental cost-effectiveness. The probabilities for anthrax exposure and infection; vaccine and antibiotic benefits, risks, and costs; and associated clinical outcomes were derived from the medical literature and from bioterrorism experts. RESULTS: Postattack antibiotic therapy and vaccination of exposed postal workers is the most cost-effective response compared with other strategies. The incremental cost-effectiveness is $59 558 per quality-adjusted life-year compared with postattack antibiotic therapy alone. Preattack vaccination of all distribution center workers is less effective and more costly than the other 2 strategies. Assuming complete adherence to preattack vaccination, the incremental cost-effectiveness compared with postattack antibiotic therapy alone is almost $2.6 million per quality-adjusted life-year. CONCLUSION: Despite uncertainties about a future anthrax attack and exposure risk, postattack antibiotic therapy and vaccination of exposed personnel seems to be the optimal response to an attack perpetrated through the US Postal Service.

Screening for inhalational anthrax due to bioterrorism: evaluating proposed screening protocols.

Eleven known cases of bioterrorism-related inhalational anthrax (IA) were treated in the United States during 2001. We retrospectively compared 2 methods that have been proposed to screen for IA. The 2 screening protocols for IA were applied to the emergency department charts of patients who presented with possible signs or symptoms of IA at Inova Fairfax Hospital (Falls Church, Virginia) from 20 October 2001 through 3 November 2001. The Mayer criteria would have screened 4 patients (0.4%; 95% CI, 0.1%-0.9%) and generated charges of 1900 dollars. If 29 patients (2.6%; 95% CI, 1.7%-3.7%) with >or=5 symptoms (but without fever and tachycardia) were screened, charges were 13,325 dollars. The Hupert criteria would have screened 273 patients (24%; 95% CI, 22%-27%) and generated charges of 126,025 dollars. In this outbreak of bioterrorism-related IA, applying the Mayer criteria would have identified both patients with IA and would have generated fewer charges than applying the Hupert criteria.

Is it influenza or anthrax? A decision analytic approach to the treatment of patients with influenza-like illnesses.

STUDY OBJECTIVE: We analyze the risks and benefits of alternative treatment strategies for non-septic-appearing febrile patients with influenza-like illnesses and possible exposure to anthrax. METHODS: We used a decision analytic model to evaluate 6 testing and treatment strategies in an emergency department. Patients were non-septic-appearing and had influenza-like illnesses but low likelihood of exposure to anthrax. The following interventions were used: (1) no empiric antibiotics; (2) blood culture and treatment only if the result was positive; (3) rapid testing for influenza and, for those who tested negative, treatment with 60 days of ciprofloxacin; (4) a two-test strategy in which all patients were first tested for influenza; those who tested negative had a blood culture test and were treated empirically with ciprofloxacin for 3 days while waiting for blood culture results; (5) culture test for all patients and treatment with ciprofloxacin for up to 3 days while waiting for blood culture results; and (6) treatment of all patients with ciprofloxacin empirically for 60 days. Main outcome measures were deaths, complications from anthrax, adverse events from ciprofloxacin, and ciprofloxacin patient-days. RESULTS: For nonzero probabilities of anthrax, patient mortality was always lowest in the strategies in which all patients were treated empirically for anthrax either for 60 days or for 3 days pending blood culture results. These strategies, however, were associated with more morbidity (more ciprofloxacin patient-days and more antibiotic adverse events) than were strategies without empiric treatment. The numbers of adverse events and antibiotic patient-days were reduced substantially with the two-test strategy, in which patients with influenza were identified early and not treated. In general, for probabilities of anthrax equaling or exceeding 2%, treating all patients empirically for 60 days was best, but for probabilities between 0.1% and 2%, the sensitivity of blood culture for anthrax determined the optimal strategy: when the sensitivity exceeded 95%, a short course of empiric ciprofloxacin until blood culture results became available was best, but for sensitivities below 95%, more aggressive empiric antibiotics use was warranted. The proportion of patients with influenza in the community affected the choice of strategy, so that seasonal variation exists. CONCLUSION: During influenza season, our findings support rapid testing for influenza, followed by empiric treatment for anthrax pending blood culture results for those who test negative for influenza. Our results help to highlight the importance of developing rapid and sensitive tests for anthrax and of developing improved surveillance and methods to calculate the previous probability of attacks.

Bioterrorism: a new frontier for drug discovery and development.

Only a few years ago bioterrorism was considered a remote concern but today it has reached the forefront of the public imagination following recent terrorist attacks around the world. The disaster of September 11 2001, followed by anthrax letters sent via the US postal system, and now the renewed tension in the Middle East, have all brought the possibility of bioterrorism a little closer to reality. A number of biological agents could be used in a terrorist attack, including anthrax, botulinum, plague, smallpox, staphylococcal and streptococcal toxins, and the list of emerging pathogens is evolving rapidly. The serious diseases that these agents produce could cause considerable morbidity and mortality if used in a terrorist attack. This evolving threat presents the medical, public health and scientific communities with pressing challenges. The present research efforts in academia are primarily focused on the basic research on the pathogens that are considered to be bioweapons for terrorist attack. Thus, collaborative efforts between academic institutes, pharmaceutical industries and governmental agencies are warranted to translate basic research into drugs, vaccines and diagnostic tests. This review provides a brief overview of the threat from biological weapons and the current biodefense strategy to prevent and control outbreaks of diseases caused by intentional release of these bioweapons of mass destruction.