Peter Q. Eichacker

Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis

Dr. Charles Natanson (Critical Care Medicine Department, Clinical Center, National Institutes of Health [NIH], Bethesda, Maryland): Sepsis and septic shock are heterogeneous clinical syndromes that can be triggered by many microorganisms, including gram-negative bacteria, gram-positive bacteria, and fungi [1-3]. Participants in a recent consensus conference tried to define sepsis and septic shock. Sepsis was characterized as a systemic response to infection manifested by tachycardia, tachypnea, change in temperature, and leukopenia or leukocytosis. Septic shock was defined as severe sepsis accompanied by hypotension [4]. However, patients with sepsis may have one or several signs and symptoms, and no single physiologic or laboratory parameter can universally identify this syndrome. Advances in molecular biology and immunology during the past decade have increased our understanding of the pathogenesis of septic shock (Figure 1). In particular, we now believe that the hosts inflammatory response to infection contributes substantially to the development of septic shock [5-7]. Infections begin when microorganisms circumvent or penetrate host barriers such as skin and mucosa. Depending on the infecting agents virulence and the patients immunocompetence, local host defenses may be overwhelmed, resulting in microbial invasion of the bloodstream. Toxic bacterial products present in the circulation activate systemic host defenses, including plasma factors (complement and clotting cascades) and cellular components (neutrophils, monocytes, macrophages, and endothelial cells). In turn, activated cells produce potentially toxic host mediators (cytokines such as tumor necrosis factor [TNF] and interleukin-1 [IL-1], kinins, eicosinoids, platelet-activating factor, and nitric oxide) that augment the inflammatory response. This escalating immune response, in concert with microbial toxins, can lead to shock, multiple organ failure, and death. Figure 1. The pathogenesis and treatment of septic shock. Standard sepsis treatment strategies include use of antibiotics to kill invading bacteria, surgical procedures to eradicate the nidus of infection, and intensive life-support procedures such as dialysis, mechanical ventilation, and use of vasoactive drugs. Despite these approaches, the mortality rate from septic shock is high, ranging from 25% to 75% [1, 8-12]. In addition, the reported incidence of sepsis syndrome in U.S. hospitals increased 139%, from 73.6 to 175.9 per 100 000 persons discharged between 1979 and 1987 [13]. This increase may be caused by several medical trends: improved life-support technology that keeps patients who have a high risk for infection alive at the extremes of age; increased use of invasive medical procedures; advances in cancer chemotherapy and immunotherapy; and the prevalence of acquired immunodeficiency syndrome. The increasing incidence of sepsis and its high mortality rate have mobilized a search for new therapies. Development of new drugs to treat sepsis has been based in part on the premise that neutralizing bacterial toxins and potentially harmful host mediators could stop or slow this syndrome. The discussants in this conference review several of these new therapies that are directed at different elements of the inflammatory cascade, including a bacterial toxin (endotoxin), host proteins that mediate the inflammatory response (TNF and IL-1), an inflammatory cell (the neutrophil), and a low-molecular-weight messenger (nitric oxide) that causes hypotension. Other targets (eicosinoids, platelet-activating factor, bradykinin, and so on) are being evaluated to treat this syndrome. Each target selected for discussion was studied in our laboratories or evaluated in human clinical trials. Each discussant offers unique insight into the pathogenesis of septic shock and into the difficulties inherent in inhibiting a potentially toxic inflammatory mediator that may also play a role in host defense. Antiendotoxin Therapies in Septic Shock Dr. William D. Hoffman (Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland): The outer membrane of gram-negative bacteria contains lipopolysaccharides called endotoxin [14]. Endotoxin induces an inflammatory response that may protect the host from infection but may also cause multiple-organ failure and death when present in excess amounts. Specific immunochemical properties have been associated with different components of the endotoxin molecule. The O-polysaccharide chain (O-side chain) of endotoxin is exposed on the outside surface of gram-negative bacteria. The O-side chain is not toxic when injected into animals and has a molecular structure that varies among gram-negative bacteria. The core sugar and lipid A regions of endotoxin are embedded deeply in the outer bacterial membrane, and their molecular structures are similar for all gram-negative bacteria. In contrast to the O-side chain, lipid A is toxic when given to animals [14]. Effects of Endotoxin Challenge-Endotoxemia in Sepsis Experimental observations have supported and challenged the concept that endotoxin-directed therapies can benefit patients with septic shock. Reversible organ dysfunction and hemodynamic changes that are qualitatively similar to those seen in patients with septic shock develop in animals injected with endotoxin [15] and healthy human volunteers injected with safe doses of endotoxin [16]. In addition, development of endotoxemia in patients with septic shock has been associated with severe organ damage [9]. However, neither induced tolerance to endotoxin in humans [17] nor genetic resistance to endotoxin in mice [18] is protective during gram-negative infections. In addition, increased sensitivity to endotoxin does not alter the course of gram-negative infection in animals [19]. Finally, endotoxin and endotoxemia are not necessary to produce the septic shock syndrome, and endotoxin may be only one of many bacterial products that can trigger the septic response [3, 15]. Approaches to Antiendotoxin Therapy Although no antiendotoxin therapy is in clinical use, several are being investigated (Table 1). Antibodies to the O-side chain produce serotype-specific [20], complement-dependent bactericidal activity [21]. However, serotype specificity limits the clinical utility of O-side chain therapies because treating patients empirically with an effective dose of antibody for every probable infecting bacterial strain would be difficult. This problem led to investigation of antibodies directed at core and lipid A structures of endotoxin, because these antibodies might cross-protect against diverse gram-negative bacteria [22]. Although core or lipid A antibodies were thought to mediate antiendotoxin [23] or endotoxin-clearing effects [24], the function of these antibodies is unknown and controversial [25-28]. Nevertheless, core-directed antibodies are the only antiendotoxin therapies studied in clinical trials. Other antiendotoxin agents listed in Table 1 may reduce the host inflammatory response by directly neutralizing endotoxin, increasing its clearance, antagonizing its effects on host cells, or inducing tolerance. Controlled therapeutic trials of agents that reduce the bioactivity of endotoxin and have no antibacterial effect may determine whether circulating endotoxin is a useful therapeutic target in septic shock. Table 1. Approaches to Antiendotoxin Therapies for Septic Shock* Polyclonal Antibodies Directed at Core Epitopes and Lipid A The first clinical trial of core-directed antibodies studied patients with gram-negative bacteremia treated with control (n = 100) or J5 antiserum (n = 91) [8]. In that study, 21 of 39 patients with localized gram-negative infection but no bacteremia were included in the gram-negative bacteremia group because they had been given appropriate antibiotics before blood cultures were obtained [8]. The sepsis-related mortality rate for patients with gram-negative bacteremia given J5 antiserum was 22% (compared with 39% with control serum). In a subgroup of patients who required vasopressor drugs for more than 6 hours, the mortality rate was 44% (compared with 77% with control serum). The effect of J5 antiserum on mortality from all causes or in patients with gram-negative infection was not reported [8]. Five subsequent clinical trials (Table 2) using polyclonal core-reactive antiserum or immunoglobulin to prevent or treat gram-negative sepsis showed essentially no survival benefit [29-34]. Table 2. Summary of 10 Clinical Trials with Lipopolysaccharide Core-Directed Antibodies* Monoclonal Antibodies Directed at Core Epitopes and Lipid A: E5 and HA-1A Monoclonal antibodies were developed to produce a more specific antiendotoxin therapy with less risk for transmission of infection. E5, a murine IgM, protected mice injected with bacteria [35], and HA-1A, a human IgM, protected mice and rabbits injected with bacteria [36]. However, E5 did not protect sheep given endotoxin [37], and other researchers subsequently could not reproduce the beneficial effects of HA-1A in mice and rabbits [38]. E5 Clinical Trials E5 was tested in two multicenter, randomized, placebo-controlled clinical trials (Table 2). In the first trial of 468 patients, E5 provided no significant benefit to patients with gram-negative infection. The antibody improved survival in a retrospectively identified subgroup of 137 patients with gram-negative infection without refractory shock (30% compared with 43%; P = 0.01) [39]. A second trial of 847 patients was conducted to confirm this favorable effect (Table 2). However, in the second study, E5 did not significantly improve survival in the 530 patients who had gram-negative infection without refractory shock (E5, 30% mortality compared with control, 26%; P = 0.21) [40]. Using a meta-analysis and combining data from the two trials, researchers found that E5 substantially decreased the time to recovery from organ dysfunction and improv

Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose

Despite effective antibiotics, septic shock remains the most common cause of death in the intensive care unit, incurring a mortality rate of 30% to 50% (1, 2). Several therapies targeting the upregulated inflammatory pathways of sepsis have been studied to improve survival. However, few therapies have proven beneficial (3-10). In the 1960s, preclinical studies reported that high doses of glucocorticoids in models of Escherichia coli and endotoxic shock improved survival. These studies prompted the initiation of human sepsis trials (11-13). Subsequently, more than 50 human trials have examined the role of high-dose steroid therapy in sepsis. These trials administered doses of methylprednisolone as high as 30 to 120 mg/kg of body weight over 24 hours. Because the reported results of these trials were inconsistent, there was little consensus on the appropriate use of steroids in patients with septic shock. To clarify the treatment effects of high-dose steroids, 3 meta-analyses performed in the 1990s examined the more rigorously conducted randomized, controlled clinical trials of sepsis (7, 14, 15). The meta-analysis by Lefering and colleagues (14) incorporated 10 trials and found no overall beneficial effect of glucocorticoid therapy on mortality in septic patients (absolute difference in mortality rates between treatment and control groups, 0.2 percentage point [95% CI, 9.2 percentage points to 8.8 percentage points]). A second meta-analysis by Cronin and colleagues (15) examined 9 trials with variable effects (P= 0.02) and reported no evidence of a beneficial effect of high-dose steroids on mortality from sepsis (relative risk for death with treatment, 1.13 [CI, 0.99 to 1.29]). A third meta-analysis, performed by our group (7), examined the trials included in the previous meta-analyses. Nine trials, which were the same as those investigated by Cronin and colleagues (15), met inclusion criteria for that analysis (7). In this group of trials, we identified 1 study (16) as a statistical outlier that accounted for the variability reported by Cronin and colleagues. After exclusion of this outlier, our analysis revealed a homogenous group of 8 studies (P> 0.2) that demonstrated an overall increase in mortality associated with the use of high-dose steroids in septic patients (odds ratio of survival with treatment, 0.70 [CI, 0.55 to 0.91]; P= 0.008) (7). The increased mortality in these studies may have been due to the immunosuppressive effects of steroids, which led to more severe secondary infections (17-19). In response to these overall discouraging results, the use of high-dose glucocorticoids in septic patients decreased in the late 1980s and 1990s. Recently, interest in examining the role of the adrenal axis in sepsis has been renewed. Briegel and colleagues (20) reported that septic patients have an attenuated response to corticotropin stimulation testing during their acute illness. Furthermore, Annane and colleagues (21) demonstrated that a high cortisol level and an attenuated response to corticotropin stimulation indicate relative adrenal insufficiency during sepsis that may increase mortality. On the basis of these findings, several clinical trials have been performed to determine whether administering glucocorticoids in dosages similar to the amount produced physiologically during a stressful state (that is, 300 mg of cortisol per day) affects outcome in septic patients. We performed the current study to update our previous meta-analysis and compare recent clinical trials with previous clinical trials of steroid use in patients with sepsis (22). Methods Literature Search We searched MEDLINE for medical literature published from 1988 to December 2003 by using the following keywords: steroids and sepsis, steroids and septic shock, glucocorticoids and sepsis, glucocorticoids and septic shock, corticosteroids and sepsis, and corticosteroids and septic shock. Studies were included if they met all of the following criteria: randomized, controlled trial design; enrollment of adult patients who met criteria for sepsis or septic shock; and a primary end point, including either the discontinuation of vasopressor therapy or a change in survival comparing glucocorticoid treatment with a control group with or without placebo. Included studies must have administered similar treatments to both the control and steroid groups, with the exception of the administration of a predetermined glucocorticoid regimen. Criteria for sepsis or septic shock needed to be clearly defined in each study and be consistent with the American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference (23) definition for sepsis (including documented site or strong suspicion of infection, temperature > 38 C or < 36 C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min, and leukocyte count > 12 109 cells/L), severe sepsis (sepsis plus organ dysfunction; hypotension or hypoperfusion, including oliguria, altered mental status, or lactate acidosis), and septic shock (hypotension despite fluid resuscitation plus hypoperfusion abnormalities) (23). Data Collection Two investigators trained in critical care medicine independently reviewed the included studies by using a standardized protocol and data collection form. A third author trained in critical care medicine evaluated and resolved discrepancies. We collected data on patient characteristics, study characteristics, treatment interventions, and treatment outcomes. Abstracted data included the presence of sepsis, severe sepsis, or septic shock; type, dose, and duration of glucocorticoid administered; incidence and severity of secondary infections; response to corticotropin stimulation testing; the number of patients with shock reversal; and the number of patient deaths. We evaluated the quality of the included trials by assessing the method and adequacy of randomization, blinding protocols, completeness of follow-up, adherence to treatment protocols, and co-interventions or treatments to each group in the studies. Our primary goal was to compare the effect of glucocorticoid administration on survival in the recent studies with the effects reported in the previously analyzed trials (22). Since the glucocorticoid regimen differed among the trials, we converted all dosages to hydrocortisone equivalents (24). Statistical Analysis Survival data were analyzed by using a Cochran-Mantel-Haenszel test to estimate the pooled effect of steroids (25). The similarity of the effect across studies was assessed by using a Breslow-Day test and reported with an I2 value (26, 27). When statistically significant heterogeneity of treatment effects was observed, studies were partitioned (for example, early vs. late studies) to decrease the heterogeneity of studies in a particular partition and increase the differences among the partitions, which can be seen when the I2 value is substantially lower in each partition as compared with the overall I2 value (28). One study increased the I2 value substantially in the set of early studies and was removed from all subsequent analyses. Partitioning variables were determined by regressing study characteristics (for example, steroid dose in first 24 hours) on mortality, specifically the log relative survival benefit (29). Regression was performed by using an inverse-variance-weighted restricted maximum likelihood random-effects method. When the regression was performed by using log steroid dose in the first 24 hours as the independent variable, 1 study was observed to be both a statistical outlier and influential. An indicator variable for this study was included in the regression analysis. Similar estimates of the slope associated with the effect of log steroid dose in the first 24 hours were observed when the influential study was removed and for early and late studies separately. A regression analysis that included control group mortality rate as an additional independent variable did not change the relationship between steroid dose in the first 24 hours and relative survival benefit. All pooled relative survival benefits are reported with associated 95% CIs by using a fixed-effects model. Random-effects estimates of survival were also calculated and reported. Statistically significant differences in characteristics between early and late studies were assessed by using analysis of variance (ANOVA) (when a weighted analysis was needed) or a 2-sample Wilcoxon test (when an unweighted analysis was performed). To analyze the different types of severity of illness scores used in the studies, we computed an effect size for each. This effect size was calculated by determining the difference between the mean steroid severity score and the mean control severity score, divided by the control standard deviation in each study. Role of the Funding Sources The Warren G. Magnuson Clinical Center at the National Institutes of Health, Bethesda, Maryland, provided intramural funds for this study. The funding source played no role in the design, conduct, or reporting of the study or decision to submit the manuscript for publication. Data Synthesis Comparison of Study Methods Since 1988, more than 1300 articles on steroids and sepsis have been published. Five randomized, controlled trials, all published after 1997, met inclusion criteria and were included in our analysis (30-34) (Figure 1). Four of these studies were published manuscripts, and 1 study was reported in abstract form (33). Figure 1. Flow diagram of the published articles evaluated for inclusion in this meta-analysis. The 5 studies published after 1997 were randomized, double-blind, placebo-controlled trials (Table 1). Each study listed specific inclusion and exclusion criteria that were consistent with American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference definitions of sepsis and septic shock (23). Each study used a severity of illness score (Simplified Ac

Bundled care for septic shock: An analysis of clinical trials

Context: Sepsis bundles have been developed to improve patient outcomes by combining component therapies. Valid bundles require effective components with additive benefits. Proponents encourage evaluation of bundles, both as a whole and based on the performance of each component. Objective: Assess the association between outcome and the utilization of component therapies in studies of sepsis bundles. Data Source: Database searches (January 1980 to July 2008) of PubMed, Embase, and the Cochrane Library, using the terms sepsis, bundles, guidelines, and early goal directed therapy. Data Extraction: Inclusion required comparison of septic adults who received bundled care vs. nonprotocolized care. Survival and use rates for individual interventions were abstracted. Main Results: Eight unblinded trials, one randomized and seven with historical controls, were identified. Sepsis bundles were associated with a consistent (I2 = 0%, p = .87) and significant increase in survival (odds ratio, 1.91; 95% confidence interval, 1.49–2.45; p < .0001). For all studies reporting such data, there were consistent (I2 = 0%, p ≥ .64) decreases in time to antibiotics, and increases in the appropriateness of antibiotics (p ≤ .0002 for both). In contrast, significant heterogeneity was seen across trials for all other treatments (antibiotic use within a specified time period; administration of fluids, vasopressors, inotropes, and packed red blood cells titrated to hemodynamic goals; corticosteroids and human recombinant activated protein C use) (all I2 ≥ 67%, p < .002). Except for antibiotics, sepsis bundle components are still being investigated for efficacy in randomized controlled trials. Conclusion: Bundle use was associated with consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain. However, this analysis should be interpreted cautiously as these studies were unblinded, and only one was randomized.

Randomization in clinical trials of titrated therapies: unintended consequences of using fixed treatment protocols.

Objective:Clinical trial designs that randomize patients to fixed treatment regimens may disrupt preexisting relationships between illness severity and level of therapy. The practice misalignments created by such designs may have unintended effects on trial results and safety. Methods:To illustrate this problem, the Transfusion Requirements in Critical Care (TRICC) trial and the Acute Respiratory Distress Syndrome Network low tidal volume (ARMA) trial were analyzed. Results:Publications before TRICC indicated that clinicians used higher transfusion thresholds in patients with ischemic heart disease compared with younger, healthier patients (p = .001). The trial, however, randomized patients (n = 838) to liberal (10 g/dL hemoglobin) or restrictive (7 g/dL) transfusion thresholds. Thirty-day mortality was different and opposite in the liberal compared with the restrictive arm depending on presence (21 vs. 26%) or absence (25 vs. 16%) of ischemic heart disease (p = .03). At baseline in ARMA, consistent with prior publications, physicians set ventilator volumes lower in patients with high airway pressures and poor compliance (8.4–10.6 mL/kg interquartile range) than patients with less severe abnormalities (9.6–12 mL/kg) (p = .0001). In the trial, however, patients (n = 861) were randomized to low (6 mL/kg) or high (12 mL/kg) tidal volumes. In patients with low compliance (<0.6 mL/kg), 28-day mortality was higher when tidal volumes were raised rather than lowered (42 vs. 29%), but this effect was reversed in patients with higher compliance (21 vs. 37%; p = .003). Conclusions:In TRICC and ARMA, randomization to fixed treatment regimens disrupted preexisting relationships between illness severity and therapy level. This created noncomparable subgroups in both study arms that received care different and opposite from titrated care, that is, practice misalignments. These subgroups reduced the interpretability and safety of each trial. Characterizing current practice, incorporating current practice controls, and using alternative trial designs to minimize practice misalignments should improve trial safety and interpretability.

Mechanical ventilation in ARDS: One size does not fit all.

In this issue of Critical Care Medicine, Dr. Kallet and colleagues (1) report a significant improvement in mortality in patients with adult respiratory distress syndrome (ARDS) and acute lung injury (ALI) who received lung protective ventilation based on the recommendations of the ARDS Network trial

Neutrophil and endothelial cell interactions in sepsis. The role of adhesion molecules.

Although adhesion molecules present on circulating neutrophils and endothelial cells are essential for normal host defense, generalized activation of these molecules has been implicated in the inflammatory tissue injury occurring during sepsis and septic shock. A review of both preclinical and clinical studies suggests, however, that although these molecules mediate tissue injury related to a variety of microbial and host inflammatory mediators, their predominant role during sepsis with infection is a protective one.

Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies.

Introduction: Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4. Areas covered: This review focuses on the rationale for the use of eritoran tetrasodium in sepsis as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Preclinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms ‘eritoran’ and ‘E5564’ are discussed. Expert opinion: Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis are currently under investigation. Even if the ongoing Phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies would be necessary to define its clinical usage.

The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis

A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I(2) = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I(2) = 14%, OR of death 1.39 (95% CI 1.04-1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I(2) = 0%, OR of shock reversal 1.66 [95% CI 1.25-2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I(2) = 25%, OR of death 0.64 (95% CI 0.45-0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis.

CARDIOPULMONARY TOXICITY AFTER LIPOSOMAL AMPHOTERICIN B INFUSION

Liposomal and lipid-complex drug delivery systems are being developed to enhance the therapeutic activity, decrease the toxicity, and provide site-specific delivery of high doses of amphotericin B ...

An overview of anthrax infection including the recently identified form of disease in injection drug users

PurposeBacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world.MethodsThis review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax.Results and conclusionsAnthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax.