Treatment of anthrax

INTRODUCTION — 

The incidence of anthrax in humans has decreased during the past century, and it is now very rare in resource-rich countries, including the United States. However, anthrax remains endemic in certain areas of the world and is a concern because of its potential as an agent of bioterrorism. Anthrax meningitis and the fulminant phase of inhalation anthrax are associated with extremely high mortality rates.

The treatment of anthrax will be reviewed here. The microbiology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and prevention of anthrax are discussed separately. (See "Microbiology, pathogenesis, and epidemiology of anthrax" and "Clinical manifestations and diagnosis of anthrax" and "Prevention of anthrax".)

The treatment recommendations presented here are in agreement with the recommendations of the United States Centers for Disease Control and Prevention (CDC) [1].

INITIAL GENERAL MEASURES

Contact public health officials — In many countries, public health institutions recommend that anthrax be reported to them once suspected or diagnosed.

In the United States, anthrax is an immediately notifiable disease, meaning that as soon as clinicians or laboratory personnel reasonably suspect the diagnosis, they should contact the state health department for assistance in diagnosis and treatment. Since antitoxin treatment is available only through the Strategic National Stockpile, clinicians can obtain them only through a state health department, which coordinates with the Centers for Disease Control and Prevention (CDC).

Evaluation for systemic anthrax and meningitis — Systemic anthrax is defined as inhalation, gastrointestinal, or injection anthrax; anthrax meningitis; Bacillus anthracis bacteremia; or cutaneous anthrax with systemic involvement (eg, signs of sepsis). All patients suspected of having systemic anthrax should be evaluated for meningitis. Patients with cutaneous anthrax who have symptoms that could reflect central nervous system involvement (eg, headache, altered mental status, meningeal signs, or other neurologic features) should also be evaluated for meningitis. The evaluation is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of anthrax", section on 'Meningitis'.)

Meningitis and hemorrhagic brain infection have been observed in up to one-half of systemic anthrax cases; thus, meningitis must be considered in all cases of systemic anthrax [2]. In a mass casualty situation, especially if resources become limited, it may be necessary to use clinical criteria for the diagnosis of meningitis [3,4].

Indications for hospitalization — All patients with systemic anthrax should be hospitalized [2]. Because inhalation anthrax can have a prodromal phase followed by a fulminant phase characterized by sudden decompensation, hospitalized patients should have careful hemodynamic monitoring, including continuous pulse oximetry and telemetry.

SYSTEMIC ANTHRAX, INCLUDING MENINGITIS — 

Patients suspected of having inhalational, gastrointestinal, or injection anthrax, or anthrax meningitis should be treated urgently with intravenous antimicrobial combination therapy and antitoxin (raxibacumab, obiltoxaximab, or anthrax immunoglobulin). Additional management needs include adequate supportive care and management of complications.

Although cutaneous anthrax with signs of systemic illness (eg, sepsis) is also considered systemic anthrax, it can generally be treated the same as cutaneous anthrax without signs of systemic illness, as long as meningitis has been ruled out [1]. (See 'Cutaneous anthrax without meningitis' below.)

Supportive care — Patients with systemic anthrax warrant standard sepsis care, including intravenous fluids, hemodynamic monitoring, and potentially vasopressors and blood products. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Patients with anthrax may require mechanical ventilation for respiratory distress, airway protection (for those with altered mental status), and/or airway edema. As an example, substantial airway edema can occur with cutaneous lesions involving the head, neck, or thorax, and with oropharyngeal lesions.

Microangiopathic hemolytic anemia, coagulopathy, thrombocytopenia, and hemorrhage occur frequently with anthrax infection; bleeding complications should be managed aggressively [2]. (See "Use of blood products in the critically ill".)

Urgent antimicrobial therapy — Early and aggressive multidrug therapy of systemic anthrax is considered crucial due to the rapid progression and high mortality of systemic anthrax, especially if meningitis is present [5-7]. Treatment is usually empiric. (See 'Empiric intravenous regimens' below.)

However, if susceptibilities of the infecting isolate are known prior to antibiotic selection, a regimen tailored to those results can be used, as discussed elsewhere. (See 'Tailored regimens once susceptibilities known' below.)

Empiric intravenous regimens — For empiric therapy of patients with systemic anthrax, with or without suspected meningitis, we suggest combination antimicrobial therapy with two drugs from two different classes that have bactericidal activity and one drug that inhibits protein synthesis, specifically the following first-line agents:

●One bactericidal agent – Meropenem

Plus

●A second bactericidal agent – Ciprofloxacin or levofloxacin

Plus

●A protein synthesis inhibitor – Minocycline (for nonpregnant individuals only) or doxycycline

For adults, imipenem or ampicillin-sulbactam is another bactericidal first-line agent if meropenem cannot be used. However, imipenem should be used with caution in patients with meningitis since it is associated with an increased seizure risk.

Doses of these agents and second-line alternatives, which are reserved for patients who cannot use first-line agents, are listed in the table (table 1). These suggestions are aligned with those from the Centers for Disease Control and Prevention (CDC) in the United States [1]. First-line agents are likely appropriate for the majority of patients; however, the CDC has designated an extensive list of alternatives in the event of limited availability in a crisis situation or resistant isolates.

The rationale for using two bactericidal agents is to increase the likelihood of using at least one active agent in the event of antibiotic resistance; bactericidal agents are preferred for their immediate killing effect and they have been associated with better outcomes than protein synthesis inhibitors when each is given alone [8]. The rationale for adding a protein synthesis inhibitor is to suppress toxin production; this is supported by preclinical evidence that such agents can reduce B. anthracis toxin production [9,10] and indirect observational evidence that suggests a benefit with toxin inhibition in other systemic toxin-mediated infections (eg, streptococcal toxic shock syndrome). (See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention", section on 'General principles'.)

Clinical data informing use and selection of combination regimens for systemic anthrax are limited to observational studies, and results from these studies should be interpreted with caution because of potential confounding and other sources of bias [5,8,11]. As an example, in one systematic review of observational studies performed between 1880 and 2018, use of a bactericidal agent alone was associated with a lower mortality rate than a protein synthesis inhibitor alone for patients with systemic anthrax; however, the analysis did not find any statistically significant differences with other comparisons (eg, combination therapy versus monotherapy, bactericidal agents with versus without a protein synthesis inhibitor) [8]. Differences in outcomes with different treatments may have been difficult to identify because this analysis grouped a broad spectrum of patients, including those with sepsis from a cutaneous source, those with inhalational anthrax, and those with meningitis, under the category of systemic anthrax, even though the different patient groups have disparate prognoses regardless of treatment. The numbers of patients in each comparison group were also small, resulting in imprecise estimates.

In another systematic review that included 123 cases of severe anthrax (with an overall mortality rate of 67 percent), combination antimicrobial therapy was associated with lower mortality rates than monotherapy, although the difference was not statistically significant in this analysis either [11].

Given limitations in the clinical data, categorization of antimicrobials as preferred or alternative agents is based additionally on animal studies, in vitro data, and pharmacologic data, including modeling studies [1,12]. As an example, doxycycline and minocycline are the preferred protein synthesis inhibitors, in part because pharmacologic simulations suggest a higher likelihood of microbiologic cure in the plasma and cerebrospinal fluid (CSF) with those agents than with clindamycin and linezolid. Additionally, for anthrax meningitis, there is a theoretical benefit of using agents that have been associated with neuroprotective effects in other diseases (eg, minocycline and doxycycline, as well as clindamycin and beta-lactam-beta-lactamase inhibitor combinations).

Several first-line agents have also received US Food and Drug Administration (FDA) approval for the prevention or treatment of anthrax (ciprofloxacin, levofloxacin, doxycycline, and other tetracyclines) based on limited clinical and animal data [13]. Penicillin G is also FDA approved but is not a first-line agent for empiric therapy because of the possibility for resistance. (See 'Antimicrobial susceptibility' below.)

Tailored regimens once susceptibilities known — When the antimicrobial susceptibilities of the infecting B. anthracis isolate are known, clinicians should confirm that the empirically selected regimen is active. If not, the empiric regimen should be adjusted to include active agents. The number of agents to continue depends on the presence of meningitis.

●Patients with meningitis – For these patients, we suggest continuing a combination regimen with two bactericidal drugs and one protein synthesis inhibitor even after susceptibilities are known. Although the studies have not demonstrated a clear clinical benefit of combination therapy with three active drugs in patients with meningitis, we favor the most conservative approach given the high mortality rates associated with anthrax meningitis.

●Patients without meningitis – For these patients, the regimen can be transitioned to a combination of one active bactericidal drug and one active protein synthesis inhibitor.

The preferred antibiotic choices are generally the same as for empiric therapy (eg, meropenem, ciprofloxacin, and levofloxacin are preferred bactericidal agents, and minocycline and doxycycline are preferred protein synthesis inhibitors), as long as testing confirms susceptibility to these agents. However, if the isolate has documented susceptibility to penicillin or ampicillin, these are also considered first-line agents. (See 'Empiric intravenous regimens' above.)

Doses and alternative agents are listed in the table (table 1).

Duration of therapy (and potential transition to prophylaxis) — The optimal duration of antibiotic therapy is uncertain, so recommendations are conservative.

●Duration of intravenous therapy – The duration of intravenous combination therapy is at least two weeks; for patients who have meningitis, we suggest at least three weeks of intravenous combination therapy [1]. In general, patients should have clear clinical improvement prior to discontinuing intravenous antibiotic therapy. In some patients, especially those who have meningitis, more prolonged intravenous therapy (eg, for six weeks) may be warranted to treat ongoing infection and inflammation. In contrast, individuals without meningitis who appear well and have no ongoing signs or symptoms of active infection may transition to an oral medication before completing two weeks of intravenous therapy [1,14,15].

●Transition to oral prophylaxis for selected patients with aerosol exposure – Recommendations on prophylaxis following the course of intravenous therapy depend on the type of exposure and the immune status or age of the patient.

•If there was no aerosol exposure (eg, naturally acquired noninhalational anthrax), then prophylaxis following treatment is not necessary.

•If there was aerosol exposure (eg, bioterrorism-associated infection, inhalational anthrax), prophylaxis is recommended for newborns and immunocompromised individuals. Such patients should transition to a single active oral agent (table 2) to complete at least a 60-day post-exposure prophylactic course of antibiotics (inclusive of initial therapy) in order to prevent reinfection from inhaled, surviving B. anthracis spores [1]. Post-exposure prophylaxis is discussed in detail elsewhere. (See "Prevention of anthrax", section on 'Regimen selection'.)

Immunocompetent adults and non-newborn children who were treated for systemic anthrax do not need prophylaxis after potential aerosol exposure since they are considered to have developed natural immunity following infection.

Adjunctive antitoxin therapy — Antitoxin therapies are a recommended component of treatment of systemic anthrax, with or without meningitis, and are used in combination with antimicrobial therapy. Antitoxin therapy is also an alternative treatment for cutaneous anthrax in the rare event that antibiotics cannot be used (table 3).

Antitoxin therapies include the monoclonal antibodies raxibacumab and obiltoxaximab as well as anthrax immunoglobin derived from human plasma. They inhibit binding of protective antigen and translocation of the two primary toxins, lethal toxin and edema toxin, into cells [2]. These agents may have their greatest benefit when used early in the course of disease [16]. In the United States, supplies are held in the Strategic National Stockpile for use by the CDC in the event of an anthrax emergency. Thus, they are only available through the CDC by way of the state health department, which should be consulted as soon as anthrax is reasonably suspected. (See 'Contact public health officials' above.)

Data supporting the use of antitoxin therapy are limited. Animal origin antiserum was used with some success in the treatment of anthrax prior to the advent of antimicrobial therapy [17-19]. In a systematic review of inhalation anthrax cases from 1900 to 2005, mortality was lower among patients who received antiserum than those who received no treatment [5]. In subsequent systematic reviews of randomized trials in animals, antitoxin therapy using the monoclonal antibodies or human anthrax immunoglobulin improved survival compared with placebo [20,21], consistent with the observed benefit of anthrax antiserum in the pre-antibiotic era [22]. However, there was no clear benefit of these agents compared with antibiotics or when added to antibiotics [20].

Evidence in humans is limited to case series; among the 25 patients reported to receive antitoxin or antiserum since 1960, the mortality rate was approximately 35 percent, even among those considered to have fulminant disease [20]. Antitoxin may have the greatest value in mass casualty situations where antibiotics are in short supply. Nevertheless, given the severity of systemic anthrax and the paucity of human data, antitoxin administration as early as possible and in conjunction with antibiotic therapy remains the recommended approach for systemic anthrax.

Monoclonal antibodies (preferred)

Raxibacumab — Raxibacumab is a human IgG1-gamma monoclonal antibody directed against protective antigen of B. anthracis [23]. It is used in combination with antimicrobial therapy for systemic anthrax and is an alternative to antimicrobial therapy for cutaneous anthrax. It is the only antitoxin preparation that does not interfere with vaccine-induced immunity. (See 'Adjunctive antitoxin therapy' above.)

Raxibacumab is given as a single dose following premedication with diphenhydramine; dosing recommendations are listed in the table (table 3) [1,24]:

The efficacy of raxibacumab has been systematically evaluated only in animals; in randomized trials involving rabbits, monkeys, and dogs, it improved mortality after experimentally induced inhalational anthrax [25,26]. In safety studies among humans, the therapeutic levels of the antibody achieved were equal to or greater than those that provided protection in animal models [27]. Common adverse effects in 326 healthy humans included rash, extremity pain, pruritus, and drowsiness [23].

Obiltoxaximab — Obiltoxaximab is a monoclonal antibody directed against the protective antigen of B. anthracis [28,29]. It is used in combination with antimicrobial therapy for systemic anthrax and is an alternative to antimicrobial therapy for cutaneous anthrax. (See 'Adjunctive antitoxin therapy' above.)

Obiltoxaximab is given as a single dose following premedication with diphenhydramine; dosing recommendations are listed in the table (table 3) [1,29].

The evidence supporting its efficacy comes from studies in animal models of inhalational anthrax, in which it improved survival [28]. Its safety has been evaluated in humans. In a study that included 320 individuals, the most common adverse reactions reported following a dose of obiltoxaximab included headache, pruritus, upper respiratory tract infection, cough, vessel puncture site bruise, infusion site swelling, urticaria, nasal congestion, infusion site pain, and pain in an extremity [29]. Obiltoxaximab was discontinued in 8 of 320 individuals (2.5 percent) due to hypersensitivity reactions or anaphylaxis.

Anthrax immunoglobulin — Anthrax immunoglobulin is derived from the plasma of Anthrax Vaccine Adsorbed (AVA)-immunized persons and can neutralize toxins produced by B. anthracis [30,31]. It is used in combination with antimicrobial therapy for systemic anthrax when monoclonal antibodies are not available. It is also an alternative to antimicrobial therapy and monoclonal antibodies for cutaneous anthrax. (See 'Adjunctive antitoxin therapy' above.)

Anthrax immunoglobulin is given as a single dose, as listed in the table (table 3) [1].

Clinical use has been described in a series of 19 patients with anthrax who were treated with anthrax immunoglobulin and antimicrobial therapy under an expanded access program [31]. Three had inhalation anthrax, 1 had gastrointestinal anthrax, and 15 had injection anthrax caused by contaminated heroin. Of these patients, 13 survived, including 2 of the 3 patients with inhalation anthrax.

The safety of anthrax immunoglobulin was tested in 72 healthy human volunteers [31]. The most common side effects were headache, back pain, nausea, and infusion site pain and swelling.

Management of complications

Drainage of effusions — Early drainage of effusions associated with anthrax (eg, pleural effusions, ascites, hemodynamically significant pericardial effusions) is recommended [1].

●Pleural fluid should be drained early and aggressively; chest tubes are preferred over needle thoracentesis because many effusions require prolonged drainage [1]. Thoracotomy or video-assisted thoracic surgery might be necessary to remove gelatinous or loculated pleural effusions.

●Ascites removal is also preferably achieved with continuous drainage [1]. If continuous drainage is not performed, monitoring for reaccumulation (and repeat drainage) is warranted; this is a reasonable approach in resource-limited situations [3].

Pleural fluid drainage has been associated with improved survival in a case series of 82 patients with inhalation anthrax [5]. Drainage of both pleural fluid and ascites is also thought to improve outcomes by reducing the lethal toxin level and by decreasing mechanical lung compression [1,3].

Complications of meningitis — Individuals with anthrax meningitis should be managed in a neuro-critical care unit or in consultation with a neuro-critical care specialist, if possible. Intracranial and subarachnoid hemorrhage are frequent complications [32] that may further result in severe cerebral edema. Potential interventions for elevated intracranial pressure related to anthrax meningitis include osmotic therapy, such as hypertonic saline and mannitol.

Details on management of intracranial hemorrhage and elevated intracranial pressure are found elsewhere. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Evaluation and management of elevated intracranial pressure in adults" and "Elevated intracranial pressure (ICP) in children: Management".)

Potential indications for invasive procedures — Some patients have complications of anthrax that may warrant surgical intervention [2]:

●Patients with gastrointestinal anthrax who have severe bowel ischemia, necrosis, and perforation. (See "Colonic ischemia", section on 'Treatment overview'.)

●Patients with injection anthrax, who may need removal of a necrotic tissue, which may serve as a nidus for toxin and spores; in such cases, debridement just to healthy tissue is recommended, which may be more limited than that for other necrotizing soft tissue infections [2]. (See "Surgical management of necrotizing soft tissue infections".)

●Patients with airway obstruction who require tracheostomy. (See "Tracheostomy: Rationale, indications, and contraindications".)

●Patients with large cutaneous lesions on the extremities that cause compartment syndrome. (See "Acute compartment syndrome of the extremities", section on 'Management'.)

●Although surgery for cutaneous anthrax should generally be avoided because of concern for dissemination and adverse outcomes, life- or limb-threatening circumstances are appropriate exceptions.

Uncertain role for adjunctive glucocorticoids — Some patients with anthrax may have conditions that potentially warrant adjunctive glucocorticoids, including:

●Meningitis (see "Initial therapy and prognosis of community-acquired bacterial meningitis in adults", section on 'Adjunctive dexamethasone')

●Vasopressor-refractory shock (see "Corticosteroid therapy for refractory septic shock in adults", section on 'Patient selection')

●Adrenal insufficiency in the setting of recent glucocorticoid use (see "Treatment of adrenal insufficiency in adults", section on 'Adrenal crisis')

If glucocorticoids are indicated for these reasons, there is no clear evidence that use would be harmful in patients with anthrax. However, supporting data for glucocorticoids in anthrax are limited, and conversely, there may be no benefit (eg, for reducing the inflammation resulting from toxin-mediated tissue edema). Systematic reviews of case reports and observational studies do not identify a clear benefit to glucocorticoids in patients with shock, meningitis, or head and neck involvement; however, the number of patients who received glucocorticoids in each group was very small, and confounding factors may have impacted the results [8]. Individual studies have suggested potential benefits of glucocorticoids for cutaneous anthrax of the head and neck [33,34] and meningitis [7], but confident conclusions cannot be drawn from such small studies.

Monitoring — Close monitoring is essential for care of patients with systemic anthrax (table 4). Because there can be a prodromal phase followed by a fulminant phase characterized by sudden decompensation, hospitalized patients should have careful hemodynamic monitoring, including continuous pulse oximetry and telemetry [2].

●Routine laboratory monitoring includes:

•Complete blood count

•Electrolytes and kidney function tests

•Liver enzymes and bilirubin

•Prothrombin time (PT) and activated partial thromboplastin time (aPTT).

●Imaging includes:

•Initial computed tomography (CT) of chest followed by daily chest radiographs until abnormalities (eg, pleural effusion) are stable or improving

•Repeat CT of the chest for major changes in clinical status

•Echocardiography to evaluate for pericardial effusions, which were reported in 3 of 10 patients with bioterrorism-related inhalational anthrax [35]

•Abdominal imaging as clinically indicated

Patients who develop headache, nausea or vomiting, seizure, meningeal signs, confusion, or other neurologic symptoms should undergo head imaging and repeat lumbar puncture to evaluate for meningitis or other central nervous system complications.

CUTANEOUS ANTHRAX WITHOUT MENINGITIS — 

For patients with cutaneous anthrax who do not have meningitis we suggest treatment with antimicrobial monotherapy, even if they have evidence of systemic symptoms. Antitoxin is an alternative therapy in the rare event that antimicrobial agents are not available.

●Regimen selection – For antimicrobial therapy of cutaneous anthrax, we suggest one of the following:

•Doxycycline or

•Minocycline (for nonpregnant individuals only) or

•Ciprofloxacin or

•Levofloxacin

Once susceptibility testing results on the isolate are available, activity of the empirically chosen agent should be confirmed. If the isolate has documented susceptibility to penicillin and ampicillin, amoxicillin and penicillin-VK are also first-line options. For children, amoxicillin-clavulanate and clindamycin are also considered first-line options.

Doses of these agents and alternative agents are listed in the table (table 2).

Although untreated cutaneous anthrax is associated with considerable mortality, survival rates with monotherapy were 98 percent among 62 patients with localized and 45 patients with systemic cutaneous anthrax in the absence of meningitis [8]. Rationale for categorization of first-line versus alternative agents is the same as for systemic anthrax and based on animal studies, in vitro data, and pharmacokinetic data, which are discussed elsewhere. (See 'Empiric intravenous regimens' above.)

●Duration of therapy (and potential need for post-exposure prophylaxis) – The duration of therapy depends on whether there is concern for exposure to aerosolized B. anthracis spores.

•For naturally acquired infection in which no aerosol exposure is suspected, the duration of therapy is 7 to 10 days; patients should have clear clinical improvement before antibiotics are discontinued.

•If an aerosol exposure is a possibility (eg, bioterrorism-associated infection), the antibiotic should be continued for a total of 42 to at least 60 days (depending on whether vaccine was given) since the time of exposure for post-exposure prophylaxis against reinfection from inhaled, surviving B. anthracis spores [1]. The antimicrobial options for post-exposure prophylaxis are the same as those for treatment of cutaneous anthrax. The duration of post-exposure prophylaxis and use of anthrax vaccine are discussed in detail elsewhere. (See "Prevention of anthrax", section on 'Regimen selection'.)

SPECIAL SITUATIONS

Pregnant and postpartum individuals — The treatment of pregnant, lactating, and postpartum individuals is largely the same as the treatment of nonpregnant adults (table 1 and table 2). (See 'Systemic anthrax, including meningitis' above and 'Cutaneous anthrax without meningitis' above.)

In particular, we strongly prefer ciprofloxacin as a bactericidal agent for patients with systemic anthrax or the single agent for cutaneous anthrax because it crosses the placental barrier [36]. If ciprofloxacin is not included in the regimen, a different agent that crosses the placental barrier should be included in the regimen. Other agents that likely cross the placenta adequately include levofloxacin, moxifloxacin, amoxicillin, penicillin, and rifampin. Clindamycin and doxycycline are also likely to cross the placenta, but data are limited.

Because pregnancy can affect drug metabolism, clinicians should consult a clinical pharmacist, if available, for assistance with drug dosing in pregnant patients. Pharmacokinetic data indicate that penicillin, ampicillin, and carbapenems may require higher doses in pregnant and postpartum women than those recommended for nonpregnant adults [36,37]. Serum levels of ciprofloxacin were also lower in pregnant individuals in one study [38].

Some agents that are first-line or alternative options for nonpregnant adults are not recommended for pregnant individuals because of maternal or fetal toxicity concerns; these include minocycline and tetracycline.

Children — The treatment for children is largely the same as the treatment for adults, although certain agents that are first line for adults are alternative agents for children, and vice versa (table 1 and table 2). (See 'Systemic anthrax, including meningitis' above and 'Cutaneous anthrax without meningitis' above.)

In particular, if the infecting isolate has confirmed susceptibility to penicillins, a penicillin (eg, penicillin, amoxicillin) is preferred for cutaneous anthrax (or as part of a combination regimen for systemic anthrax) over other first-line agents, such as fluroquinolones and tetracyclines, because of more established safety data. When penicillins should not be used (eg, for empiric therapy or for resistant isolates), given the morbidity and mortality associated with anthrax, the potential benefits of fluoroquinolones and tetracyclines outweigh the potential toxicities in children. The risk of these agents in children is discussed elsewhere. (See "Fluoroquinolones", section on 'Children' and "Tetracyclines", section on 'Young children'.)

Limited resources — In settings where resources are constrained, such as crisis conditions during a widespread outbreak of anthrax, use of the recommended combination therapies may not be feasible. In such settings, the United States Centers for Disease Control and Prevention (CDC) have presented the following alternative regimens for treatment of systemic anthrax, in order of decreasing preference:

●One bactericidal agent plus one protein synthesis inhibitor (eg, meropenem plus doxycycline)

●Two bactericidal agents from different drug classes (eg, meropenem plus ciprofloxacin)

●One bactericidal drug plus one RNA inhibitor (eg, meropenem plus rifampin)

●One protein synthesis inhibitor plus one RNA inhibitor (eg, doxycycline plus rifampin)

●Two protein synthesis inhibitors from different drug classes (eg, minocycline plus clindamycin)

●One bactericidal agent as monotherapy (eg, meropenem)

●One protein synthesis inhibitor as monotherapy (eg, doxycycline)

Furthermore, if intravenous agents are not available, the oral formulations of highly bioavailable agents (eg, fluoroquinolones, doxycycline, linezolid) can also be used if the patient is not expected to have poor drug absorption.

ANTIMICROBIAL SUSCEPTIBILITY — 

Naturally occurring B. anthracis isolates are highly susceptible to a variety of antimicrobial agents, including penicillins, carbapenems, fluoroquinolones, tetracyclines, aminoglycosides, clindamycin, vancomycin, and linezolid, although specific breakpoints for susceptibility have not been formally established for all these drug classes [11,39-42].

However, B. anthracis is not susceptible to cephalosporins, aztreonam, and trimethoprim-sulfamethoxazole [39-41,43-45].

Furthermore, because B. anthracis possesses beta-lactamase genes, beta-lactam use can induce resistance during treatment, and a small minority (up to 10 percent) of naturally occurring isolates are penicillin resistant [42]. Thus, use of penicillin, ampicillin, or amoxicillin is only recommended when susceptibility has been confirmed, and their use warrants a high index of suspicion for emergent resistance [2,46]. Furthermore, adequate dosing of penicillin and amoxicillin is particularly important because of the potential for emergent resistance with subtherapeutic doses [2].

Clinical microbiologists should also be aware that the antibiotic breakpoints for B. anthracis are in some cases different from those of Bacillus species in general [47].

OUTCOMES — 

Outcomes of anthrax vary depending on the site(s) of involvement:

●Cutaneous anthrax – Without therapy, mortality has ranged from 16 to 39 percent [2]. With antibiotic therapy, the mortality rate is <2 percent, and with antitoxin therapy (as given in the preantibiotic era), the mortality rate ranged from 0 to 28 percent.

●Inhalation anthrax – In studies prior to 2001, mortality rates associated with inhalation anthrax were nearly 90 percent [2,5]. Subsequent studies reported mortality rates of approximately 50 percent; early diagnosis, combination antimicrobial therapy, and drainage of pleural effusions were associated with survival. However, patients with inhalational anthrax often present later in the course of illness, and progression to the fulminant phase was associated with a mortality rate of 97 percent, regardless of therapy [5].

●Anthrax meningitis – This has an extremely poor prognosis. With or without treatment, the mortality rate approaches 100 percent [2,5,14].

●Other forms – Even with antimicrobial therapy and modern intensive care, injection and gastrointestinal anthrax have been associated with mortality rates of 28 and ≥40 percent, respectively [2].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anthrax".)

SUMMARY AND RECOMMENDATIONS

●Contact public health officials – In many countries, public health institutions recommend that anthrax be reported to them once suspected or diagnosed. In the United States, anthrax is an immediately notifiable disease, and clinicians should contact the state health department as soon as there is reasonable suspicion for anthrax. (See 'Contact public health officials' above.)

●Management of systemic anthrax – Systemic anthrax includes inhalation, gastrointestinal, or injection anthrax; anthrax meningitis; and B. anthracis bacteremia. All patients with systemic anthrax should be hospitalized, be evaluated for meningitis, and receive urgent combination intravenous antimicrobial therapy and antitoxin therapy. Critically ill patients may require vasopressor support and/or mechanical ventilation. (See 'Initial general measures' above and 'Supportive care' above.)

•Urgent antimicrobial therapy – For empiric antimicrobial therapy of patients with systemic anthrax, with or without meningitis, we suggest meropenem plus either ciprofloxacin or levofloxacin plus either minocycline or doxycycline (Grade 2C). Doses and alternatives are listed in the table (table 1). Clinical data informing the optimal regimen are limited; this regimen provides two bactericidal agents (to safeguard against potential resistance) and a protein synthesis inhibitor (to suppress toxin formation). In vitro and pharmacologic data also support these options. (See 'Empiric intravenous regimens' above.)

The empiric regimen can be tailored once susceptibility testing results are available; the regimen is continued until the patient is clinically stable and for at least two (without meningitis) to three (with meningitis) weeks. For newborns and immunocompromised individuals who have had an aerosol exposure (eg, bioterrorism-associated infection, inhalational anthrax), we suggest transitioning to post-exposure prophylaxis to prevent reinfection from inhaled, incubating anthrax spores (table 2) (Grade 2C). Other patients with systemic anthrax and potential aerosol exposure are expected to develop immunity. (See 'Tailored regimens once susceptibilities known' above and 'Duration of therapy (and potential transition to prophylaxis)' above and "Prevention of anthrax", section on 'Regimen selection'.)

•Adjunctive antitoxin therapy – For patients with systemic anthrax, we suggest raxibacumab or obiltoxaximab in addition to antimicrobial therapy (table 3) (Grade 2C). Anthrax immunoglobulin is an alternative. These antitoxin therapies have been associated with survival benefits in animal studies. In the United States, they are only available through the Centers for Disease Control and Prevention (CDC) by way of the state health department. (See 'Adjunctive antitoxin therapy' above.)

•Management of complications – We recommend early drainage of effusions associated with anthrax (eg, pleural effusions, ascites, hemodynamically significant pericardial effusions) (Grade 1C). Patients with anthrax meningitis should be monitored for intracranial hemorrhage and cerebral edema. (See 'Management of complications' above.)

•Monitoring – This includes close hemodynamic monitoring (eg, telemetry and pulse oximetry), daily laboratory testing (complete blood count, electrolytes, kidney function and liver tests, and markers of coagulation), and daily chest radiographs until improvement. (See 'Monitoring' above.)

●Management of cutaneous anthrax without meningitis – For empiric antimicrobial therapy of patients with cutaneous anthrax without meningitis, we suggest monotherapy with doxycycline, minocycline, ciprofloxacin, or levofloxacin (Grade 2C). If the isolate has documented susceptibility to penicillin and ampicillin, amoxicillin and penicillin-VK are also first-line options. Doses and alternatives are listed in the table (table 2). Limited clinical data suggest high survival rates with antimicrobial monotherapy. Antitoxin is an alternative if antimicrobials are not available. (See 'Cutaneous anthrax without meningitis' above.)

The duration of therapy is 7 to 10 days. For individuals who have had an aerosol exposure (eg, bioterrorism-associated infection), we suggest transitioning to post-exposure prophylaxis to prevent reinfection from inhaled incubating anthrax spores (table 2) (Grade 2C). (See 'Cutaneous anthrax without meningitis' above.)