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Anthrax is an optimal biologic weapon because of its fatal course, if the infection is left untreated. Ob/gyns have a critical role to play in recognizing the infection, providing timely and appropriate treatment or prophylaxis, and monitoring patients for adverse pregnancy outcomes.
|Jump to:||Choose article section... Microbiology and transmission Clinical presentation Making the diagnosis Choosing antimicrobial therapy Managing active infection in pregnant and lactating women Postexposure prophylaxis and pregnancy Postexposure antimicrobial prophylaxis and lactation Conclusion Key points|
Anthrax is a perfect biologic weapon because of its fatal course, if the infection is left untreated. Ob/gyns can play a critical role in recognizing the infection, providing timely and appropriate treatment or prophylaxis, and monitoring patients for adverse pregnancy outcomes.
When bioterrorists intentionally disseminated Bacillus anthracis through the mail in the Fall of 2001, 22 people contracted anthrax infection. Eleven of these individuals had confirmed inhalational anthrax, the most dangerous form of the infection.1 And five of those people died despite aggressive intervention. In addition, the Centers for Disease Control and Prevention recommended that the more than 10,000 persons with potential anthrax exposure take at least 60 days of postexposure antimicrobial prophylaxis.2
Given the scope of this event and the possibility of intentional release of anthrax in the future, it is imperative for clinicians to be familiar with the clinical presentation of anthrax infections. Rapid recognition of a potential infection by a primary care provider can be the critical first step in identifying an anthrax outbreak and minimizing its impact. Because pregnant women comprise a unique clinical category, obstetricians and gynecologists must be familiar with the most up-to-date guidelines for prevention and treatment of anthrax infection in order to safeguard the health of a mother and her baby.
Unfortunately, little information is readily available about the potential effects of long-term postexposure antimicrobial prophylaxis on pregnant women. This article outlines current recommendations for antimicrobial prophylaxis and treatment of B anthracis infections in pregnant and lactating women and summarizes available information about the effects of these medications on the fetus. These recommendations may be updated in the future as additional information and research are accumulated.
B anthracis is a large, aerobic, gram-positive, nonmotile, spore-forming rod. The nonflagellated vegetative cell is approximately 1 to 8 µm long and 1 to 1.5 µm wide.3 The vegetative bacilli proliferate rapidly in the presence of the nutrient-rich tissues and blood of animals and humans. Spores do not form in living tissue, but rather, when the host dies and the bacilli are exposed to ambient air.4 They then settle into the environment and remain dormant until an appropriate host comes in contact with the organism. Extremely hardy, B anthracis spores resist environmental degradation and have the potential to survive for decades. Measuring approximately 2 to 6 µm in diameter, they are an ideal size for deposition in the human lower respiratory tract.5
B anthracis spores are found in soil throughout the world. The disease primarily affects herbivores such as cows or sheep that come in contact with the organism through infected soil. In the natural setting, humans contract anthrax through contact with infected animals or contaminated animal products, such as the ingestion of undercooked, infected meat or contact with infected animal hides.
Anthrax infection has three clinical manifestations: cutaneous, gastrointestinal, and inhalational. Cutaneous anthrax is the most common naturally occurring form. Localized skin involvement occurs after direct contact with either spores or vegetative bacilli. The incubation period is generally hours to days after contact. The first symptom is itching of the exposed skin surface, followed by the emergence of a primary skin lesion, usually a nondescript, painless, pruritic papule that forms a vesicle. The vesicle undergoes central necrosis and drying, leaving a characteristic black eschar.6 Moderate-to-severe localized edema is usually present, sometimes accompanied by smaller, secondary vesicles. Pain is unusual and, if present, is generally attributable to edema or secondary infection. Untreated cutaneous anthrax can spread to regional lymph nodes and to the bloodstream, resulting in overwhelming bacteremia. Without antibiotic treatment, cutaneous anthrax can have a mortality rate as high as 20%, compared to less than 1% with antibiotic treatment.4,7
GI anthrax is extremely rare and has never been reported in the United States.6,8 In general, symptoms manifest within 1 to 7 days after consumption of undercooked endospore-contaminated meat. The clinical manifestation depends upon the location in the GI tract where the spores are deposited. Upper GI involvement usually presents with oral, oropharyngeal, or esophageal lesions that are initially edematous but subsequently develop pseudomembranous necrosis.9 Accompanying symptoms include fever, pharyngeal and cervical lymphadenopathy, dysphagia, sore throat, and respiratory distress. Lower GI involvement usually presents with primary ulcerative lesions in the ileum or cecum. Accompanying symptoms include pain, fever, nausea, vomiting, bloody diarrhea and, frequently, hemorrhagic mesenteric lymphadenitis, often with marked ascites. Intestinal anthrax is fatal in 25% to 60% of cases; the effect of early antibiotic therapy is currently unknown.7,10
Inhalational anthrax can result from the aerosolized release of B anthracis spores. This is the clinical manifestation of the disease that is the most dreaded, and when preparing for the possibility of a bioterrorist attack, of the most concern. The incubation period is typically 1 to 7 days but incubation periods of more than 60 days theoretically are possible.11 The clinical illness is biphasic but symptoms can progress rapidly with little distinction between the phases. During the first phase, symptoms are nonspecific and often mimic a viral respiratory illness with low-grade fever, myalgias, malaise, nonproductive cough, and possibly chest and/or abdominal discomfort. Few physical findings are noted at this time.8 Most of the 11 patients diagnosed with inhalational anthrax in the Fall of 2001 initially had fever, chills, malaise, nonproductive cough, and/or chest discomfort.12-15 These nonspecific, vague symptoms may make the initial presentation of inhalational anthrax difficult to distinguish from an influenza-like illness (ILI). Unlike ILI, however, nasal congestion and rhinorrhea are not prominent symptoms in inhalational anthrax.16
Some patients may experience a slight improvement in symptoms before their clinical condition deteriorates rapidly. The second phase of the illness is characterized by sudden onset of high fever and severe respiratory distress resulting in respiratory failure, pulmonary edema, and shock. Hemorrhagic meningitis occurs in about half of all inhalational anthrax patients.5 Chest x-rays usually reveal mediastinal widening from lymphadenopathy, though not all patients with inhalational anthrax will have this classic finding. Bloody pleural effusions are common; lung infiltrates might also be present but are less common. All 11 patients diagnosed with inhalational anthrax in the Fall of 2001 had abnormal chest radiographs, but in three patients, the abnormalities were very subtle and initially interpreted as normal.13,16 Therefore, it is advisable to consult with a radiologist to rule out such subtle findings.12 Mortality for inhalational anthrax is extremely high. Death is universal for untreated patients, and the rate may be as high as 95% in treated patients if therapy is begun more than 48 hours after the initial onset of symptoms.5
If a patient's clinical presentation is such that you suspect anthrax, or if she may have been exposed, the first step is to contact your state's health department, which will provide instructions on how to evaluate and confirm the diagnosis. For patients with clinical symptoms, obtain specimens appropriate to the system affected (such as blood, pleural fluid, cerebral spinal fluid, skin lesion). A presumptive diagnosis can be made by isolating gram-positive bacilli on an unspun peripheral blood smear or cerebrospinal fluid, or by aerobic blood culture growth of large, gram-positive bacilli.17 Collect the specimens for testing before initiating antimicrobial therapy. Confirmatory diagnostic tests, such as rapid diagnostic immunoassays and polymerase chain reaction testing, are available through a level B laboratory of the Laboratory Response Network for Bioterrorism (LRN). State and local departments of health have contact information for the LRN serving their areas. Anthrax is not generally transmitted from person to person; therefore, standard precautions are adequate protection for health-care workers.
Before deciding on a course of treatment or prophylaxis for anthrax, it is imperative that you contact your state health department to obtain the most recent updates to these recommendations. In the setting of a documented exposure to anthrax, the risk for untreated infection far outweighs the risks of antimicrobial therapy to the developing fetus. When considering antibiotic therapy, women should be counseled about the potential for any effects on fetal development. It is also important to understand that congenital malformations occur in approximately 2% to 3% of births in the general population even in the absence of a known teratogenic exposure.18
While several antibiotics exhibit in vitro activity against B anthracis, only ciprofloxacin, doxycycline, and penicillin are labeled for use in treating anthrax infection or exposure. Extended-spectrum cephalosporins and trimethoprim/sulphamethoxazole are not recommended for treating or preventing any form of anthrax infection because B anthracis has shown resistance to these drugs.7 The choice of antimicrobials to treat an individual case of anthrax infection or exposure should be made in consultation with an infectious disease specialist, and in the event of a bioterrorism attack, with public health officials.
Ciprofloxacin. Ciprofloxacin is usually the first choice of treatment and prophylaxis for B anthracis infection until sensitivity of the organism is established. Ciprofloxacin is a quinolone antibiotic, with a wide spectrum of activity, and no controlled clinical studies of the effects of use in human pregnancy have been conducted.19-21 Reports in the literature of pregnancies exposed to ciprofloxacin estimate the frequency of malformations among offspring at 2.2% to 9.5%.22-25 However, no common pattern was observed among the malformations reported in each series.
Based on these data, a panel of clinical experts for the Teratogen Information System concluded that therapeutic doses of ciprofloxacin during pregnancy are unlikely to pose a substantial teratogenic risk but that the data are insufficient to state that there is no risk.19 Quinolones have a high affinity for bone tissue, and in animal studies, have induced arthropathy when given to juveniles.26,27 Although rare, arthropathy with quinolone use has been observed in children and nonpregnant adults. For these reasons their use is not recommended in children under age 18 or in pregnant women. However, the risk for morbidity and mortality from untreated anthrax infection is high and ciprofloxacin remains the cornerstone of prophylaxis and treatment.
Doxycycline. Doxycycline is a lipophilic tetracycline antibiotic with a wide spectrum of activity. Limited data are available on the effects of doxycycline during pregnancy.19-21 A large casecontrol study of 18,515 mothers of infants with congenital malformations in Hungary showed a weak but statistically significant relationship with doxycycline at any time during pregnancy and total malformations in the offspring (OR=1.6, 95% CI: 1.02.4). However, this relationship was not apparent when use was restricted to the period of organogenesis, and no convincing pattern of abnormalities was observed among the 56 children with malformations who were exposed in utero. The authors felt that recall bias could explain the significance of this weak association between doxycycline and total malformations.28 No human data exist regarding the effects of longer-duration therapies such as that used for anthrax prophylaxis.
Other tetracyclines. Because other tetracyclines can cause staining of the primary teeth and suppression of fetal bone growth, it is assumed that in utero exposure to doxycycline may have similar effects. However, no data are available to establish this.29-31 Tetracyclines are also known to cause a rare but often fatal complication in pregnant womenhepatic necrosisfollowing intravenous dosing.32 For these reasons, doxycycline should be used with caution in pregnant women for prophylaxis or treatment of anthrax infections, and then only under life-threatening circumstances or when other therapeutic alternatives are contraindicated.
Amoxicillin. Amoxicillin is a penicillin derivative that has been widely used during pregnancy without incident. Numerous studies have failed to document adverse effects on the fetus.33-35 However, as with most drugs, the data remain insufficient to confirm that amoxicillin carries absolutely no risk during pregnancy.19-21 In individuals who are allergic to penicillin, amoxicillin may produce anaphylaxis during pregnancy or immediately postpartum and should not be used.36 Amoxicillin alone is not recommended for the treatment of symptomatic anthrax infections. Although isolates of B anthracis may be susceptible to amoxicillin, they may also produce constitutive and inducible beta-lactamases, which can decrease antibiotic effectiveness.
Tables 1 and 2 provide the CDC recommendations for treatment of anthrax infection in the setting of the bioterrorist attacks in the fall of 2001. Treating symptomatic inhalational or GI anthrax in a pregnant or lactating woman should be the same as for nonpregnant adults (Table 1). The risk of death or adverse pregnancy outcome from anthrax infection far outweighs the potential risk to the fetus or infant posed by antibiotic therapy. Again, the choice of antimicrobials to treat an individual case of anthrax infection or exposure should be made in consultation with an infectious disease specialist, and in the event of a bioterrorist attack, with public health officials.
|Category||Initial therapy (intravenous||Duration|
|Adults||Ciprofloxacin 400 mg every 12 hr*||IV treatment initially|
|Children||Ciprofloxacin 10-15 mg/kg every 12 hr||IV treatment initially.|
|Pregnant women||Same for nonpregnant adults (the high death rate from the infection outweighs the risk posed by the antimicrobial agent)||IV treatment initially. Switch to oral antimicrobial therapy when clinically appropriate.|
|Immunocompromised persons||Same for nonimmunocompromised persons and children||Same for nonimmunocompromised persons and children|
|Category||Initial therapy (oral)||Duration|
|Adults*||Ciprofloxacin 500 mg bid||60 days|
|Children*||Ciprofloxacin 10-15 mg/kg every 12 hr (not to exceed 1 g/day)||60 days|
|Pregnant women||Ciprofloxacin 500 mg bid||60 days|
|Immunocompromised persons*||Same for nonimmunocompromised persons and children||60 days|
Because of the high mortality associated with inhalational and GI anthrax, CDC recommends a multidrug treatment approach. Initial therapy should consist of IV ciprofloxacin or doxycycline plus one or two additional antimicrobials. Agents with in vitro activity suggested for use in conjunction with ciprofloxacin or doxycycline include rifampin, vancomycin, imipenem, chloramphenicol, penicillin and ampicillin, clindamycin, and clarithromycin.37 Because of concerns of constitutive and inducible beta-lactamases in B anthracis, neither penicillin nor ampicillin should be used alone to treat active infection even when sensitivity to these agents has been documented. Treatment can be changed to an oral regimen as soon as clinically appropriate, and should be continued for a full 60 days.
There are no published epidemiologic studies on the possible human reproductive effects of imipenem or vancomycin. Limited data exist regarding the effects of clarithromycin, clindamycin, rifampin, or chloramphenicol on the human fetus. A complete review of the literature for each of these compounds is beyond the scope of this article; however, no known documented human teratogenic risks have been reported. Prenatal exposure to rifampin may induce bleeding in the newborn; prophylactic treatment with vitamin K can be considered if use of this medication is essential.38 Grey baby syndrome, a serious and often fatal condition, has been reported with the use of chloramphenicol in infants; therefore, this drug should be considered only if the mother is unlikely to respond to alternative antibiotics.39 Although clindamycin and rifampin are considered compatible with breastfeeding, chloramphenicol may cause idiosyncratic bone marrow suppression in the breast-fed infant.40
For treating cutaneous anthrax in a pregnant woman with signs of systemic involvement, extensive edema, or lesions on the head and neck, IV therapy and a multidrug approach are warranted (Table 1). For treatment of localized cutaneous anthrax infection, oral ciprofloxacin or doxycycline is the first line of therapy (Table 2). In pregnant women, doxycycline should be used only if ciprofloxacin is contraindicated. If isolates are sensitive to penicillin, amoxicillin may be an option for completing therapy for cutaneous anthrax after clinical symptoms have improved. The oral amoxicillin dose should be based on achieving appropriate minimum inhibitory concentration levels.
Among asymptomatic persons whose potential exposure places them at minimum risk, antimicrobials may not be warranted unless an actual exposure threat is documented through microbial testing of the exposure source.10 Consultation with an infectious disease specialist is advised. During a bioterrorist attack, consultation with public health and/or law enforcement officials is also advisable to obtain the most accurate results of microbial testing of exposure sources.
Both CDC and the American College of Obstetricians and Gynecologists Committee on Obstetric Practice recommended ciprofloxacin, 500 mg po bid for 60 days, as the first-line antimicrobial postexposure prophylaxis therapy for asymptomatic pregnant women exposed to B anthracis during the fall 2001 bioterrorism attacks.10,18 Because of concerns about constitutive and inducible beta-lactamases in B anthracis, amoxicillin should not be used alone for anthrax prophylaxis in asymptomatic individuals when the dose of exposure is likely to be high with a large number of organisms, even if the anthrax isolate is proven to be penicillin sensitive. Amoxicillin is likely to be effective for prophylaxis when the dose of exposure is low and when the anthrax isolate is penicillin sensitive.18,37 In this circumstance, amoxicillin, 500 mg po tid for 60 days, may be considered. If the isolate is penicillin sensitive and both amoxicillin and ciprofloxacin are contraindicated, penicillin desensitization may be an option. Oral desensitization to penicillin has been shown to be an acceptably safe approach in pregnancy.41 Again, consultation with an infectious disease specialist is advised.
Whether to continue breastfeeding during postexposure antimicrobial therapy is an individual decision. A mother and her physician together should assess the benefits of breastfeeding and the potential risk to the infant from drug exposure. The American Academy of Pediatrics considers ciprofloxacin, doxycycline, and amoxicillin to be usually compatible with breastfeeding.40 All three drugs are transferred into the breast milk, but have relatively low bioavailability. As for nonbreastfeeding women, ciprofloxacin is the drug of choice for initial prophylaxis of B anthracis for a lactating woman.
It is not known whether the dose of doxycycline absorbed from breast milk over a prolonged period is large enough to induce dental staining or to inhibit bone growth, but these effects are theoretically possible.20 Therefore, doxycycline should be used for lactating women only if ciprofloxacin and amoxicillin are contraindicated. Because amoxicillin has been used safely in infants, it may be preferable for continued prophylaxis once anthrax isolates have been confirmed penicillin sensitive, provided the likely dose of organisms from the exposure is low.42 However, as with any antibiotic, an infant exposed over a long period could develop a hypersensitivity reaction to the drug. Lactating women should be encouraged to discuss the options for antimicrobial prophylaxis with their clinicians.40
Side effects. Pregnant women taking lengthy antibiotic regimens should be advised that side effects are to be expected, but that the vast majority of these effects will be mild. Ameliorating minor effects and having realistic expectations about the occurrence of such side effects are imperative if patients are to complete prolonged antibiotic regimens. Among the people who took postexposure prophylaxis after the Fall 2001 bioterrorism attacks, the most frequently reported side effects for both doxycycline and ciprofloxacin were GI complaints, headaches, lightheadedness, and dizziness. Although most of these individuals reported some side effects, only 0.3% of persons taking prophylaxis had a potentially serious side effect.43,44
Approximately 2% of women who received postexposure prophylaxis in the fall of 2001 reported a pregnancy at some time during therapy.44 There is no information about their particular experience with side effects. However, heartburn that occurs frequently among pregnant women is of particular concern. Antacids taken simultaneously with ciprofloxacin can decrease absorption of the drug by more than 90%. Instruct a pregnant patient not to take antacids within 6 hours before or 2 hours after taking ciprofloxacin.
Anthrax vaccination and pregnancy. Since 1970, Anthrax Vaccine Absorbed (AVA) (BioPort Corporation, Lansing, Mich.) has been licensed for preexposure prophylaxis by the Food and Drug Administration.45 AVA is prepared from an avirulent, nonencapsulated strain of B anthracis. The vaccine is administered subcutaneously in a series of six doses over 18 months and elicits an immune response to anthrax infection. There are very limited data in humans to evaluate the risk for congenital anomalies among offspring born to women vaccinated with AVA during pregnancy. Among a cohort of 3,136 US Army women aged 17 to 44 who received the anthrax vaccine, no effect on pregnancy rate, birth rate, or the presence of structural abnormalities was observed. However, the cohort of 385 pregnancies that occurred after vaccination did not have adequate statistical power to rule out small increases in adverse effects.46
US Department of Defense investigators are currently examining additional data from the medical records of service women to look at the frequency of birth defects among the offspring of women vaccinated for anthrax during the first trimester of pregnancy.47 The results are still pending. In the meantime, the Department of Defense recommends that anthrax vaccination of pregnant women be avoided.47 Before any anthrax vaccination, women should be asked if their menses are normal and on time, and encouraged to take a pregnancy test.48 Administration of nonlive vaccines such as the anthrax vaccine to breastfeeding mothers is not medically contraindicated.49
Anthrax is rare and rapidly fatal if left untreated, and an optimal biologic weapon. It is imperative that obstetrician/gynecologists understand the clinical presentation of anthrax infection, maintain a high degree of suspicion, and become familiar with the most recent recommendations for prophylaxis and treatment of anthrax infections in pregnant and lactating women.
In summary, treating active anthrax infection for a pregnant or lactating woman is the same as for a nonpregnant adult. The risk of death in this situation far outweighs any potential teratogenic effects of antimicrobial therapy. For pregnant and lactating women who have been exposed to anthrax but who do not have an active infection, consider the potential effects on the fetus of the different antibiotics available, or of the anthrax vaccine, before selecting the postexposure prophylaxis regimen. Consult with an infectious disease specialist for help with selecting the most safe and efficacious regimen available.
In the event that another bioterrorism attack occurs and public health officials determine that treatment or prophylaxis is necessary, obstetrician/gynecologists can play a critical role in recognizing the presence of anthrax infection, providing timely and appropriate treatment or prophylaxis, encouraging patients to adhere to the antibiotic regimen, identifying obstacles to continuing long-term prophylaxis, and monitoring for adverse pregnancy outcomes. Additional information about clinical diagnosis and management of anthrax infection and exposure can be found on the CDC's Web site ( http://www.bt.cdc.gov ), the US Army Medical Research Institute of Infectious Diseases Web site ( http://www.usamriid.army.mil/education/bluebook.html ), the Association for Professionals in Infection Control and Epidemiology Web site ( http://www.apic.org ), and the Johns Hopkins Center for Civilian Biodefense Strategies ( http://www.hopkins-biodefense.org ).50
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40. The American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108:776-789.
41. Wendel GD Jr, Stark BJ, Jamison RB, et al. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med. 1985;312:1229-1232.
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43. Williams JL, Noviello SS, Griffith KS, et al. Anthrax postexposure prophylaxis in postal workers, Connecticut, 2001. Emerg Infect Dis. 2002;8. Available at http://www.cdc.gov/ncidod/EID/vol8no10/02-0346.htm . Accessed February 26, 2003.
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45. CDC. Anthrax vaccine and antibiotics availability program. BB-IND 10061; FY 2001; Version 2.
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50. Centers for Disease Control and Prevention. Recognition of illness associated with the intentional release of a biologic agent. MMWR Morb Mortal Wkly Rep. 2001;50:893-897.
Jenny Williams, Sheryl Lyss, Janet Cragan. Your pregnant or lactating patient has been exposed to anthrax: now what?
Sep. 1, 2003;48:84-100.