Policy: These standing orders allow eligible health care ptoviders to treat persons exposed to anthrax.

STANDING ORDERS FOR ANTIMICROBIAL THERAPY OF MASS CASUALTY INHALATIONAL ANTHRAX AND POST-EXPOSURE PROPHYLAXIS TO BACILLUS ANTHRACIS: CIPROFLOXACIN, DOXYCYCLINE, AND AMOXICILLIN. Purpose: To reduce the motbidity and mortality from B. anthracis infection by providing treatment and post-exposure ptophylaxis with ciprofloxacin, doxycycline, or amoxicillin. Policy: These standing orders allow eligible health care ptoviders to treat persons exposed to anthrax. Indications, Contraindications, Precautions, Special Populations, and Side Effects: The dose and safety precautions for these drugs can change over time. Clinicians should seek the most current and comprehensive product information before using these drugs as treatment or ptophylaxis for anthrax. Persons infected or exposed Persons infected or exposed. Persons infected or exposed to aetosolized B. anthrads. to aerosolized B. anthrads. to aerosolized B. an/brads. Allergy to ciprofloxacin or Hypersensitivity to History of allergic reaction other quinolone medicine tetracyclines. Concurrent to any of the penicillins (e.g., norfloxacin, ofloxacin, use of tetracycline and (e.g., ampicillin, nalidixic acid). Conncurrent methoxyflurane (methyl dicloxacillin, penicillin), administration with ether) may result in fatal cephalosporins, or betatizanidine renal toxicity. lactams. Hypersensitivity reactions are more likely in patients with a history of allergy, asthma, hay fever, or urticaria. Chronic renal or liver Breastfeeding or pregnant Persons with disease, myasthenia gravis, women, liver disease, kidney phenylketonuria (PKU), history of seizures or stroke, disease, pyrosis, infants less Clostridium diffidle infection, breastfeeding, pregnancy, than 6 months of age. breastfeeding or pregnant pyrosis, joint or tendon Avoid direct sunlight. If women, liver disease, kidney disease, unusual bleeding or using oral contraceptives, disease, persons taking bruising. Avoid direct use alternative forms of probenecid. Ifusing oral sunlight and alcohol. birth control during and 1 contraceptives, use Women may be at increased week after taking alternative forms ofbirth risk for yeast infections. doxycycline. Women may control during and 1 week Ciprofloxacin may increase be at increased risk for yeast after taking amoxicillin. the effects of caffeine and infections. Children: Doxycycline is Children: Pediatric patients October 11, 2011 Page 1 of6 Version 3.1

flouroquioolones are not used in children less than 18 years of age, however, risk/ benefitconrrprucison regarding anthrax infection indicates use. Children under the age of 18 years may experience joint pain. If this occurs, a doctor must be consulted immediately. Nausea, vonrriting, diarrhea, fatigue, dizziness, headache, pain in arms or legs, vision changes, restlessness, ringing of ears, mental changes, or photosensitivity / phototoxic ity. not typically used in children less than 9 years of age, however, it is indicated if antibiotic susceptibility testing, limited drugs supplies or adverse reactions precludes ciprofloxacin usage. Children less than 8 years of age may experience teeth staining. Premature infants may experience temporary bone O't" )urj"h Nausea, vonrriting, diarrhea, dark urine, jaundice, sore throat, fever, unusual bleeding or bruising, fatigue, white patches in mouth. less than 12 weeks of age should have modified dosing. Temporary tooth discoloration may appear. Pregnant Women: Generally safe unless allergic to penicillins. Nursing Women: May be excreted in human breast milk. Nausea, vonrriting, diarrhea, black hairy tongue, pseudomembranous colitis, mucocutaneous candidiasis, serum sickness-like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, hepatic dysfunction, anemia, crystalluria, or mental Inhalational Anthrax Infection Associated with a Mass Casualty Event Criteria (Table 1): Successful medical management is related to early use of antibiotics and aggressive use of supportive care. Optimally, persons diagnosed with inhalational anthrax should initially receive intravenous antibiotics. However, in a mass casualty setting this may not be feasible and an oral only regiment must be utilized. The recommendation for initial treatment of inhalational anthrax is a multi-drug regimen of either ciprofloxacin or doxycycline along with one or more agents to which the organisnrr is typically sensitive. After susceptibility testing and clinical improvement, the regimen may be altered. (Table 1). Pregnant women should receive ciprofloxacin in usual adult dosages as part of combination therapy for treatment of inhalational anthrax. Doxycycline should not be used ifmeningitis is suspected because it does not adequately penetrate the blood brain barrier. Additional antibiotics not listed in these standing orders have been approved for treatment of anthrax infection. Bacillus Anthracis Post-Exposure Prophylaxis (PEP) Criteria (Table 2): October 11, 2011 Page 2of6 Version 3.1

Atnoxicillin may be substituted as PEP in pregnant women only after 14 21 s of luoroqtrinolone or doxycycline administration pending susceptibility testing. PEP is not indicated for health care and mortuary workers ifthey use standard precautions (airborne ifindicated). Cipro loxacin and doxycycline should be used as first-line PEP. Penicillin G procaine has also been approved by the FDA. Additional regimen options include: >- 60 s of antibiotic plus anthrax vaccine (3 doses over 4 week period) as per protocol for Investigational New Drug or Emergency Use Authorization. >- 60 s of antibiotic prophylaxis. ' Additional antibiotics not listed in these standing orders have been approved for post-exposure prophylaxis of B. anthrads. Medical Emergency or Anaphylaxis: Written emergency medical protocols, as well as equipment and medications, must be available at administration site. Anaphylaxis includes rash, difficulty breathlng, swollen tongue or throat, itchlness of throat, and collapse. Dosage Information: See Table 1 for recommended therapy for inhalational anthrax infection and Table 2 for recommended post-exposure prophylaxis. Table 3 and 4 provide simplified pediatric dosing by weight for cipro loxacin and doxycycline respectively when used for treatment ofinhalational anthrax. For more infonnation regarding doxycycline crushlng and admlnistration visit: http://www.fda.govi downloads IDrng LEmergenc:yPreparedness IBioterrorismandDrugPre parednesslucm131006.pdf. This protocol shall remain in effect for all persons infected or exposed to B. anthracis until rescinded. Approved by: ~\ I/Ir/2-'>1 ( Chief Medical Executive Date Michigan Departlrft~~ 7 -I '2..~ Date October 11, 2011 Page 3 of6 Version 3.1

... Table 1. Recommended antimicrobial therapy for cases associated with exposure to aerosolized Bacillus anthracis '. Population Initial Intravenous Therapyb,c OIal Regimens (continue therapy for 60 s [IV and PO combined]) :idults (18-65 yrs) Ciprofloxacin, 400 mg every 12 hr Patients should be treated with lv therapy Includes or initially.d immunocompromised Doxycycline, 100 mg every 12 hi" person8 Treatment can be switched to oral therapy when and clinically appropriate: One or two additional antimicrobials (agents with in vitro activity include rifampin, vancomycin. Gprofloxacin, 500 mg PO penicillin, ampicillin, chloramphenicol. imipenem. or dindamycin, and clarithromycin)f Doxycycline, 100 mg PO Pregnant women Same as for nonpregnant adults (high death rate Patients should be treated with lv therapy from the infection outweighs risk posed by initially. Treatment can be switched to PO when antimicrobial agent) clinically appropriate. Oral therapy regimens are the same as for nonpregnant adults. Children «18 yrs) Gprofloxacin, 10-15 mg/kg every 12 hr, not to Patients should be treated with lv therapy exceed 1 g/& initiallyd or Doxycycline.,h: Treatment can be switched to oral therapy when >8 yr and >45 kg: 100 mg every 12 hr clinically appropriate: >8 yr and.:s;45 kg: 2.2 mg/kg every 12 hr.:s;8 yr: 2.2 mg/kg every 12 hr Ciprofloxacin, 10-15 mg/kg PO every 12 hr, not and One or two additional antimicrobials (see agents listed under therapy for adults? to exceed 1 g/ or Doxycyclineh: >8 yr and >45 kg: 100 mg PO every 12 hr >8 yr and.:s;45 kg: 2.2 mg/kg PO every 12 hr <8 yt; 2.2 mgjkg PO every 12 Abbreviations: lv, intravenously; PO, orally. 'Meningitis involvement must be assumed in all systemic infections. Antibiotic selection must consider penetration across blood-brain barrier. These treatment recommendations were made during US 2001 anthrax outbreak. In other situations, antimicrobial susceptibility testing should be used to guide therapy decisions. bciprofloxacin or doxycycline should be considered an essential part of first-line therapy for inhalational anthrax. CSteroids may be considered an adjunct therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies. djnitial therapy may be altered based on clinical course of patient; one or two antimicrobial agents (eg, ciprofloxacin or doxycycline) may be adequate as patient improves. eif meningitis is suspected, doxycycline may be less optimal because ofpoor central nervous system penetration.!because of concerns of constitutive and inducible beta-lactamases in B anthracis isolates, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised. Other agents with in vitro activity include tetracycline, linezohd, macrolides, aminoglycosides, and cefazolin. B anthraci.r strains are naturally resistant to sulfamethoxazole, trimethoprim, cefuroxime, cefotaxime sodium, aztreonarn, and ceftazidime. gif intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1-2 hr after oral doing but may not be achieved ifvomiting or ileus is present. bamerican Academy of Pediatrics recommends treatment ofyoung children with tetracyclines for serious infections (eg, Rocky Mountain Spotted Fever). ialthough tetracyclines are not recommended for pregnant women, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose-related; therefore, doxycycline might be used for a short time (7-14 s) before 6 months of gestation. October 11, 2011 Page 4 of6 Version 3.1

Table 2. Recommended initial antimicrobial agent and anthrax vaccine adsorbed (AVA) dosages for postexposure prophylaxis (PEP) after exposure to aerosolized Bacillus antbrads spores. Population Antimicrobials for 60-* PEP AVA dosage and routet One oftbejo/lmvingjor 60 dt:!js: Adults (18-65 yrs) Includes immunocompromised persons Pregnant women'\[ Children «18 yrs)tt Ciprofloxacin, 500 mg orally Doxycycline, 100 mg orally One ofthe jolkjwingjor 60 dt:!js: Ciprofloxacin, 500 mg orally Doxycycline, 100 mg orally Amoricillin,** 500 mg every 8 hrs One ofthe folkjwingjor 60 c!qys: Ciprofloxacin,,tt, 15 mg/kg every 12 hrs Doxycycline,tt,1M[ (ma..'cimum of 100 mg/dose) >8 yrs and >45 kg; 100 mg every 12 hrs >8 yrs and S45 kg: 2.2 mg/kg every 12 hrs S8 yrs: 2.2 mg/kg every 12 hrs Amoricillin,**,*** 45 mg/kg/ orally divided into 3 daily doses given every 8 hrs; each dose should not exceed 500 mg 3-dose subcutaneous (SC) series: first dose administered as soon as possible, second and third doses administered 2 and 4 wks after the first dose 3-dose sc series; first dose administered as soon as possible, second and third doses administered 2 and 4 wks after the first dose Recommendations for use of A VA in children are made on an event-by-event basis..\.ntimicrobials should continue for 14 s after administration of the third dose of vaccine. t A VA used for PEP must be administered subcutaneously. Levofloxacin is a second-line antimicrobial agent for PEP for persons aged 2:6 mos with medical issues (e.g., tolerance or resistance to ciprofloxacin) that indicate its use. Children: 16 mg/kg/ divided every 12 hrs; each dose should not exceed 250 mg. Adults: 500 mg every 24 hrs. Safety data on extended use oflevofloxacin in any population for >28 s are limited; therefore, levofloxacin PEP should only be used when the benefit outweighs the risk. '\[ The antimicrobial of choice for initial prophylactic therapy among pregnant women is ciprofloxacin. Doxycycline should be used with caution in asymptomatic pregnant women and only when other appropriate antimicrobial drugs are contraindicated. Although tetracyclines are not recommended during pregnancy, their use might be indicated for life-threatening illness. ** If susceptibility testing demonstrates an amoxicillin.r-.fic S0.125 pg/ml, oral amoxicillin should be used to complete therapy. tt Use of tetracyclines and fluoioquinolones in children can have adverse effects. These effects must be weighed carefully against the risk for developing life-threatening disease. If exposure to B. anthrads is confirmed, children may be treated initially with ciprofloxacin or doxycycline as prophyla.'os. However, amoricillin is preferred for antimicrobial PEP in children when susceptibility testing indicates that the B. anthracis isolate is susceptible to penicillins. Each ciprofloxacin dose should not exceed 500 mg, or 1 g/. 1M[ In 1991, the American Academy of Pediatrics (A.liP) amended the recommendation to allow treatment of young children with tetracyclines for serious infections such as Rocky Mountain spotted fever for which doxycycline might be indicated. Doxycycline is preferred for its dosage and low incidence of gastrointestinal side effects. *** Because of the lack of data on amoxicillin dosages for treating anthraj: (and the associated high mortality rate), AAP recommends a higher dosage of 80 mg/kg/, divided into 3 daily doses; each dose should not e.."'{ceed 500 mg. Ifthis higher dosage of amoricillin is used, recipients should be carefully monitored for side effects from long-term treatment. October 11, 2011 Page 5 of 6 Version 3.1

Table 3: Ciprofloxac:in - Pediatric Dosing by Weight for Inhalational Anthtax Infection* Dosage Forms of Ciprofloxacin Weight Dose (mg) Suspension 500 mg Tablet 250mg/5 m1 Crushed & Mixed 1OOmg/teaspoon 7-121bs/3-5 kg 50mgPOBID 1 m1 Use susp. 13-221bs/6-10 kg 100 mgpo BID 2 m1 Use susp. 18-281bs/8-13 kg 125 mgpo BID 2.5 m1 1 lj.i teaspoons I 22-331bs/l0-15 kg 150 mg PO BID 3 m1 I 1 Yz teaspoons! 29-441bs/13-20 kg 200 mgpo BID 4 m1 2 teaspoons 36-561bs/16-25 kg I 250 mg PO BID 5 m1 2 Vz teaspoons 55-83Ibs/25-37 kg 375mgPOBID 7.5 m1 3 % teaspoons ;?: 731bs/;?: 33 kg 500mgPOBID 10 m1 5 teaspoons *This chart purposefully reflects more than one dose for a particular weight to permit flexibility in dosing based on the products that are available at the time of dispensing. These doses are within the recommended dosing range of ciprofloxac:in 10-15 mg/kg. Table 4: Doxycycline Pediatric Dosing by Weight for Inhalational Anthrax Infection** Dosage Forms of Doxycycline Weight Dose (mg) Suspension, loomgtablet 25mg/5 m1 I Crushed & Mixed 25 / teaspoon T> 12.51bs 1.;. <J 'ce 2.5 m1 (1/2 teaspoon Vz teaspoon mixture twice twice 12.5-251bs (6-12 kg) 25 mg 5 m1 (1 teaspoons) 1 teaspoon mixture 2x 2x 25-50 lbs (12-24 kg) 37.5 mg twice 7.5 m1 (1 Vz teaspoons) 1Vz teaspoon mixture daily 2x 2x 50 75lbs (24-36 kg) 50 rag 10 m1 (2 teaspoons) 2x 2 teaspoons mixture 2x 75-99lbs (36 45 kg) 75 rag 15 m1 (3 teaspoons) 2x 3 teaspoons mixture 2x **Above 991bs (45kg) or >8 years of age (if weight unavailable) use standard adult dosing of 100 mg. October 11, 2011 Page 6of6 Version 3.1