- Recommendations regarding antibiotic and vaccine use
in the setting of a biological anthrax attack are conditioned by a limited
number of studies in experimental animals, current understanding of antibiotic
resistance patterns, and the possible requirement to treat large numbers
of casualties. A number of possible therapeutic strategies have yet to
be fully-explored experimentally or submitted for approval to the FDA.
For these reasons, the working group offers consensus recommendations based
on the best available evidence. The recommendations do not represent uses
currently approved by the FDA or an official position on the part of any
of the federal agencies whose scientists participated in these discussions
and will need to be revised as further relevant information becomes available.
-
- Given the rapid course of symptomatic inhalational anthrax,
early antibiotic administration is essential. A delay of antibiotic treatment
for patients with anthrax infection even by hours may substantially lessen
chances for survival. http://jama.ama-assn.org/issues/v281n18/ffull/#r56
Given the difficulty in achieving rapid microbiologic diagnosis of anthrax,
all persons with fever or evidence of systemic disease in an area where
anthrax cases are occurring should be treated for anthrax until the disease
is excluded.
-
- There are no clinical studies of the treatment of inhalational
anthrax in humans. Thus, antibiotic regimens commonly recommended for empirical
treatment of sepsis have not been studied in this setting. In fact, natural
strains of B anthracis are resistant to many of the antibiotics used in
these empirical regimens, such as those of the extended-spectrum cephalosporins.
http://jama.ama-assn.org/issues/v281n18/ffull/#r58
http://jama.ama-assn.org/issues/v281n18/ffull/#r59
-
- Most naturally occurring anthrax strains are sensitive
to penicillin, and penicillin historically has been the preferred therapy
for the treatment of anthrax. Penicillin is approved by the FDA for this
indication, http://jama.ama-assn.org/issues/v281n18/ffull/#r41
http://jama.ama-assn.org/issues/v281n18/ffull/#r56
http://jama.ama-assn.org/issues/v281n18/ffull/#r57
as is doxycycline. http://jama.ama-assn.org/issues/v281n18/ffull/#r6
-
- Doxycycline is the preferred option from the tetracycline
class of antibiotics because of its proven efficacy in monkey studies and
its ease of administration. Other members of this class of antibiotics
are suitable alternatives. Although treatment of anthrax infection with
ciprofloxacin has not been studied in humans, animal models suggest excellent
efficacy. http://jama.ama-assn.org/issues/v281n18/ffull/#r28
http://jama.ama-assn.org/issues/v281n18/ffull/#r41
http://jama.ama-assn.org/issues/v281n18/ffull/#r61
-
- In vitro data suggest that other fluoroquinolone antibiotics
would have equivalent efficacy in treating anthrax infection, although
no animal data exist for fluoroquinolones other than ciprofloxacin. http://jama.ama-assn.org/issues/v281n18/ffull/#r59
-
- Reports have been published of a B anthracis vaccine
strain that has been engineered by Russian scientists to resist the tetracycline
and penicillin classes of antibiotics. http://jama.ama-assn.org/issues/v281n18/ffull/#r62
Although the engineering of quinolone-resistant B anthracis may also be
possible, to date there have been no published accounts of this.
-
- Balancing considerations of efficacy with concerns regarding
resistance, the working group recommends that ciprofloxacin or other fluoroquinolone
therapy be initiated in adults with presumed inhalational anthrax infection.
Antibiotic resistance to penicillin- and tetracycline-class antibiotics
should be assumed following a terrorist attack until laboratory testing
demonstrates otherwise. Once the antibiotic susceptibility of the B anthracis
strain of the index case has been determined, the most widely available,
efficacious, and least toxic antibiotic should be administered to patients
and persons requiring postexposure prophylaxis.
-
- In a contained casualty setting (a situation in which
a modest number of patients require therapy), the working group recommends
intravenous antibiotic therapy, as shown in http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html
Table 2.
-
- If the number of persons requiring therapy is sufficiently
high (ie, a mass casualty setting), the working group recognizes that intravenous
therapy will no longer be possible for reasons of logistics and/or exhaustion
of equipment and antibiotic supplies, and oral therapy will need to be
used http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html
Table 3.
-
- The threshold number of cases at which parenteral therapy
becomes impossible depends on a variety of factors, including local and
regional health care resources.
-
- In experimental animals, antibiotic therapy during anthrax
infection has prevented development of an immune response. http://jama.ama-assn.org/issues/v281n18/ffull/#r28
http://jama.ama-assn.org/issues/v281n18/ffull/#r62
-
- This suggests that even if the antibiotic-treated patient
survives anthrax infection, risk for recurrence remains for at least 60
days because of the possibility of delayed germination of spores. Therefore,
the working group recommends that antibiotic therapy be continued for 60
days, with oral therapy replacing intravenous therapy as soon as a patient's
clinical condition improves. If vaccine were to become widely available,
postexposure vaccination in patients being treated for anthrax infection
might permit the duration of antibiotic administration to be shortened
to 30 to 45 days, with concomitant administration of 3 doses of anthrax
vaccine at 0, 2, and 4 weeks.
-
- The treatment of cutaneous anthrax historically has been
with oral penicillin. The working group recommends that oral fluoroquinolone
or tetracycline antibiotics as well as amoxicillin in the adult dosage
schedules described in http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html
Table 2 and http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html
Table 3 would be suitable alternatives if antibiotic susceptibility is
proved. Although previous guidelines have suggested treating cutaneous
anthrax for 7 to 10 days, http://jama.ama-assn.org/issues/v281n18/ffull/#r23
http://jama.ama-assn.org/issues/v281n18/ffull/#r49
the working group recommends treatment for 60 days in the setting of bioterrorism,
given the presumed exposure to the primary aerosol. Treatment of cutaneous
anthrax generally prevents progression to systemic disease, although it
does not prevent the formation and evolution of the eschar. Topical therapy
is not useful.
-
- Other antibiotics effective against B anthracis in vitro
include chloramphenicol, erythromycin, clindamycin, extended-spectrum penicillins,
macrolides, aminoglycosides, vancomycin hydrochloride, cefazolin, and other
first-generation cephalosporins. http://jama.ama-assn.org/issues/v281n18/ffull/#r58
http://jama.ama-assn.org/issues/v281n18/ffull/#r59
http://jama.ama-assn.org/issues/v281n18/ffull/#r64
-
- The efficacy of these antibiotics has not been tested
in humans or animal studies. The working group recommends the use of these
antibiotics only if the previously cited antibiotics are unavailable or
if the strain is otherwise antibiotic resistant. Natural resistance of
B anthracis strains exists against sulfamethoxazole, trimethoprim, cefuroxime,
cefotaxime sodium, aztreonam, and ceftazidime. http://jama.ama-assn.org/issues/v281n18/ffull/#r58
-
- Postexposure Prophylaxis
-
- Guidelines regarding which populations would require
postexposure prophylaxis following the release of anthrax as a biological
weapon would need to be developed quickly by state and local health departments
in consultation with national experts. These decisions require estimates
of the timing and location of the exposure and the relevant weather conditions
in an outdoor release. http://jama.ama-assn.org/issues/v281n18/ffull/#r65
-
- Ongoing monitoring of cases would be needed to define
the high-risk areas, direct follow-up, and guide the addition or deletion
of groups to receive postexposure prophylaxis.
-
- There are no FDA-approved postexposure antibiotic regimens
following exposure to an anthrax aerosol. For postexposure prophylaxis,
the working group recommends the same antibiotic regimen as that recommended
for treatment of mass casualties; prophylaxis should be continued for 60
days http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html
Table 3.
-
- Management of Special Groups
-
- Consensus recommendations for special groups as set forth
herein reflect the clinical and evidence-based judgments of the working
group and at this time do not necessarily correspond with FDA-approved
use, indications, or labeling.
-
- Children
-
- It has been recommended that ciprofloxacin and other
fluoroquinolones should not be used in children younger than 16 to 18 years
because of a link to permanent arthropathy in adolescent animals and transient
arthropathy in a small number of children. http://jama.ama-assn.org/issues/v281n18/ffull/#r60
-
- However, balancing these risks against the risks of anthrax
caused by an engineered antibiotic-resistant strain, the working group
recommends that ciprofloxacin be used in the pediatric population for initial
therapy or postexposure prophylaxis following an anthrax attack http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html
Table 2.
-
- If antibiotic susceptibility testing allows, penicillin
should be substituted for the fluoroquinolone.
-
- As a third alternative, doxycycline could be used. The
American Academy of Pediatrics has recommended that doxycycline not be
used in children younger than 9 years because the drug has resulted in
retarded skeletal growth in infants and discolored teeth in infants and
children. http://jama.ama-assn.org/issues/v281n18/ffull/#r60
-
- However, the serious risk of infection following an anthrax
attack supports the consensus recommendation that doxycycline be used in
children if antibiotic susceptibility testing, exhaustion of drug supplies,
or allergic reaction preclude use of penicillin and ciprofloxacin.
-
- In a contained casualty setting, the working group recommends
that children receive intravenous antibiotics http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html
Table 2.
-
- In a mass casualty setting and as postexposure prophylaxis,
the working group recommends that children receive oral antibiotics http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html
Table 3.
-
- The US vaccine is licensed for use only in persons aged
18 to 65 years because studies to date have been conducted exclusively
in this group. http://jama.ama-assn.org/issues/v281n18/ffull/#r52
No data exist for children, but based on experience with other inactivated
vaccines, it is likely that the vaccine would be safe and effective.
-
- Pregnant Women
-
- Fluoroquinolones are not generally recommended during
pregnancy because of their known association with arthropathy in adolescent
animals and small numbers of children. Animal studies have discovered no
evidence of teratogenicity related to ciprofloxacin, but no controlled
studies of ciprofloxacin in pregnant women have been conducted. Balancing
these possible risks against the concerns of anthrax due to engineered
antibiotic-resistant strains, the working group recommends that ciprofloxacin
be used in pregnant women for therapy and postexposure prophylaxis following
an anthrax attack http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html
Table 2 and http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html
Table 3. No adequate controlled trials of penicillin or amoxicillin administration
during pregnancy exist. However, the CDC recommends penicillin for the
treatment of syphilis during pregnancy and amoxicillin as a treatment alternative
for chlamydial infec
-
- The working group recommends that pregnant women receive
fluoroquinolones in the usual adult dosages. If susceptibility testing
allows, intravenous penicillin in the usual adult dosages should be substituted
for fluoroquinolones. As a third alternative, intravenous doxycycline could
be used. The tetracycline class of antibiotics has been associated with
both toxic effects in the liver in pregnant women and fetal toxic effects,
including retarded skeletal growth. http://jama.ama-assn.org/issues/v281n18/ffull/#r60
-
- Balancing the risks of anthrax infection with those associated
with doxycycline use in pregnancy, the working group recommends that doxycycline
be used in pregnant women for therapy and postexposure prophylaxis if antibiotic
susceptibility testing, exhaustion of drug supplies, or allergic sensitivity
preclude the use of penicillin and ciprofloxacin. If doxycycline is used
in pregnant women, periodic liver function testing should be performed
if possible.
-
- Ciprofloxacin (and other fluoroquinolones), penicillin,
and doxycycline (and other tetracyclines) are each excreted in breast milk.
Therefore, a breast-feeding woman should be treated or given prophylaxis
with the same antibiotic as her infant based on what is most safe and effective
for the infant (see pediatric guidelines herein) to minimize risk to the
infant.
-
- Immunosuppressed Persons
-
- The antibiotic treatment or postexposure prophylaxis
for anthrax among those who are immunosuppressed has not been studied in
human or animal models of anthrax infection. Therefore, the working group
consensus recommendation is to administer antibiotics as for immunocompetent
adults and children link
1 Table 2 and link
2 Table 3). ___
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