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P. Brandon Bookstaver,1,* Christopher M. Bland,2 Brooke Griffin,3 Kayla R. Stover,4 Lea S. Eiland,5
and Milena McLaughlin,3
1
Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, University of
South Carolina, Columbia, South Carolina; 2Department of Clinical and Administrative Pharmacy, University of
Georgia College of Pharmacy, Savannah, Georgia; 3Department of Pharmacy Practice, Midwestern University
Chicago College of Pharmacy, Downers Grove, Illinois; 4Department of Pharmacy Practice, University of
Mississippi School of Pharmacy, Jackson, Mississippi; 5Department of Pharmacy Practice, Auburn University
Harrison School of Pharmacy, Meridian, Mississippi
During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately
one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of
prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut
microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of
medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as
beta-lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally
considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided
in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate,
increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment.
KEY WORDS antibiotic therapy, pregnancy, teratogenicity, pharmacokinetics.
(Pharmacotherapy 2015;35(11):10521062) doi: 10.1002/phar.1649
Reports suggest that antibiotics account for
nearly 80% of all prescription medications during pregnancy and that approximately 2025%
of women will receive an antibiotic during pregnancy.13 The most common infections encountered during pregnancy include urinary tract
infections (UTIs), including pyelonephritis; sexually transmitted infections (STIs); and upper
respiratory tract infections (URTIs).1 Although
use of any medication during pregnancy is a
risk-versus-benefit decision, untreated infections
such as UTIs or STIs are associated with significant fetal risk including spontaneous abortion,
prematurity, and low birth weight.4, 5 Safety and
efficacy information are not usually available
from randomized controlled trials, as these studies are often not feasible in pregnant women and
are potentially unethical. Thus, pregnancy is
often a standard criterion for exclusion from
clinical trials. It is estimated that only 10% of
medications marketed since 1980 have sufficient
data regarding infantile risk in pregnancy.6
1053
1054
Table 1. Food and Drug Administration Pregnancy Category Ratings with Required Package Labeling Statements Prior to
June 201514
Pregnancy
Category Rating
A
Level of Evidence
None
8.2 Lactaon
Figure 1. Labeling changes for the new pregnancy and lactation section. Adapted from www.fda.gov Available at: http://
www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm.
26
Antibiotic
Aminoglycosides
FDA Pregnancy
Category Ratingb
Notes
B
C
B
C
B
C
C
Should be avoided
Daptomycin
Fidaxomicin
B
B
Fosfomycin
Metronidazole
Nitrofurantoin
Polymyxins
Polymyxin B, polymyxin E
B
B
B
C
Folate antagonists
Sulfamethoxazole, trimethoprim
C
B
C
C
Tigecycline
Antimycobacterial agents
Isoniazid (INH)
Ethambutol
Pyrazinamide
Rifampin, rifabutin,
rifapentine
Bedaquiline
a
1055
Ceftolozane-tazobactam and ceftazidime-avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy
Category B rating.
b
Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language.
26
Antibiotic
Aminoglycosides
FDA Pregnancy
Category Ratingb
Notes
B
C
B
C
B
C
C
Should be avoided
Daptomycin
Fidaxomicin
B
B
Fosfomycin
Metronidazole
Nitrofurantoin
Polymyxins
Polymyxin B, polymyxin E
B
B
B
C
Folate antagonists
Sulfamethoxazole, trimethoprim
C
B
C
C
Tigecycline
Antimycobacterial agents
Isoniazid (INH)
Ethambutol
Pyrazinamide
Rifampin, rifabutin,
rifapentine
Bedaquiline
a
1055
Ceftolozane-tazobactam and ceftazidime-avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy
Category B rating.
b
Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language.
1056
Carbapenems
There is a paucity of data regarding the use of
carbapenems during pregnancy. Ertapenem,
meropenem, and doripenem are Pregnancy Category B, while imipenem-cilastatin is Pregnancy
Category C.19 Pharmacokinetic changes associated with pregnancy have shown decreased imipenem concentrations.19 Carbapenem therapy
should be reserved for pregnant women with
infections that are resistant to penicillin and
cephalosporin therapy with limited alternatives.
Monobactams
While its lack of cross-reactivity with penicillins and cephalosporins makes aztreonam an
appealing choice, there are inconclusive data
regarding its safety in pregnancy. Most safety
data are in the perinatal period, which supports
its Pregnancy Category B rating.19 Aztreonam
should be used with caution during the first trimester as data are limited.27 Due to a lack of
data at this time, aztreonam use should be
restricted to patients with severe penicillin
allergy for whom beta-lactam therapy is contraindicated.
Fluoroquinolones
1057
1058
versus other antibiotics or nonteratogens, no differences were found in the rates of major malformations between groups.36 Similar to erythromycin,
data from studies of clarithromycin (Pregnancy
Category C) have been conflicting. In animal
studies, some rats exposed to clarithromycin in
the first trimester did not result in teratogenicity, while other rats showed low incidences of
cardiac abnormalities after clarithromycin exposure.35 Other data report cleft palate in murine
studies and retarded fetal growth in monkeys.35
In clinical reports, including a prospective
controlled study, clarithromycin exposure has
not been associated with increased incidence of
major malformations.23, 37, 38 Although data are
conflicting, it is generally thought that azithromycin is safe to use in pregnancy, while clarithromycin should be used with caution and
only when benefit outweighs risk.
Telithromycin is a ketolide antibacterial with
similar structure and activity as the macrolides.
There are no human data for the use of telithromycin in pregnancy, and it is Pregnancy Category C.26 In rats and rabbits, telithromycin was
not teratogenic at doses ranging from 0.5 to 1.8
times the human doses. At higher doses, delayed
fetal maturation was observed, possibly related
to maternal toxicity. Given its relative limited
utility and potential risks, telithromycin should
be avoided in pregnancy.
Oxazolidinones
Currently, there are a lack of pharmacokinetic
and controlled studies of linezolid and tedizolid
in pregnant women. Linezolid distributes well
into tissue and has 31% protein binding,
whereas tedizolid is highly protein bound (70
90%).26 Positive maternal outcomes without fetal
teratogenesis were detailed in a case report of
4 weeks of linezolid use starting at 14 weeks of
pregnancy.39 Both agents are Pregnancy Category C and animal studies in mice, rats, and rabbits have not shown teratogenic effects.19
However, in rats, linezolid and tedizolid resulted
in mild fetal toxicities, including decreased fetal
body weight and reduced ossification of the
sternebrae at maternally toxic doses.26 A reduction in fetal weight and increase in costal cartilage abnormalities were seen with tedizolid use
in mice with the absence of maternal toxicities
(4-fold increase in the estimated human exposure based on area under the concentration
curve [AUC]).26 Fetal weight loss and maternal
toxicity were identified with tedizolid use in
1059
1060
Polymyxins
Tigecycline
Sulfamethoxazole-Trimethoprim
Sulfamethoxazole and trimethoprim are both
rated FDA Pregnancy Category C.19 They are
bound to plasma proteins (sulfamethoxazole >
trimethoprim) and eliminated renally primarily
through glomerular filtration and renal tubular
secretion.26 Animal studies have demonstrated
teratogenic effects. Sulfamethoxazole and
trimethoprim both cross the placenta and should
be avoided in the first trimester due to the
mechanism of trimethoprim as a folate antagonist. Exposure during this period can significantly increase the risk of major congenital
malformations, primarily neural tube and cardiac
defects.54 Trimethoprim has also been associated
with an increase in cleft palates with first trimester use.55 Approximately 2-fold increases in cardiac and limb malformations were seen with
trimethoprim use 12 weeks prior to conception.56 However, maternal folic acid supplementation reduces the risk of major fetal
malformations from trimethoprim. Sulfonamides
should not be used in the third trimester as they
theoretically result in an increase of unbound
bilirubin due to competitive protein binding.
Sulfamethoxazole-trimethoprim use during the
first trimester has been also associated with a
3-fold increase in urinary tract defects and its
use during the last two trimesters has been
associated with small for gestational age newborns.54, 57 Overall, sulfamethoxazole-trimethoprim should be avoided in the first trimester and
after 32 weeks gestation if other treatment
options are available. In the second and third
trimesters, use in pregnant women should be
limited to those situations when the benefits
outweigh the potential risks.
Antimycobacterial Agents
First-line therapy for tuberculosis (TB) in
pregnant women is consistent with the nonpregnant populations and includes isoniazid (INH),
rifampin, ethambutol, and pyrazinamide.58, 59 A
systematic review demonstrated overall safety of
first-line therapy comparable to the general population.59 Of note, many patients were not
exposed to anti-TB medications during the first
trimester, representing the most critical time of
fetal development and risk of abnormalities.
INH, Pregnancy Category C, has not produced
a signal of increased fetal abnormalities in animal
or human data.59, 60 A nonsignificant increase in
hepatitis has been observed in pregnant women
receiving INH, particularly in those with preexisting liver disease and HIV.60 Monitoring of
liver enzymes is important and is recommended
throughout pregnancy.59, 60 An elevation of 35
times the upper limit of normal may prompt
discontinuation of anti-TB therapy. INH is also
recommended for latent TB infection (LTBI) in
pregnancy as a first-line treatment. Low-risk
patients may be advised to defer treatment of
LTBI until after pregnancy because of concerns
about medication exposure. High-risk patients
(e.g., HIV) should be initiated on INH therapy. Pyridoxine (B6) daily oral supplementation (2550 mg/day) is advised in all pregnant
women receiving INH to mitigate neurologic complications in the mother and newborn.59, 60
Rifampin use in animals at up to ten times the
normal human dose did not produce any fetal
abnormalities; however, increasing the dose to
15 times human exposure at the time of conception was associated with significant fetal malformations.60 Use of rifampin in more than 2000
pregnant women has not produced an increase
in fetal abnormalities.60 Rifampin has a Pregnancy Category C rating.19 INH coupled with
rifampin is known to increase liver enzymes
additively; thus, careful monitoring is advised.
An association between rifampin and newborn
1061
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