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C H A P T E R 3 1 

Other Infectious Conditions


MARK H. YUDIN

to T-cell receptors and the class II major histocompatibility


INTRODUCTION complex (MHC) without first undergoing antigen process-
Infections are an important contributor to maternal and peri- ing and presentation. The cross-linking of a T-cell receptor
natal morbidity and mortality rates. The relative immuno- with a class II MHC molecule by a superantigen stimulates
suppression that occurs during pregnancy may alter the the proliferation and activation of T cells and macrophages,
natural course of many infectious diseases. Higher attack causing them to release large amounts of cytokines, which
rates for a variety of bacterial and viral infections are seen can cause shock or inflammation and tissue damage.2,6 A
in pregnancy. Furthermore, many of these infections may be large number of SPE superantigens have been identified, but
associated with adverse outcomes, including preterm labor SPE A, SPE B, SPE C, SPE F, and streptococcal superantigen
and delivery, low birth weight, and stillbirth. This chapter (SSA) are among the best characterized. By stimulating
addresses a large group of infectious diseases and conditions cytokine production, these streptococcal exotoxins likely
not discussed in other chapters, including streptococcal play an important role in the pathogenicity of invasive GAS
infections, listeriosis, common sexually transmitted infec- infections by exacerbating the onset of clinical signs and
tions (STIs), and vaginitis. symptoms of infection.

GROUP A STREPTOCOCCUS Maternal and Fetal Risks


Group A streptococcus (GAS; Streptococcus pyogenes) has been GAS may be recovered from the skin or mucous mem-
associated with obstetric and neonatal infections since the branes of asymptomatic colonized patients. GAS may gain
16th century. It is probable that GAS was responsible for entry to the body via the skin, mucosa, pharynx, and
much of puerperal sepsis, or “childbed fever,” described by vagina and cause infections with both suppurative and
Semmelweis in 19th-century Vienna.1 However, with the nonsuppurative complications.2,7 The most notable GAS
advent of the antibiotic era, GAS infections became increas- infections encountered during pregnancy are presented in
ingly infrequent until the 1980s, when GAS infections dra- Table 31–2 and include bacteremia without a focus of
matically increased again for poorly understood reasons.2 infection and endometritis, but invasive infections includ-
GAS causes a broad spectrum of invasive and noninvasive ing STSS and necrotizing fasciitis also occur. The reasons
diseases, including bacterial pharyngitis, impetigo, scarlet for the increased susceptibility seen during the puerperium
fever, necrotizing fasciitis, and the more recently recognized include the breach of integrity in the integumentary system
streptococcal toxic shock syndrome (STSS), as outlined in associated with either vaginal delivery or cesarean section.
Table 31–1.2,3 Invasive infections are characterized by hypotension and
S. pyogenes, the etiologic agent for GAS infections, was first shock, multiple organ failure, systemic toxicity, severe
described by Louis Pasteur in 1879. The Streptococcus genus local pain, rapid necrosis of subcutaneous tissues and skin,
is classified into groups, based upon polysaccharide capsular renal dysfunction, and fever.2,7 GAS invasive disease is
antigens and the cell wall M protein, as first described by characterized by a rapid, often fatal course and by difficul-
Lancefield.4 S. pyogenes is divided into serotypes according to ties in the early diagnosis, when intervention may be more
the M protein, and to date, more than 80 M protein sero- successful.
types have been identified. Different serotypes are associ- Postpartum invasive GAS infection occurs in approxi-
ated with different forms of infection, and M1 and M3 have mately 1 in 11,000 to 1 in 17,000 births, with an average of
been the most common serotypes identified in serious infec- 220 cases occurring in the United States every year.8,9 The
tion in more recent years.5 rate of invasive GAS infection is 1.6- to 2.0-fold greater
M protein is also important as a virulence factor because among black patients than white patients.8 Maternal case
of its antiphagocytic properties. Other significant virulence fatality rate ranges from 3.5% to 30% in postpartum invasive
factors are the streptococcal pyrogenic exotoxins (SPE), GAS. Maternal GAS disease has also been associated with
which act as superantigens. Superantigens are able to bind stillbirth.

521
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522    S ECTION F OUR • Infection

T A B L E 3 1 – 1  T A B L E 3 1 – 3 
Classification of Group A Streptococcal Diagnostic Criteria for Streptococcal Toxic
Infections Shock Syndrome
1. Streptococcal toxic shock syndrome (streptococcal TSS) I. Isolation of Streptococcus pyogenes
2. Other invasive infections (isolation of Streptococcus pyogenes from A. From a normally sterile site
a normally sterile site in patients not fulfilling criteria from B. From a nonsterile site (throat, sputum, vagina, superficial skin
streptococcal TSS) lesion)
a. Bacteremia with no identifiable focus II. Clinical evidence of severity
b. Focal infection with or without bacteremia (meningitis, A. Hypotension (systolic blood pressure ≤ 90 mm Hg in adults or
pneumonia, peritonitis, puerperal sepsis, osteomyelitis, septic ≤ 5th percentile for age in children) and
arthritis, necrotizing fasciitis, surgical wound infections, B. Two or more of the following:
erysipelas, cellulitis) 1. Renal impairment (serum creatinine ≥ 2.0 mg/dL or a twofold
3. Scarlet fever elevation over baseline level in patients with preexisting renal
4. Noninvasive infections (recovery of S. pyogenes from a nonsterile impairment)
site) 2. Coagulopathy (platelets ≤ 100 × 106/L or disseminated
a. Mucous membranes (pharyngitis, tonsillitis, otitis media, intravascular coagulation)
sinusitis, vaginitis) 3. Liver involvement (AST, ALT, or total bilirubin ≥ two times
b. Cutaneous (impetigo) upper limits of normal)
5. Nonsuppurative sequelae (specific clinical findings with evidence of 4. Adult respiratory distress syndrome
a recent group A streptococcal infection) 5. Generalized erythematous macular rash
a. Acute rheumatic fever 6. Soft tissue necrosis (necrotizing fasciitis, myositis, or
b. Acute glomerulonephritis gangrene)

Adapted from The Working Group on Severe Streptococcal Infections: Defining ALT, alanine aminotransferase; AST, aspartate aminotransferase.
the group A streptococcal toxic shock syndrome. JAMA 1993;269:390– Adapted from The Working Group on Severe Streptococcal Infections: Defining
391. the group A streptococcal toxic shock syndrome. JAMA 1993;269:
390–391.

T A B L E 3 1 – 2  Diagnosis
Diseases Seen among Patients with Postpartum GASs can be readily recovered from most patients with
Group A Streptococcus Infection evidence of GAS disease. GASs are catalase-negative gram-
INFECTION NUMBER OF PATIENTS (N = 87) positive cocci that are β-hemolytic on blood agar. The colo-
nies may appear as highly mucoid to nonmucoid, and the
Bacteremia without focus 40 (46%) organisms are usually 1 to 2 mm in diameter. Although cul-
Endometritis 24 (28%) tures may be helpful in confirming the diagnosis of GAS
Peritonitis 7 (8%) disease, they are seldom available when considering the
Septic abortion 6 (7%) initial diagnosis. GAS disease may progress rapidly, and
Cellulitis 3 (3%) therapy must be initiated before cultures are generally
Septic arthritis 3 (3%) available.
Necrotizing fasciitis 3 (3%)
Therefore, the diagnosis of GAS disease depends upon a
high index of suspicion. Fever is the most common present-
Streptococcal toxic shock syndrome 3 (3%)
ing sign, and 20% of patients have a flulike syndrome with
Chorioamnionitis 3 (3%)
fever, chills, myalgia, nausea, vomiting, and diarrhea.13 Con-
Pneumonia 1 (1%) fusion or altered mental status is present in over one half of
Other 3 (3%) patients. Renal dysfunction occurs in 80% of patients and
Adapted from Chuang I, Van Beneden C, Beall B, Schuchat A: Population-based
may precede hypotension or shock. The presence of hema-
surveillance for postpartum invasive group A streptococcus infections, globinuria or an elevated serum creatinine is evidence of
1995–2000. Clin Infect Dis 2002;35:665–670. renal involvement. Hemoconcentration, as a result of a fluid
shift to the extravascular compartment, and leukocytosis
(often > 20,000/mm3), with a predominance of immature
Neonatal invasive GAS has also been reported and has a neutrophils, are common. Respiratory failure and adult respi-
case fatality rate of up to 30%.9–11 Although the neonate may ratory distress syndrome occur in approximately 50% of
be colonized following horizontal transmission within the patients but usually develop after the onset of clinically
nursery, vertical transmission from a colonized mother has recognized shock. Criteria for the diagnosis of STSS are
also been demonstrated.10,12 Furthermore, 50% of neonatal outlined in Table 31–3.
cases of invasive GAS disease occur within the first week of Eighty percent of patients have evidence of soft tissue
life, suggesting that vertical transmission from a colonized infection characterized by induration and erythema, which
parturient may be the most important route of infection. The progress to necrotizing fasciitis in 70% of cases.13 The hall-
most frequent manifestation of neonatal GAS disease is mark of these soft tissue infections is the abrupt onset of
omphalitis, but cellulitis, meningitis, sepsis, and fasciitis may severe pain, which usually precedes physical findings or is
also occur. Fortunately, neonatal GAS disease is rare, with out of proportion to physical findings. Any patient suspected
an estimated incidence of 1 in 18,000 births. of having GAS-associated necrotizing fasciitis must have the

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C HAPTER 31 • Other Infectious Conditions    523

diagnosis confirmed by immediate wound exploration and Broad-spectrum parenteral antibiotics should be admin-
débridement. A purulent discharge is usually not present, istered promptly. Penicillin G (200,000–400,000 U/kg/
and a limited wound inspection may fail to confirm the day) is the drug of choice for GAS invasive infections.
diagnosis. When the wound is opened, a thin, watery, non- However, studies in mice have demonstrated that even a
malodorous discharge is frequently present. The diagnosis short delay of 2 hours after initiation of infection dramati-
of necrotizing fasciitis can be easily confirmed by the blood- cally reduces the efficacy of penicillin G.17 Some studies
less blunt dissection of the superficial fascia and by patho- indicate that clindamycin may be more efficacious than
logic frozen section. penicillin when therapy is delayed. In an experimental
In summary, the diagnosis of GAS disease should be con- model with mice, survival was 70% even when initiated 16
sidered in any patient with the sudden onset of hypotension hours after GAS infection.17 Several potential advantages
and shock, the abrupt onset of severe pain in a wound, or to clindamycin therapy (900 mg IV q8h) have been identi-
systemic signs and symptoms such as confusion, renal fied.7 First, in contrast to penicillins, clindamycin is not
impairment, or respiratory distress in a patient with a wound affected by bacterial inoculum size or rate of growth.
or episiotomy infection. Aggressive intravenous fluid resus- Second, clindamycin suppresses the synthesis of bacterial
citation, antibiotic therapy, and wound débridement are toxins. Third, clindamycin facilitates phagocytosis of S.
necessary in these patients. pyogenes by inhibition of M protein synthesis. Fourth,
clindamycin has a longer postantibiotic effect than penicil-
lin. Last, clindamycin suppresses lipopolysaccharide-
Management Options induced monocyte synthesis of tumor necrosis factor-alpha
(TNF-α), a cytokine that contributes to hypotension and
Prepregnancy shock. However, a small proportion of GAS infections are
No current evidence suggests that the identification of GAS resistant to clindamycin, and clindamycin should not be
carriers prior to pregnancy is predictive of subsequent used alone until the organism is demonstrated to be sus-
pregnancy outcome or effective in reducing puerperal ceptible by susceptibility testing. Therefore, initial therapy
infectious morbidity. Therefore, prepregnancy screening is usually includes a combination of both penicillin G and
not recommended. clindamycin.
Some data also indicate that intravenous immunoglobu-
Prenatal lin (IVIG) (1–2 g/kg given once) may be a useful adjunct
Women may be identified as being GAS carriers as a result to antibiotic therapy in the treatment of STSS. Commer-
of routine screening for group B streptococcus (GBS) near cial preparations of IVIG have been shown to contain
the end of pregnancy. In one study, 0.03% of women neutralizing antibodies to several streptococcal virulence
screened at 35 to 37 weeks’ gestation were found to have factors.18 Recently, investigators reported a significant
vaginal colonization with GAS.14 At present, there are not reduction in mortality rate among patients with GAS
sufficient data to make a recommendation regarding man- disease treated with IVIG when compared with a historical
agement of asymptomatic carriers. However, there are pub- cohort.
lished case reports of women identified as carriers during Thus, the optimal treatment for invasive GAS disease
pregnancy who then developed GAS sepsis after delivery.15 includes a high index of suspicion, aggressive fluid resuscita-
A case of puerperal sepsis in a woman with a strain of GAS tion and hemodynamic support, surgical exploration and
identical to that identified in her husband’s throat swab has aggressive débridement, parenteral antibiotics including
also been reported.16 penicillin G and clindamycin, and possibly IVIG.
A high index of suspicion is necessary for the early diag-
nosis of GAS infection. Unfortunately, diagnosis may be Labor and Delivery
difficult in the early stages of GAS infection, and delays in GAS may be associated with intra-amniotic infection and
therapy may be associated with increased morbidity and with stillbirth. However, most patients with invasive GAS
mortality rates. Many patients die within 24 to 48 hours of disease usually present in the postpartum period, frequently
infection.17 In general, treatment must be directed at hemo- within the first 24 to 48 hours. Treatment should follow the
dynamic stabilization with intravenous fluids and vasopres- general guidelines provided earlier.
sors, antibiotic therapy, and in the case of soft tissue
infections, surgical exploration and aggressive débridement Postnatal
of involved tissues. Massive amounts of intravenous crystal- There are no current recommendations for screening for or
loids, in the range of 10 to 20 L/day, are often necessary to treating asymptomatic parturients colonized with GAS.
maintain blood pressure and tissue perfusion. Vasopressors However, careful attention should be given to any parturient
such as dopamine are also frequently required. In soft tissue with the sudden onset of systemic signs such as hypotension
GAS infections such as necrotizing fasciitis, antibiotic or shock or to parturients with severe pain out of proportion
therapy alone, without surgical débridement, usually results of physical findings or rapidly progressive soft tissue infec-
in maternal death. Intraoperative Gram stain and histologic tions, as noted earlier. Although these findings, which are
frozen section may be necessary to fully delineate the extent consistent with necrotizing fasciitis, usually suggest a
of involved tissues. Hyperbaric oxygen therapy has no role polymicrobial infection, GAS should be considered in the
in the treatment of necrotizing fasciitis but might be a useful diagnosis, and broad-spectrum antibiotics including peni-
adjunct in delineating necrotic tissue that must be surgically cillin and clindamycin should be utilized in the initial
débrided. management.

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524    S ECTION F OUR • Infection

SUMMARY OF MANAGEMENT OPTIONS

Group A Streptococcal Infection


Evidence Quality and
Management Options Recommendation References
Prepregnancy
No benefit to screening. —/GPP —
Prenatal, Labor, and Delivery
No benefit to screening. —/GPP —
May cause intra-amniotic infection. —/GPP —
Diagnosis requires a high index of suspicion: III/B 13
● Severe pain.
● Hypotension or shock.
● Altered mental status.
● Renal or respiratory impairment.
Treatment requires prompt intervention: Ib/A 17,18
● IV antibiotics (penicillin G, clindamycin).
● IV fluids and circulatory support including vasopressors.
● IVIG in nonresponsive cases.
● Surgical débridement if appropriate
Postnatal
Infection may cause toxic shock syndrome or soft tissue infection. —/GPP —
Diagnosis requires a high index of suspicion: III/B 13
● Severe pain.
● Hypotension or shock.
● Altered mental status.
● Renal or respiratory impairment.
Therapy: Ib/A 17,18
● Broad-spectrum antibiotics (penicillin and clindamycin).
● Surgical wound exploration and débridement.

GPP, good practice point; IVIG, intravenous immunoglobulin.

This practice has resulted in a significant reduction in early-


GROUP B STREPTOCOCCUS onset disease, as well as a smaller impact on maternal mor-
GBS (Streptococcus agalactiae) has become recognized since bidity. Based upon these results, updated guidelines were
the 1980s as one of the most important causes of neonatal issued by the CDC in 200223 to recommend optimization of
infection and is currently considered one of the leading screening and treatment of pregnant women in an attempt
infectious causes of neonatal morbidity and death. Although to improve upon the success already demonstrated.
early reports in the 1930s and 1940s linked GBS with post- GBSs are one of many serologically distinct species within
partum infections and neonatal meningitis, it was not until the genus Streptococcus. Streptococci are facultatively anaero-
the early 1960s that the scope of perinatal and neonatal GBS bic gram-positive cocci, usually arranged in chains on Gram
infections became evident.19 Initial case series reported case stain. The most important pathogenic streptococcal species
fatality rates as high as 50%. In the 1980s, trials of empirical for humans include group A (S. pyogenes), group B (S. agalac-
intrapartum antibiotics to women at risk of transmitting tiae), group D (enterococci), Streptococcus pneumoniae, and Strep-
infection to their newborns demonstrated a protective tococcus viridans. Definitive identification is based on the
benefit against neonatal infection in the first week of life presence of a polysaccharide group-specific antigen common
(early-onset disease). In the 1990s, these efforts led to the to all group B streptococcal strains as determined by sero-
implementation of guidelines for intrapartum antibiotic pro- logic testing. GBSs can be further subdivided into eight
phylaxis of at-risk mothers, endorsed and issued by the distinct serotypes (Ia, Ib, Ia/c, II, III, IV, V, and VI) on the
American College of Obstetricians and Gynecologists basis of distinctive type-specific polysaccharide antigens.
(ACOG),20 the Centers for Disease Control and Prevention About 99% of strains can be typed into one of these six
(CDC),21 and the American Academy of Pediatrics (AAP).22 antigen types. GBSs can be recovered from the vagina or

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C HAPTER 31 • Other Infectious Conditions    525

cervix in 10% to 30% of pregnant women at some point intrapartum, postpartum, and occasionally prenatal infec-
during gestation.24 The colonization may be transient, tions. Data from an early report suggest puerperal septice-
chronic, or intermittent, and the rate of colonization does mia due to GBS occurs with an incidence of approximately
not vary with gestational age. Women with GBS coloniza- 1 to 2 per 1000 deliveries and accounts for up to 15% of
tion in one pregnancy are at increased risk, relative to positive blood cultures from postpartum patients.28 Postpar-
women who are negative in the initial pregnancy, for colo- tum endometritis is reported to be more frequently observed
nization in a subsequent pregnancy.25 There is evidence that among GBS-colonized parturients than among noncolo-
the gastrointestinal tract is the major primary reservoir and nized parturients. GBS is also associated with clinical intra-
that vaginal or cervical contamination and colonization amniotic infection and is a frequent isolate from amniotic
occur from a gastrointestinal source. The frequency of GBS fluid of patients with intra-amniotic infection. Finally, GBS
isolation increases as one proceeds from the cervix to the has been isolated from the urine of pregnant women, with
introitus, and GBS can be recovered twice as frequently from or without symptoms of urinary tract infection. Untreated
rectal cultures as from vaginal cultures. GBSs can also be antepartum GBS bacteriuria has been associated with intra-
recovered from the urethra of 45% to 63% of the male partum chorioamnionitis.29
consorts of female carriers, implying that sexual transmission GBS has also been associated with premature rupture of
may also occur. membranes (PROM) and with preterm delivery prior to the
Neonatal GBS colonization may occur either by vertical 32nd gestational week in some, but not all, studies.30 Previ-
transmission from a colonized mother as the neonate passes ous studies have indicated that this association may be
through the birth canal or by horizontal transmission, strongest for patients with GBS bacteriuria.31 Thomsen
including both nosocomial spread in the nursery from colo- and coworkers32 have demonstrated significant reductions in
nized personnel or other colonized neonates and acquisition PROM and preterm labor among patients with asymptom-
from community sources. Overall, 3% to 12% of all neo- atic GBS bacteriuria who were treated with penicillin.
nates are colonized with GBS in the first week of life. Forty However, antepartum antibiotic treatment to eradicate GBS
percent to 70% of neonates born to colonized mothers from patients with asymptomatic vaginal colonization
become colonized, usually with the same serotype that is without bacteriuria has not been demonstrated to alter preg-
present in the mother. In contrast, only 1% to 12% of neo- nancy outcome. Thus, a causal relationship between GBS
nates born to noncolonized mothers will become culture- colonization and prematurity remains to be established.
positive. Several additional factors may modify or enhance Since the 1970s, GBS has become a leading cause of
the risk of GBS vertical transmission. Higher neonatal trans- septicemia and meningitis during the first 3 months of life
mission rates occur when women are persistently culture- in neonates. Early surveillance data in the 1990s suggested
positive carriers or when women are heavily colonized with an incidence of 1.8 cases per 1000 live births. Two distinct
GBS as demonstrated by semiquantitative vaginal cultures.26 clinical syndromes occur among neonates with GBS infec-
The site of maternal carriage is also important; vertical trans- tions. These differ in the age at onset, pathogenesis, and
mission is more likely to occur with cervical GBS carriage outcome. The first clinical syndrome, early-onset infection,
than with rectal carriage. occurs within the first 7 days of life and represents nearly
The most important determinant of susceptibility to inva- three fourths of all cases in infants younger than 3 months.
sive infection after colonization may be maternal antibodies The mean age at onset is 20 hours of life, and 72% will
directed against the capsular polysaccharide antigens of present within the first 24 hours of life.33 A significant
GBS. Immunity to GBS is mediated by antibody-dependent portion of these infections are apparent at birth or become
phagocytosis. Mothers of infants with type III GBS invasive symptomatic within the first 90 minutes of life, indicating
disease have lower serum levels of type-specific antibodies that in utero GBS exposure and infection often occur. Early
than women giving birth to asymptomatically colonized infection attack rates were estimated at 1.5 per 1000 for all
infants. This antibody, which has some broad reactivity to live births prior to widespread use of intrapartum antibiotics.
all GBS types, is an immunoglobulin G (IgG) that readily Among offspring of maternal GBS carriers, however, the
crosses the placenta. When measured in mother-infant pairs, attack rate is much higher, ranging from 10 to 60 per 1000
an excellent correlation exists between maternal and cord live births.
antibody levels. Baker and associates27 demonstrated that Early neonatal infection is presumed to result from vertical
73% of 45 GBS-colonized mothers with healthy neonates transmission of GBS from a colonized mother. There is a
had high serum levels of type III antibody in contrast to only direct relationship between neonatal attack rates and the
19% of 32 GBS-colonized mothers whose neonates devel- size of the inoculum and number of colonized neonatal sites.
oped early-onset septicemia or meningitis (P < .001). Strain In one epidemiologic review, early-onset infection presented
virulence is also an important determinant of disease. as bacteremia (80%), pneumonia (7%), or meningitis (6%).33
Although type III strains of GBS represent approximately Eighty-three percent of cases were in term infants (≥37 wk’
one third of isolates from symptomatically colonized infants, gestation). The overall case fatality rate was approximately
they account for over 85% of the isolates from early-onset 4% but was significantly higher in preterm infants, approach-
meningitis or late-onset disease. Overall, type III strains ing 30% in infants of 33 weeks’ gestation or less.
account for more than 60% of isolates from infants with all The second type of disease (late-onset infection) occurs
varieties of invasive GBS infections. in infants after the first week of life until 3 months of age,
with a typical range of 3 to 4 weeks. The overall attack rate
is estimated to be 0.5 cases per 1000 live births, and these
Maternal and Fetal Risks cases represent 28% of infections in infants younger than 3
Although most research has focused on GBS neonatal infec- months.33 In contrast to early-onset infection, nosocomial
tion, GBS is also an important pathogen for maternal transmission may be as important as vertical transmission,

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526    S ECTION F OUR • Infection

although it is believed that some infants are colonized at assays that demonstrate excellent sensitivity and specificity
birth, with subsequent development of invasive disease. The compared with traditional culture methods, but these assays
serotype distribution of strains recovered from late-onset await further testing to determine the feasibility of wide-
infection does not reflect the serotypes present in the mater- spread application.43–45 A cost-benefit analysis showed that
nal genital tract; over 90% of late-onset infection is caused the use of a rapid PCR test resulted in fewer courses of
by type III GBS. Late-onset disease also presents most com- maternal antibiotics, fewer perinatal GBS infections, and
monly as bacteremia (63%), but may appear as meningitis fewer infant deaths compared with culture.46 However, only
(24%, relative risk [RR] 4.3 vs. early-onset disease; P < .001) culture techniques currently allow for antibiotic sensitivity
and may demonstrate other sites of infection, such as septic profiling of positive cultures, which is particularly important
arthritis or osteomyelitis. The overall case fatality rate for in cases of maternal penicillin hypersensitivity.
late-onset disease is 2.8%.33 Approximately 50% of menin-
gitis survivors will have neurologic sequelae, including corti- Management Options
cal blindness, diabetes insipidus, deafness or other cranial
nerve deficits, and spasticity. Prepregnancy
No current evidence suggests that the identification of GBS
carrier status prior to pregnancy is predictive of subsequent
Diagnosis pregnancy outcome. Similarly, treatment of asymptomatic
The recommended technique for collecting specimens for women found to be colonized with GBS prior to pregnancy
culture of GBS in pregnant women involves obtaining a does not impart any recognized benefit, with the possible
combined vaginal-rectal swab. Although some studies have exception of women with asymptomatic bacteriuria.
shown that the GBS detection rate is not significantly dif-
ferent when comparing vaginal-rectal specimens with vagi- Prenatal, Labor, and Delivery
nal-perianal specimens,34,35 the current standard of care is GBS rarely causes maternal symptoms in the prenatal period,
still to obtain a combined vaginal-rectal swab. A speculum but may cause symptoms of urinary tract infection. However,
is not necessary, and there is no difference in detection rates GBS bacteriuria (whether symptomatic or not) provides a
or accuracy if the culture is collected by the patient or the significant risk factor for neonatal disease, as previously
health care provider.36 mentioned. When detected, GBS bacteriuria should be
GBS can be easily grown on selective or nonselective treated according to current standard of care for urinary tract
media. Most GBS colonies appear on blood plates as small, infections during pregnancy. Pregnant women with docu-
1- to 2-mm, gray-white colonies surrounded by a zone of mented GBS bacteriuria at any time during their prenatal
β-hemolysis, although 2% of strains are nonhemolytic. Pre- course do not require routine screening cultures and should
liminary identification and distinction of GBS from other receive intrapartum antibiotics, which are discussed in
streptococci is based on biochemical reactions including further detail later.
resistance to bacitracin, hydrolysis of sodium hippurate, Although the attack rate for neonatal GBS infection is
and the production of a soluble hemolysin that acts syner- low, a variety of prevention strategies have been advocated
gistically with B-lysin of Staphylococcus aureus to produce because of the high mortality and morbidity rates seen in
hemolysis (CAMP [Christie-Atkins-Munch-Petersen] test). neonatal GBS disease. These strategies have involved che-
Although GBS can be recovered after overnight growth on moprophylaxis, aimed at eradicating the organism from the
nonselective media, such as blood agar, the use of a selective mother or the neonate, or immunoprophylaxis, aimed at
broth medium such as Todd-Hewitt broth or Lim broth inducing humoral immunity.
greatly enhances the isolation rate of GBS from any culture Antibiotic chemoprophylaxis has been advocated for the
site. pregnant patient in either the antepartum or the intrapartum
A major limitation of cultures is the length of time neces- period or for the neonate in the immediate neonatal period.
sary for growth and identification. Therefore, research has Attempts to eradicate GBS colonization with antepartum
been focused on developing a more rapid screening test that treatment have been unsuccessful, and early neonatal pro-
could be used at the time of labor and delivery to identify phylaxis is also frequently unsuccessful because many neo-
colonized women. A number of rapid screening tests have nates are already septic at birth as a result of in utero
been developed to directly detect GBS in either body fluids infection.47 Initial chemoprophylactic prevention strategies
or cervical-vaginal secretions. These culture-independent released in the 1990s focused upon selective intrapartum
tests include Gram stain, latex particle agglutination treatment based on either the presence of risk factors associ-
(LPA), optical immunoassay, enzyme immunoassay, DNA ated with neonatal infection, the maternal genital tract colo-
hybridization, and polymerase chain reaction (PCR). A nization, or both.
large number of studies have evaluated the ability of these Major risk factors for neonatal early-onset GBS disease
indirect tests to rapidly detect GBS colonization of the include low birth weight (<2500 g), premature delivery
maternal lower genital tract. Such identification is important (<37 wk’ gestation), prolonged duration of rupture of mem-
to interrupt maternal-neonatal vertical transmission that branes (≥18 hr), and intrapartum fever (≥38.0°C). Boyer and
leads to early-onset neonatal disease. Initial results were colleagues47 have demonstrated that 74% of neonates with
encouraging,37,38 although subsequent studies have demon- early-onset infection and 94% of those infections with a fatal
strated that these tests do not always perform well.39,40 PCR outcome occur among those neonates with one or more of
tests appear to have the most promise and the best test these risk factors. Additional risk factors include having pre-
performance characteristics relative to culture.41–43 Recent viously had a neonate with invasive GBS disease and mater-
studies from the United States and Canada have used PCR nal GBS bacteriuria during the current pregnancy. A study

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C HAPTER 31 • Other Infectious Conditions    527

in 1985 documented that the overall attack rate for early- 18.3% of pregnancies were estimated to merit chemopro-
onset neonatal GBS disease increased from the then-observed phylaxis and 68.8% of early-onset neonatal disease would
3.0 per 1000 births in the total population to 8.4 per 1000 be potentially prevented.21
births among those pregnancies in which risk factors were The impact of implementing these guidelines has been
present.48 The attack rate rose even more dramatically to studied extensively in the period following their initial rec-
40.8 per 1000 births if risk factors were present and the ommendation. In the surveillance areas studied, the inci-
mother was colonized with GBS. dence of early-onset disease declined from 1.7 per 1000 in
Several studies utilizing the presence of risk factors, 1993 to 0.6 per 1000 in 1998, a 65% reduction, with the
maternal colonization status, or both, as a determinant for steepest decline occurring in 1996 following the initial
prophylaxis have documented the efficacy of intrapartum release of consensus guidelines from the CDC. Schrag and
chemoprophylaxis in reducing neonatal early-onset GBS associates57 published the first comprehensive study directly
disease.49–55 A meta-analysis of these studies demonstrated a comparing the two management strategies and found that
30-fold reduction in early-onset disease with intrapartum the universal screening-based approach was greater than
chemoprophylaxis.56 The two alternative approaches to 50% more effective in preventing perinatal GBS disease.
intrapartum chemoprophylaxis were proposed in the United This result was felt to stem from two main factors. First, the
States by the CDC in 199621 and have been endorsed by screening-based approach identified mothers who were
both ACOG20 and AAP.22 The first approach is based upon GBS-positive but did not exhibit risk factors during preg-
universal screening for maternal GBS colonization at 35 to nancy or labor, a group representing 18% of all parturients
37 weeks’ gestation. Cultures remote from term might not during the study period. Second, women identified as being
be accurate and should not be used. Intrapartum chemopro- GBS-positive were more likely to receive intrapartum anti-
phylaxis is offered to all pregnant women identified as GBS biotics than women who qualified on the basis of risk factors
carriers. In addition, intrapartum chemoprophylaxis is (89% vs. 61%, P < .001), indicating improved compliance
offered to women with a previous neonate with GBS infec- with the guidelines utilizing the screening-based approach.
tion, GBS bacteriuria during the current pregnancy, or deliv- In this study, similar numbers of patients (24%) in each
ering prior to 37 weeks’ gestation, regardless of maternal group received intrapartum prophylaxis, negating previous
colonization status. Women with an unknown carrier status concerns that the screening-based approach would result in
are offered prophylaxis in the event of an intrapartum fever a significant increase in the use of antibiotics and potential
of 38.0°C or higher or rupture of membranes at 18 hours or contribution to antibiotic resistance. Also, other studies have
before. It was estimated that this screening-based approach suggested that the increased cost of performing routine cul-
would result in intrapartum chemoprophylaxis of 26.7% of tures on all eligible pregnant women would be offset by the
all deliveries and prevent 86% of early-onset neonatal GBS impact of disease prevention. This idea led to the release of
disease (Table 31–4).21 new guidelines by the CDC in 2002,23 recommending a
An alternative prophylactic strategy, also initially universal screening-based approach (Fig. 31–1). The risk-
endorsed by the CDC, is based upon offering intrapartum based approach should be used only for women who arrive
chemoprophylaxis only in the presence of risk factors. In in labor with no documented culture results. In addition, a
this risk-factor approach, antepartum cultures are not new algorithm was provided for the management of women
obtained, and prophylaxis is offered only to those women with preterm delivery, summarized in Figure 31–2. An evalu-
with delivery prior to 37 weeks’ gestation, rupture of mem- ation of the universal antenatal screening approach for GBS
branes for greater than 18 hours, an intrapartum fever at or was recently published, highlighting the efficacy achieved
above 38.0°C, a previously infected neonate, or with GBS and areas in which further improvements in management
bacteriuria in the current pregnancy. With this approach, might result in the additional reductions in neonatal disease.58

T A B L E 3 1 – 4 
Intrapartum Chemoprophylaxis Trials for the Prevention of Neonatal Early-onset Group B
Streptococcus Disease
EARLY-ONSET DISEASE
STUDY CASE SELECTION COMPARISON GROUP ICP NO ICP P VALUE
49
Allardice I Nonrandom 0/57 9/136 .06
Boyer50 PC Random 0/85 5/79 .02
Morales51 PC Random 0/135 3/128 .2
Morales52 I Nonrandom 0/36 13/48 .002
Tuppurainen53 PC Random 1/88 10/111 .03
Matorras54 I Random 0/60 3/65 .14
Garland55 PC Nonrandom 16/30,197 27/26,915 .04

I, intrapartum colonization; ICP, intrapartum chemoprophylaxis; PC, prenatal colonization.


Adapted from American Academy of Pediatrics: Revised guidelines for prevention of early-onset group B streptococcus (GBS) infection. Pediatrics 1997;
99:489–496.

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528    S ECTION F OUR • Infection

FIGURE 31–1 
Vaginal and rectal GBS screening cultures at 35–37 weeks’ gestation
Indications for intrapartum antibiotic prophylaxis to prevent
for ALL pregnant women (unless patient had GBS bacteriuria during pregnancy
prenatal group B streptococcus (GBS) disease under a
or a previous infant with invasive GBS disease)
universal prenatal screening strategy based on combined
vaginal and rectal cultures collected at 35 to 37 weeks’
gestation from all pregnant women. (From Centers for Disease
Control and Prevention [CDC]: Prevention of perinatal group B
streptococcal disease: Revised guidelines from CDC. MMWR Morb
Intrapartum prophylaxis indicated Intrapartum prophylaxis not indicated Mortal Wkly Rep 2002;51[RR-11]:1–18.)
• Previous infant with invasive • Previous pregnancy with a positive
GBS disease GBS screening culture (unless a
• GBS bacteriuria current culture was also positive during the
pregnancy current pregnancy)
• Positive GBS screening culture • Planned cesarean delivery
during current pregnancy (unless performed in the absence of labor
a planned cesarean delivery, in or membrane rupture (regardless of
the absence of labor or amniotic maternal GBS culture status)
membrane rupture, is performed) • Negative vaginal and rectal GBS
• Unknown GBS status (culture screening culture in late gestation
not done, incomplete or results during the current pregnancy,
unknown) and any of the following: regardless of intrapartum risk
Delivery at ≤37 weeks’ factors
gestation
Amniotic membrane
rupture ≥18 hours
Intrapartum temperature
≥100.4° F (≥38.0° C)

Onset of labor or rupture of membranes at <37 weeks’


minimum duration of therapy for effective prophylaxis, in
gestation with significant risk for imminent preterm delivery terms of length of therapy versus number of doses of anti-
biotics administered prior to delivery. Vaginal GBS colony
counts fall rapidly after intrapartum penicillin administra-
tion.59 Some evidence has confirmed that an initial dose of
No GBS culture GBS + GBS – antibiotics at least 4 hours prior to delivery is as effective as
two or more doses of antibiotics in preventing GBS transmis-
sion60 and early-onset disease,61 and this emphasis is main-
Obtain GBS + Penicillin IV No GBS tained in the current guidelines.
vaginal for ≥48 hrs prophylaxis If penicillin resistance is documented but the risk of ana-
and rectal phylaxis is judged to be low, cefazolin (2 g IV initial dose,
GBS culture
and initiate
then 1 g q8h) may be used. Clindamycin (900 mg IV q8h)
IV penicillin or erythromycin (500 mg IV q6h) may be used in the
severely penicillin-allergic patient. However, increasing
resistance to both of these agents has led to the recommen-
No growth Intrapartum dation of routine susceptibility testing of positive cultures if
at 48 hrs antibiotic penicillin allergy is suspected or documented. In surveillance
prophylaxis studies in the United States covering the time period 1999
to 2005, 32% of isolates were resistant to erythromycin and
Stop penicillin 15% were resistant to clindamycin.62 In cases of resistant
organisms (or unknown susceptibility) and high risk for ana-
FIGURE 31–2 
phylaxis to penicillins and cephalosporins, vancomycin (1 g
Sample algorithm for GBS prophylaxis for women with threatened q12h) is the preferred treatment. This underscores the need
preterm delivery. This algorithm is not an exclusive course of manage- to accurately determine true β-lactam allergy as well as risk
ment. Variations that incorporate individual circumstances or institutional for anaphylaxis.
preferences may be appropriate. (From Centers for Disease Control and An alternative approach to intrapartum chemoprophy-
Prevention [CDC]: Prevention of perinatal group B streptococcal disease: Revised
guidelines from CDC. MMWR Morb Mortal Wkly Rep 2002;51[RR-11]:1–18.)
laxis is to immunize pregnant women. As noted previously,
women delivering neonates with invasive early-onset
disease usually have very low (<2 µg/mL) serum concen-
trations of type III GBS antibody.27 More recent prelimi-
Intravenous penicillin G (5 million units IV initially, then nary trials have been conducted among nonpregnant
2.5 million units q4h until delivery) is preferred for intrapar- adults utilizing monovalent protein-conjugate vaccines
tum chemoprophylaxis. Ampicillin (2 g IV initial dose, then containing capsular polysaccharide antigens against sero-
1 g q4h until delivery) is an acceptable alternative, but peni- types Ia and Ib,63 type II,64 and type III.65 Further work is
cillin G is preferable because its narrower spectrum of needed in this area prior to the implementation of a vacci-
activity may be less likely to select for antibiotic-resistant nation strategy toward women of childbearing age and
microorganisms. Previous debate had centered on the pregnant women.

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C HAPTER 31 • Other Infectious Conditions    529

Postnatal significant reduction in invasive GBS disease, including


In the asymptomatic parturient receiving intrapartum che- postpartum endometritis, among pregnant women follow-
moprophylaxis, there is no need to continue antibiotics fol- ing implementation of the original guidelines for intrapar-
lowing delivery. Conversely, in the symptomatic patient tum prophylaxis, from 0.29 cases per 1000 live births in
with intra-amniotic infection, therapy should be continued 1993, to 0.23 per 1000 in 1998 (P < .03). It should be rec-
as described previously. Because GBS may also be associ- ognized that postpartum endometritis is frequently a poly-
ated with postpartum endometritis, known carriers should microbial infection and broad-spectrum antibiotics should
be observed closely for this and treated accordingly. Of be utilized, even among those patients known to be colo-
note, Schrag and associates57 reported a modest but nized with GBS.

SUMMARY OF MANAGEMENT OPTIONS

Group B Streptococcal Infection


Evidence Quality and
Management Options Recommendation References
Prepregnancy
Treatment of GBS carriers before pregnancy has no benefit. —/GPP —
Immunization strategies are being evaluated currently. —/GPP —
Prenatal, Labor, and Delivery
Treat symptomatic bacteriuria during prenatal period. IIa/B 29
Recommended universal screening–based approach: IIa/B 23,57
● Perform combined vaginal and rectal cultures on all pregnant women
at 35–37 wk’ gestation. (Exception: women with documented GBS
bacteriuria during current pregnancy or history of previous GBS-
infected infant warrant intrapartum prophylaxis and do not require
screening.)
● IAP is recommended for all women with positive culture unless
delivery by cesarean section prior to rupture of membranes and onset
of labor.
● If culture status is unknown at time of delivery, administer IAP for
gestation < 37 wk, rupture of membranes ≥ 18 hr, or intrapartum
temperature ≥ 38.0°C.
Suggested management of threatened preterm delivery: III/B 21
● No culture done: obtain cultures and initiate IAP for 48 hr until
results obtained or delivery occurs.
● Culture positive prior to or during labor: IAP for 48 hr or until delivery
occurs.
● Culture negative prior to labor (or after 48 hr): no IAP (or stop IAP).
Recommended prophylaxis regimens: Ia/A 23,56,60,61
● Penicillin G 5 million U IV followed by 2.5 mU IV q4h until delivery
(ampicillin 2 g IV initially followed by 1 g IV q4h until delivery is
acceptable but less preferred owing to broader-spectrum activity).
● For penicillin allergic (low anaphylaxis risk), cefazolin 2 g IV initial
dose followed by 1 g IV q8h until delivery.
● For penicillin allergic (high anaphylaxis risk, documented susceptibility
of GBS), clindamycin 900 mg IV q8h, or erythromycin 500 mg IV q6h.
● For penicillin allergic (high anaphylaxis risk and resistance to
clindamycin and erythromycin or susceptibility unknown), vancomycin
1 g IV q12h.
Postnatal
Antibiotic prophylaxis need not be continued after delivery. —/GPP —
Diagnosis of postpartum endometritis in a GBS-positive woman should be —/GPP —
treated with broad-spectrum antibiotics.

GBS, group B streptococcus; GPP, good practice point; IAP, intrapartum antibiotic prophylaxis.

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530    S ECTION F OUR • Infection

METHICILLIN RESISTANT Management Options


STAPHYLOCOCCUS AUREUS Prenatal, Labor, and Delivery
Regardless of the source of infection, antibiotic treatment
Maternal and Fetal Risks usually begins with systemic vancomycin for invasive disease.
Staphylococcus aureus is a commonly encountered organ- Incision and drainage of any localized abscess collection is
ism, colonizing the anterior nares, other mucus membranes required. These infections are often slow to respond, and
and skin surfaces. Resistance to penicillin, and later methi- sensitivity testing should be initiated early to assess ade-
cillin, has made these bacteria of particular concern as a quacy of therapy. Alternative or adjunctive agents include
nosocomial pathogen. Over the last decade, methicillin daptomycin, linezolid and tigecycline. Few data, and much
resistant strains (MRSA) have been increasingly isolated debate, surround the discussion of the merits of these latter
from patients in the community setting, without typical agents; consultation with a health care provider with exper-
risk factors such as recent antibiotic treatment, ICU admis- tise in this area would likely be beneficial.67
sion, known contact with an infected individual or surgical Mild to moderate skin and soft tissue infection due to
exposure.66 Community acquired MRSA usually has chro- community associated MRSA begins with incision and drain.
mosomal DNA restriction patterns that are different from Again, despite a paucity of data, the CDC has published
the hospital-associated strains, commonly contain the guidelines for the outpatient antimicrobial theraphy of
Panton Valentine Leukocidin (PVL) virulence toxin, and MRSA (www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_skin.html)
are generally less resistant to multiple antibiotic classes of not specific to pregnancy.
drugs.67 Whereas hospital-acquired strains most commonly Whether to perioperatively decolonize the nose, genital
present within the bloodstream, urinary tract, or in associ- tract or skin to prevent MRSA infection before vaginal or
ation with device or surgical site infections, community cesarean delivery remains controversial.67 At the present
associated MRSA presents as “spider bite” lesions, localized time, the cumulative data do not support routine screening
skin or other soft tissue infections or as necrotizing pneu- for MRSA carriers or decolonization with mupirocin oint-
monia after an influenza episode.67 Community associated ment (for nasal site) or oral or vaginal chlorhexidine (genital
MRSA has now been identified as an emerging concern site). An exception may be if the patient has a prior history
among pregnant and postpartum women, with infections of MRSA infection, or is at particularly high risk for post-
in the breast, buttocks, vulva and groin reported.68,69 More operative infection. This latter consideration would also
invasive disease has also been noted, including nonmen- apply to perioperative antimicrobial prophylaxis prior to
strual toxic shock syndrome and neonatal sepsis due to cesarean delivery, where an agent that is active against
this organism.67 Recent United States national surveillance MRSA should be considered for those known to carry or be
data have documented an MRSA nasal colonization rate of at risk for MRSA.
1.5%.66 Prevalence studies specific to pregnancy have MRSA carriage or infection is not a contraindication to
reported recto-vaginal colonization rates of 0.5–3.5%.68,69 breast feeding. As with other types of mastitis, breast feeding
Fortunately only a small fraction of those who are colo- may be continued as antimicrobial therapy is instituted. Any
nized go on to develop clinical disease. Vertical transmis- draining lesion should be covered to limit infant exposure.
sion to the neonate has been suggested in isolated case If a significant breast abscess is identified, temporary cessa-
reports, although the frequency of this event must be tion of feeding on that side may be needed for a few days
exceedingly low. after surgical drainage.67

SUMMARY OF MANAGEMENT OPTIONS

Methicillin Resistant Staphylococcus Aureus


Evidence Quality and
Management Options Recommendation References
Prenatal, Labor, and Delivery
For Severe Invasive Disease
Systemic vancomycin (alternative or adjunctive agents include daptomycin, IV/C 67
linezolid and tigecyline).
Incision and drainage of abscess. IV/B 67
For Mild to Moderate Skin and Soft Tissue Infection
Incision and drain. IV/C 67
For recommendations pertaining to oral antimicrobial therapy, see www.
cdc.gov/ncidod/dhqp/ar_mrsa_ca_skin.html.

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C HAPTER 31 • Other Infectious Conditions    531

Evidence Quality and


Management Options Recommendation References
General
Decolonization of nose (mupirocin), genital tract (oral or genital IV/C 67
chlorhexidine) or skin (chlorhexidine) to prevent MRSA infection before
vaginal or cesarean delivery is controversial.
Current cumulative data do not support routine screening for MRSA IV/C 67
carriers or decolonization.
Exceptions: Prior history of MRSA infection
High risk for infection
MRSA and its associated antimicrobial treatment are not contraindications IV/C 67
to breast feeding. Cover any draining lesion to limit infant exposure.
Temporary cessation of feeding on relevant side if abscess occurs.

increased risk for listeriosis, as reported by Mascola and


LISTERIOSIS coworkers.76
Listeriosis is caused by the organism Listeria monocytogenes, an Pregnant women with listeriosis most commonly suffer
aerobic and facultatively anaerobic, non–spore-forming, from a flulike illness, with fever, general malaise, and other
motile, gram-positive bacillus. This bacterium is widespread nonspecific symptoms. Rarely, it might cause meningoen-
in the environment in soil, vegetation, water, and sewage. It cephalitis or sepsis-like manifestations. In one large series,
is also found in humans and has been isolated in the stool 65% of patients had fever (defined usually as temperature
of 1% to 5% of healthy adults. It is a relatively uncommon ≥ 38.2°C), 32% a “flulike” illness, 21.5% abdominal or back
infection, although there is a predilection for populations pain, and less commonly, headache, myalgia, or sore throat.77
with relative immunosuppression, including infants, the The average duration of symptoms prior to diagnosis was
elderly, and the pregnant woman, with the latter group 6.6 days. Of note, 29% of patients were asymptomatic.
demonstrating an incidence of 12 per 100,000 (compared The primary mode of transmission to the fetus or newborn
with 0.7 per 100,000 in the general population, a 17-fold has not been proved, but is suspected to occur either via
increase).70 Most cases of human listeriosis during pregnancy ascending infection through the vagina or transplacentally
are sporadic with occasional epidemic common-source out- secondary to maternal bacteremia.70 Neonatal listeriosis
breaks. It can contaminate a variety of foods including might present as respiratory distress, fever, neurologic symp-
uncooked meat and vegetables, raw milk, and processed toms, or skin rash, or it might be asymptomatic. Rarely, the
foods that become contaminated after processing, such as infant might present with granulomatosis infantisepticum,
soft cheeses and cold cuts at the deli counter. In certain which classically exhibits disseminated granulomatous reac-
ready-to-eat foods such as hot dogs and deli meats, contami- tion in the lung, skin, liver, and other locations. Similar to
nation can occur after cooking but before packaging. Con- GBS infection in the neonate, there is a bimodal distribution
taminated food looks, tastes, and smells normal. Unlike most of disease. Early-onset infection (usually defined as < 5 days
bacteria, Listeria can survive on food stored in the refrigera- of life) is more commonly associated with maternal illness
tor. It is killed with proper cooking and pasteurization and produces a sepsis-like illness, with onset of disease
procedures. exhibited within hours of birth. Late-onset disease presents
more commonly as meningitis, is less commonly associated
with maternal symptoms or positive Listeria cultures, and
Maternal and Fetal Risks may be associated with nosocomial or environmental
Listeria exhibits an unusual life cycle, demonstrating obligate acquisition.78
intracellular replication and spread, without significant Outcomes of pregnancies complicated by listeriosis vary.
exposure to the extracellular environment and its defense In the study by Mylonakis and colleagues,77 one in five
mechanisms. Thus, cell-mediated immunity is the primary pregnancies resulted in spontaneous abortion or stillbirth. In
host defense, and this may explain the unique susceptibility the remainder, 68.3% of the infants demonstrated infection
of humans to this infection during periods of relative sup- with a positive culture from one or more sites. Of these
pression of cell-mediated immunity, including pregnancy.71 infants for which follow-up was available, 62.8% recovered
Listeria infection is well established as a cause of preg- completely, 24.5% died, and 12.7% recovered with neuro-
nancy loss in domestic and wild animals. Subsequently, it logic sequelae or other long-term complications. The worst
was implicated as a possible cause for recurrent spontane- prognosis occurred in patients with meningeal involvement.
ous abortion in pregnant women. An Israeli study reported Similar data were reported in a British review of 248 perina-
a significantly increased rate of multiple positive cervical tal cases of listeriosis from 1967 to 1985 in which 19% of
cultures for Listeria in women with a history of recurrent cases in which the outcome was known resulted in abortion
losses compared with a control group without such or stillbirth.78 Of the remaining infants in which gestational
history.72 However, subsequent studies failed to replicate age was known, 58% were delivered prematurely (defined as
this association, and at this time, the association is contro- < 38 wk). The overall neonatal mortality rate in known
versial.73–75 Multiple gestation pregnancies may also be at outcome cases was 35%.

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532    S ECTION F OUR • Infection

Diagnosis T A B L E 3 1 – 5 
Listeria grows well on most routine media, although the use Dietary Recommendations for Pregnant Women
of selective media may be required when cultures are
obtained from sites of heavy bacterial colonization such as Do not eat hot dogs, luncheon meats, or deli meats unless they are
the vagina or rectum. Owing to morphologic similarity, reheated until steaming hot.
Do not eat soft cheeses such as feta, Brie, Camembert, blue-veined
it may be confused with nonpathogenic diphtheroids. cheeses, and Mexican-style cheeses such as “queso blanco fresco.”
However, the organism produces a characteristic tumbling Hard cheeses, semisoft cheeses such as mozzarella, pasteurized
motion when viewed on wet preparation, allowing it to be processed cheese slices and spreads, cream cheese, and cottage
distinguished. Of the four serotypes, subtypes 1/2a, 1/2b, cheese can be safely consumed.
Do not eat refrigerated pâté or meat spreads. Canned or shelf-stable
and 4b are responsible for the vast majority of infections, pâté and meat spreads can be eaten.
and serotype analysis may be useful in epidemic settings.70 Do not eat refrigerated smoked seafood unless it is an ingredient in a
The diagnosis depends upon clinical suspicion and isola- cooked dish such as a casserole. Examples of refrigerated smoked
tion of the organism from a culture of appropriate source. In seafood include salmon, trout, whitefish, cod, tuna, and mackerel,
the large series mentioned previously, Listeria was most com- which are most often labeled as “nova-style,” “lox,” “kippered,”
“smoked,” or “jerky.” This fish is found in the refrigerated section or
monly isolated from cultures of the blood (43%), cervix/ sold at deli counters of grocery stores and delicatessens. Canned
vagina (34%), and placenta (12%). It may also be cultured fish such as salmon and tuna or shelf-stable smoked seafood may
from amniotic fluid obtained by amniocentesis performed be safely eaten.
for suspected intra-amniotic infection. Staining of amniotic Do not drink raw (unpasteurized) milk or eat foods that contain
unpasteurized milk.
fluid by meconium, especially in the preterm infant, may
increase clinical suspicion for listeriosis, because this was
observed in 12 of 23 infants in a reported series from
Australian authors.79

100,000 (1989) to 8.6 per 100,000 (1993), (P < .003).83 A


Management Options list of at-risk food substances has been summarized in a
handout for pregnant women on the FSIS website and may
Prepregnancy be viewed in Table 31–5.84
Treatment of listeriosis in the nonpregnant woman is identi- For women with suspected or confirmed listeriosis during
cal to that of other adult patients and dependent on the site pregnancy, intravenous antibiotics are indicated. Multiple
of the infection (i.e., bacteremia vs. meningitis or other loca- cases have been reported of successful antepartum treatment
tion). As mentioned, the possibility of Listeria colonization of listeriosis with normal neonatal outcome, including cases
or carriage as a risk factor for subsequent pregnancy loss has diagnosed in the first and second trimesters.84–86 First-line
been previously evaluated with inconclusive results. Thus, therapy consists of ampicillin 2 g given every 6 hours for 10
the role of Listeria as a cause of poor obstetric outcome in to 14 days. The addition of gentamicin for synergistic activ-
asymptomatic patients is questionable, and routine screen- ity has been recommended in some cases but lacks adequate
ing is not recommended at this time.70 study to determine a conclusive advantage. Because of its
bactericidal activity and excellent intracellular concentra-
tion, trimethoprim/sulfamethoxazole (20 mg/kg/day TMP
Prenatal, Labor, and Delivery component IV divided into four daily doses) is the recom-
Prevention of maternal listeriosis has been targeted as a mended second-line therapeutic agent in cases of penicillin-
primary objective following epidemiologic data confirming allergic patients.71 However, because of fetal effects, its
the role of contaminated food products as a major source for utility must be evaluated in each case individually, weighing
listeriosis, in both epidemic and sporadic cases. The first the potential risks and benefits. This underscores the neces-
outbreak confirming an indirect transmission from animals sity of accurately determining true penicillin-allergy status
to humans was reported in 1983 in Canada’s Maritime Prov- and consideration of desensitization therapy. Other second-
inces.80 A subsequent large outbreak occurred in 1985 in the line considerations include erythromycin, vancomycin, or
Los Angeles area, in which 65.5% of all cases were pregnant the carbapenems, but experience is limited. Cephalosporins
women or their offspring.81 In 2008, a large outbreak are not effective against Listeria.
occurred in several Canadian provinces resulting in 56 con-
firmed cases and 20 deaths.82 A surveillance project followed
the Los Angeles outbreak, beginning in 1986, coordinated Postnatal
between the U.S. Food and Drug Administration (FDA) and For mothers with proven listeriosis, antibiotic therapy
CDC over multiple diverse demographic areas throughout should be continued for a total of 10 to 14 days for bacte-
the United States. This effort led to identification of many remia or superficial infections or 14 to 21 days for meningi-
at-risk food sources and implementation of more stringent tis. Care of the neonate should involve obtaining blood and
regulations for these food groups over the next several cerebrospinal fluid (CSF) cultures to assess potential infec-
years.83 In 1992, multiple agencies including the CDC, FDA, tion and empirical treatment with ampicillin and gentamicin
and Food Safety and Inspection Service (FSIS) issued dietary pending culture results. Antibiotic therapy is recommended
recommendations for persons at increased risk, including for a minimum of 14 days in cases of bacteremia or pneu-
pregnant women. Results of this project resulted in a decrease monia and 21 days in cases involving the central nervous
of perinatal listeriosis in the surveillance areas from 17.4 per system.

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C HAPTER 31 • Other Infectious Conditions    533

SUMMARY OF MANAGEMENT OPTIONS

Listeriosis Monocytogenes
Evidence Quality and
Management Options Recommendation References
Prepregnancy
No benefit to screening. III/B 70
Treatment of documented infection depending on the site (see later). IV/C 84–86
Prenatal, Labor, and Delivery
Avoid unpasteurized dairy products and certain meat products (see III/B 83,84
Table 31–5)
Culture appropriate sites if listeriosis suspected (blood, CSF, cervix, —/GPP —
amniotic fluid).
Treatment IV/C 84–86
● First-line therapy: IV ampicillin 200 mg/kg/day (divided into four
doses), max = 12 g/day.
● For penicillin-sensitive patients: trimethoprim/sulfamethoxazole
(20 mg/kg/day in three or four doses).
● Other antibiotics: erythromycin, vancomycin. Note: cephalosporins
not effective.
● Duration of therapy: 10–14 days for superficial infection/
bacteremia; 14–21 days for meningitis.
Postnatal
Evaluate neonate with blood and CSF cultures. —/GPP —

CSF, cerebrospinal fluid; GPP, good practice point.

SEXUALLY TRANSMITTED INFECTIONS wrists, or ankles. Acute salpingitis secondary to gonococcal


infection may occur during the first trimester but is rare after
Gonorrhea the 12th week of gestation because obliteration of the endo-
Gonorrhea is the second most commonly reported bacterial metrial cavity by the pregnancy prevents ascending infec-
STI in the United States. It is caused by Neisseria gonorrhoeae, tion. In pregnancy, gonococcal cervicitis has been associated
a gram-negative diplococcus. The prevalence of gonococcal with PROM, premature delivery, chorioamnionitis, and
infection in pregnancy varies, depending upon the popula- both postabortion and postpartum endometritis.92,93 In addi-
tion studied, from 0.5% to 7.4% in the United States.87,88 tion, gonococcal ophthalmia neonatorum may develop in up
Nationally reported gonorrhea rates have been roughly to 40% of newborns exposed to maternal infection who did
stable since 1996, although the rate increased in 2005 for not receive ocular prophylaxis.
the first time since 1999 to 115.6 cases per 100,000 popula-
tion.89 Risk factors for gonococcal infection include multiple Diagnosis
sexual partners, young age, nonwhite race, low socioeco- It is estimated that up to 80% of women with gonococcal
nomic status, and being unmarried. infection of the cervix are asymptomatic; for this reason,
prevention of sequelae of gonorrhea depends upon prenatal
Maternal and Fetal Risks screening to detect infected parturients. Screening should
The most prevalent type of gonococcal infection in preg- occur during pregnancy, and late pregnancy rescreening is
nancy is asymptomatic infection of the cervix. N. gonorrhoeae advised for patients in a high-prevalence population.94 Diag-
may also cause acute cervicitis, proctitis, pharyngitis, and nosis depends upon the demonstration of gram-negative
disseminated systemic infection. The rate of pharyngeal intracellular diplococci within leukocytes of a smear obtained
gonococcal infection increases during pregnancy, possibly from an exudate, if present, or upon culture. Cultures should
as a result of altered sexual practices.90 Disseminated gono- be inoculated immediately after collection onto a selective
coccal infection (DGI) also occurs more frequently in preg- medium such as Thayer-Martin. Culture-independent iden-
nant than in nonpregnant women.91 DGI is characterized by tification of N. gonorrhoeae by immunoassay or DNA detec-
a bacteremic phase associated with malaise, fever, and a tion assays are also available and have been demonstrated to
pustular hemorrhagic rash and a secondary septic arthritis be highly specific and sensitive for the detection of gono-
stage usually with asymmetrical involvement of the knees, coccal infections.

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534    S ECTION F OUR • Infection

T A B L E 3 1 – 6  not recommended for areas with increased prevalence of


quinolone-resistant N. gonorrhoeae.
Treatment of Uncomplicated Gonococcal or
Chlamydial Infections in Pregnancy LABOR AND DELIVERY
Gonococcal Infection
Rapid diagnostic screening tools such as Gram stain,
immune-based assays, and DNA detection assays are avail-
Recommended:
Cefixime 400 mg orally in a single dose or able. These tests can be useful in evaluating the intrapartum
Ceftriaxone 125 mg IM in a single dose patient at risk for infection. Intrapartum treatment of the
Alternative: mother may reduce the neonate’s risk for infection, although
Spectinomycin 2 g IM in a single dose specific treatment and ocular prophylaxis of the infant after
All regimens followed by azithromycin 1 g orally in a single dose or delivery are usually done.
amoxicillin 500 mg orally three times daily for 7 days
Chlamydial Infections POSTNATAL
Recommended: Treatment guidelines for the postpartum patient are similar
Azithromycin 1 g orally in a single dose or to those outlined previously. However, doxycyline or the
Amoxicillin 500 mg orally three times daily for 7 days
quinolone antibiotics may be used in nonlactating women.
Alternative:
Erythromycin base 500 mg orally four times daily for 7 days
Erythromycin base 250 mg orally four times daily for 14 days Chlamydia Trachomatis
Erythromycin ethylsuccinate 800 mg orally four times daily for 7 days
Erythromycin ethylsuccinate 400 mg orally four times daily for C. trachomatis is the cause of one of the most prevalent sexu-
14 days ally transmitted bacterial infections in the world and is the
From Centers for Disease Control and Prevention (CDC): Sexually transmitted
most prevalent sexually transmitted bacterial organism in
diseases treatment guidelines, 2006. MMWR Morb Mortal Wkly Rep 2006; the United States.75 Chlamydiae are obligate intracellular
55(RR-11):1–94. organisms. C. trachomatis may be differentiated into 15 sero-
types. Serotypes A, B, and C cause endemic trachoma, a
chronic ocular infection considered to be the leading cause
of blindness in the world. Serotypes L1, L2, and L3 cause
Management Options lymphogranuloma venereum, discussed later in this chapter.
Serotypes D through K cause genital and ocular infections,
PREPREGNANCY discussed in this section. The prevalence of genital infec-
The CDC published new guidelines for the treatment of tion in pregnant women in the United States has been
STIs in 2006.95 Guidelines are similar for most STIs with reported as between 2% and 37%, with an average esti-
regard to the identification and treatment of these diseases mate of 5% to 7%.98–100 Risk factors for cervical infection
prior to pregnancy, with partner notification and treatment include young age, single marital status, multiple sexual
an important component to prevent reinfection. For non- partners, and previous history of sexually transmitted
pregnant women, recommended antibiotics for treatment of disease.101
gonorrhea include cephalosporins and quinolones.95
Maternal and Fetal Risks
PRENATAL The majority of infected patients have asymptomatic cervi-
Uncomplicated gonorrhea in pregnancy should be treated cal infection. In the nonpregnant female, chlamydial infec-
with cefixime 400 mg orally in a single dose, ceftriaxone tions may cause mucopurulent cervicitis, endometritis, acute
125 mg intramuscularly in single dose, or spectinomycin, 2 g salpingitis, infertility and ectopic pregnancy, and acute ure-
intramuscularly in a single dose (Table 31–6). Because con- thral syndrome. The role of maternal chlamydial infection
current cervical infection with Chlamydia trachomatis occurs in pregnancy is more controversial. Several studies have
frequently,96,97 azithromycin 1 g orally in a single dose or found an association between maternal cervical infection
amoxicillin 500 mg orally three times daily for 7 days should and preterm delivery, PROM, low birth weight, perinatal
also be administered, unless specific testing for C. trachomatis death, and late-onset postpartum endometritis.102–106 Two
has been done and the results are negative. For DGI, hospi- prospective studies have found that only those women with
talization and parenteral therapy are recommended for initial recently acquired infection, as detected by the presence of
therapy. Recommended regimens include ceftriaxone 1 g IgM serum antibody to C. trachomatis, are at increased risk for
intramuscularly or intravenously once daily, ceftizoxime 1 g PROM, preterm delivery, and low birth weight.100,107 Treat-
intravenously every 8 hours, or cefotaxime 1 g intravenously ment and eradication of maternal cervical chlamydial infec-
every 8 hours. Parenteral therapy should be continued until tion reduces the risk of PROM and premature delivery.108–110
24 to 48 hours after symptoms resolve and then converted to Thus, the available data suggest an association between
oral therapy for a total of 1 week of antibiotics. Identifica- maternal chlamydial infection and adverse pregnancy
tion, screening, and treatment of sexual contacts of patients outcome and that screening and treatment in pregnancy is
with gonococcal infection are recommended. warranted.
Tetracyclines and the quinolone antibiotics may be used Maternal chlamydial infection also poses significant risk
in the nonpregnant population, although they are contrain- to the neonate. Approximately 50% to 60% of the neonates
dicated in pregnancy because of potential adverse fetal delivered vaginally to women with chlamydial cervicitis will
effects. As well, because of the emergence of quinolone be colonized with C. trachomatis.99 The most common mani-
resistance in some areas of the United States, quinolones are festations of neonatal infection are inclusion conjunctivitis

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C HAPTER 31 • Other Infectious Conditions    535

and pneumonia. Eighteen percent to 50% of exposed infants LABOR AND DELIVERY
develop conjunctivitis within the first 2 weeks of life, and See the section on “Gonorrhea.”
11% to 18% will develop pneumonia in the first 4 months
of life. POSTNATAL
The incidence of neonatal inclusion conjunctivitis can be
Diagnosis reduced by ocular prophylaxis at birth with 0.5% erythro-
The diagnosis of chlamydial infections is based upon isola- mycin ocular ointment or 1% tetracycline ointment, but not
tion of the organism, or culture-independent detection by as well by 1% silver nitrate drops. Conjunctivitis that does
immunoassay and DNA detection by PCR and serologic occur, or pneumonia, should be treated with oral erythro-
testing. Because chlamydiae are obligatory intracellular bac- mycin for 2 weeks.
teria, isolation by culture requires inoculation onto a suscep-
tible tissue culture cell line. Cell cultures are both Genital Mycoplasmas
labor-intensive and expensive and are not readily available
to most clinicians. Antigen detection kits are widely avail- Maternal and Fetal Risks
able to detect chlamydia and represent a less costly alterna- Mycoplasmas are a ubiquitous group of microorganisms that
tive to culture. More recently, detection of C. trachomatis inhabit the mucosa of the genital and respiratory tracts.
DNA from the genital tract, or from urine, by PCR or ligase They differ from bacteria in that they lack a cell wall, but
chain reaction (LCR) has been demonstrated to be greater they are susceptible to antibiotics that inhibit protein syn-
than 90% sensitive and specific for the detection of C. tra- thesis. The two most common genital mycoplasmas are
chomatis and has largely replaced cultures and antigen detec- Mycoplasma hominis and Ureaplasma urealyticum. The prevalence
tion assays. A serum microimmunofluorescent antibody test of these two microorganisms in the lower genital tract in
is also available to detect recent or past infection but is more sexually active women has been reported to be 40% to 95%
useful as a research tool than for the clinical diagnosis of for U. urealyticum and 15% to 70% for M. hominis. Their high
chlamydial infection. prevalence rates among otherwise healthy women make it
difficult to determine their role in adverse pregnancy out-
Management Options comes. In general, M. hominis has been associated in some,
but not all, studies with septic abortion, postpartum endo-
PREPREGNANCY metritis, and postpartum fever.107,108,114 U. urealyticum has
C. trachomatis is susceptible to a wide range of antibiotics been associated with histologic chorioamnionitis, low birth
including azithromycin, erythromycin, doxycycline, tetra- weight, and perinatal death.115–119
cycline, and ofloxacin. For the nonpregnant patient, Serologic evidence of infection with M. hominis has been
azithromycin 1 g orally in a single dose or doxycycline found in 50% of febrile abortions versus 17% of afebrile
100 mg orally two times a day for 7 days is the recom- abortions.113 In one study of early postpartum endometritis
mended regimen.95 Alternate regimens include erythromy- among women, genital mycoplasmas, including M. hominis,
cin base 500 mg orally four times daily for 7 days, accounted for 30% of the total endometrial isolates and 19%
erythromycin ethylsuccinate 800 mg orally four times daily of the total blood isolates, but were usually recovered in
for 7 days, ofloxacin 300 mg orally twice a day for 7 days, association with other pathogenic bacteria, suggesting a
or levofloxacin 500 mg orally once daily for 7 days. For mixed infection.114 M. hominis has also been isolated from
nonpregnant women, test of cure is not required, but fol- amniotic fluid of patients with amniotic fluid infection, but
low-up testing approximately 3 months after treatment is almost always in association with other bacteria, again
recommended.95 implying a mixed infection.28 Significantly, infected patients
from whom M. hominis is recovered almost always respond to
PRENATAL therapy with β-lactam antibiotics, which have no activity
In pregnancy, azithromycin 1 g orally in a single dose or against genital mycoplasmas.
amoxicillin 500 mg orally three times a day for 7 days is A number of studies have found an association between
recommended. Alternate regimens include erythromycin U. urealyticum and chorioamnionitis116,117,119 and with peri-
base 500 mg orally four times a day for 7 days or 250 mg natal death.117,120 In one study, U. urealyticum was isolated as
orally four times daily for 14 days, or erythromycin ethyl- the sole isolate from fetal lungs in 24 (8%) of 290 perina-
succinate 800 mg orally four times a day for 7 days or tal deaths.120 Twenty-two of these deaths occurred in utero
400 mg four times daily for 14 days (see Table 32–6).95 and all but 1 were associated with pneumonia and chorio-
Erythromycin estolate should probably not be used because amnionitis, implying an ascending intrauterine infection.
it may be associated with hepatotoxicity when given during Some studies have also found decreased birth weight
pregnancy. Because erythromycin therapy is frequently among offspring of women colonized with U. urealyticum,115
associated with gastrointestinal intolerance in pregnancy, but this association has not been confirmed by others.106
regimens avoiding erythromycin might be preferable. Intervention treatment trials have also been inconclusive.
Therapy with either amoxicillin, 500 mg orally three times McCormack and associates121 demonstrated an increase in
a day for 7 days, or clindamycin, 450 mg orally four times birth weight among the offspring of women colonized
a day for 14 days, results in cure rates (98% and 93%, with U. urealyticum treated with erythromycin in the third
respectively) comparable with cure rates with erythromy- trimester compared with colonized women treated with
cin base therapy and are better tolerated by the placebo. Because the presence of potential genital patho-
patient.111,112 Sexual contacts should be examined and gens was not ascertained, their potentially confounding
treated. influence upon birth weight cannot be excluded. In

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536    S ECTION F OUR • Infection

contrast, Eschenbach and coworkers122 found no beneficial be taken from the base of the ulcer and placed on selective
effect of erythromycin taken for up to 14 weeks by a large media. Cultures are both sensitive and specific in the diag-
cohort of women colonized for U. ureaplasma on birth nosis of H. ducreyi infection, but might not be readily avail-
weight, gestational age at delivery, frequency of PROM, able from commercial sources. An enzyme-linked
or neonatal outcome. In this study, women also colonized immunosorbent assay has been developed that is both sensi-
with either C. trachomatis or GBS were excluded from analy- tive and specific and may represent a good alternative when
sis, eliminating any potential confounding bias from culture is not available.
co-infection.
Management Options
Management Options H. ducreyi is susceptible to a variety of antibiotics, although
Taken collectively, the data linking either M. hominis or U. resistance to sulfonamides and tetracycline has emerged that
urealyticum to adverse pregnancy outcome are inconclusive. precludes their use. Quinolones, which are very active
At present, antenatal vaginal cultures for either of these against H. ducreyi, are contraindicated during pregnancy.
mycoplasmas cannot be recommended. Current evidence Current recommended regimens that may be given in preg-
does not support the treatment of colonized patients for nancy include (1) azithromycin 1 g orally in a single dose;
the prevention of adverse pregnancy outcomes. If treat- (2) erythromycin base 500 mg three times daily for 7 days;
ment is deemed necessary, tetracycline is effective against and (3) ceftriaxone 250 mg intramuscularly as a single dose.
both M. hominis and U. urealyticum but should not be used in Azithromycin and ceftriaxone offer the advantage of single-
pregnancy. U. urealyticum is also sensitive to erythromycin dose therapy. It is recommended that patients are tested for
but is resistant to clindamycin; M. hominis is resistant to HIV at the time of diagnosis, and retested for syphilis and
erythromycin but sensitive to clindamycin. Because the HIV 3 months after diagnosis, and that sexual partners of
mycoplasmas lack a cell wall, they are resistant to β-lactam patients are examined and treated.95
antibiotics.
Lymphogranuloma Venereum
Chancroid Lymphogranuloma venereum (LGV) is a sexually trans­
Chancroid is an acute ulcerative disease, usually of the geni- mitted disease caused by C. trachomatis serovars L1, L2, and
tals, caused by infection with Haemophilus ducreyi, a faculta- L3. Transmission occurs through vaginal, anal, or oral
tive gram-negative bacillus. Although rare in North America sexual contact with mucosal damage. It is characterized by
and Europe, it remains an important public health concern inguinal lymphangitis, anogenital lesions, and fibrosis with
in developing countries and can potentially be introduced gross distortion of the perineal tissues. LGV is endemic in
into other geographic areas as a result of travel. Chancroid certain parts of the world, including Africa, India, South-
may occur more frequently in individuals infected with east Asia, and parts of South America.124 It occurs sporadi-
HIV, genital herpes, or syphilis. Chancroid is spread only cally in other geographic locations and was very rarely
through sexual contact with individuals with ulcers and is seen in industrialized countries in North America, Europe,
much more prevalent in men than in women. The incuba- or Australia until more recently. Beginning in 2003, clus-
tion period after transmission is usually between 4 and 7 ters of cases have been identified in Europe, Canada, and
days. A painful chancre then develops at the site of entry, the United States.125 LGV is predominantly a disease of
beginning as a small papule that over the course of 1 to 2 lymphatic tissue characterized by thrombolymphangitis
days, becomes eroded and ulcerated. Multiple ulcers are and spread of the inflammatory process into the adjacent
common, with the majority occurring on the external geni- tissues. Three stages of infection are recognized: primary,
tals and only rarely on the cervix or vagina. The classic ulcer secondary, and tertiary. The primary lesion is character-
of chancroid is shallow with an irregular border surrounded ized by a small shallow genital papule or ulcer that appears
by erythema. The base of the ulcer is frequently covered at the site of infection after an incubation period of 3 to
with a necrotic exudate. Painful inguinal adenopathy devel- 12 days, heals rapidly, and is often associated with few
ops in about 50% of cases and may lead to suppuration and symptoms. The secondary stage occurs 10 to 30 days later
spontaneous rupture if untreated. These buboes appear 7 to and is characterized by systemic symptoms and painful
10 days after the initial ulcer and are unilateral in two thirds inguinal lymphadenitis or buboes, loculated abscesses, and
of cases. anorectal symptoms such as pain and bleeding. The ter-
tiary stage is characterized by a chronic inflammatory
Maternal and Fetal Risks response with progressive tissue destruction, ulceration,
H. ducreyi has not been shown to cause systemic infection fistula formation, and lymphatic obstruction. Antibiotic
or spread to distant sites and poses no special risk to treatment during the secondary stage will prevent these
pregnancy. tertiary complications.
Diagnosis
The diagnosis of chancroid is based upon clinical character- Maternal and Fetal Risks
istics (the presence of a painful ulcer and tender adenopathy) The course of the disease is not dramatically altered by
and Gram stain and culture of the ulcer or aspirated bubo. pregnancy, and transmission to the fetus does not occur.
The Gram stain may reveal gram-negative rods that form However, infection may be acquired during birth and
chains but has a sensitivity of only 50%.123 Cultures should passage through the infected birth canal.

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C HAPTER 31 • Other Infectious Conditions    537

Diagnosis painless. Redundant, beefy-red granulation tissue may be


The diagnosis of LGV is based upon clinical appearance, present, giving an exophytic appearance to the lesion.
serologic tests, and recovery of C. trachomatis from infected These lesions are highly vascular and may bleed on contact.
tissue or its identification by the direct immunofluorescent In the female, these lesions are found most commonly on
antibody test. Serology showing complement fixation titers the labia.
greater than 1 : 64 support the diagnosis. Routine testing for
C. trachomatis is not specific enough, and confirmatory Maternal and Fetal Risks
serovar-specific testing using DNA sequencing techniques is Pregnancy may accelerate the growth of these lesions. The
necessary to confirm the diagnosis. effects of GI upon the fetus are not completely understood,
but perinatal transmission at the time of birth through an
Management Options infected birth canal has been reported.128
A variety of antibiotics have been used to treat LGV. First-
line treatment for nonpregnant patients and sexual partners Diagnosis
of pregnant patients is doxycycline 100 mg orally two times The diagnosis of GI is based upon the clinical appearance
a day for 21 days.95 An alternative regimen is erythromycin of the disease. The diagnosis is readily confirmed by exami-
base 500 mg orally four times a day for 21 days. Pregnant nation of a smear of a crushed tissue preparation of the
women should be treated with erythromycin.95 Azithromy- lesion. The smear is stained with Wright or Giemsa stain
cin may be an alternative, but there are not yet any pub- and examined for Donovan bodies. Donovan bodies are the
lished studies regarding its efficacy and safety. Late sequelae darkly stained organisms within cytoplasmic inclusions con-
such as fistulas or strictures may require subsequent surgical tained in infected mononuclear cells. Their presence is diag-
repair. nostic for GI. Neither cultures nor serologic tests are
available.
Granuloma Inguinale (Donovanosis) Management Options
Granuloma inguinale (GI) is a rare, chronic genital infec- The recommended treatment of GI for nonpregnant patients
tion characterized by granulomatous ulcers. It is common in is doxycycline 100 mg orally twice daily for a minimum of
tropical climates and developing countries, but extremely 3 weeks and until all lesions have completely healed.91
rare in temperate climates.126 GI is caused by infection with Chloramphenicol and gentamicin have been used success-
Klebsiella granulomatis, formerly known as Calymmatobacterium fully for resistant cases. Pregnant women should be treated
granulomatis, a facultative, gram-negative bacillus. Although with erythromycin base 500 mg orally four times a day for
most infections probably result from sexual transmission, at least 3 weeks. Azithromycin may also be effective, but
autoinoculation and nonsexual transmission also occur. The published data are currently lacking. The addition of a par-
infection is only mildly contagious, and repeated close enteral aminoglycoside should be considered if improve-
physical contact is necessary for transmission.127 Following ment is not evident within the first few days of therapy.
acquisition of infection, the incubation period varies from 8 Treatment should continue for a minimum of 3 weeks and
to 80 days. The disease begins as a subcutaneous nodule until lesions are completely healed to prevent recurrence.
that erodes through the skin and slowly enlarges to form an Treatment of asymptomatic sexual partners is generally not
exuberant, granulomatous heaped ulcer, which is usually recommended.

SUMMARY OF MANAGEMENT OPTIONS

Sexually Transmitted Diseases


Evidence Quality and
Management Options Recommendation References

Gonorrhea

Prepregnancy
Identify and treat prior to pregnancy. III/B 92,95
Contact tracing and treatment. III/B 92,95
Confirm response with follow-up swabs. III/B 92,95
Prenatal
Give antibiotics (see Table 31–6). III/B 92
Contact tracing and treatment. III/B 92
Exclude chlamydia infection. III/B 96
Postnatal
Screen newborn for infection, although most units treat anyway. —/GPP —

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538    S ECTION F OUR • Infection

SUMMARY OF MANAGEMENT OPTIONS

Sexually Transmitted Diseases—cont’d


Evidence Quality and
Management Options Recommendation References

Chlamydia

Prepregnancy
Identify and treat with doxycycline or ofloxacin. Ia/A 95,109,111,112
Contact tracing and treatment. Ia/A 95,109,111,112
Prenatal Treatment
If diagnosed, give antibiotics (see Table 31–6). Ia/A 95,109,111,112
Contact tracing and treatment. Ia/A 95,109,111,112

Mycoplasma

Prenatal
If treatment necessary, use erythromycin. Ia/A 122

Chancroid

Prenatal
Treatment of patient and partner with either azithromycin, IV/C 95,124
erythromycin, or a cephalosporin.

Lymphogranuloma Venereum

Prenatal
Erythromycin if diagnosed in pregnancy. Azithromycin is a IV/C 95,124
possible alternative.
Fistulas or strictures may need repair after pregnancy. IV/C 95,124

Granuloma Inguinale

Prenatal
Erythromycin if diagnosed in pregnancy. Azithromycin is a IV/C 95,126,127
possible alternative. Treatment should continue for a minimum
of 3 wk.

GPP, good practice point.

vaginal pH to less than 4.5, inhibiting the growth of non–


VAGINITIS acid-tolerant, potentially pathogenic microorganisms. They
Vaginal discharge is one of the most common complaints of also produce hydrogen peroxide, a potent antimicrobial
pregnant patients. The discharge may be the result of normal toxin to other microorganisms including Candida albicans,
physiologic adaptations of pregnancy or may result from Gardnerella vaginalis, and anaerobic bacteria.130,131 When this
infectious vaginitis, with possible increased risk for preg- complex relationship is changed, potentially pathogenic
nancy complications. The vagina has both a nutrient-rich microorganisms indigenous to the vagina such as C. albicans
biochemical milieu and a complex microbial flora. Normal or G. vaginalis and anaerobes may proliferate and cause
vaginal discharge consists of water (primarily as a serum vaginal discharge. Alternatively, sexually transmitted exog-
transudate), desquamated epithelial cells, microorganisms, enous microorganisms, such as Trichomonas vaginalis, may
electrolytes, and organic compounds including organic disrupt the normal vaginal ecosystem and lead to symptom-
acids, fatty acids, proteins, and carbohydrates (primarily gly- atic vaginitis.
cogen).129 Normal vaginal fluid contains two to nine species Pregnancy itself may also lead to physiologic changes of
of facultative and anaerobic bacteria in concentrations of 109 the lower genital tract, which may predispose to vaginitis.
colony-forming units/mL.130 Normally, facultative Lactobacil- During pregnancy, the vaginal walls become engorged with
lus species account for the majority of the total organisms blood, leading to increased transudation, and the glycogen
present. These microorganisms utilize the available glyco- content of the vagina increases.130 Elevated levels of proges-
gen, producing lactic acid, which serves to acidify the terone seen during pregnancy enhance the adherence of C.

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C HAPTER 31 • Other Infectious Conditions    539

albicans to vaginal epithelial cells. Finally, cell-mediated studies demonstrating an association between bacterial
immunity is impaired during pregnancy, predisposing to vaginosis and preterm birth. Despite this evidence, the
candidal infections. strategy of screening for and treatment of bacterial vagino-
The three most commonly occurring causes of infectious sis in large-scale studies of women at low risk of adverse
vaginitis in pregnancy are bacterial vaginosis, candidiasis, obstetric outcomes has not resulted in a reduction in the
and trichomoniasis. Although frequently asymptomatic, incidence of prematurity. Thus, the U.S. Preventive Ser-
these infections have been implicated in a variety of adverse vices Task Force published a statement in 2001 concluding
pregnancy outcomes. that the available evidence was insufficient to recommend
for or against routinely screening women at high risk
preterm birth for bacterial vaginosis and recommending
Bacterial Vaginosis against screening average risk asymptomatic pregnant
Bacterial vaginosis is the most common lower genital tract women.139
disorder among women of reproductive age (pregnant and Little is known about the mechanisms by which bacterial
nonpregnant) and the most prevalent cause of vaginal dis- vaginosis may cause prematurity. The increased intravaginal
charge and malodor.132,133 It is a polymicrobial syndrome concentrations of bacteria may simply overwhelm the local
resulting in a decreased concentration of lactobacilli and an host defenses, allowing for ascending infection. Alterna-
increase in pathogenic bacteria (mainly anaerobic). Specifi- tively, these bacteria could also produce protease or phos-
cally, there is an increased prevalence of G. vaginalis, selected pholipases, which weaken the membranes or stimulate
anaerobes (Bacteroides, Peptostreptococcus, and species), and M. prostaglandin production.140 Although the magnitude of the
hominis and a decreased prevalence of hydrogen peroxidase– increased risk for prematurity noted in these studies is
producing Lactobacillus.131,134 In addition, there is a 100-fold modest (approximately a twofold increased risk compared
increase in the intravaginal concentration of G. vaginalis and with patients without bacterial vaginosis), the total impact
a 1000-fold increase in the concentration of anaerobes.134 upon prematurity may be much greater given the high prev-
Thus, the diagnosis of bacterial vaginosis does not depend alence of 20% for bacterial vaginosis in pregnancy. It has
upon the recovery or identification of any single microor- been estimated that as many as 6% of preterm deliveries of
ganism from the vagina, but rather requires the recognition infants with low birth weight may be attributable to bacterial
of an altered vaginal microbial milieu. vaginosis.135
Maternal and Fetal Risks Diagnosis
The presence of bacterial vaginosis has consistently been The most common symptom among women with bacterial
shown to be a risk factor for adverse pregnancy outcomes vaginosis is a thin, watery, nonpruritic discharge with a fishy
such as preterm labor and delivery, preterm PROM, spon- odor. However, one half of women with bacterial vaginosis
taneous abortion, chorioamnionitis, and postpartum infec- are asymptomatic.
tions such as endometritis and cesarean section wound Criteria for the clinical diagnosis of bacterial vaginosis are
infections.118,135–139 Table 31–7 presents a summary of well established, with the diagnosis confirmed if three of the
four following signs are present141: (1) an adherent and
homogeneous vaginal discharge; (2) a vaginal pH above 4.5;
(3) detection of clue cells on saline wet mount; and (4) the
T A B L E 3 1 – 7  release of an amine (fishy) odor after the addition of 10%
Association between Bacterial Vaginosis and potassium hydroxide (positive whiff test). The diagnosis of
Preterm Labor or Preterm Birth bacterial vaginosis can also be made by direct Gram stain of
the vaginal discharge. The Gram stain is the most widely
RISK RATIO OR 95% CONFIDENCE used and evaluated microbiologic diagnostic method for this
STUDY ODDS RATIO INTERVAL
condition. Most laboratories use an objective diagnostic
Case-Control scheme that quantifies the number of Lactobacillus morphot-
Eschenbach, 1984131 3.1 1.6–6.0 ypes and pathogenic bacteria, resulting in a score that is used
Gravett, 1986166 3.8 1.2–11.6
to determine whether the infection is present. The most
commonly used system is the Nugent score.142 The criterion
Martius, 1988167 2.3 1.1–5.0
for bacterial vaginosis is a score of seven or higher. A score
Prospective Cohort of four to six is considered intermediate, and a score of zero
Minkoff, 1984136 2.3 0.96–5.5 to three is considered normal.
Gravett, 1986103 2.0 1.1–3.7
McGregor, 1990168 2.6 1.1–6.5 Management Options
McDonald, 1991169 1.8 1.01–3.2 The treatment of choice for symptomatic bacterial vaginosis
Kurki, 1992170 6.9 2.5–18.8 in pregnancy is metronidazole given orally in a dose of
Riduan, 1993171 2.0 1.0–3.9 500 mg twice daily for 7 days or 250 mg three times daily
McGregor, 1994146 3.3 1.2–9.1 for 7 days.95 This results in cure rates of 90%. A single 2-g
Hay, 1994172 5.2 2.0–13.5
oral dose of metronidazole is also effective. Oral clindamy-
cin 300 mg twice a day for 7 days may be used as an alterna-
McGregor, 1995173 1.9 1.2–3.0
tive. Nitroimidazoles cross the placenta and are mutagenic
Meis, 1995174 1.8 1.15–2.95
in bacteria and carcinogenic in some animals. However,
Hillier, 1995135 1.4 1.1–1.8 there is no evidence that metronidazole is teratogenic or

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540    S ECTION F OUR • Infection

mutagenic in human studies, and it is considered safe for be recovered from the vagina in 25% to 40% of asymptom-
use in pregnancy.143,144 Cure rates utilizing topical therapy atic women. Candida also accounts for approximately 25% of
are comparable with those of systemic therapy.145 However, all symptomatic vaginitis among nonpregnant patients and
vaginal preparations such as metronidazole vaginal gel up to 45% of vaginitis in pregnancy. In pregnancy, altera-
0.75%, given intravaginally once daily for 5 days, or clinda- tions in the vaginal microflora, glycogen availability, and a
mycin cream 2.0%, given intravaginally once daily for 7 depression in maternal cellular immunity may all contribute
days have not been shown to be effective for preterm to increase the risk of Candida overgrowth leading to vagini-
birth prevention, and therefore, oral agents are preferred. tis. Although rare, C. albicans has been reported as a cause of
Further studies are necessary to address this important amniotic fluid infection and congenital cutaneous candidia-
consideration. sis of the newborn.157
The results of trials examining whether the treatment of
bacterial vaginosis in pregnancy can affect the frequency of
adverse pregnancy outcomes, especially preterm birth, have Diagnosis
been inconsistent. In trials enrolling women from the general Women with vaginal candidiasis experience vulvar and
population who are not at increased risk for preterm birth, vaginal pruritus, external dysuria, and a nonmalodorous floc-
there does not appear to be any benefit to screening for and culent discharge. Examination usually reveals an erythema-
treating bacterial vaginosis. These results have been repli- tous vulvar rash and a characteristic white “cottage cheese”
cated in many studies from different countries, enrolling discharge that adheres to the vaginal walls. The vaginal pH
women at a range of gestational ages, and using both oral is usually normal (<4.5) and no odor is present. Microscopic
and vaginal medications (metronidazole and clindamy- examination of material suspended in 10% potassium
cin).146–151 However, in women at increased risk for prema- hydroxide reveals typical mycelial forms and pseudohyphae
ture birth (often defined as having a history of a previous in 80% of patients with symptomatic infection. Because
preterm delivery), there have been more promising results. Candida species may exist in the vaginal flora in low concen-
Several studies have shown that women randomized to treat- trations among normal asymptomatic patients, cultures are
ment with oral metronidazole had lower rates of adverse usually not indicated. Cultures should be limited to women
outcomes, including preterm labor and delivery, than women in whom candidiasis is suspected but cannot be confirmed
randomized to placebo.150,152,153 In a Cochrane Collaboration by microscopic examination.
review154 of 15 treatment trials involving 5888 women, there
was a statistically significant decrease in the rate of preterm
prelabor rupture of membranes and low birth weight in Management Options
treated women with a history of previous preterm birth, but Treatment by local application of antifungals results in relief
no effect on preterm delivery rates. However, in the same of symptoms and eradication of yeast in 70% to 90% of
review, there was a statistically significant decreased risk of patients. The mainstay of treatment has been with imidaz-
preterm birth in five trials of 2387 women treated before 20 oles. These broad-spectrum antifungals include miconazole,
weeks’ gestation.154 clotrimazole, teraconazole, and butaconazole. These agents
In published studies, vaginal therapy has not been shown inhibit fungal ergosterol synthesis, resulting in disruption of
to be effective in preventing preterm birth in women with the cell membrane. They are available as a one-time intra-
bacterial vaginosis.146–149 The one exception to this is a trial vaginal suppository or as either 3-day or 7-day courses of
by Lamont and colleagues155 that demonstrated a statistically intravaginal suppositories or creams given once daily at
significant reduction in preterm birth (4% vs. 10%) in bedtime. These imidazoles are not absorbed systemically
women randomized to clindamycin vaginal cream at 13 to and are safe to use in pregnancy. In pregnant women, the
20 weeks’ gestation compared with placebo. A meta-analysis 7-day course is recommended.95 Boric acid powder, in
exploring the issue of oral or vaginal treatment in women at 600 mg vaginal suppositories, placed intravaginally daily for
low risk versus those at high risk for preterm birth found no 14 days is also 90% effective in eradicating symptomatic
significant reduction in preterm delivery by treatment of all vaginal candidiasis and has the advantage of being very
women, women with a previous preterm birth, or women at inexpensive.158 Although borate is poorly absorbed systemi-
low risk for preterm birth.156 However, in the subgroup of cally in nonpregnant women, its absorption during preg-
women who had a previous preterm delivery and who had nancy is uncertain, and therefore, alternative therapies with
received oral treatment for at least 7 days, there was a highly topical imidazoles are preferable. Two other antifungal
significant decrease in preterm delivery (odds ratio [OR] agents that are systemically absorbed after oral or intrave-
0.42; 95% confidence interval [CI] 0.27–0.67). There was nous administration are ketoconazole, an imidazole, and
no benefit seen in the group of women receiving vaginal fluconazole, a triazole. These both have superb activity
treatment. against Candida species and are useful in the treatment of
systemic fungal infections or vaginal candidiasis in nonpreg-
Candida Vaginitis nant women.
Maternal and Fetal Risks
Candida vaginitis may be caused by many species of Candida, Trichomoniasis
but the predominant species is C. albicans, which is respon- Trichomoniasis is caused by T. vaginalis, a sexually transmit-
sible for 80% to 90% of infections. The remainder of cases ted anaerobic protozoan. T. vaginalis may be recovered from
are caused by Candida (Torulopsis) glabrata and other Candida 40% of women screened in sexually transmitted disease
species. These organisms are saprophytic fungi, which may clinics and from the prostatic fluid of 70% of the male

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C HAPTER 31 • Other Infectious Conditions    541

contacts of the women with symptomatic trichomonia- However, cultures have limited practicality in the clinical
sis.159,160 The prevalence of trichomoniasis in pregnancy setting because 3 to 7 days are needed for growth before the
ranges from 6% to 22%. Risk factors associated with T. vagi- diagnosis can be confirmed. Trichomonads can also be seen
nalis colonization include black race, cigarette smoking, on a Pap smear with a similar sensitivity to the wet mount,
greater number of sexual partners, and a history of gonor- but with a higher rate of false-positive results. Other sensi-
rhea.161 It is estimated that approximately 50% of women tive and specific rapidly performed diagnostic tests have
harboring T. vaginalis are asymptomatic.159 recently been developed, including direct immunofluores-
cence assay, enzyme-linked immunoassay, and LPA. These
are not, however, in widespread use currently. All women
Maternal and Fetal Risks with trichomoniasis, whether symptomatic or not, should
Pregnant women with T. vaginalis infection may be asymp- have a culture taken for N. gonorrhoeae because of the fre-
tomatic or may have clinical vaginitis. T. vaginalis may also quency of coinfection.
cause other infections of the lower genitourinary tract
including bartholinitis, urethritis, periurethral gland infec-
tion, and cystitis. Although the risk of infection to the Management Options
neonate is low (<1%), vaginitis and cystitis may occur as Because T. vaginalis resides not only in the vagina but also in
manifestations of neonatal disease. T. vaginalis has also been the urethra and bladder, systemic therapy is necessary for
rarely suspected as a cause of neonatal pneumonitis. Although treatment. The only effective therapy for trichomoniasis are
the relationship between vaginal trichomoniasis and adverse the nitroimidazole antibiotics, including metronidazole,
pregnancy outcome has not been well studied, two prospec- ornidazole, and tinidazole. For pregnant women who are
tive studies have found a decrease in mean gestational age symptomatic, treatment is recommended. However, it is
at delivery and an increase in PROM among women infected important to note that, although trichomoniasis has been
with T. vaginalis.99,136 Further studies are necessary to confirm associated with adverse pregnancy outcomes, treatment has
these relationships. not been shown to reduce the incidence of these adverse
events,135 and some studies have even documented an
Diagnosis increased risk with treatment. Therefore, treatment is not
Women with symptomatic trichomoniasis characteristically indicated in asymptomatic T. vaginalis infection in preg-
complain of a profuse and malodorous vaginal discharge. nancy. In a randomized, controlled trial of pregnant women
Vulvar pruritus, dysuria, dyspareunia, and lower abdominal with asymptomatic trichomoniasis, the preterm birth rate
tenderness may also be present. On examination, a gray or was 19% in those given two 2-g doses of oral metronidazole
yellow-green frothy discharge is frequently present. The pH and 10% in the placebo group (RR 1.8; 95% CI 1.2–2.7; P
of the discharge is usually higher than 4.5 and may have an = .004).163 In another randomized trial, children of women
amine odor after addition of 10% potassium hydroxide. treated with several antibiotics including metronidazole had
Small submucosal punctate hemorrhages of the cervix, the an increased risk of low birth rate, preterm delivery, and
so-called strawberry cervix, are sometimes present. Micro- 2-year mortality.164 Finally, a meta-analysis of 14 studies
scopically, motile trichomonads may easily be identified on revealed that metronidazole treatment increased the inci-
a saline wet mount by their characteristic pear shape, fla- dence of preterm birth.165
gella, and rapid, jerking motility. Polymorphonuclear leuko- For pregnant women in whom treatment is chosen, the
cytes are also present on saline wet mount microscopy and preferred regimen is a single 2-g dose of oral metronidazole.
may be so abundant that they obscure the trichomonads. Simultaneous treatment of sexual partners is required to
The sensitivity of the saline wet mount, when compared prevent reinfection. As previously mentioned, there is no
with culture, is 60%, but its specificity is near 100%.162 evidence that metronidazole is teratogenic or mutagenic in
Trichomonas cultures are easily performed utilizing Diamond’s human studies, and it is considered safe for use in
medium and are highly sensitive (92%–95%) and specific. pregnancy.143,144

SUMMARY OF MANAGEMENT OPTIONS

Bacterial Vaginosis, Candidiasis, Trichomonas


Evidence Quality and
Management Options Recommendation References

Bacterial Vaginosis

Prepregnancy and Postnatal


Treat with oral metronidazole. Ib/A 95
Give intravaginal metronidazole gel or clindamycin cream. Ib/A 95

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542    S ECTION F OUR • Infection

SUMMARY OF MANAGEMENT OPTIONS

Bacterial Vaginosis, Candidiasis, Trichomonas—cont’d


Evidence Quality and
Management Options Recommendation References
Prenatal
For symptom relief, treat with oral metronidazole or intravaginal Ib/A 145
metronidazole gel.
For preterm birth prevention in women at increased risk, consider Ia/A 139,146–156
screening for and treating with oral metronidazole.

Candidiasis

Prepregnancy and Postnatal


Treat topically with an imidazole (miconazole, clotrimazole, —/GPP 95
teraconazole, butaconazole) or oral fluconazole.
Prenatal
Topical therapy should be administered with a 7-day course. GPP 95
Ketoconazole and fluconazole are best avoided in pregnancy —/GPP —
except for severe systemic infection.

Trichomonas

Prepregnancy and Postnatal


Treat patient and partner systemically with a nitroimidazole IV/C 95,162
antibiotic (metronidazole, ornidazole, tinidazole).
Prenatal
For symptom relief, treat with oral metronidazole. Ib/A 95
If asymptomatic, do not treat because treatment has been Ib/A 163,164
associated with an increased risk of preterm birth.

GPP, good practice point.

Nugent RP, Krohn MA, Hillier SL: Reliability of diagnosing bacterial vagi-
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Morb Mortal Wkly Rep 2002;51(RR-11):1–18. strategies to prevent early-onset group B streptococcal disease in neo-
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2006;55(RR-11):1–94. the era of intrapartum antibiotic prophylaxis. N Engl J Med
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REFERENCES
J Obstet Gynecol 1995;173:1231–1235. For a complete list of references, log onto www.expertconsult.com.

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