Epidemiology

Streptococcus agalactiae is a gram-positive encapsulated coccus that produces β-hemolysis when grown on blood agar. On average, about 20% to 25% of pregnant women in the United States harbor this group B Streptococcus (GBS) in their lower genital tract and rectum. GBS is one of the most important causes of early-onset neonatal infection. The prevalence of neonatal GBS infection now is about 0.5 per 1000 live births, and about 10,000 cases of neonatal streptococcal septicemia occur each year in the United States.

Neonatal GBS infection can be divided into early-onset and late-onset infection, and Table 54-1 summarizes characteristics of both. About 80% to 85% of cases of neonatal GBS infection are early in onset and result almost exclusively from vertical transmission from a colonized mother. Early-onset infection presents primarily as a severe pneumonia and overwhelming septicemia. In preterm infants, the mortality rate from early-onset GBS infection may approach 25%. In term infants, the mortality rate is lower, averaging about 5%. Late-onset neonatal GBS infection occurs as a result of both vertical and horizontal transmission. It is typically manifested by bacteremia, meningitis, and pneumonia. The mortality rate from late-onset infection is about 5% for both preterm and term infants. Unfortunately, obstetric interventions have proved ineffective in preventing late-onset neonatal infection. Therefore the remainder of this discussion focuses on early-onset infection.

Major risk factors for early-onset infection include preterm labor, especially when complicated by preterm premature rupture of the membranes (PROM); intrapartum maternal fever (chorioamnionitis); prolonged rupture of membranes, defined as greater than 18 hours; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. About 25% of pregnant women have at least one risk factor for GBS infection. The neonatal attack rate in colonized patients is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present but is less than 5% when a risk factor is absent.

Maternal Complications

Several obstetric complications occur with increased frequency in pregnant women who are colonized with GBS. The organism is one of the major causes of chorioamnionitis and postpartum endometritis . It may cause postcesarean delivery wound infection , usually in conjunction with other aerobic and anaerobic bacilli and staphylococci. The organism also is responsible for approximately 2% to 3% of lower urinary tract infections in pregnant women. GBS urinary tract infection, in turn, is a risk factor for preterm PROM and preterm labor. For example, Thomsen and colleagues reported a study of 69 women at 27 to 31 weeks’ gestation who had streptococcal urinary tract infections. Patients were assigned to treatment with either penicillin or placebo. Treated patients had a significant reduction in the frequency of both preterm PROM and preterm labor.

Other investigations have confirmed the association between GBS colonization and preterm labor and preterm PROM. Women with the latter complication who are colonized with GBS tend to have a shorter latent period and higher frequency of chorioamnionitis and puerperal endometritis compared with noncolonized women.

Diagnosis

The gold standard for the diagnosis of GBS infection is bacteriologic culture. Todd-Hewitt broth or selective blood agar is the preferred medium. Specimens for culture should be obtained from the lower vagina, perineum, and perianal area using a simple cotton swab. In recent years, considerable research has been devoted to assessment of rapid diagnostic tests for the identification of colonized women. Table 54-2 summarizes the results of several investigations of rapid diagnostic tests. The information in this table is based on the review by Yancey and associates. These authors noted that, although the rapid diagnostic tests had reasonable sensitivity in identifying heavily colonized patients, they had poor sensitivity in identifying lightly and moderately colonized patients.

Although the first-generation rapid diagnostic tests were not as valuable as originally hoped, Bergeron and colleagues reported exceptionally favorable results with a new polymerase chain reaction (PCR) assay for GBS. In a series of 112 patients, the authors documented a sensitivity of 97%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99%. This PCR assay now is commercially available and offers clear promise as a rapid test for screening patients at the time of admission for labor. Ahmadzia and colleagues recently reviewed the diagnostic accuracy of intrapartum nucleic acid amplification tests (NAATs) for GBS and reported that the sensitivity ranged from 91% to 94%.

Prevention of Group B Streptococcal Infection

In the past 20 years, several strategies have been proposed for the prevention of neonatal GBS infection. Each strategy has had major imperfections. In 1996, however, the Centers for Disease Control and Prevention (CDC) published a series of recommendations that incorporated the major advantages of previous protocols and minimized some of the more problematic aspects of selected strategies. The initial CDC guidelines recommended either universal culturing of all patients at 35 to 37 weeks’ gestation and intrapartum treatment of all colonized women or selective treatment on the basis of identified risk factors. Subsequently, in a large population-based survey, Rosenstein and Schuchat assessed the theoretic impact of the CDC recommendations and showed that a strategy of universal culturing and treatment of all colonized patients would prevent 78% of cases of neonatal infection. In contrast, only 41% of cases were prevented when patients were targeted for prophylaxis just on the basis of risk factors. In addition, Locksmith and colleagues confirmed that universal culturing also was of value in decreasing the rate of maternal infection compared with a strategy of only treating on the basis of risk factors.

In 2010, the CDC issued its most recent guidelines for prevention of early-onset GBS infection. The newest guidelines recommend universal cultures in all patients as the optimal method of prevention. Cultures should be performed at 35 to 37 weeks’ gestation. All patients who test positive should receive intrapartum antibiotic prophylaxis with one of the regimens outlined in Figure 54-1 . Ideally, antibiotics should be administered at least 4 hours before delivery. DeCueto and coworkers demonstrated that the rate of neonatal GBS infection was reduced significantly when patients were treated for at least this long. In a subsequent investigation to assess timing of antibiotic prophylaxis, McNanley and associates showed that mean vaginal GBS counts decreased fivefold within 2 hours of antibiotic administration, fiftyfold within 4 hours, and almost a thousandfold within 6 hours.

Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset group B Streptococcus (GBS) disease. IV, intravenously.

The new CDC guidelines also addressed issues that previously had been imprecisely defined. Colonized patients scheduled for a planned cesarean delivery do not require intrapartum prophylaxis. Patients who tested positive for GBS in a previous pregnancy should not be assumed to be colonized and should be retested with each pregnancy. This recommendation is supported by a later report from Edwards and coworkers. These authors noted that only 59% of patients who were culture positive in a previous pregnancy were positive in the current pregnancy. Conversely, however, patients who have GBS bacteriuria in pregnancy, even if treated, should be considered heavily colonized and should be targeted for intrapartum prophylaxis. Moreover, patients who had a previous infant with GBS infection also should be considered colonized and should be treated during labor. Table 54-3 outlines indications and nonindications for intrapartum prophylaxis against GBS.

Acute Urethritis

Acute urethritis, or acute urethral syndrome, is usually caused by one of three organisms: coliforms (principally Escherichia coli ) , Neisseria gonorrhoeae, and Chlamydia trachomatis. Coliform organisms are part of the normal vaginal and perineal flora and may be introduced into the urethra during intercourse or when wiping after defecation. N. gonorrhoeae and C. trachomatis are sexually transmitted pathogens. Patients affected by urethritis typically experience frequency, urgency, and dysuria. Hesitancy, dribbling, and a mucopurulent urethral discharge also may be present. On microscopic examination, the urine usually has white blood cells, but bacteria may not be consistently present. Urine cultures may have low colony counts of coliform organisms, and cultures of the urethral discharge may be positive for gonorrhea and chlamydia . A rapid diagnostic test, such as a NAAT, is now the preferred method for identification of gonorrhea and chlamydia .

Most patients with acute urethritis warrant empiric treatment before the results of laboratory tests are available. Infections caused by coliforms usually respond to the antibiotics described later for treatment of asymptomatic bacteriuria and cystitis. If gonococcal infection is suspected, the patient should be treated with intramuscular ceftriaxone (250 mg in a single dose) plus 1000 mg oral azithromycin. If the patient is allergic to β-lactam antibiotics, an effective alternative is azithromycin 2000 mg orally in a single dose. This high dose of azithromycin is more likely to be associated with gastrointestinal side effects than more conventional lower doses. An alternative choice in the penicillin-allergic patient is ciprofloxacin 500 mg orally in a single dose. If chlamydial infection is suspected or confirmed, the patient should be treated with azithromycin 1000 mg in a single dose.

Asymptomatic Bacteriuria and Acute Cystitis

The prevalence of asymptomatic bacteriuria in pregnancy is 5% to 10%, and most cases antedate the onset of pregnancy. The frequency of acute cystitis in pregnancy is 1% to 3%. Some cases of cystitis arise de novo, whereas others develop as a result of failure to identify and treat asymptomatic bacteriuria.

E. coli is responsible for at least 80% of cases of initial infections and about 70% of recurrent cases. Klebsiella pneumoniae and Proteus species also are important pathogens, particularly in patients who have a history of recurrent infection. Up to 10% of infections are caused by gram-positive organisms such as GBS, enterococci, and staphylococci.

All pregnant women should have a urine culture at their first prenatal appointment to detect preexisting asymptomatic bacteriuria. If the culture is negative, the likelihood of the patient subsequently developing an asymptomatic infection is less than 5%. If the culture is positive—defined as greater than 10 ⁵ colonies/mL urine from a midstream, clean-catch specimen—prompt treatment is necessary to prevent ascending infection. In the absence of effective treatment, about one third of pregnant women with asymptomatic bacteriuria will develop acute pyelonephritis. In a recent report, treatment of asymptomatic bacteriuria was also associated with a reduction in the incidence of low-birthweight babies (relative risk [RR], 0.66; 95% confidence interval [CI], 0.49 to 0.89), but no difference in preterm delivery was seen.

Patients with acute cystitis usually have symptoms of frequency, dysuria, urgency, suprapubic pain, hesitancy, and dribbling. Gross hematuria may be present, but high fever and systemic symptoms are uncommon. In symptomatic patients, the leukocyte esterase and nitrate tests are usually positive. When a urine culture is obtained, a catheterized sample is preferred because it minimizes the probability that urine will be contaminated by vaginal flora. With a catheterized specimen, a colony count greater than 10 ² /mL is considered indicative of infection.

Asymptomatic bacteriuria and acute cystitis characteristically respond well to short courses of oral antibiotics. Single-dose therapy is not as effective in pregnant women as in nonpregnant patients. However, a 3-day course of treatment appears to be comparable to a 7- to 10-day regimen for an initial infection. Longer courses of therapy are more appropriate for patients with recurrent infections. Table 54-4 lists several antibiotics of value for treatment of asymptomatic bacteriuria and cystitis.

When sensitivity tests are available—for example, for patients with asymptomatic bacteriuria—they may be used to guide antibiotic selection. When empiric treatment is indicated, the choice of antibiotics should be based on established patterns of susceptibility. In recent years, 20% to 30% of strains of E. coli and more than half the strains of Klebsiella have developed resistance to ampicillin. Thus this drug should not be used when the results of sensitivity tests are unknown unless the suspected pathogen is enterococci, in which case ampicillin or amoxicillin is the drug of choice.

When choosing among the drugs listed in Table 54-4 , the clinician should consider several factors. First, the sensitivity patterns of ampicillin, amoxicillin, and cephalexin are the most variable. Second, these drugs—along with amoxicillin-clavulanic acid—also have the most pronounced effect on normal bowel and vaginal flora and thus are the most likely to cause diarrhea or monilial vulvovaginitis. In contrast, nitrofurantoin monohydrate has only minimal effect on vaginal and bowel flora. Moreover, it is more uniformly effective against the common uropathogens, except for Proteus species, than trimethoprim-sulfamethoxazole. Third, amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole usually are the best empiric agents for treatment of patients with suspected drug-resistant pathogens. However, sulfonamides should be avoided in the first trimester of pregnancy because of possible teratogenicity, and they should be avoided immediately prior to delivery because of concern about displacement of bilirubin from protein binding sites, with resultant neonatal jaundice (see Chapter 8 ).

For patients who have an initial infection and experience a prompt response to treatment, a urine culture for test of cure may not be clinically necessary or cost effective. Cultures during or immediately after treatment are indicated for patients who have a poor response to therapy or who have a history of recurrent infection. During subsequent clinic appointments, the patient’s urine should be screened for nitrites and leukocyte esterase. If either of these tests is positive, repeat urine culture and retreatment are indicated.

Acute Pyelonephritis

The incidence of pyelonephritis in pregnancy is 1% to 2%. Most cases develop as a consequence of undiagnosed or inadequately treated lower urinary tract infection. Two major physiologic changes occur during pregnancy that predispose to ascending infection of the urinary tract. First, the high concentration of progesterone secreted by the placenta has an inhibitory effect on ureteral peristalsis. Second, the enlarging gravid uterus often compresses the ureters, particularly the right, at the pelvic brim, thus creating additional stasis. Stasis, in turn, facilitates migration of bacteria from the bladder into the ureters and renal parenchyma ( Fig. 54-2 ).

Intravenous pyelogram in a pregnant woman shows marked dilation of the right ureter and mild dilation of the renal collecting system.

About 75% to 80% of cases of pyelonephritis occur on the right side, 10% to 15% are left sided, and a slightly smaller percentage are bilateral. E. coli is again the principal pathogen. K. pneumoniae and Proteus species also are important causes of infection, particularly in women with recurrent episodes of pyelonephritis. Highly virulent gram-negative bacilli such as Pseudomonas, Enterobacter, and Serratia are unusual isolates except in immunocompromised patients. Gram-positive cocci do not frequently cause upper tract infection. Anaerobes also are unlikely pathogens unless the patient is chronically obstructed or instrumented.

The usual clinical manifestations of acute pyelonephritis in pregnancy are fever, chills, flank pain and tenderness, urinary frequency or urgency, hematuria, and dysuria. Patients also may have signs of preterm labor, septic shock, and acute respiratory distress syndrome (ARDS). Urinalysis is usually positive for white blood cell casts, red blood cells, and bacteria. Urine colony counts greater than 10 ² colonies/mL in samples collected by catheterization confirm the diagnosis of infection.

Pregnant patients with pyelonephritis may be considered for outpatient therapy if their disease manifestations are mild, they are hemodynamically stable, and they have no evidence of preterm labor. If an outpatient approach is adopted, the patient should be treated with agents that have a high level of activity against the common uropathogens. Acceptable oral agents include amoxicillin-clavulanic acid 875 mg twice daily or double-strength trimethoprim-sulfamethoxazole twice daily for 7 to 10 days. Alternatively, a visiting home nurse may be contracted to administer a parenteral agent such as intravenous (IV) or intramuscular (IM) ceftriaxone 2 g once daily. Although an excellent drug for lower tract infections, nitrofurantoin monohydrate does not consistently achieve the serum and renal parenchymal concentrations necessary for successful treatment of more serious infections.

Patients who appear to be moderately to severely ill or who show any signs of preterm labor should be hospitalized for IV antibiotic therapy. They should receive appropriate supportive treatment and should be monitored closely for complications such as sepsis, ARDS, and preterm labor. One reasonable choice for empiric IV antibiotic therapy is ceftriaxone 2 g every 24 hours. Compared with a first-generation cephalosporin like cefazolin, ceftriaxone has expanded coverage against aerobic gram-negative bacilli and has the advantage of once-daily dosing. If the patient is critically ill or is at high risk for a resistant organism, a second antibiotic, such as gentamicin (7 mg/kg/ideal body weight every 24 hours) or aztreonam (500 mg to 1 g every 8 to 12 hours) should be administered, along with ceftriaxone, until the results of susceptibility tests are available.

Once antibiotic therapy is initiated, about 75% of patients defervesce within 48 hours. By the end of 72 hours, almost 95% of patients are afebrile and asymptomatic. The two most likely causes of treatment failure are a resistant microorganism and obstruction. The latter condition is best diagnosed with computed tomography (CT) scan or renal ultrasonography and typically results from a stone or physical compression of the ureter by the gravid uterus.

Once the patient has begun to defervesce and her clinical condition has improved, she may be discharged from the hospital. Oral antibiotics should be prescribed to complete a total of 7 to 10 days of therapy. Selection of a specific oral agent should be based on considerations of efficacy, toxicity, and expense. A repeat urine culture should be obtained after therapy is completed to ensure that the infection has been adequately treated.

About 20% to 30% of pregnant patients with acute pyelonephritis develop a recurrent urinary tract infection later in pregnancy. The most cost-effective way to reduce the frequency of recurrence is to administer a daily prophylactic dose of an antibiotic such as nitrofurantoin monohydrate 100 mg. Patients receiving prophylaxis should have their urine screened for bacteria at each subsequent clinic appointment. They also should be questioned about recurrence of symptoms. If symptoms recur, or the dipstick test for nitrite or leukocyte esterase is positive, a urine culture should be obtained to determine whether retreatment is necessary.

Chorioamnionitis

Chorioamnionitis—or amnionitis, intraamniotic infection—may present with fever and fetal tachycardia. Because both the mother and infant may experience serious complications when chorioamnionitis is present, prompt diagnosis is imperative.

Management

Both the mother and infant may experience serious complications when chorioamnionitis is present. Bacteremia occurs in 3% to 12% of infected women. When cesarean delivery is required, up to 8% of women develop a wound infection, and about 1% develop a pelvic abscess. Fortunately, maternal death due to infection is exceedingly rare.

Of neonates delivered to mothers with chorioamnionitis, 5% to 10% have pneumonia or bacteremia. The predominant organisms responsible for these infections are GBS and E. coli . Meningitis occurs in less than 1% of term infants and in a slightly higher percentage of preterm infants. Mortality due to infection ranges from 1% to 4% in term neonates but may approach 15% in preterm infants because of the confounding effects of other complications such as hyaline membrane disease, intraventricular hemorrhage, and necrotizing enterocolitis.

To prevent maternal and neonatal complications, parenteral antibiotic therapy should be initiated as soon as the diagnosis of chorioamnionitis is made, unless delivery is imminent. Three separate investigations have demonstrated that mother-infant pairs who receive prompt intrapartum treatment have better outcomes than patients treated after delivery. The principal benefits of early treatment include decreased frequency of neonatal bacteremia and pneumonia and decreased duration of maternal fever and hospitalization.

The most extensively tested IV antibiotic regimen for treatment of chorioamnionitis is the combination of ampicillin (2 g every 6 hours) or penicillin (5 million U every 6 hours) plus gentamicin (1.5 mg/kg every 8 hours or 5 to 7 mg/kg/ideal body weight every 24 hours). The latter regimen of gentamicin is the most cost-effective. These antibiotics specifically target the two organisms most likely to cause neonatal infection: GBS and E. coli . With rare exceptions, gentamicin is preferred to tobramycin or amikacin because it is available in an inexpensive generic formulation. Amikacin should be reserved for immunocompromised patients who are particularly likely to be infected by highly virulent, drug-resistant aerobic gram-negative bacilli. In patients who are allergic to β-lactam antibiotics, clindamycin (900 mg every 8 hours) should be substituted for ampicillin.

If a patient with chorioamnionitis requires cesarean delivery, a drug with activity against anaerobic organisms should be added to the antibiotic regimen. Either clindamycin (900 mg) or metronidazole (500 mg) is an excellent choice for this purpose. Failure to provide effective coverage of anaerobes may result in treatment failures in 20% to 30% of patients.

Extended-spectrum cephalosporins, penicillins, and carbapenems also provide excellent coverage against the bacteria that cause chorioamnionitis. Dosages and dose intervals for several of these agents are listed in Table 54-6 . As a general rule, these drugs are more expensive than the generic combination regimens outlined earlier.

TABLE 54-6

SINGLE AGENTS OF VALUE IN TREATMENT OF CHORIOAMNIONITIS AND PUERPERAL ENDOMETRITIS

DRUG	DOSAGE AND DOSE INTERVAL	RELATIVE COST TO THE PHARMACY *
Extended-Spectrum Cephalosporins
Cefepime	2 g every 12 hours	Intermediate
Cefotaxime	2 g every 8-12 hours	Intermediate
Cefotetan	2 g every 12 hours	Low
Cefoxitin	2 g every 6 hours	Intermediate
Ceftizoxime	2 g every 12 hours	Intermediate
Extended-Spectrum Penicillins
Ampicillin-sulbactam	3 g every 6 hours	Low
Mezlocillin	3 to 4 g every 6 hours	Intermediate
Piperacillin	3 to 4 g every 6 hours	Intermediate
Piperacillin-tazobactam	3.375 g every 6 hours	Intermediate
Ticarcillin–clavulanic acid	3.1 g every 6 hours	Low
Carbapenem
Ertapenem	1 g every 24 hours	High
Imipenem-cilastatin	500 mg every 6 hours	High
Meropenem	1 g every 8 hours	High

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