Chapter 292. Ureaplasma Urealyticum Infections

Shepard first described Ureaplasma urealyticum in 1954 after recovery of these organisms from male patients with nongonococcal urethritis.1 Initially referred to as T-strain (“tiny strain”) mycoplasma, these pleomorphic organisms measure less than 500 nm in diameter, lack a cell wall, and are classified as members of the family Mycoplasmatacea.2Ureaplasma differ from other Mycoplasmatacea in that they produce urease and therefore are capable of generating adenosine triphosphate from hydrolysis of urea. This activity serves as the primary energy source for Ureaplasma. Ureaplasma urealyticum has historically been subtyped into 14 serovars. However, recent molecular characterization of these serovars has resulted in a reclassification of U urealyticum into 2 distinct species: U parvum (serovars 1, 3, 6, and 14) and U urealyticum (serovars 2, 4, 5, and 7–13).3

Epidemiology

Ureaplasma spp are found on the cervical or vaginal mucosal surfaces of the majority of asymptomatic women and may therefore be considered commensal organisms of the adult female genital tract.4 Colonization of the male urethra has also been described, although it appears to occur less frequently. Although they may colonize in the absence of symptoms or pathology, there is ample evidence implicating Ureaplasma as the primary etiologic agent in a variety of urogenital diseases in both men and women.

Mucosal colonization with Ureaplasma occurs less commonly in adolescents and young children than in adults and increases in frequency with the onset of sexual activity. Vertical transmission of Ureaplasma with resulting mucosal colonization of the neonate occurs commonly (> 10% of births to colonized mothers), is increased in frequency in the setting of prolonged rupture of membranes and low birth weight, and may persist for several months postnatally.

Ureaplasma spp produce a number of virulence factors including immunoglobulin A protease, phospholipases A and C, hydrogen peroxide, NH3, and the more recently recognized hemolysins.4 Phospholipases may be of particular importance as they are hypothesized to play a role in the development of preterm labor in colonized, pregnant women by liberating arachidonic acid and increasing prostaglandin synthesis.

Clinical Features

Genitourinary Infection

Ureaplasma spp may cause urethritis in both men and women. Ureaplasma urealyticum in particular is frequently isolated from male adolescent and adult patients with nongonoccal urethritis. Epididymitis and prostatitis secondary to U urealyticum have also been described.5,6 The presence of Ureaplasma in the urinary tract has been linked to local formation of stones, possibly mediated by urease activity. Colonization and/or infection of the female genital tract are associated with numerous obstetrical complications including infertility, spontaneous abortion, chorioamnionitis, preterm labor, and postpartum endometritis.2,4,7 It is important to note that Ureaplasma are capable of invading the intrauterine space including the maternal–fetal membranes and are the most common organisms isolated from amniotic fluid, infected placentas, and neonatal cord blood.8,9

Neonatal Infection

Ureaplasma spp are now recognized to play an etiologic role in neonatal respiratory disease. The organism has been isolated from the lungs of stillborn infants with pneumonitis Subsequent data confirmed the etiologic role of Ureaplasma spp in congenital pneumonia. These included isolation of the organism from amniotic fluid as well as the lungs of affected neonates less than 24 hours after birth, the presence of histologic pneumonia, and a concomitant increase in fetal Ureaplasma-specific IgM antibiodies.4,11 Clinically, the manifestations of congenital Ureaplasma pneumonia may be difficult to distinguish from those of respiratory distress syndrome commonly seen in these infants.

Ureaplasma infection in the newborn is not limited to the respiratory tract, as these organisms have been isolated from both the blood and cerebral spinal fluid (CSF), particularly in preterm infants and those with positive endotracheal tube aspirates.4 Studies have shown that Ureaplasma can be isolated from the cord blood of 17% of very low birth weight (VLBW) infants using culture-based techniques. The culture-positive infants had increased rates of systemic inflammatory response syndrome and bronchopulmonary dysplasia (BPD) compared to culture-negative infants.12Ureaplasma spp can cause neonatal meningitis and associated complications, including hydrocephalus. A recent study demonstrated the presence of Ureaplasma by polymerase chain reaction (PCR) in the blood and/or CSF in 23% of very low birth weight infants.13 However, the clinical relevance and long-term implications of these findings remain unclear, as most PCR-positive infants were asymptomatic.

Chronic Lung Disease

The relationship between Ureaplasma respiratory tract colonization of preterm infants and the subsequent development of bronchopulmonary dysplasia (BPD) has been the subject of much investigation over the past several decades. In 1995, Wang and colleagues performed a meta-analysis and reported that the relative risk for the development of BPD in infants colonized with Ureaplasma spp was 1.72 times that of noncolonized infants.14 Subsequent studies examining this association have been plagued with conflicting data. These inconsistencies may be secondary to variations in defining outcome measures, culture techniques, and small sample sizes. The most recent meta-analysis examined 26 peer-reviewed clinical studies published from 1966 through 2004 involving infants with positive culture or polymerase chain reaction (PCR) analysis for the presence of Ureaplasma in the nasopharynx or tracheal aspirates and concluded that a positive correlation between Ureaplasma colonization and the development of BPD does exist.15

Other Infections

Although Ureaplasma pneumonia is exceedingly uncommon in older children and adolescents, it may be problematic for the immune-compromised host. Infectious arthritis secondary to Ureaplasma has been described, particularly in patients with hypogammaglobulinemia.19 Case reports implicating Ureaplasma spp as causative agents in abscesses associated with fetal monitoring, nonimmune fetal hydrops, and surgical wound infections may be found in the literature.20,21

Diagnostic Evaluation

Routine culture of the vagina and cervix is not indicated, owing to the large number of asymptomatically colonized adults. Similarly, a high rate of perinatal colonization argues against routine screening of asymptomatic newborns. However, evidence of respiratory compromise, pneumonia, sepsis, and/or meningitis in the absence of positive cultures for typical neonatal pathogens warrants consideration of Ureaplasma infection. Ureaplasma may be difficult to culture, and therefore careful attention must be given to specimen collection. For maximum yield, specimens must be inoculated into appropriate growth medium at the bedside and processed immediately.

Detection of Ureaplasma by polymerase chain reaction (PCR) based techniques may exhibit sensitivity superior to traditional culture techniques and has been described in the literature, although its clinical availability remains limited at this time. Efforts to develop serologic assays for the detection of the host immune response to Ureaplasma infection are ongoing. However, antibody titers remain difficult to interpret in the setting of chronic colonization.

Treatment

Macrolides are the most widely used antimicrobial agents in treatment of Ureaplasma infections. Although the newer macrolides such as azithromycin are most frequently utilized in older children and adults, erythromycin is the treatment of choice for neonatal infections that do not involve the central nervous system. Of note, erythromycin therapy use in infants has been associated with the development of hypertrophic pyloric stenosis and should thus be used with care. Ureaplasma spp are generally susceptible to tetracyclines, although resistance has been reported to occur in as many as 10% of clinical isolates.4 The ability of tetracycline agents to penetrate the blood-brain barrier makes them a treatment option for infants with meningitis. However, tetracycline use in children under age 8 years is reserved for settings in which the benefits clearly outweigh the risks, as these agents may cause abnormal bone and tooth development in children.

Newer generation fluoroquinolones such as ofloxacin are active against Ureaplasma spp, although naturally occurring resistance has been documented in adult patients. Ureaplasma are universally resistant to β-lactam antibiotics as they lack a cell wall.

Despite the clear association of Ureaplasma colonization with spontaneous abortion, chorioamnionitis, and the onset of preterm labor, the efficacy of antimicrobial treatment both before and during pregnancy in preventing these outcomes remains unclear. Kiss and colleagues published data suggesting that early screening and treatment of vaginal infections in pregnant women may reduce the incidence of preterm birth.22 The ORACLE trial evaluated the use of broad-spectrum, antepartum antibiotics in the setting of premature rupture of fetal membranes and reported some benefits for infants whose mothers received erythromycin. These included a decreased need for oxygen during hospitalization and a trend toward a reduction in the composite primary outcome of neonatal death, chronic lung disease, or major cerebral abnormality before discharge.23 Although both of these studies suggest that antimicrobial therapy during pregnancy may improve obstetric and neonatal outcomes, their inclusion criteria were not specific for women with Ureaplasma infections. Toth and colleagues provided data to suggest that treatment of couples colonized with Ureaplasma may reduce the incidence of spontaneous pregnancy loss.24 A Cochrane Review concluded there was insufficient evidence to determine whether giving antibiotics to women with vaginal Ureaplasma colonization would prevent preterm birth.25

The association of Ureaplasma spp with the subsequent development of bronchopulmonary dysplasia (BPD) raises the possibility that early treatment and eradication of this organism in at-risk infants may be beneficial. To date, two small, randomized, prospective, and controlled studies have not shown a benefit for infants receiving erythromycin therapy with respect to rates or severity of BPD.26,27 It is possible that postnatal antimicrobial therapy for Ureaplasma-associated BPD may not be effective because the responsible inflammatory processes may be initiated in utero.