Ureaplasma urealyticum

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Ureaplasma species (U. urealyticum and U. parvum) are commensal organisms commonly found in the urogenital tract of sexually active men and women.^[1] These organisms are considered to be of low virulence although several studies have demonstrated an association between vaginal colonization by Ureaplasma species and adverse pregnancy outcomes including perinatal morbidity and mortality.^[2][3][4][5] Some studies also show an association between urogenital colonization by U. urealyticum and nongonococcal urethritis in men.^[6][7][8] However, the pathogenic role of Ureaplasma urealyticum in nongonococcal urethritis is still not clear.^[9][10][11] Colonization with Ureaplasma species occur in asymptomatic and symptomatic infants and adults, and further investigations to determine the exact pathogenic role of Ureaplasma is required.^[5] There is often a medical dilemma as to whether an isolation of Ureaplasma represents a ‘true’ infection or ‘mere’ colonization. Hence, the challenge in making a decision whether medical treatment is necessary.

T-strain mycoplasma (now known as Ureaplasma urealyticum) was first discovered in the human urogenital tract in 1954 by Shepard et al.^[10][7] Tiny (T)-strain mycoplasma was renamed Ureaplasma urealyticum in 1974.^[10][7]

U. urealyticum was previously classified into two biotypes:^[7][10]

• Biovar 1 ( parvo biovar): Ureaplasma urealyticum biovar 1 is now known as U. parvum.
• Biovar 2 (T960 biovar): Ureaplasma urealyticum biovar 2 strain retained its designation as U. urealyticum.

Ureaplasma raises the pH of the vagina by hydrolyzing urea into carbon dioxide and ammonia, increasing the susceptibility to mixed infection with other pathogenic bacteria.^[5] These pathogens stimulate the secretion of pro-inflammatory cytokines and chemokines, leading to the recruitment of leukocytes and production of prostaglandins, which subsequently result in preterm birth.^[1][5] Vertical transmission of Ureaplasma has also been associated with neonatal complications such as pneumonitis, bacteremia, and meningitis, following stimulation of fetal inflammatory responses by the organism.^[12][13] Some studies conducted in men show there is an association between urogenital colonization by Ureaplasma urealyticum and nongonococcal urethritis, however, the pathogenic role of Ureaplasma urealyticum in nongonococcal urethritis is not clear.^{[6][7][8][9][10][11]}

Ureaplasma species are bacteria belonging to the family Mycoplasmataceae.^[14]

There are no specific signs and symptoms that can distinguish Ureaplasma infection from infection caused by other microorganisms. Ureaplasma species cannot be cultured on conventional culture media for most bacteria and special culture media for Mycoplasma is often needed.

Ureaplasma species colonize 40-80% of the genital tract of healthy women.^{[13] [4][15][12]} They are the most common pathogen identified in VLBW infants.^[12] Ureaplasma colonization of the respiratory tract is more common in preterm VLBW infants compared to term infants.^[16][17] 20-45% of VLBW infants have Ureaplasma colonization of the respiratory tract.^[4]

Several risk factors have been identified for Ureaplasma infection such as heavy urogenital colonization in adults, multiple sexual partners, immunosuppression, and prematurity in neonates.^{[13][4][12][5][18][19]}

The genital tract of adult men and women serve as the main reservoirs for Ureaplasma species.^[7][4] Pregnancy complications such as chorioamnionitis, preterm labor, and miscarriages have been associated with Ureaplasma.^{[5][20][18][21][19]} Neonatal complications associated with Ureaplasma include prematurity, pneumonia, pneumonitis, bronchopulmonary dysplasia, respiratory distress syndrome of the newborn and sepsis. Urogenital tract infections such as nongonococcal urethritis in men have also been associated with Ureaplasma urealyticum.^[11][22]

It is important to take a history of the underlying risk factors for Ureaplasma colonization/infection. Nonspecific symptoms such as irritability, lethargy, convulsions and dyspnea can be seen in neonatal infection associated with Ureaplasma.^[23]

There is no physical examination finding that is specific or pathognomonic for Ureaplasma infection, and a laboratory diagnosis is required.

Ureaplasma species are diagnosed based on culture results and/or PCR.^[24][25]

Early dysplastic pulmonary changes have been observed to occur more frequently in preterm infants with Ureaplasma colonization, although a previous study suggests there are no unique radiographic changes associated with Ureaplasma.^[1][26]

There are no specific CT findings associated with Ureaplasma colonization or infection.

Microbial culture methods and/or PCR-based techniques are the only reliable methods for diagnosing Ureaplasma colonization/infection.

Antibiotics are the mainstay of treatment for Ureaplasma infection, and antibiotic susceptibility testing is advised prior to treatment due to geographical differences in antibiotic resistance pattern. Doxycycline is recommended as the drug of first choice in non-pregnant women and adults. Josamycin is often recommended for neonates and pregnant women, especially when mixed infection is present. Clarithromycin and pristinamycin are also effective for treating Ureaplasma infection.^[27][4][28]

There are no guidelines for the prevention of Ureaplasma colonization or infection.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Tiny(T)-strain Mycoplasma was first discovered in 1954, and it was ascribed to the genus and specie Ureaplasma urealyticum in 1974.^[1][2]

T-strain mycoplasma (now known as Ureaplasma urealyticum) was first discovered in the human urogenital tract in 1954 by Shepard et al.^[2][1] In 1974, the tiny (T)-strain mycoplasma was renamed Ureaplasma urealyticum.^[1][2] U. urealyticum was further subdivided into two biotypes; biovar 1 ( parvo biovar) and biovar 2 (T960 biovar). Ureaplasma urealyticum biovar 1 was later designated as a separate specie called U. parvum following phylogenetic analysis done in 1999, but the biovar 2 strain retained its designation as U. urealyticum.^[2] Investigations carried out in the mid 1970’s by Tafari et al. described the isolation of Ureaplasma urealyticum from the lungs of stillborn infants with pneumonitis, and it is one of the earliest investigations that suggested the possible pathogenic role of U. urealyticum in neonatal disease.^[3] Waites et al. reported the first case of suspected neonatal ureaplasmal pneumonia with sepsis and persistent pulmonary hypertension of the newborn in the 1980’s.^[4] Several case reports are now available in the literature documenting the isolation of Ureaplasma urealyticum and Ureaplasma parvum in fetal lung tissue, cord blood, pulmonary secretions, pleural fluid, lung tissue, and blood stream of neonates with pneumonia.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Ureaplasma urealyticum was previously classified into biovar 1 and biovar 2 which are now referred to as U. parvum and U. urealyticum respectively.^[1]

Tiny (T)-strain Mycoplasma was ascribed to the genus and specie Ureaplasma urealyticum in 1974.^[2][1] U. urealyticum was later subdivided into two biotypes consisting of 14 recognized serotypes:^[1][3]

• Biovar 1 or B ( parvo biovar): Ureaplasma urealyticum biovar 1 was later designated as a separate specie called U. parvum following phylogenetic analysis done in 1999. It has four serotypes (serotypes 1, 3, 6, and 14).

• Biovar 2 or A (T960 biovar): Ureaplasma urealyticum biovar 2 strain (also known as T960 biovar) retained its designation as U. urealyticum, and it consists of the remaining ten serotypes.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Ureaplasma species have been associated with several conditions such as preterm delivery, perinatal mortality, neonatal infection, and urogenital infection in adults.^[1][2] Stimulation of host inflammatory responses by Ureaplasma has been implicated in most of these conditions.^[1][2][3]

• Ureaplasma species are considered to be of low virulence, and 40-80% of healthy women have Ureaplasma species (U. urealyticum and U. parvum) in their genital tract.^[4][5][6][7]
• Controversial evidence exists supporting the association between genital colonization by Ureaplasma species and complications of pregnancy such as preterm delivery.^[1]
• Lactobacilli help maintain the vaginal acidity, preventing the invasion of bacteria. However, the urease activity of Ureaplasma species such as U. urealyticum increases the pH of the vagina via the hydrolysis of urea into carbon dioxide and ammonia. This increases the susceptibility to mixed infection with other pathogenic bacteria.^[8]
• Ureaplasma and other pathogenic bacteria induce the secretion of pro-inflammatory cytokines such as IL-1, TNF-α, IL-6, and chemokines such as IL-8, leading to the recruitment of leukocytes and production of prostaglandins.^[2][1] Uterine stimulation by prostaglandins result in preterm delivery.^[8][2]
• Ureaplasmal lipoprotein also induce apoptosis, and it is possible that the apoptotic cells sustain genital tract inflammation which promote preterm delivery.^[8]
• Studies have also shown a higher rate of vaginal colonization by Ureaplasma species in women with preterm deliveries compared to those with full-term deliveries.^[8]

• Ureaplasma urealyticum and U. parvum are the most common organisms isolated from infected amniotic fluid and placenta, suggesting the potential role of Ureaplasma species in the development of disseminated neonatal infection.^[9][5][6][7]
• The infection is commonly acquired via vertical transmission by three main mechanisms:^[6]

1. Maternal placental infection with umbilical vessels involvement result in the hematogenous dissemination of infection in the neonate.
2. Passage of the organism into the fetal lung via an infected amniotic fluid.
3. Perinatal acquisition of infection following passage of the baby through an infected maternal birth canal.

• Pneumonitis, bacteremia, or meningitis can occur following stimulation of host inflammatory responses by the organism.^[7][6]
• Preterm neonates are most commonly affected, and very low birth weight (VLBW) infants have been noted to have invasive Ureaplasma infection.^[7] Preterm infants weighing <5.5 pounds are nearly four times more likely to develop systemic infection compared to full term infants weighing above 5.5 pounds.
• It has been suggested that severe Ureaplasma infection in VLBW infants may contribute to the development of severe intraventricular hemorrhage.^[7]
• There may also be an association between necrotising enterocolitis and Ureaplasma colonization in preterm neonates.^[5]

• There is no significant association between Ureaplasma colonization of the lower genital tract and symptomatic urogenital infection in females.^[10]
• The detection of Ureaplasma urealyticum and U. parvum in fluid samples obtained from the pouch of Douglas in 60% of women with lower urogenital tract Ureaplasma colonization confirms the fact that asymptomatic infection of the upper genital tract can occur in women following direct ascent of these organisms from the cervix and vagina to the sterile upper reproductive tract.^[11]
• Ureaplasma colonization of the genital tract is common following puberty and it is directly related to sexual activity.^[2]
• Ureaplasma urealyticum has been detected in men with nongonococcal urethritis, and also in those without nongonococcal urethritis.^[12] Some studies conducted in men show there is an association between urogenital colonization by Ureaplasma urealyticum and nongonococcal urethritis.^[12][13][14] However, the pathogenic role of Ureaplasma urealyticum in nongonococcal urethritis is still not clear.^[15][3][16]
• Men with higher bacterial load of U. urealyticum (≥5 x 10³) in first-void urine were found to have higher leukocyte counts (in their first-void urine sample) and symptomatic urethritis, suggesting there could be a positive correlation between the bacteria load of U. urealyticum and the development of inflammatory responses to the organism.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Ureaplasma species are bacteria belonging to the family Mycoplasmataceae.^[1]

Taxonomy of Ureaplasma urealyticum^[1]

• Kingdom: Bacteria
• Division: Firmicutes
• Class: Mollicutes
• Order: Mycoplasmatales
• Family: Mycoplasmataceae
• Genus: Ureaplasma
• Species: U. urealyticum

Some of the characteristics of Ureaplasma species^[1]

• Self-replicating biological entities.
• Exist in tiny colonies that are smaller than colonies of other members of the Mycoplasmataceae family.
• Unusual optimal pH growth of 6–6.5.
• Unique ability to hydrolyze urea.
• Urease activity is essential for ATP generation by a chemiosmotic mechanism.
• Express human immunoglobulin A1 protease activity.
• Ureaplasma from humans do not exhibit serological cross-reactivity with ureaplasmas from other hosts.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Ureaplasma species can be distinguished from other bacteria via culture on specific media for Mycoplasma and/or PCR-based techniques.^[1]

There are no specific signs and symptoms that can distinguish Ureaplasma infection from infection caused by other microorganisms. Ureaplasma species cannot be cultured on conventional culture methods for most bacteria. Special culture media for Mycoplasma is often needed and/or PCR-based tecniques.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Genital tract colonization by Ureaplasma occur in over 40% of healthy women.^[1][2][3][4] Ureaplasma species are the most common pathogen identified in VLBW infants.^[4] Respiratory tract colonization by Ureaplasma is more common in preterm VLBW infants compared to term infants.^[5][6] 20-45% of VLBW infants have Ureaplasma colonization of the respiratory tract.^[2]

Ureaplasma species are commensal organisms in the female genital tract, colonizing 40-80% of the genital tract of healthy women.^{[1] [2][3][4]} The prevalence of vaginal colonization with U. urealyticum in pregnant women is 29-42%.^[7] Ureaplasma species are the most common pathogen identified in VLBW infants.^[4] Ureaplasma colonization of the respiratory tract is more common in preterm VLBW infants compared to term infants.^[5][6] 20-45% of VLBW infants have Ureaplasma colonization of the respiratory tract.^[2] The incidence of Ureaplasma species in cord blood cultures of VLBW neonates was found to be 17%.^[8] Ureaplasma species have also been shown to invade the bloodstream and cross the blood–brain barrier in 23% of VLBW infants in another study.^[4] The prevalence of Ureaplasma positive CSF culture from preterm infants investigated for suspected meningitis was 8%.^[9]

Colonization by Ureaplasma species can be seen in both the pediatric and adult population. Genital tract of adult men and women are the main reservoirs of Ureaplasma species.^[2][10] However, symptomatic Ureaplasma infection is seen more often in preterm neonates.^[4] Colonization of neonates by U. urealyticum increases with decreasing gestational age and birth weight.^[11]

There is no known gender predilection for Ureaplasma infection.

A study conducted in the United States in the 1980’s in 13,747 women of low socioeconomic status from four different ethnic groups revealed that women of black ethnicity were more likely to have genital tract colonization with potentially pathogenic organisms such as U. urealyticum ^[12] Another study was carried out by Doh et al. in healthy pregnant women from different ethnic groups, and it revealed no racial predilection for Ureaplasma colonization.^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Risk factors that have been identified for Ureaplasma colonization/infection include factors such as heavy urogenital colonization in adults, multiple sexual partners, immunosuppression, and prematurity in neonates.^{[1][2][3][4][5][6]}

Risk factors for Ureaplasma infection in infants include the following:^{[1][2][3][4][5][6]}

Neonatal factors

• Prematurity
• Low birth weight
• Perinatal asphyxia (Apgar score less than 6 at 5min)
• Mechanical ventilation of the infant
• Tracheal colonization of the infant by Ureaplasma species: The risk of developing moderate-severe bronchopulmonary dysplasia is increased by 7-9 folds in mechanically ventilated infants with Ureaplasma positive tracheal aspirate compared to mechanically ventilated infants with Ureaplasma positive nasopharyngeal sample.
• Congenital anomalies such as meningomyelocele

Maternal factors

• Prolonged or preterm rupture of membranes
• Chorioamnionitis
• Heavy vaginal colonization by Ureaplasma species
• Low socioeconomic status

Risk factors for Ureaplasma colonization/infection in adult men and women:^{[7][8][9][10][11][12]}

• Multiple sexual partners
• Younger age
• Urogenital colonization/infection with other microorganisms
• Low socioeconomic status
• Immunosuppresion such as congenital immunodeficiency disorders like hypogammaglobulinemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

The genital tract of adult men and women serve as the main reservoirs for Ureaplasma species.^[1][2] Pregnancy complications such as chorioamnionitis, preterm labor, and miscarriages have been associated with Ureaplasma.^{[3][4][5][6][7]} Neonatal complications associated with Ureaplasma include prematurity, pneumonia, pneumonitis, bronchopulmonary dysplasia, respiratory distress syndrome of the newborn and sepsis. Urogenital tract infections such as nongonococcal urethritis in men have also been associated with Ureaplasma urealyticum.^[8][9]

The genital tract of adult men and women serve as the main reservoirs for Ureaplasma species.^[1][2] Colonization by Ureaplasma species has been documented in sick as well as healthy infants.^[10]

Infection with Ureaplasma species has been associated with the following complications:

Pregnancy complications^{[3][4][5][6][7]}

• Histologic chorioamnionitis
• Preterm labor
• Preterm rupture of membranes
• Pregnancy loss
• Postpartum endometritis

Fetal/neonatal complications^{[2][10][11][12][13][14][15][16][17][18][19]}

Common

• Umbilical cord vasculitis

• Prematurity
• Pneumonia
• Pneumonitis
• Bronchopulmonary dysplasia
• Hyaline membrane disease (respiratory distress syndrome of the newborn)
• Sepsis

Uncommon

• Persistent pulmonary hypertension of the newborn
• Meningitis
• Periventricular hemorrhage
• Intraventricular hemorrhage
• Necrotizing enterocolitis
• Stillbirth

Complications in adult men and women^{[1][20][21][22][23][24][25][26][27][8][9]}

• Urogenital tract infections such as nongonococcal urethritis and prostatitis in men
• Infertility
• Pelvic inflammatory disease in females
• Septic arthritis
• Prosthetic joint infection
• Post-operative mediastinitis with persistent pleural and pericardial effusion
• Possible association with dry eye disease

Polymicrobial infection of the amniotic fluid with Ureaplasma species and other bacteria is associated with poor perinatal prognosis in preterm labor.^[28] Despite macrolide antibiotic treatment, there is a significant association between U. urealyticum infection and pulmonary morbidity and mild cerebral impairment in preterm infants.^[2]

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