Chapter 216 Genital Mycoplasmas (Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum)
Three Mycoplasma species, Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum, are human urogenital pathogens. They are often associated with sexually transmitted infections such as nongonococcal urethritis (NGU) or puerperal infections such as endometritis. M. hominis and U. urealyticum commonly colonize the female genital tract and can cause chorioamnionitis, colonization of neonates, and perinatal infections. Two other genital Mycoplasma species, M. fermentans and M. penetrans, are identified in respiratory or genitourinary secretions more in HIV-infected patients.
M. hominis and U. urealyticum require sterols for growth, can grow in cell-free media, and produce characteristic colonies on agar. Colonies of M. hominis are 200-300 µm in diameter with a “fried-egg” appearance, and colonies of U. urealyticum are 16-60 µm in diameter. These organisms are resistant to β-lactams because they lack a cell wall and are resistant to sulfonamides and trimethoprim because they do not produce folic acid. M. hominis is susceptible to clindamycin and quinolones but resistant to macrolides and rifampin. Increasing numbers of tetracycline-resistant strains are being reported. Using 16s ribosomal RNA sequencing, U. urealyticum has been subdivided into two species: U. urealyticum and U. parvum. Most are susceptible to macrolides and advanced generation quinolones but resistant to ciprofloxacin and clindamycin. Susceptibility to aminoglycosides and tetracyclines is variable. M. genitalium can be isolated only in cell culture systems and with difficulty. Identification in most studies has required polymerase chain reaction (PCR).
M. hominis and U. urealyticum colonize the genital and urinary tracts of postpubertal women and men. Female colonization is maximal in the vagina and less in the endocervix, urethra, and endometrium. Male colonization occurs primarily in the urethra. Colonization rates are directly related to sexual activity and are highest among persons with multiple sexual partners. Colonization rates are <10% among prepubertal children and sexually inactive adults and vary from 40% to 90% among pregnant women.
Genital mycoplasmas are transmitted by sexual contact. M. genitalium has been identified predominantly in the male urethra and is capable of attaching to human spermatozoa, suggesting a mechanism for sexual transmissibility.
Vertical transmission rates among neonates born to colonized women are 25-60%. The usual route of neonatal acquisition is contamination from colonized amniotic fluid or during vaginal delivery. However, neonatal colonization can occur in the presence of intact amniotic fluid membranes and with delivery by cesarean section. Neonatal colonization rates are higher among infants who weigh <1,500 g, are born in the presence of chorioamnionitis, and are born to mothers of lower socioeconomic status. Organisms are recovered from the newborn’s throat, vagina, rectum, and, occasionally, eyes for as long as 3 mo after birth.
Genital mycoplasmas can produce chronic inflammation of the genitourinary tract and amniotic fluid membranes. U. urealyticum can infect the amniotic sac early in gestation without rupturing the amniotic membranes, resulting in a clinically silent, chronic chorioamnionitis characterized by an intense inflammatory response. Attachment to fetal human tracheal epithelium can cause ciliary disarray, clumping, and loss of epithelial cells. U. urealyticum induces macrophages in vitro to increase production of interleukin 6 (IL-6) and tumor necrosis factor 2. Very low birthweight infants colonized with U. urealyticum have increased levels of monocyte chemoattractant protein and IL-8, which are proinflammatory agents possibly associated with development of chronic lung disease of prematurity (CLD). Immunity appears to require serotype-specific antibody. Thus, a lack of maternal antibody might account for a higher risk for disease in premature newborns.
In adults and sexually active adolescents, genital mycoplasmas are associated with sexually transmitted diseases and are uncommonly associated with focal infections outside the genital tract. M. hominis has been described causing septicemia, endocarditis, wound infection, osteomyelitis, lymphadenitis, pneumonia, meningitis, brain abscess, arthritis, amnionitis, and postpartum fever. Life-threatening mediastinitis, sternal wound infections, pleuritis, peritonitis, and pericarditis have been reported with high mortality rates in patients following organ transplantation. Extragenital U. urealyticum infections are rarely described but include osteomyelitis, arthritis, meningitis, mediastinitis, infection of aortic grafts, and postcesarean wound infections. Patients with hypogammaglobulinemia appear to be at high risk for chronic arthritis caused by various Mycoplasma spp.
U. urealyticum and M. genitalium are recognized pathogens of NGU. Approximately 30% of NGU in male patients may be caused by these organisms either alone or with Chlamydia trachomatis (Chapter 516.1). Disease is most common in young adults but is also prevalent in sexually active adolescents. The average incubation period is 2-3 wk, with symptoms typically consisting of scant mucoid-white urethral discharge, dysuria, and penile discomfort. The discharge is often evident only in the morning or after the urethra is stripped. Rare complications of NGU are epididymitis and proctitis. Approximately 20-60% of patients with M. genitalium NGU develop recurrent or chronic urethritis despite 1-2 wk of treatment with doxycycline alone.
Genital mycoplasmas are associated with a variety of fetal and neonatal infections. U. urealyticum can cause clinically inapparent chorioamnionitis resulting in an increase in fetal death or premature delivery. Up to 50% of infants <34 wk of gestational age may have U. urealyticum recovered from tracheal, blood, cerebrospinal fluid (CSF), or lung biopsy specimens. In a study of 351 preterm infants between 23-32 wk of gestational age, isolation of U. urealyticum or M. hominis from cord blood correlated with the development of systemic inflammatory response syndrome. The role of these organisms causing severe respiratory insufficiency, the need for assisted ventilation, the development of CLD, or death remains controversial. Two meta-analyses of published studies showed a relative risk of 1.72 and 2.83 for the relationship between respiratory colonization with U. urealyticum and development of CLD. However, 2 small randomized, controlled trials of erythromycin therapy in high-risk preterm infants with tracheobronchial colonization of U. urealyticum failed to show any difference in treated vs nontreated infants in the development of CLD.
M. hominis and U. urealyticum have been isolated from the CSF of premature and, in a few cases, full-term infants. Simultaneous isolation of other pathogens is unusual, and most infants have no overt signs of central nervous system (CNS) infection. CSF pleocytosis is not a consistent observation, and spontaneous clearance of mycoplasmas has been documented without specific therapy. U. urealyticum meningitis has been associated with intraventricular hemorrhage and hydrocephalus. Meningitis caused by M. hominis was thought to be benign but in a review of 29 reported cases, 8 (28%) died and 8 (28%) were left with neurologic sequelae. The onset of meningitis varies from 1 to 196 days of life; organisms can persist in the CSF without therapy for days to weeks. M. hominis and U. urealyticum have also been described to cause neonatal conjunctivitis, lymphadenitis, pharyngitis, pneumonitis, osteomyelitis, brain abscess, pericarditis, meningoencephalitis, and scalp abscess.
Confirmation of genital tract infection is difficult because of high colonization rates in the vagina and urethra. NGU is confirmed by Gram stain of urethral discharge showing ≥3 polymorphonuclear leukocytes per oil-immersion field and the absence of gram-negative diplococci (i.e., Neisseria gonorrhoeae). A urethral swab or exudate should be cultured for C. trachomatis and U. urealyticum. M. genitalium can only be identified by PCR testing.
U. urealyticum and M. hominis have been isolated from urine, blood, CSF, tracheal aspirates, pleural fluid, abscesses, and lung tissue. Premature neonates who are clinically ill with pneumonitis, focal abscesses, or CNS disease (particularly progressive hydrocephalus with or without pleocytosis) for whom bacterial cultures are negative or in whom there is no improvement with standard antibiotic therapy warrant cultures for genital mycoplasmas. Isolation requires special media, and clinical specimens must be cultured immediately or be frozen at −80°C to prevent loss of organisms. When inoculated into broth containing arginine (for M. hominis) or urea (for U. urealyticum), growth is indicated by an alkaline pH. Identification of U. urealyticum on agar requires 1-2 days of growth and visualization with the dissecting microscope, whereas M. hominis is apparent to the eye but can require 1 wk to grow. Cultures from the upper respiratory tract are probably meaningless owing to high colonization rates. Cultures of the lower respiratory tract through endotracheal aspirate or biopsy are essential.
Recommended treatment for NGU in boys is azithromycin (1 g PO as a single dose) and doxycycline (100 mg PO twice daily for 7 days). Recurrent NGU after completion of treatment suggests the presence of azithromycin-resistant M. genitalium. Retreatment with moxifloxicin may be most effective. Sexual partners should also be treated to avoid recurrent disease in the index case. Nongenital mycoplasmal infections can require surgical drainage and prolonged antibiotic therapy.
Therapy for neonatal genital mycoplasma infections is indicated in infections associated with a pure growth of the organism and evidence that the disease manifestations are compatible with an infectious process rather than merely colonization. The role of therapy in preventing CLD in very low birthweight infants awaits results of further studies. Treatment is based on predictable antimicrobial sensitivities, because susceptibility testing is not readily available for individual isolates. For symptomatic CNS infections, cures have been described with chloramphenicol, doxycycline, and moxifloxacin. The long-term consequences of asymptomatic CNS infection with genital mycoplasmas, especially in the absence of pleocytosis, are unknown. Because mycoplasmas can spontaneously clear from the CSF, therapy should involve minimal risks.
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