Ureaplasma Infection

Mycoplasma species are the smallest free-living organisms and are unique among prokaryotes in that they lack a cell wall. This feature is largely responsible for their biologic properties, including lack of a Gram stain reaction and nonsusceptibility to many commonly prescribed antimicrobial agents, including beta-lactams. Mycoplasma organisms usually are associated with mucosae. They usually reside extracellularly in the respiratory and urogenital tracts and rarely penetrate the submucosa, except in the case of immunosuppression or instrumentation, when they may invade the bloodstream and disseminate to numerous organs and tissues. Some species also occur as intracellular pathogens.

Among the 17 species isolated from humans, 4 types of organisms are of major concern. Mycoplasma pneumoniae is a well-established pathogen; it is rarely isolated from healthy persons. Mycoplasma hominis and Ureaplasma species, known collectively as the genital mycoplasmal organisms, are generally considered opportunists that cause invasive infections in susceptible populations.

The 2 Ureaplasma biovars, Ureaplasma urealyticum and Ureaplasma parvum, are now designated as separate species. Separation of these species is not possible except via molecular techniques such as polymerase chain reaction (PCR). Therefore, they are now considered together as Ureaplasma species.[1] U parvum generally is the most common species detected in various clinical specimens but U urealyticum is apparently more pathogenic in conditions such as male urethritis. This differential pathogenicity at the species level has not been shown consistently for other disease conditions.[2, 3, 4]

Serologic studies and PCR have enhanced knowledge of several other fastidious and slow-growing mycoplasmal organisms, including Mycoplasma genitalium, Mycoplasma fermentans, Mycoplasma pirum, and Mycoplasma penetrans, Mycoplasma amphoriforme, and their possible roles in certain pathologic conditions in humans. Relatively little is known about their importance as human pathogens, with the notable exception of M genitalium, an organism that has been the focus of a considerable number of clinical research studies in recent years.

Although M hominis and Ureaplasma species are frequently detected in the lower urogenital tracts of healthy adults, they can also produce localized urogenital diseases. In some settings, particularly in immunosuppressed hosts, they can produce infection in extragenital sites, as does M genitalium. Recent studies with PCR assays expanded the understanding of sites of mycoplasmal localization within the human body. The presence of M fermentans was demonstrated in the throats of children with pneumonia and in the synovial fluid of persons with rheumatoid arthritis. M genitalium is found in the lower urogenital tracts of men with urethritis and women with cervicitis and pelvic inflammatory disease. M penetrans is found in the urine of children and homosexual males infected with HIV and has been implicated as a possible cause of male urethritis.[5]  No credible evidence indicates that mycoplasmal organisms have a role in the pathogenesis of Gulf War syndrome.[6]

The newest mycoplasmal species to be detected in humans is Mycoplasma amphoriforme, an organism initially detected in the lower respiratory tract of immunosuppressed persons with chronic bronchitis.[7] Its true role as a human pathogen has not yet been determined, but evidence of person-to-person transmission is accumulating, as well as the possibility that it causes illness in immunocompetent persons.[8]

In humans, both Mycoplasma and Ureaplasma species may be transmitted by direct contact between hosts (ie, venereally through genital-to-genital or oral-to-genital contact), vertically from mother to offspring (either at birth or in utero), or by nosocomial acquisition through transplanted tissues. Respiratory infections caused primarily by M pneumoniae are usually transmitted through respiratory aerosols.

U urealyticum and M genitalium are causes of nonchlamydial nongonococcal urethritis in men.[1, 9] No evidence indicates that that M hominis causes female urethral syndrome; however, Ureaplasma species may be involved. M hominis and Ureaplasma species have not been detected via culture of prostatic biopsy samples from patients with chronic abacterial prostatitis,[10] and M genitalium has been found rarely via PCR assay.[11]  Ureaplasma species and M genitalium have been recovered from epididymis from patients with acute epididymoorchitis and may be an infrequent cause of the disease. M hominis has been isolated from the upper urinary tract of patients with symptoms of acute pyelonephritis and may cause approximately 5% of cases.

Mycoplasma species may proliferate in patients with bacterial vaginosis and may contribute to the condition. M hominis has been isolated from the endometria and fallopian tubes of approximately 10% of women with salpingitis; M genitalium may also be involved in pelvic inflammatory disease and cervicitis. M genitalium can be found more frequently at both urethral and rectal sites of HIV-positive homosexual men than those who are HIV- negative,[12] and M genitalium cervicitis is more common in HIV-positive than in HIV-negative women.[13]  

Whether Ureaplasma infection causes involuntary infertility remains speculative, but some infertility specialists recommend testing infertile women and their sexual partners for ureaplasmas and treating them if positive. Ureaplasma species can cause placental inflammation and may invade the amniotic sac early, causing persistent infection and adverse pregnancy outcomes, including premature birth. M hominis has been isolated from the blood of approximately 10% of women with postpartum or postabortal fever, but not from afebrile women who had abortions or from healthy women who are pregnant. Similar observations have been made for Ureaplasma species.

Colonization of infants by genital mycoplasmal organisms may occur by ascension of the microorganisms from the lower genital tract of the mother at the time of delivery or by direct invasion of the fetus in utero. Congenital pneumonia, bacteremia, meningitis, and death have occurred in infants with very low birth weight due to Ureaplasma or M hominis infection of the lower respiratory tract. In several large studies, chronic lung disease of prematurity or bronchopulmonary dysplasia has also been associated with the presence of Ureaplasma organisms in the lower respiratory tract, presumably because of low-grade inflammation in the airways that causes a prolonged need for supplemental oxygen coupled with barotrauma of mechanical ventilation and oxidant damage due to oxygen administration.[1, 14]

Experimental infection studies using nonhuman primate models have shown that Ureaplasma in amniotic fluid causes up-regulation of proinflammatory cytokines, leukocytes, and prostaglandins, potentially contributing to premature delivery and fetal lung injury.[15]

Both M hominis and Ureaplasma species have been isolated from maternal blood, umbilical cord blood, and neonatal blood. Both organisms can invade the cerebrospinal fluid (CSF) and induce pleocytosis. While M fermentans has been detected in pure culture from placentae and amniotic fluid in the presence of inflammation, no studies confirm its occurrence and significance in neonates.[1] Although few studies have investigated the role of M genitalium infection in adverse pregnancy outcomes and neonatal diseases, recent evidence suggests that this mycoplasma can play a role in spontaneous abortion and preterm birth.[16, 17]

Both Mycoplasma and Ureaplasma species can cause invasive disease of the joints and respiratory tract with bacteremic dissemination, particularly in persons with antibody deficiencies, indicating the importance of the humoral immune system in host defense against these organisms.[18, 19] Ureaplasma species are the most common nonbacterial etiologies of infectious arthritis in persons who are hypogammaglobulinemic. M fermentans, M hominis, and Ureaplasma species can be detected with culture or PCR in the synovial fluid of persons with rheumatoid arthritis. Their precise contribution to this disease is uncertain.[6]

M hominis bacteremia has been demonstrated after renal transplantation, trauma, and genitourinary manipulations. This organism has also been found in the lower respiratory tract of persons with pneumonia, surgical wound infections, fluids from pericardial effusions, prosthetic valves affected by endocarditis, and abscesses in various locations, including the brain. Both organisms can cause osteomyelitis and meningitis.[20, 21] Ureaplasma species have also been associated with culture-negative endocarditis. Production of urease by Ureaplasma species is a mechanism by which these organisms can produce struvite calculi in the urinary tract.[1] Ureaplasma species and M hominis have been shown to cause systemic and sometimes fatal infections leading to hyperammonemia in immunosuppressed transplant recipients.[22, 23, 24]  Disseminated urogenital Mycoplasma and Ureaplasma infections outside the neonatal period are most often associated with a defect in humoral immunity and very rarely occur in hosts with a normally functioning immune system.

The significance of M fermentans, M penetrans, M pirum, and other mycoplasmal infections in persons also infected with HIV has received a great deal of attention and is a matter of debate. M fermentans has also been detected in adults with an acute influenzalike illness and in the bronchoalveolar lavage fluids of patients with AIDS and pneumonia. Apparently, respiratory tract infection with M fermentans is not necessarily linked with immunodeficiency, but it may behave as an opportunistic respiratory pathogen.[1]

Frequency

United States

Ureaplasma species have been isolated from cervicovaginal specimens in 40-80% of women who are asymptomatic and sexually active. M hominis has been isolated from cervicovaginal specimens in 21-53% of women who are asymptomatic and sexually active.[1] These rates are somewhat lower in males. Only a subgroup of adults who are colonized in the lower urogenital tract develop symptomatic illness from these organisms. Nongonococcal urethritis is the most common sexually transmitted infection. Ureaplasma species and M genitalium may account for a significant portion of cases that are not due to chlamydiae. M genitalium is much less likely to be present in the urogenital tract of asymptomatic persons, occurring in about 1% to 6.4% of men and women in the general population. However, it has a much higher prevalence (sometimes exceeding 20%) in persons with urogenital symptoms and in those who attend clinics providing sexual health services.[25]  

More than 20% of liveborn infants may be colonized by Ureaplasma, and infants born preterm most likely harbor the organisms. Colonization declines after age 3 months. Less than 5% of children and 10% of adults who are not sexually active are colonized with genital mycoplasmal microorganisms.[1]

Immunosuppression (eg, from antibody deficiency or prematurity) increases the likelihood of developing disseminated disease. Much less is known about the epidemiology of species such as M genitalium and M fermentans. Some organisms, such as M pirum and M penetrans, have been primarily isolated from persons with HIV infection but their significance as pathogens in this population has not been established.[1]

International

Although few studies have investigated the geographic distribution of genital mycoplasmal infections, the facts that they (1) are present on mucosal surfaces in so many healthy persons and (2) can be transmitted venereally suggest that variation in prevalence of these organisms in adults is more likely related to behavioral variables such as number of sexual partners and socioeconomic status rather than to geographic or climatic differences.

Mortality/Morbidity

Assessing morbidity and mortality for diseases specifically caused by genital mycoplasmal infections is difficult because few studies systematically evaluate them and some conditions with which they are involved can be polymicrobial (eg, pelvic inflammatory disease, urethritis). Difficulty in detecting the more fastidious species, such as M genitalium and M fermentans, further complicates such assessments.

In adults with an intact and functional immune system, infections associated with genital mycoplasmal organisms are usually localized and do not result in severe illness, attesting to their relatively low virulence and perceived status as opportunists.

Persons with antibody deficiencies reportedly have developed severe pulmonary infections, destructive arthritis and osteomyelitis associated with subcutaneous abscesses, and other disseminated infections of various organ systems. Fatal cases of hyperammonemia in lung transplant recipients who had systemic infections with M hominis and Ureaplasma species are now well known.[22, 23]

Deaths have occurred in neonates with bloodstream invasion by Ureaplasma species and meningitis caused by M hominis; however, in some instances, the organisms spontaneously disappeared from CSF without treatment.[1]

Sporadic case reports document fatal infections caused by Mycoplasma species of animal origin, including Mycoplasma arginini in immunosuppressed hosts, but these are extremely rare.[6]

Race

Differences in carriage of genital mycoplasmal organisms and subsequent disease are more likely related to sexual behavior and socioeconomic status than to race. Colonization appears to be more common in African Americans than in Whites, but it is not clear whether this is a true racial difference as opposed to a socioeconomic factor.

Sex

No obvious sex predilection is reported for infections due to genital mycoplasmal species, except for the differences in urogenital diseases such as salpingitis and endometritis, which are gender specific. The carriage rate of genital Mycoplasma species in the lower urogenital tract is somewhat greater for females than for males. Most people who are colonized with the genital mycoplasmas do not develop clinical illnesses.

Age

M hominis and Ureaplasma species are common commensal inhabitants of the lower genitourinary tract in adolescents and adult men and women who are sexually active. Larger numbers of sexual contacts may result in greater likelihood of colonization and disease with these organisms which can be transmitted venereally as well as vertically from mother to offspring.[1]

Neonates who acquire the organisms are usually colonized in the upper and sometimes lower respiratory tracts with occasional dissemination to the bloodstream and CSF. Clinically significant infections may ensue in individuals who are sexually active and in neonates but are rare to nonexistent in older children and adolescents who are not sexually active, except for those with immunodeficiencies.[1]

M fermentans has been recovered from the throats of children with pneumonia; however, the frequency of its occurrence in healthy children is unknown.[1]

Little is known about the occurrence of other mycoplasmal species in different populations and specific associations with disease.

Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma parvum, and Ureaplasma urealyticum are fairly low-grade pathogens that usually cause severe illness only in immunosuppressed hosts. This can include persons with congenital antibody deficiencies, persons undergoing iatrogenic immunosuppression following organ transplantation, and preterm neonates. Treatment with the proper antimicrobial agents will usually clear mucosal infections such as urethritis in normal hosts, but systemic infections in immunosuppressed hosts can be extremely difficult to eradicate and may evolve into chronic conditions in which the organisms and symptoms return once antimicrobial agents are discontinued. 

Patients who are shown by culture or molecular-based testing to have an infection known to be caused by M hominis, M genitalium, U urealyticum, or U parvum should receive appropriate antimicrobial treatment. Clinical infection should be distinguished from colonization, and other causes of illness should be excluded before assuming it is due to one of the genital mycoplasmas. Sexually active men and women may have long-term asymptomatic colonization in the urethra and vagina that cannot be eradicated with multiple courses of antimicrobials and should be told this. Abstinence from sexual relations can help prevent recurrence once an infection is eradicated. All sexual partners of persons proven to be infected should be treated with the same antimicrobial, especially if the causative organism is M genitalium. There are no recommendations for screening or treating asymptomatic persons who have a positive culture or molecular-based test for these organisms.[26]  There also is no justification in treatment of any clinical condition not known to be associated with the presence of the genital mycoplasmas, even in the setting of a positive laboratory test indicating their presence.

The clinical history of patients with urogenital or extragenital infections caused by Mycoplasma or Ureaplasma species is syndrome-specific, not organism-specific, and, as in the case of M pneumoniae respiratory tract infection, no distinguishing features indicate the microbiologic etiology of these conditions.

Many clinicians are unfamiliar with Mycoplasma and Ureaplasma species as etiologic agents. This unfamiliarity is further complicated by a lack of facilities to diagnose mycoplasmal infections in many clinical settings. Subsequently, identification of these organisms may be achieved only as a last resort, particularly if initial treatment with drugs that are ineffective against Mycoplasma or Ureaplasma species is unsuccessful. The following conditions may be caused by infection with M hominis, M genitalium, and/or Ureaplasma species in various patient populations:

• Urethritis
• Pyelonephritis 
• cervicitis 
• Cystitis
• Pelvic inflammatory disease 
• Urinary calculi
• Endometritis or chorioamnionitis
• Bacterial vaginosis
• Infectious arthritis
• Surgical and nonsurgical wound infections
• Osteomyelitis
• Preterm labor 
• Bacteremia
• Pneumonia
• Meningitis
• Hyperammonemia
• Endocarditis
• Abscesses

Mycoplasma and Ureaplasma organisms often play minor roles as causes of the above-named conditions, which may be caused by various other microorganisms. When present in patients with some of these conditions, such as pelvic inflammatory disease, urethritis, and septic arthritis, one of several etiologic organisms may be present simultaneously.

M genitalium is known to cause male urethritis, female cervicitis, and pelvic inflammatory disease, clinically indistinguishable from these conditions as caused by other microorganisms such as Chlamydia trachomatis and Neisseria gonorrhoeae.[9]

Rather than listing the many nonspecific historical and clinical findings of various entities that may be associated with infection with Mycoplasma or Ureaplasma species, emphasizing the need to consider these organisms as potential etiologic agents in the conditions named above is more important to perform the necessary diagnostic tests and to provide appropriate antimicrobial treatment that provides coverage for them.

Consider a Mycoplasma or Ureaplasma infection when persons with hypogammaglobulinemia present with septic arthritis, chronic pulmonary infection, and any other inflammatory condition or infection that does not respond to antimicrobial treatment that is not likely to be effective against these organisms.

Consider a Mycoplasma or Ureaplasma infection likely in any person who has received a lung transplant and develops hyperammonemia syndrome.

Refer to specific articles on urogenital (eg, Urethritis; Pyelonephritis, Acute; Pyelonephritis, Chronic), obstetric and gynecologic (eg, Pelvic Inflammatory Disease, Endometritis), and neonatal infections (eg, Pneumonia; Meningitis, Bacterial) for additional information regarding history and physical examination findings associated with these conditions.

Physical presentation of M hominis or Ureaplasma infection in neonates includes the following considerations:

• Neonates, particularly those born preterm, are especially vulnerable to dissemination of infectious organisms (acquired in utero or at birth) in the bloodstream and, ultimately, the central nervous system.
• Conventional gram-negative and gram-positive bacteria are usually considered the primary culprits of neonatal sepsis; however, when  Mycoplasma and  Ureaplasma organisms are specifically sought, evidence proves they may be of etiologic significance in neonatal lung disease, bacteremia, and meningitis.
• As with most neonatal infections, no characteristic signs and symptoms predict the type of organism present. Subtle manifestations, such as temperature instability, blood pressure fluctuations, heart rate, and respiratory efforts, may be the only clues that an infection is present.
• Consider  Mycoplasma and  Ureaplasma species if signs and symptoms of infection are present; if the neonate does not respond to beta-lactam drugs; and if cultures from blood, the lower respiratory tract, and CSF do not reveal a more common microbiological etiology.
• Radiographic evidence of pneumonitis in the absence of a proven bacterial or viral etiology and mononuclear or polymorphonuclear pleocytosis of CSF with a negative Gram stain and culture result are consistent with infection associated with  M hominis or  Ureaplasma species.

The Ureaplasma genus now is subdivided into 2 species: U urealyticum and U parvum. For clinical purposes, separating infections caused by the 2 different species is not possible without molecular testing, nor is it necessary. In both the clinical setting and in the diagnostic laboratory, they are usually considered Ureaplasma species. Mycoplasma hominis and Mycoplasma genitalium may coexist with ureaplasmas and require separate laboratory detection and identification procedures. 

The clinical conditions associated with the genital mycoplasmas are syndrome-specific and not organism specific. As such, there may be polymicrobial causes for many of them. Clinical presentation and physical examination findings are not unique for any of these organisms. Physical findings for non-gonococcal urethritis, for example, which could be due to C trachomatis, U urealyticum, M genitalium, and/or Trichomonas vaginalis, would appear similar, ie, urethral discharge no matter which organism(s) were primarily responsible.

Women with M genitalium cervicitis may develop pelvic inflammatory disease as a complication. M hominis has been associated with a small portion of cases of pelvic inflammatory disease as well. Immunosuppressed hosts, which includes persons with congenital antibody deficiencies, iatrogenic immunosuppression following organ transplantation, and preterm neonates may become colonized on mucosal surfaces with these organisms, which then disseminate to involve the bloodstream and multiple organs, including joints. In the case of lung transplant recipients, the hyperammonemia syndrome is a significant and potentially life-threatening condition that is due to the metabolic byproduct ammonia being produced through breakdown of urea by Ureaplasma species and breakdown of arginine by M hominis. 

Perform diagnostic tests for Mycoplasma and Ureaplasma species when a patient presents with a clinical condition known to be caused by or associated with these organisms and when more common etiologies are excluded. The correct microbiological diagnosis takes on greater importance in patients who are immunosuppressed and at greater risk for disseminated infection and a poor outcome. 

Examination of slides prepared from urethral exudate in male patients can be useful to quantitate neutrophils in order to document the presence of urethritis. Gram stains are useful in males to detect Neisseria gonorrhoeae, but they are not useful for detection of ureaplasmas or M genitalium since their lack of a cell wall precludes use of a Gram stain for detection. Likewise, examination of a Gram stain of CSF in a neonate with meningitis for the presence of inflammatory cells and to exclude the presence of other bacteria is valuable before proceeding to tests for detection of the genital mycoplasmas.

Culture

Obtain culture results.

M hominis and Ureaplasma species can be detected in culture using specialized media and techniques within 2-5 days. These organisms can also be detected by PCR assays. M genitalium requires a molecular-based assay due to its slow growth and fastidious nature.

Specialized culture media and growth conditions are necessary, and most hospital-based laboratories do not offer these services on site, except for some of the larger tertiary care university hospitals. Regional or national microbiology reference laboratories usually offer these cultures. Routine bacterial cultures are not sufficient to recover M hominis and cannot detect Ureaplasma species. Detailed laboratory procedures for detection and characterization of genital Mycoplasma and Ureaplasma infections can be found in reference texts.[27]

Specimens can be collected in a specialized liquid transport system, a growth medium designed for mycoplasmal organisms (eg, 10-B broth), or some of the common transport systems for Chlamydia species or other bacteria and viruses and shipped to a reference laboratory for testing if necessary. Preventing desiccation and protecting the specimen from adverse temperature extremes is essential if the organisms are to remain viable.

In men, urethral swabs are preferred over urine samples for detection of genital mycoplasmal infections because the organisms are cell associated. Use Dacron polyester swabs with plastic shafts, not wooden cotton-tipped swabs, because the latter may inhibit growth of Mycoplasma and Ureaplasma organisms. Prostatic secretions, semen, and urinary calculi can also be cultured.

For females, urine, cervical swabs, or vaginal swabs are acceptable. Avoid specimens contaminated by lubricants or antiseptics. Urine samples from females are most useful when obtained by catheter or suprapubic aspiration. Endometrial tissue, tubal samples, or pouch of Douglas fluid can be obtained to confirm a mycoplasmal etiology for pelvic inflammatory disease or postpartum fever. For women with clinical amnionitis, culture amniotic fluid, blood, and placenta.

Culture of nasopharyngeal, throat, and endotracheal secretions from neonates is appropriate, especially if their birth weight is less than 1500 g and they have clinical, radiographic, laboratory, or other evidence of pneumonia.

Extragenital or extrapulmonary specimens submitted for culture should reflect the site of infection and disease process. Sterile fluids, including synovial fluid, peritoneal fluid, pericardial fluid, CSF, and blood, are suitable for culture. Bone chips from patients with chronic osteomyelitis without a proven bacterial etiology are also appropriate for culture, as are wound aspirates and tissue collected after biopsy or autopsy. Successful isolation of M hominis and Ureaplasma species from blood can be achieved by inoculating 5-10 mL directly into liquid mycoplasmal growth medium in at least a 1:10 ratio. Smaller volumes can be used for neonates or children.

The recommended specimens for testing for the presence of M genitalium by molecular methods are first void urine for men and vaginal swabs for women.[26]

Proper specimen collection and handling

Proper specimen collection and handling are of utmost importance in detecting these fastidious organisms. Inquiring about the services of a suitable reference laboratory and maintaining the appropriate specimen transport medium in clinical facilities is worthwhile if Mycoplasma or Ureaplasma infections are frequently encountered. Numerous references describe the optimum conditions for specimen collection, handling, and detecting these organisms in culture.[27]  Obtain specific instructions from the laboratory when testing is performed. If commercial molecular-based testing is available, the manufacturer of the test kit to be used will have specific instructions that must be followed.

Serologic studies

Serologic studies are not useful for evaluating genital mycoplasmal infections and none is commercially available in the United States.

Molecular techniques

Molecular techniques such as the PCR assay are available from research or reference laboratories using published methods or their own internally developed protocols. Three FDA-approved molecular tests are commercially available for detection of M genitalium, but not for M hominis or Ureaplasma species. Therefore, the availability of molecular testing is quite limited for these organisms.

Molecular techniques such as PCR are not required when culture is available for M hominis and Ureaplasma species, although it should be acknowledged that PCR assays may be inherently more sensitive for detection of small numbers of organisms in clinical material. Fastidious slow-growing mycoplasmal species, such as M genitalium and M fermentans, may cause clinically significant illnesses in the respiratory tract, urogenital tract, or other sites. The presence of M genitalium can be reliably detected only by molecular techniques such as the PCR assay or transcription mediated amplification.[28]

Imaging studies are not usually performed as part of a workup for uncomplicated infections due to Mycoplasma or Ureaplasma. Exceptions include persons who are immunosuppressed and have apparent septic arthritis or suspected pulmonary infection and neonates with clinical evidence of pneumonitis or chronic lung disease of prematurity. In each of these instances, genital Mycoplasma species may be involved.

CT scanning

Case reports describe neonates with congenital infections in whom intracranial calcifications and necrosis consistent with congenital cytomegalovirus infection were observed, yet the only infectious organism detected was M hominis; thus, in neonates with unexplained neurologic abnormalities and CSF pleocytosis, CT scanning of the head may be useful to further characterize the intracranial pathologic effects.

Radiography

Radiographic features typical of neonatal pneumonitis caused by chlamydiae and other pathogens are associated with congenital Ureaplasma infection. Infants who are culture-positive in the lower respiratory tract for Ureaplasma species develop radiographic lung findings consistent with bronchopulmonary dysplasia more rapidly than neonates with negative cultures.

Specimen collection

Collection of adequate culture specimens from the infected site is of utmost importance if the microbiological diagnosis of an infection due to Mycoplasma or Ureaplasma species is to be determined because none of the clinical manifestations or other laboratory tests is definitive.

Collection techniques include the following:

• Lumbar puncture to obtain CSF
• Arthrocentesis to obtain synovial fluid
• Tracheal aspiration to obtain lower respiratory tract secretions or tissues
• Lung biopsy to obtain lower respiratory tract secretions or tissues
• Bronchoalveolar lavage to obtain lower respiratory tract secretions or tissues
• Nasopharyngeal aspiration to obtain respiratory secretions in neonates who are not intubated
• Blood collection to detect bacteremia
• Urethral or cervicovaginal swabs to detect urethritis or pelvic inflammatory disease.

The nature of the procedure reflects the infection suspected.

Severity of illness dictates the extent to which invasive procedures (eg, lumbar puncture, bronchoalveolar lavage, lung biopsy) are necessary.

Biopsies and examination of histopathology are not usually performed in the workup of suspected infections caused by genital mycoplasmas. These organisms do elicit an acute inflammatory response in immunocompetent hosts. 

Successful treatment hinges on promptly considering Mycoplasma and Ureaplasma species as potential etiologic agents, performing proper diagnostic tests for their detection, and providing appropriate antimicrobial coverage.

Although persons who are immunosuppressed (eg, those with antibody deficiencies) are rarely encountered in some practices, such individuals may have a disproportionately high frequency of serious infections caused by Mycoplasma and Ureaplasma species; therefore, always consider these organisms in the patient's differential diagnosis.

Handle medical treatment according to the patient involved, the presence of underlying disease or immunodeficiency, and whether the infection is localized or disseminated. Key to providing pathogen-specific management is obtaining adequate material for microbiologic diagnosis and properly handling this material once it is collected.

Choose general treatment guidelines for conditions such as acute salpingitis, endometritis, pyelonephritis, urethritis, septic arthritis, neonatal pneumonia, and other conditions associated with or attributed to genital Mycoplasma species according to standard care practices for the various clinical syndromes.

Other than providing specific antimicrobial agents to cover Mycoplasma and Ureaplasma species, no other unique aspects to the management of these conditions are beneficial.

Note that Mycoplasma and Ureaplasma organisms are often opportunists and may be present simultaneously with other pathogens in many of the above-described conditions. Treatment decisions should reflect this possibility.

In circumstances such as chronic joint involvement or abscesses caused by genital mycoplasmas in antibody-deficient hosts, surgical drainage and debridement may sometimes be indicated. 

An oral tetracycline administered for at least 7 days historically has been the drug of choice for urogenital infections due to M hominis, but resistance due to ribosomal modification now occurs in 20-40% of isolates. A survey performed in several states between 2000 and 2004 detected tetracycline resistance in 45% of Ureaplasma isolates, indicating that the susceptibility of these organisms can no longer be assumed.[1] However, a 2016 US study reported that only 1 of 202 U parvum isolates were resistant to doxycycline.[29] The degree of resistance may vary according to geographic area, patient population, and previous exposure to antimicrobial agents.

If tetracyclines are relied upon as first-line drugs, consider alternative agents in the event of treatment failures. In vitro susceptibility testing is sometimes indicated for Mycoplasma and Ureaplasma species recovered from a normally sterile body site, from hosts who are immunocompromised, or from persons who have not responded to initial treatment. Minimal inhibitory concentrations (MICs) for doxycycline are typically lower than those of tetracycline against these organisms.

Clindamycin is an alternative treatment for tetracycline-resistant M hominis but is much less effective against Ureaplasma species. Clindamycin resistance among M hominis isolates appears to be extremely rare, with only a few reported cases. Macrolides, fluoroquinolones, or tetracyclines are the DOCs for Ureaplasma infections. Although tetracycline resistance is described in Ureaplasma species, high-level erythromycin resistance is uncommon, although it has been described in the United States and elsewhere due to ribosomal modification.[29, 30, 31] A single 1-g dose of azithromycin is approved for treatment of urethritis due to Chlamydia trachomatis and works as well clinically as 7 days of doxycycline in persons with urethritis due to Ureaplasma species.

Clarithromycin, although active against Ureaplasma species in vitro at concentrations comparable to or lower than erythromycin, has not been approved for use in the treatment of urogenital infections. M hominis is resistant to 14- and 15-membered macrolides, including erythromycin, azithromycin, and clarithromycin. Despite apparent in vitro susceptibility of Ureaplasma species to tetracycline or erythromycin, treatment of vaginal organisms with these agents is not always successful.

Fluoroquinolones are useful alternatives for treatment of certain infections caused by M hominis or Ureaplasma species within the urogenital tract and in some extragenital locations. Activity of quinolones is not affected by tetracycline resistance, making these drugs attractive alternatives for tetracycline-resistant M hominis or Ureaplasma infections. Levofloxacin and moxifloxacin have the greatest in vitro potency. In general, M hominis is more susceptible to quinolones in vitro than Ureaplasma species based on MICs. Fluoroquinolone resistance among M hominis and Ureaplasma species has been reported, often in patients with prior exposure to these drugs, and especially in immunosuppressed persons.[32, 33] In a 2016 US study, the rate of resistance to levofloxacin was 6% for U parvum and 5% for U urealyticum.[29]

Most clinical trials for treatment of genitourinary infections focus primarily on other pathogens, such as C trachomatis, Neisseria gonorrhoeae, and/or M genitalium. Few studies include microbiologic data specific to Ureaplasma species or M hominis, and no systematic comparative evaluations have been performed on treatment regimens for extragenital infections in adults or infections in neonates.

Treatment recommendations, including dosage and duration of therapy, are based largely on in vitro susceptibility data, outcomes of treatment trials evaluating clinical response to syndromes such as pelvic inflammatory disease and urethritis that may be due to genital Mycoplasma, and individual case reports. For infections such as urethritis that may be transmitted venereally, sexual contacts of the index case should also receive treatment.

Experience with Mycoplasma or Ureaplasma infections in patients who are immunocompromised, especially those with hypogammaglobulinemia (who have been studied most extensively), demonstrates that although Mycoplasma species are primarily noninvasive mucosal pathogens in healthy hosts, they have the capacity to produce destructive and progressive disease. Infections may be caused by resistant organisms refractory to antimicrobial therapy and may require prolonged administration of a combination of intravenous antimicrobials for several weeks or even months, intravenous immunoglobulin, and antisera prepared specifically against the infecting species. Even with aggressive therapy, relapses are likely. Repeat cultures of affected sites may be necessary to gauge in vivo response to treatment. 

Isolation of M hominis or Ureaplasma species from neonatal pericardial fluid; pleural fluid; tracheal aspirate in association with respiratory disease; abscess material; CSF from those with pleocytosis, progressive hydrocephalus, or other neurologic abnormality; or blood justifies specific treatment in neonates who are critically ill when no other verifiable microbiologic etiologies of the clinical condition are apparent. Whether treatment should be given for a positive CSF culture in neonates when inflammation or other evidence of clinical illness is not observed should be handled on a case-by-case basis. Monitoring the patient, repeating the lumbar puncture, and reexamining for inflammation and organisms may be appropriate before initiating treatment because some cases may resolve spontaneously without intervention.

Parenteral tetracyclines are used most often to treat neonatal meningitis caused by either M hominis or Ureaplasma species, despite relative contraindications. Macrolides for Ureaplasma species and clindamycin for M hominis are alternatives. Treatment of ureaplasmal respiratory infections in neonates with erythromycin or azithromycin may be effective in eradicating the organisms from the lower airways, but treatment failures are known to occur.[1, 34] If possible, erythromycin should be avoided in neonates because of an association with pyloric stenosis. Azithromycin is a reasonable alternative to erythromycin in neonates with Ureaplasma respiratory tract infections. In a small study of preterm infants, azithromycin effectively eradicated Ureaplasma from the respiratory tract.[35] No single drug is successful in every instance for eradication of these organisms from the CSF of neonates.

Drugs such as the aminoglycosides and chloramphenicol sometimes demonstrate activity against genital mycoplasmas in vitro. However, their toxicities and the availability of better agents means they are not normally considered as suitable antimycoplasmal agents, except for occasional use of chloramphenicol for treatment of systemic infections in neonates caused by M hominis or Ureaplasma species in the setting of tetracycline resistance or clinical failure with other agents.

Overall treatment alternatives for neonates are the same as for urogenital and systemic mycoplasmal infections in adults, with appropriate dosage modifications based on weight, except that the intravenous route should be used for serious systemic infections. Duration of treatment and drug dosages for neonatal mycoplasmal infections have not been evaluated critically, but a minimum duration of 10-14 days is suggested based on experience in individual cases when microbiologic follow-up care has been assessed.[1, 36] M fermentans has in vitro susceptibilities comparable to M hominis, demonstrating resistance to macrolides and susceptibility to clindamycin, but little clinical data are available to guide therapeutic choices for this mycoplasma.

Azithromycin has historically been recommended as a treatment for M genitalium urethritis in view of clinical failures with the tetracyclines, which appear to be less active overall. However, several reports of azithromycin treatment failure with documentation of elevated MICs to this drug have been reported and continue to spread.[37, 38] Treatment failure has also been described in patients with urethritis in whom M genitalium was isolated following treatment with levofloxacin or moxifloxacin. Mutations in the gyrA and parC genes of M genitalium, and more recently in gyrB and parE, have been detected by molecular methods in M genitalium.[3] Minocycline appears to be more effective than tetracycline or doxycycline against M genitalium and has been clinically successful in the treatment of multidrug-resistant M genitalium genitourinary infections.[39]  

The US Centers for Disease Control and Prevention 2021 Sexually Transmitted Infection Guidelines[26] specify that due to the high rates of macrolide resistance, a single 1-g dose of azithromycin should not be used. Two-stage therapy approaches, ideally using resistance-guided therapy made possible by molecular-based tests for macrolide-resistance mutations are recommended. Resistance tests for mutations in 23S ribosomal RNA that confer macrolide resistance are available only through specialized reference laboratories. Doxycycline is provided as initial empiric therapy, which reduces the organism load and facilitates organism clearance, followed by macrolide-susceptible infections treated with high-dose azithromycin.

Macrolide-resistant infections are treated with moxifloxacin. If M genitalium resistance testing is available and shows the infection to be macrolide susceptible, use doxycycline 100 mg orally 2 times/day for 7 days, followed by azithromycin 1 g orally initial dose, followed by 500 mg orally once daily for 3 additional days (2.5 g total). If macrolide-resistant, use doxycycline 100 mg orally 2 times/day for 7 days followed by moxifloxacin 400 mg orally once daily for 7 days. If M genitalium resistance testing is not available and the organism is detected by an FDA-cleared molecular-based test use doxycycline100 mg orally 2 times/day for 7 days, followed by moxifloxacin 400 mg orally once daily for 7 days.

In vitro susceptibility testing for macrolides, quinolones, and tetracyclines is available for M hominis and Ureaplasma species through specialized reference laboratories and is recommended in the case of clinical treatment failure or any systemic infection in a normally sterile body site in a person who is immunosuppressed. 

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Erythromycin (E.E.S., E-Mycin, Eryc)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Does not affect M hominis.

Clarithromycin (Biaxin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Does not affect M hominis. No data support use in urogenital infections.

Azithromycin (Zithromax)

Treats mild-to-moderate microbial infections. Does not affect M hominis. Has been used to successfully treat Ureaplasma lower respiratory tract infection in neonates. Has been used to treat M. genitalium but acquired resistance and treatment failures have made it necessary for guidelines for its use to be revised. 

Clindamycin (Cleocin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Does not affect Ureaplasma.

Doxycycline (Vibramycin, Bio-Tab, Doryx)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Some M hominis strains and Ureaplasma species may be resistant.

Levofloxacin (Levaquin)

Inhibits DNA gyrase and prevents DNA replication. Active against most M hominis, M genitalium, and Ureaplasma species.

Ofloxacin (Floxin)

Inhibits DNA gyrase and topoisomerase IV and prevents bacterial DNA replication. Active against most M hominis, M genitalium, and Ureaplasma isolates.

Chloramphenicol (Chloromycetin)

Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Has been used to successfully treat Mycoplasma and Ureaplasma neonatal meningitis.

Minocycline (Dynacin, Minocin)

Treats infections caused by susceptible gram-negative and gram-positive organisms. Some M hominis strains and Ureaplasma species maybe resistant. Has been used to successfully treat multidrug-resistant M genitalium infections.

Moxifloxacin (Avelox, Moxifloxacin Systemic)

Inhibits DNA gyrase and prevents DNA replication. Active against most M hominis, M genitalium, and Ureaplasma isolates. More potent against these organisms than levofloxacin.

For serious systemic infections, especially in immunosuppressed hosts, it may be advisable to perform follow-up cultures to determine if infection has been eradicated. If using a molecular-based test, at least 3 weeks should elapse before retesting because dead organisms may still amplify and yield a false positive result.

Because of the frequency with which genital Mycoplasma and Ureaplasma organisms are carried in the lower urogenital tract in persons who are asymptomatic and sexually active, use of barrier protection methods (eg, condoms) is of little benefit because the organisms most often act as opportunistic normal florae. In cases of U urealyticum or M genitalium urogenital infections, sexual partners should also undergo treatment.

Delivery of infants by cesarean delivery has not prevented colonization in the lower respiratory tract because acquisition of the organisms can occur in utero by ascending infection, even through intact fetal membranes.

Although no systematic studies have been performed, the epidemiology of these organisms suggests that persons who are sexually inactive do not usually harbor them and, therefore, cannot be expected to develop clinically significant infections. Abstinence may prevent spread of the organisms among adolescents and adults.