Mycoplasma hominis and Ureaplasma infections

INTRODUCTION — 

Mycoplasma hominis and Ureaplasma species are associated with a number of urogenital infections and complications of pregnancy. They also cause various infections at nongenital sites, especially in immunocompromised patients and neonates.

The clinical associations, diagnosis, and treatment of infections caused by M. hominis and Ureaplasma species will be reviewed here.

Infections caused by other pathogenic mycoplasmas, specifically Mycoplasma pneumoniae and Mycoplasma genitalium, are discussed separately. (See "Mycoplasma pneumoniae infection in adults" and "Mycoplasma pneumoniae infection in children" and "Mycoplasma genitalium infection".)

MICROBIOLOGY

Classification — The term "mycoplasma" is used to refer to any organism within the class Mollicutes, which comprises several genera. There are more than 200 named species in the genus Mycoplasma alone. Fourteen Mycoplasma species, one Acholeplasma species, and two Ureaplasma species have been isolated from humans on multiple occasions; other species of animal origin have also been rarely detected in humans, usually in immunocompromised patients, and are considered transient colonizers [1]. Only six species, five of which inhabit the genitourinary tract, are established human pathogens:

●Mycoplasma hominis

●Mycoplasma genitalium

●Mycoplasma fermentans

●Mycoplasma pneumoniae

●Ureaplasma urealyticum

●Ureaplasma parvum

Mycoplasma amphoriforme has been detected in the respiratory tracts of persons with antibody deficiency and chronic bronchitis or bronchiectasis, but its role as a true pathogen is uncertain. However, in some patients, it has been repeatedly isolated and antimicrobial therapy that eliminates the microorganism has resulted in clinical improvement, which together suggest that it may be a pathogen.

Characteristics — Mycoplasmas and ureaplasmas are the smallest free-living organisms. Because they lack a cell wall, neither mycoplasmas nor ureaplasmas can be visualized by Gram stain. In order to culture these organisms, specialized media containing animal serum is required. (See 'Diagnosis' below.)

Mycoplasma species typically utilize glucose, arginine, or both as metabolic substrates, but their metabolic properties cannot be used to distinguish them from one another. Ureaplasmas are unique because of their ability to hydrolyze urea [1].

Pathogenesis — Although M. hominis and Ureaplasma spp normally exist in a state of adherence to mucosal epithelial cells of the urogenital tracts, they can disseminate to other sites and cause infection when there is a disruption of the mucosa (eg, instrumentation, surgery, trauma) and/or an underlying immaturity or other defects in host defenses, such as in the developing fetus or premature infant or in persons with immunocompromising conditions, such as antibody deficiencies.

M. hominis and ureaplasmas have surface proteins that facilitate cytoadherence [2]. Ureaplasmas can attach to erythrocytes, white blood cells, host mucosal cells, and even spermatozoa. Ureaplasmas also produce an IgA protease to degrade immunoglobulins and release ammonia through urealytic activity [1]. Ureaplasmas also produce nucleases that degrade neutrophil extracellular traps and downregulate various endogenous antimicrobial peptides to avoid the host immune response [3]. The microbiologic burden of genitourinary mycoplasmas may be higher in individuals with HIV than in the general population. Immunosuppression, both cellular and humoral, may contribute to disseminated disease with M. hominis and Ureaplasma [4,5]. High-rate variation in cell surface protein antigens may facilitate evasion of the host immune system and their persistence in invasive sites [1].

NORMAL GENITAL AND NEONATAL COLONIZATION — 

M. hominis and Ureaplasma spp are part of the normal genital flora of many sexually experienced males and females [6]. The percentage of females with vaginal colonization with these organisms increases after puberty in proportion to the number of sexual partners [7]. Transient neonatal colonization also occurs.

●Genital colonization – The rate of colonization with M. hominis increases more rapidly with increasing sexual experience in females than in males, suggesting that females are more susceptible to colonization [8]. By adulthood, up to 80 percent of healthy females have Ureaplasma spp, and 50 percent have M. hominis in their cervical or vaginal secretions [2]. Sexually active men are also frequently asymptomatically colonized with M. hominis (25 percent in one series of 99 males attending a clinic for sexually transmitted diseases) [9].

●Neonatal colonization – Newborns who are colonized with Mycoplasma or Ureaplasma spp are presumed to have been exposed during passage through the birth canal, since colonization is less common in infants born by cesarean section. Exposure in utero also occurs [1]. Lower birthweight and preterm birth are associated with high rates of vertical transmission and colonization [1,10]. Overall, 15 to 36 percent of preterm neonates are colonized by Ureaplasma spp [11].

Neonatal colonization is transient, and the proportion of infants colonized decreases proportionately with postnatal age [12]. Infants more than three months of age are rarely colonized.

GENITOURINARY DISEASE ASSOCIATIONS

Uncertain role in disease — M. hominis and Ureaplasma spp have been associated with various genitourinary tract infections and complications of pregnancy. However, the precise roles of Mycoplasma and Ureaplasma spp in such diseases are difficult to accurately define for the following reasons [2]:

●Many healthy asymptomatic adults have genitourinary colonization with M. hominis and Ureaplasma spp. (See 'Normal genital and neonatal colonization' above.)

●Mycoplasmas are rarely the only organisms isolated from a genitourinary specimen, so it is sometimes difficult to distinguish whether they are causative pathogens or simply co-isolates.

●Published studies on the pathogenicity of these organisms commonly have important design limitations.

●Detection of these organisms has traditionally been difficult and complex. Although newer nucleic acid amplification assays increase detection, they do not necessarily contribute to establishing causality.

Vaginitis and bacterial vaginosis — M. hominis and Ureaplasma spp do not cause inflammatory vulvovaginitis; however, the bacterial load of M. hominis and, to some extent, Ureaplasma spp is higher in females with bacterial vaginosis (BV) than in those without this condition. It has therefore been suggested that M. hominis acts symbiotically with other BV pathogens (eg, Gardnerella vaginalis) or possibly as a sole pathogen. The strong association of BV with preterm birth also raises the possibility that these organisms might play an etiologic role (see 'Intra-amniotic infection and adverse pregnancy outcomes' below). Nevertheless, numerous studies performed over several years in various countries have yielded conflicting results on the significance of M. hominis in BV, and detailed examination of the vaginal microbiome has not yet provided a definitive answer [1,13].

Pelvic inflammatory disease — The role of M. hominis as a cause of PID remains controversial despite the fact that M. hominis is commonly found in the genitourinary tract of females with pelvic inflammatory disease (PID) [14]. In one study, M. hominis was isolated from 4 of 50 fluid samples taken directly from the fallopian tubes of females with salpingitis versus none of 50 samples from females in the control group [15]. Significant rises or falls in antibody titers to M. hominis occurred in 9 of the 16 females with salpingitis who had positive lower genital tract cultures for M. hominis. The presence of infection in the absence of changes in antibody titers may reflect the localized nature of salpingitis. However, M. hominis is rarely present in patients with salpingitis who do not also have evidence of concurrent chlamydial or gonococcal infections or BV. As a result, its role as a primary pathogen in salpingitis is still uncertain. (See "Pelvic inflammatory disease: Pathogenesis, microbiology, and risk factors".)

Ureaplasma spp have been isolated directly from affected fallopian tubes but not in pure culture. Moreover, negative results of serologic tests, fallopian tube cultures, and non-human primate studies do not support a causal relationship for ureaplasmas as a sole pathogen in PID [14].

Neither M. hominis nor Ureaplasma spp cause cervicitis. We are unaware of a significant association between Ureaplasma spp and chronic pelvic pain syndrome.

Nongonococcal urethritis — Ureaplasma spp have been associated with nongonococcal urethritis (NGU) in some studies [16] but not others [17,18]. In a meta-analysis of studies involving 1507 NGU patients and 1223 controls, U. urealyticum was more common in males with NGU [19]. In another study, U. urealyticum was significantly associated with NGU only among males with fewer than 10 lifetime heterosexual partners [20]. The authors postulated that adaptive immunity may attenuate the clinical manifestations of U. urealyticum infection, so that older males with more exposure to this organism are less likely to have symptoms of NGU from it. However, this hypothesis is not proven, and other explanations are possible. Overall, U. urealyticum may be responsible for approximately 3 to 11 percent of NGU cases [21,22]. Other studies have suggested that U. parvum can cause NGU, particularly when present in high numbers [21,23]. (See "Urethritis in adults and adolescents", section on 'Nongonococcal urethritis'.)

Ureaplasmas have also been recovered from an epididymal aspirate from a patient suffering from non-chlamydial, nongonococcal, acute epididymo-orchitis accompanied by a specific antibody response [24], and they could be an infrequent cause of the disease.

There is no evidence that M. hominis causes NGU.

Urinary tract infection — M. hominis and Ureaplasma spp can frequently be recovered from the lower genitourinary tract in males and females, but a causal relationship to cystitis or prostatitis has not been established. M. hominis may be responsible for up to 5 percent of cases of acute pyelonephritis, particularly when prior instrumentation has been performed or obstruction is present [14,25]. Ureaplasma spp have not been shown to cause pyelonephritis. However, they produce urease, induce crystallization of struvite and calcium phosphates in urine in vitro and calculi formation in animal models, and have been found in urinary calculi of patients with infection-associated stones more frequently than in those with metabolic-type stones; these features suggest a possible causal association with urinary tract infection [26].

In females, there is no evidence that M. hominis is a cause of the urethral syndrome, but ureaplasmas may be involved [27].

PREGNANCY-RELATED INFECTIONS

Intra-amniotic infection and adverse pregnancy outcomes — M. hominis and Ureaplasma spp are frequently found in the amniotic fluid of females with spontaneous preterm labor, preterm premature rupture of membranes, premature rupture of membranes at term, low birthweight, miscarriage, and stillbirth [28].

●Pregnancy loss – The presence of M. hominis and Ureaplasma spp in the lower genital tract and placenta has been associated with early pregnancy loss [29]. These microorganisms have been isolated from multiple organs of aborted fetuses and stillborn infants, often in the presence of an inflammatory response and in the absence of other bacteria. Ureaplasmas have been isolated in pure culture from amniotic fluid of women with intact membranes who subsequently experienced fetal loss in the presence of chorioamnionitis [30]. Ureaplasmas have also been isolated more often from the endometrium of women who have had recurrent abortion [31].

●Premature birth and low birthweight – Ample evidence demonstrates an association between cervical Ureaplasma spp infection and prematurity or low birthweight. These are believed to occur as a result of ascending maternal infection that induces an inflammatory response in the chorioamnion, resulting in cytokine and prostaglandin production and subsequent uterine contractions. In a study that included 4330 individuals who underwent Ureaplasma polymerase chain reaction (PCR) testing on vaginal swabs during the first trimester of pregnancy, the rate of spontaneous preterm birth was higher among the 37 percent who tested positive for U. parvum than those who tested negative for any ureaplasma (10 versus 6 percent), even after adjustment for other risk factors [32]. Several prospective studies have also reported a higher risk of preterm labor among pregnant individuals who have Ureaplasma spp detected (by culture or PCR) in the vagina, chorioamnion, or amniotic fluid at 12 to 20 weeks gestation [33-35]. However, screening and treating for ureaplasmas during pregnancy are not consistently associated with a lower risk of preterm labor [36,37].

●Chorioamnionitis – Some of these outcomes are the result of obvious infections, such as chorioamnionitis. Isolation of Ureaplasma spp from the chorioamnion has been consistently associated with histological chorioamnionitis, but not with clinical amnionitis, and is inversely related to birthweight, even when adjusting for duration of labor, rupture of fetal membranes, and presence of other bacteria. These organisms may invade the amniotic cavity when fetal membranes are intact and initiate an inflammatory reaction in the absence of labor [30]. Ureaplasmas are among the most common microorganisms found in inflamed placentas [1]. M. hominis commonly invades the chorion and amniotic fluid but is usually accompanied by other organisms, especially ureaplasmas. Thus, it is unclear whether M. hominis can independently cause chorioamnionitis or clinical amnionitis. (See "Clinical chorioamnionitis", section on 'Microbiology'.)

Other associations with adverse pregnancy outcomes are more tenuous and may relate to increased colonization rates and titers of the organisms [38,39]. Maternal ureaplasma colonization has also been linked to neonatal bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, and necrotizing enterocolitis, all of which are associated with prematurity [39,40].

Nevertheless, whether these organisms are causal remains controversial, since colonization rates of ureaplasmas (35 to 90 percent) and M. hominis (5 to 80 percent) are high in the normal pregnant female population. An additional unclear factor is the role that other organisms, such as those that cause bacterial vaginosis (BV), play in concert with genital mycoplasmas, leading to adverse pregnancy outcomes. While PCR-based diagnoses have yielded more information on colonization rates, they have not shed much light on whether these organisms have an etiologic role.

The role of these organisms in female infertility is also highly controversial, and no causal relationship has been shown convincingly. In one study, colonization rates were higher in infertile females than in fertile ones but did not appear to affect pregnancy rates with in vitro fertilization [41]. There also appears to be an association between M. hominis and ureaplasma colonization rates and male infertility in China [42], but again, no causality has been demonstrated.

Postpartum and postabortal bacteremia and endometritis — Both M. hominis and Ureaplasma spp can be detected in the bloodstream of females with postpartum or postabortal fever; M. hominis is more common, detected in approximately 10 percent of all cases.

In one study, M. hominis was recovered from blood cultures in 4 of 51 females (8 percent) with fever after abortion; in contrast, blood cultures were negative for M. hominis in all control females who had a recent abortion without fever and in all 102 normal pregnant controls [43]. Further evidence in support of M. hominis infection was a fourfold rise in antibody titers in approximately one-half of all females who had postabortal fever compared with only 2 of 53 controls who experienced abortion without fever. The higher frequency of antibody production than blood culture recovery suggests that many patients with postabortal fever develop nonbacteremic M. hominis infection. However, in another study, M. hominis was isolated from the blood in 10 of 327 females (3 percent) who had blood cultures taken a few minutes after delivery; none had fever, and all remained well without treatment [44].

Ureaplasmas are also associated with postpartum endometritis. Among individuals undergoing cesarean delivery with intact membranes, colonization of the chorioamnion by ureaplasmas is an independent risk factor for subsequent endometritis [45]. In another study, ureaplasmas were the most common microorganisms isolated from postcesarean wound infections, often in the absence of other microorganisms [46].

NEONATAL DISEASE

Bacteremia — M. hominis and Ureaplasma spp have been isolated from the bloodstream of newborn infants with bacteremia, particularly in preterm infants. One study found that 23 percent of 457 consecutive neonates who were born between 23 and 32 weeks of gestation had positive umbilical blood cultures for M. hominis and/or Ureaplasma spp [47]. Neonates with positive cultures more often had evidence of inflammatory response syndrome, and their placentas more often had changes compatible with chorioamnionitis than babies with negative blood cultures.

Bacteremia in neonates due to M. hominis or Ureaplasma spp can also occur in association with other complications, such as meningitis or pneumonia [2].

Lung disease — M. hominis and Ureaplasma spp have been associated with congenital pneumonia in neonates [2,48]. M. hominis and Ureaplasma pneumonia usually occur early in preterm infants but can also affect term neonates. These organisms are not thought to be significant causes of acute respiratory disease in otherwise healthy infants after the first month of life. (See "Neonatal pneumonia".)

Controversy remains about whether colonization with Ureaplasma spp contributes to bronchopulmonary dysplasia (BPD). In one meta-analysis of observational studies, maternal ureaplasma colonization was associated with subsequent BPD in the neonate [49], and several other meta-analyses have suggested an increased risk of BPD in neonates with pulmonary ureaplasma colonization [50-53]. However, in addition to the observational nature of the included studies, inconsistency across studies, variability in definitions of BPD, and small sample size further limit confidence in the findings [54]. Despite the evident association between ureaplasmas and BPD in these studies, trials have generally failed to show a reduction in BPD incidence with treatment for ureaplasmas [55-57]. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis", section on 'Postnatal risk factors'.)

Meningoencephalitis — Neonatal meningoencephalitis in association with M. hominis or Ureaplasma spp has been described; acquisition is presumed to have been in utero or via passage through the birth canal [2,58]. The frequency of mycoplasma and ureaplasma isolates from the central nervous system (CNS) in neonates may be higher than is generally appreciated. In one study, Mycoplasma cultures were performed on 100 preterm infants who underwent lumbar puncture for suspected sepsis or meningitis: M. hominis was isolated from the cerebrospinal fluid in five, and ureaplasmas were detected in eight [59]. Brain abscess caused by dual infection of M. hominis and Ureaplasma spp has also been reported in a neonate [60].

Other complications

●M. hominis has been associated with abscesses in neonates, especially at scalp electrode monitoring sites [61,62].

●In one study, respiratory Ureaplasma colonization was associated with a higher incidence of necrotizing enterocolitis among preterm infants, possibly related to intestinal mucosal injury or local immune responses [63].

OTHER EXTRAGENITAL INFECTIONS — 

Systemic infections caused by M. hominis and Ureaplasma spp are most often noted in immunocompromised persons, particularly organ transplant recipients and those with congenital antibody deficiencies and malignancies. The portal of entry is usually the genitourinary tract. Extragenital infections can also occur following instrumentation of the genitourinary tract or postpartum.

Arthritis and osteomyelitis — Joint infections due to M. hominis have primarily been reported among patients with congenital immune defects such as hypogammaglobulinemia, patients with other immunocompromising conditions (eg, solid organ transplant or lymphoma), and following trauma [14,64-67]. M. hominis arthritis can also occur in females after childbirth [68]. A few patients with prosthetic joint infections due to M. hominis have been described [66,69-72]. M. hominis and Ureaplasma spp have also been reported occasionally as causes of osteomyelitis in immunosuppressed persons [73-75].

M. hominis arthritis is usually characterized by fever, leukocytosis, and a purulent joint effusion with large numbers of polymorphonuclear cells but a negative Gram stain on synovial fluid analysis. In a review of 16 cases of septic arthritis due to M. hominis, one-half had manipulation of the urinary tract prior to the onset of infection [66]. Delays in diagnosis were common, ranging from 5 to 37 days. Ureaplasma arthritis may involve one or multiple joints and, in some cases, has been associated with subcutaneous abscesses [76].

Surgical site infections — Surgical site infections due M. hominis can occur after cesarean delivery and maxillofacial, abdominal, vascular, cardiothoracic, neurosurgical, and plastic surgical procedures [77-83]. Genomic sequencing has identified some post-transplant infections, including sternal wound infections following cardiac and lung transplantation, as donor-derived infections [83-86]. Ureaplasma spp can also cause postoperative sternal surgical site infection [87]. Since sterilization and disinfection of instruments and surfaces kill these organisms, environmental transmission is unlikely.

The clinical features of Mycoplasma or Ureaplasma surgical site infections are nonspecific. Clues to include abundant polymorphonuclear leukocytes with a negative Gram stain, negative routine cultures, and a poor response to beta-lactam or aminoglycoside therapy.

Bacteremia and endocarditis — M. hominis bacteremia can occur after renal transplantation, trauma, or genitourinary manipulation. M. hominis is a rare cause of prosthetic and native valve endocarditis in adults and children [88-90]. U. parvum can also cause endocarditis [75,91]. In one case report, a patient developed U. parvum native aortic valve endocarditis more than two years following orchitis and septic arthritis caused by the same organism [91]. (See "Blood culture-negative endocarditis: Epidemiology, microbiology, and diagnosis", section on 'Mycoplasma spp'.)

Respiratory tract infection — Finding M. hominis or Ureaplasma spp in respiratory secretions of adults does not necessarily indicate infection and must be interpreted with caution. M. hominis has been isolated from respiratory secretions in individuals without any complaints [92]. Experimental nasopharyngeal inoculation with M. hominis can cause pharyngitis, but attempts to implicate M. hominis as a cause of naturally occurring pharyngitis have been unsuccessful [93].

Case reports have implicated M. hominis as a cause of pneumonia or empyema among critically ill patients and transplant recipients [94-96]. One case report suggested that M. hominis caused necrotizing pleuropneumonia in a previously healthy adolescent [97].

Central nervous system disease — M. hominis infection has been associated with nonfunctioning central nervous system (CNS) shunts [79], brain abscess [98,99], subdural empyema [100], and meningitis [101]. U. urealyticum has been detected in the cerebrospinal fluid (CSF) of an adult with meningitis, which developed 10 weeks after a complicated kidney transplantation with organ rejection [102] and in a brain abscess of an adult with congenital hypogammaglobulinemia [103]. Disseminated ureaplasma infection involving CSF, kidney, pelvic abscess, skin, and subcutaneous tissue has also been reported in association with hypogammaglobulinemia, underscoring the importance of an intact immune system to prevent and control systemic infections caused by these organisms [104].

Post-transplant hyperammonemia — Hyperammonemia syndrome is a rare but potentially fatal post-transplant complication primarily in lung transplant recipients. This complication has also been demonstrated following hematopoietic cell transplantation. The cause is not definitively known, but Ureaplasma spp and M. hominis donor-derived infection may have a role in some cases [105-110]. Any lung transplant recipient with elevated ammonia levels should be evaluated for these organisms using culture or nucleic acid amplification testing. This is discussed in further detail elsewhere. (See "Noninfectious complications following lung transplantation", section on 'Hyperammonemia'.)

DIAGNOSIS

Clinical suspicion — Although M. hominis and Ureaplasma spp are uncommon causes of infection, it is important to maintain a high index of suspicion among neonates and immunocompromised patients, who are more vulnerable to infection with these organisms and are at high risk for adverse outcomes.

●Neonates and immunocompromised patients – Infections with M. hominis or Ureaplasma spp should be considered in preterm neonates and immunocompromised patients who present with evidence of the associated conditions detailed above, particularly systemic infection (eg, sepsis), pneumonia, central nervous system (CNS) infection, hyperammonemia, or new-onset arthritis (see 'Neonatal disease' above and 'Other extragenital infections' above). The suspicion for these organisms should be heightened when initial microbiologic testing (eg, Gram stain and early routine culture) is negative or uninformative or if the patient does not improve on antimicrobial therapy for more common pathogens (eg, with beta-lactams). Similarly, they should be suspected in immunocompromised patients with wound or surgical site infections (including sternal wound infections) when routine cultures are negative.

In such cases, microbiologic testing for M. hominis or Ureaplasma spp should be performed (see 'Microbiologic confirmation' below). Nevertheless, given the difficulty and time involved, empiric antimicrobial therapy while awaiting a microbiologic diagnosis is often warranted based on this clinical suspicion alone in vulnerable patients. (See 'Treatment' below.)

Unfortunately, extragenital M. hominis and Ureaplasma spp infections remain undiagnosed for long periods of time because they are not considered or tested for.

●Patients with genital tract symptoms – Routine testing for M. hominis or Ureaplasma spp in patients with uncomplicated genital tract disease is not warranted; it is uncertain whether detection of such organisms in the genital tract reflects normal colonization or infection [111]. (See 'Uncertain role in disease' above.)

Microbiologic confirmation

Test selection — Both culture and nucleic acid amplification tests can be used to detect M. hominis and Ureaplasma spp; the choice between them generally depends on availability and turnaround time. With the exception of M. hominis, which will sometimes grow in routine bacteriologic media, special procedures and media are required for detection of these organisms in clinical specimens.

Serology is not useful since many healthy people have underlying antibodies and, in the United States, there are no standardized commercial serologic assays available.

Culture — M. hominis and ureaplasmas often grow in broth cultures within 24 to 48 hours. Most hospital microbiology laboratories do not perform cultures for these organisms, but they are often readily available through reference laboratories. The isolation of M. hominis or Ureaplasma spp in any quantity from normally sterile body fluids or tissues is diagnostic of infection, particularly in neonates or other immunosuppressed persons. Susceptibility testing should be performed if these organisms are isolated on culture of extragenital sites, but it is limited to reference laboratories.

Appropriate clinical specimens (eg, blood, cerebrospinal fluid [CSF], synovial fluid, sputum) depend on the clinical syndrome suspected. Ideally, they should be inoculated immediately into universal transport media that does not contain antibiotics before they are allowed to dry [112]. Specimens in transport media must be refrigerated or frozen prior to shipment, depending on the time until they are expected to be received in a reference laboratory for processing.

Liquid and solid media used for culturing these organisms, such as 10B broth for Ureaplasma spp and SP4 broth for Mycoplasma spp, have pH-sensitive dye indicators that help distinguish the urea splitters (ureaplasmas) and arginine metabolizers (M. hominis), which turn media alkaline, from glucose metabolizers (M. pneumoniae), which turn media acidic. Specimens should be subcultured onto SP4 agar plates for definitive identification of M. hominis and onto A8 agar plates for Ureaplasma spp. Genital mycoplasma colonies develop best when incubated in air plus 5% CO₂ or under anaerobic conditions.

●M. hominis may take a week to develop discernible colonies. It can escape detection using automated blood culture detection systems, such as BacT/ALERT [113], unless cultures are routinely incubated for three to five days using special media and/or blind subcultures are made from blood cultures [8]. M. hominis colonies look like a "fried egg," having a denser center and paler outer zone. M. hominis can also show up on routine bacterial media as pinpoint colonies that cannot be visualized on Gram stain. An arginine-utilizing mycoplasma that produces fried-egg colonies on SP4 agar within three to four days is most likely M. hominis, but a polymerase chain reaction (PCR) assay is necessary for species confirmation, since commensal mycoplasmas may appear in a similar manner.

●Ureaplasmas may grow in one to two days. They form tiny pinpoint colonies with a brown granular appearance on A8 agar when viewed under a stereomicroscope. Their appearance is sufficient for identification to genus level. Differentiation of Ureaplasma spp requires testing by the PCR assay [114], but this is not necessary for routine diagnostic purposes.

Nucleic acid-based tests (including PCR) — Nucleic acid-based tests, such as the PCR assay, are more easily performed and generally more sensitive than culture methods and can theoretically be completed in a single day [115]. However, they are not available in most hospital diagnostic laboratories. In the United States, there are no Food and Drug Administration (FDA)-cleared nucleic acid-based assays for these organisms, although several reference labs have developed and validated their own assays using a variety of gene targets and techniques. Any specimen suitable for culture can also be tested with nucleic acid-based tests (eg, throat swabs, tracheal aspirates or sputum, pleural or synovial fluid, tissue or bone, CSF).

Nucleic acid-based assays can help in assigning causality when material from sites not ordinarily colonized (eg, joint fluid or tissue, heart valve tissue, CSF) are tested. However, positive nucleic acid tests on specimens from sites that are frequently colonized with multiple organisms (eg, genital tract) are less helpful and should not be considered diagnostic unless other causes of infection have been ruled out.

TREATMENT

Indications — Patients should be treated for a Mycoplasma or Ureaplasma spp infection if they have a compatible clinical syndrome with detection of Mycoplasma or Ureaplasma spp from a normally sterile extragenital site, from lower respiratory tract specimens, or from infected wound specimens. Immunocompromised patients who present with a compatible clinical syndrome also warrant empiric treatment given the difficulty in obtaining a timely microbiologic diagnosis. The clinical diagnosis is discussed elsewhere. (See 'Clinical suspicion' above.)

Treatment is not warranted for patients who are found to be colonized with these organisms but do not have clinical disease. For infections that are commonly polymicrobial, such as pelvic inflammatory disease (PID), if M. hominis is one of several organisms detected, it is reasonable to include coverage for the mycoplasmas as part of the broader-spectrum regimen. However, there is no definitive evidence that this affects patient outcomes.

In vitro susceptibility — Susceptibility testing results are usually not available when selecting an antibiotic regimen, since treatment is often empiric and infections are often detected by molecular tests. In vitro susceptibility testing is available through reference laboratories and should be pursued whenever there is treatment failure, in infections in immunocompromised patients, and for extragenital infections in normally sterile sites.

Historically, nearly all clinical isolates of M. hominis and Ureaplasma spp were predictably susceptible to specified agents within the tetracycline, macrolide, and fluoroquinolones classes, which are the three main classes used to treat these organisms. More recently, acquired resistance to one or more of these classes has been well documented.

The extent and frequency of resistance vary by geographic area, patient population, and previous exposure to antimicrobial agents. Alarmingly high resistance rates, including evidence of multidrug-resistant organisms, have been reported for Ureaplasma spp in some regions, particularly in Africa [116] and China [117]. Resistance rates are generally much lower in the United States and Europe.

However, variable and sometimes unreliable definitions of resistance (eg, based on phenotypic minimum inhibitory concentrations [MICs], molecular detection of resistance-associated mutations, treatment failures) limit comparisons between studies and regions. As an example, the mere presence of a resistance gene, such as tetM, which confers tetracycline resistance, does not always result in clinical treatment failure or elevated MICs. Additionally, measurements of MICs for Mollicutes can be very tedious and subjective, and endpoints may shift over time if incubation is prolonged. Although the Clinical and Laboratory Standards Institute has published standard methods for MIC determination and tentative interpretive breakpoints for a limited number of drugs [118], these techniques and interpretive criteria may not be used universally in all countries. Finally, since susceptibility testing is not routinely performed, published MIC data may reflect testing on subsets of patients who had treatment failure or extensive prior exposure and thus report a higher rate of resistance than would be seen in the general population.

Mycoplasma hominis — M. hominis is usually susceptible in vitro to the following agents:

●Tetracyclines (eg, doxycycline) – Acquired resistance results from ribosomal protection due to the tetM transposon. In some patient populations, resistance has been reported in up to 15 to 40 percent [1,119-122]. In an unpublished review from the authors’ institution (University of Alabama at Birmingham Diagnostic Mycoplasma Laboratory [UAB]) that compiled MIC data on 259 M. hominis isolates from various specimen types submitted throughout the United States between 2012 and 2023, 6.2 percent were resistant to tetracycline [123].

●Clindamycin – Resistance to clindamycin is uncommon in the United States. It is due to mutations in 23S rRNA. In the UAB MIC data review, only 2.7 percent of M. hominis isolates were resistant to clindamycin [123].

●Fluoroquinolones (eg, levofloxacin and moxifloxacin) – Naturally occurring resistance to fluroquinolones is caused by mutations in parC and parE in the chromosomal quinolone resistance-determining regions [124-126]. In one French study, quinolone resistance was less than 3 percent between 2010 and 2015 [122]. However, the UAB MIC data review identified a levofloxacin resistance rate of 19.8 percent [123].

M. hominis is intrinsically resistant in vitro to macrolides (14- and 15-membered agents such as erythromycin, azithromycin, and clarithromycin), aminoglycosides, sulfonamide, trimethoprim, and all beta-lactams [112].

Ureaplasma spp — Ureaplasma spp are generally susceptible in vitro to the following agents:

●Tetracyclines (eg, doxycycline) – Resistance is uncommon in the United States and Europe [119-121]. A French study reported tetracycline resistance in approximately 8 percent of clinical isolates from 2010 to 2015 [122]. A 2016 study from the United States reported doxycycline resistance in only 1 of 202 U. parvum isolates [127]. In a subsequent unpublished review from the authors’ institution (University of Alabama at Birmingham Diagnostic Mycoplasma Laboratory [UAB]) that compiled MIC data on 415 Ureaplasma spp isolates from various specimen types submitted throughout the United States between 2012 and 2023, 6.5 percent were resistant to tetracycline [123].

●Macrolides (erythromycin, azithromycin, clarithromycin) – Resistance due to mutations in 23S ribosomal RNA or ribosomal proteins has been described and is associated with treatment failures [106]. In the United States, such resistance remains uncommon [127,128]. The UAB review found erythromycin resistance in 2.4 percent of clinical isolates [123].

●Fluoroquinolones (eg, levofloxacin and moxifloxacin) [125]. Naturally occurring resistance caused by mutations in parC and parE in the chromosomal quinolone resistance-determining regions can occur [126]. In a 2016 study from the United States, levofloxacin resistance rate was 6 percent for U. parvum and 5 percent for U. urealyticum [127]. The UAB review identified levofloxacin resistance in 6.7 percent of clinical isolates, with no differences noted between U. urealyticum and U. parvum [123].

Ureaplasma spp are intrinsically resistant in vitro to clindamycin, aminoglycosides, sulfonamides, trimethoprim, and all beta-lactams.

Regimen selection — The choice of drug, route of administration, dose, and duration of therapy depend on the type of patient (ie, neonate, child, or adult), clinical condition (whether a urogenital infection or infection in a sterile site such as bloodstream or cerebrospinal fluid [CSF]), type of host (normal or immunosuppressed), and severity of infection.

Regimen selection is based primarily on an understanding of the in vitro susceptibility patterns of these organisms, although susceptibility testing results have not been extensively correlated with treatment outcomes beyond individual case reports. There are no specific treatment guidelines issued by any professional or regulatory organization. (See 'In vitro susceptibility' above.)

Neonatal infections — Clinical evidence informing the treatment of neonatal M. hominis and Ureaplasma infections is limited to case reports or small case series.

●M. hominis – Systemic neonatal infections caused by M. hominis are uncommon. The organism is variably susceptible to clindamycin, doxycycline, and fluoroquinolones. Dosing of clindamycin in newborn infants should be based on postmenstrual age. Experience with doxycycline and fluoroquinolone use in premature infants is limited, but these drugs have been successfully used to treat infections of the central nervous system due to M. hominis or Ureaplasma spp. There are no specific guidelines, but the duration of antibiotic therapy depends on the type of infection being treated and is generally 10 to 14 days.

●Ureaplasma spp – Detection of Ureaplasma spp does not require therapy if the infant is asymptomatic. Clear data that there is a benefit with treatment are lacking [129]. (See 'Lung disease' above.)

If treatment is provided for pulmonary infection due to Ureaplasma spp, we suggest intravenous (IV) azithromycin at a dose of 20 mg/kg per day for three days; this dose successfully eradicates the organism from the respiratory tract and maintains sufficiently high concentrations for ≥96 hours after the first dose [130-132]. Dosing for other syndromes is uncertain; IV azithromycin monotherapy for two weeks or longer has been associated with Ureaplasma eradication from the CSF [133]. Nevertheless, definitive evidence on efficacy of antimicrobial agents in the treatment of central nervous system (CNS) Ureaplasma spp infections in infants is also lacking. Sterility of CSF can occur without antimicrobial therapy [129].

Infants treated with IV azithromycin should be followed for signs and symptoms of pyloric stenosis; oral azithromycin is associated with pyloric stenosis in infants younger than six weeks of age. Erythromycin should be avoided given its association with pyloric stenosis.

Although in vitro efficacy against Ureaplasma spp is also observed with clarithromycin and fluoroquinolones, clinical data are limited. a lack of benefit precludes recommendations on treatment for preterm infants. Experience with doxycycline in premature infants is also limited.

Extragenital infections in other populations — Most extragenital infections occur in adults with underlying immunocompromising conditions. We suggest a fluoroquinolone as first-line therapy for extragenital M. hominis or Ureaplasma spp infections, based on typical in vitro susceptibility and because the fluoroquinolones have the advantage of being bactericidal. The preferred fluoroquinolones are moxifloxacin (400 mg orally or IV once daily) and levofloxacin (500 mg orally or IV once daily). Doxycycline (200 mg loading dose then 100 mg orally or IV twice daily) is an appropriate alternative agent. If possible, directed regimen selection should be guided by in vitro susceptibility testing. (See 'Culture' above.)

Although there is no clear evidence that combination therapy (eg, a fluoroquinolone plus doxycycline) results in better outcomes than monotherapy, it has been described [72,134,135] and is a reasonable approach in immunocompromised patients. In such patients, particularly in those with hypogammaglobulinemia, M. hominis and Ureaplasma spp have the capacity to produce destructive and progressive disease. Furthermore, infections may be caused by resistant organisms, and combination therapy potentially increases the likelihood of using an active agent pending susceptibility results.

In severe infections, immunosuppression should be reduced, if possible; patients with hypogammaglobulinemia should receive replacement immune globulin. Some infections (eg, bone and joint infections, deep wound infections) also warrant aggressive debridement and drainage of infected or necrotic tissue.

The duration of therapy varies with the severity of disease, the site of infection, the immune status of the patient, and response to therapy. In some cases, such as with bone infections, several weeks of therapy are warranted [66,69]. Some reports describe administering antibiotics for up to a year [136].

Even with aggressive therapy, relapses are likely to occur. Repeat cultures of affected sites, such as synovial fluid, may be necessary to monitor in vivo response to treatment.

Clinical data to support the use of fluoroquinolones are mainly from case reports and series [137]. Moxifloxacin is more potent than levofloxacin in vitro, but there are no data to demonstrate that it provides a more efficacious clinical or microbiologic outcome in vivo. Doxycycline has also been used successfully, including in CNS and bone infections [60,102,138].

Uncomplicated urogenital infection — If treatment is warranted for an uncomplicated urogenital infection caused by M. hominis or Ureaplasma spp, doxycycline (100 mg orally twice daily) is the drug of choice for nonpregnant adults and adolescents. Duration of therapy is generally seven days for lower urogenital tract infection, whereas for more extensive infections, such as PID, antibiotics are given for 14 days. We also offer treatment to sexual partners regardless of symptoms because of the potential of sexual transmission.

Despite in vitro susceptibility, doxycycline or macrolide treatment of vaginal mycoplasmas and ureaplasmas is not always successful. Furthermore, some populations have a risk of acquired tetracycline resistance. In cases of treatment failure or resistance, fluoroquinolones are another option.

For pregnant women and young children, clindamycin is appropriate for M. hominis infections and a macrolide (such as azithromycin) is appropriate for Ureaplasma infections. These are also appropriate alternative agents in nonpregnant adults or adolescents who cannot take doxycycline.

Regimen selection for urogenital infection is based primarily on in vitro susceptibility patterns (see 'In vitro susceptibility' above) and outcomes of clinical trials of nongonococcal urethritis and other genital infections that have used doxycycline successfully. (See "Urethritis in adults and adolescents", section on 'Nongonococcal urethritis'.)

SUMMARY AND RECOMMENDATIONS

●Microbiology – Mycoplasma hominis and Ureaplasma spp are small bacteria that lack a cell wall and cannot be visualized by Gram stain. They are part of the normal genital flora of sexually experienced individuals. Transient neonatal colonization also occurs. (See 'Microbiology' above and 'Normal genital and neonatal colonization' above.)

●Associated genitourinary syndromes – These organisms have been associated with various genitourinary tract infections (eg, pelvic inflammatory disease [PID] for M. hominis and nongonococcal urethritis for Ureaplasma spp), as well as complications of pregnancy, but their precise roles in some of these conditions have been difficult to define. (See 'Genitourinary disease associations' above and 'Pregnancy-related infections' above.)

●Populations at risk for extragenital infection – M. hominis and Ureaplasma can cause severe infection in specific populations. Neonatal infections include meningoencephalitis, bacteremia, and pneumonia, mainly in preterm infants. In immunocompromised patients, severe systemic infections (eg, bacteremia and bone, joint, pulmonary, and central nervous system [CNS] infections) have also been described; extragenital infections can also occur following trauma or instrumentation of the genitourinary tract. (See 'Neonatal disease' above and 'Other extragenital infections' above.)

●Clinical suspicion and diagnosis – M. hominis or Ureaplasma spp infection should be suspected in preterm neonates and immunocompromised patients with extragenital infections when initial microbiologic testing is negative or if the patient does not improve on therapy for more common pathogens. Both culture and nucleic acid amplification tests can be used for their detection; if these organisms are isolated, susceptibility testing should be performed, if available. (See 'Diagnosis' above.)

●Treatment

•Neonatal infection – For neonates, data on the treatment of M. hominis and Ureaplasma spp infections are extremely limited. M. hominis is variably susceptible to clindamycin, tetracyclines, and fluoroquinolones. Clindamycin should be dosed according to postmenstrual age; experience with doxycycline and fluoroquinolones in premature infants is limited. If treatment is warranted for Ureaplasma spp, azithromycin is an option. (See 'Neonatal infections' above.)

•Extragenital infection in other populations – For extragenital M. hominis and Ureaplasma spp infections in nonpregnant individuals, we suggest moxifloxacin or levofloxacin (Grade 2C). Doxycycline is an appropriate alternative, although resistance may be increasing; it is also reasonable to use combination therapy (eg, moxifloxacin or levofloxacin plus doxycycline). Clinical data on the optimal treatment of these organisms are limited; our preference for certain regimens are based mainly on in vitro susceptibility data and safety in different populations. (See 'Extragenital infections in other populations' above.)

•Genital infection – Routine testing for M. hominis or Ureaplasma spp in patients with uncomplicated genital tract disease is not warranted. If these organisms are detected in patients with a genitourinary syndrome (eg, nongonococcal urethritis or PID) and are thought to be the cause of the symptoms, we suggest doxycycline (Grade 2C). (See 'Uncertain role in disease' above and 'Uncomplicated urogenital infection' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Stephen G Baum, MD, who contributed to an earlier version of this topic review.