Ureaplasma Infection

Synonyms and related keywords: Ureaplasma infection, mycoplasma, Mycoplasma pneumoniae, M pneumoniae, Mycoplasma hominis, M hominis, Ureaplasma, Ureaplasma urealyticum, U urealyticum, Ureaplasma parvum, U parvum, Mycoplasma genitalium, M genitalium, Mycoplasma fermentans, M fermentans, Mycoplasma pirum, M pirum, Mycoplasma penetrans, M penetrans, urogenital disease, urethritis, urogenital infection, genital mycoplasmal organisms, ureaplasmas, ureaplasmal infection, cervicitis, pelvic inflammatory disease, PID, pneumonia, bacterial pneumonia, infectious arthritis, nongonococcal urethritis, nonchlamydial nongonococcal urethritis, female urethral syndrome, acute epididymoorchitis, acute pyelonephritis, bacterial vaginosis, salpingitis, congenital pneumonia, congenital bacteremia, congenital meningitis, bronchopulmonary dysplasia, osteomyelitis, meningitis, endometritis, chorioamnionitis, surgical wound infections, neonatal pneumonia, neonatal meningitis, septic arthritis, pneumonitis



INTRODUCTION

Background: 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 are usually associated with mucosae. They 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.

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. See Mycoplasma Infections for a discussion of M pneumoniae infection. 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, have now been designated as separate species. Separation of these species is not possible except via molecular techniques such as polymerase chain reaction (PCR). Therefore, they are considered together as Ureaplasma species (Waites, Clin Microbiol Rev, 2005).

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, and their possible roles in certain pathologic conditions in humans. Because of their extremely fastidious nature and the lack of reliable means for cultivation on artificial media, detection of these mycoplasmal organisms rests primarily with molecular techniques. 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. This research and the subsequent data are made possible by the availability of PCR assays, which can detect the presence of these organisms.

Pathophysiology: 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, 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, but the clinical significance of this is not known.

No credible evidence indicates that mycoplasmal organisms have a role in the pathogenesis of Gulf War syndrome (Waites, Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control, 2005).

The newest mycoplasmal species to be detected in humans is Mycoplasma amphoriforme, an organism detected in the lower respiratory tract of immunosuppressed persons with chronic bronchitis (Webster, 2003). Its true role as a human pathogen has not yet been determined.

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.

Ureaplasma species and M genitalium are causes of nonchlamydial nongonococcal urethritis in men (Waites, Clin Microbiol Rev, 2005; Jensen, 2004). No evidence indicates that that M hominis causes female urethral syndrome; however, Ureaplasma species may be involved. Ureaplasma organisms have been recovered from an epididymal aspirate from a patient with acute epididymoorchitis, and these organisms 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 do not cause vaginitis, but they 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. Whether Ureaplasma infection causes involuntary infertility remains speculative. 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 Mycoplasma 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 (Waites, Clin Microbiol Rev, 2005).

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.

Both Mycoplasma and Ureaplasma species can cause invasive disease of the joints and respiratory tract with bacteremic dissemination, particularly in persons with antibody deficiencies (Furr, 1994). Ureaplasma species are the most common nonbacterial etiologies of infectious arthritis in persons who are hypogammaglobulinemic. M hominis bacteremia has been demonstrated following renal transplantation, trauma, and genitourinary manipulations. This organism has also been found in surgical wound infections, fluids from pericardial effusions, prosthetic valves affected by endocarditis, and subcutaneous abscesses. Both organisms can cause osteomyelitis. 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 (Waites, Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control, 2005).

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.

Frequency:

• In the US: 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. 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. 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.

  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.

• Internationally: 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.
  
  
• 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 (Waites, Clin Microbiol Rev, 2005).

• Sporadic case reports document fatal infections caused by Mycoplasma species of animal origin, including Mycoplasma arginini in immunosuppressed hosts, but these are extremely rare (Waites, Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control, 2005).

Race:

• Differences in carriage of genital mycoplasmal organisms and subsequent disease are more likely related to sexual behavior and socioeconomic status than to race.

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 sex specific. The carriage rate of genital Mycoplasma species in the lower urogenital tract is somewhat greater for females than for males.

• Ureaplasma species have been isolated from cervicovaginal specimens in 40-80% of women who are asymptomatic and sexually active, and M hominis has been isolated from cervicovaginal specimens in 21-53% of women who are asymptomatic and sexually active. This prevalence is somewhat lower in males.

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. The organisms can be transmitted venereally and vertically from mother to offspring.

• 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, with the exception of those with immunodeficiencies.

• M fermentans has been recovered from the throats of children with pneumonia; however, the frequency of its occurrence in healthy children is unknown.
  
  
• Little is known about the occurrence of other mycoplasmal species in different populations and specific associations with disease.

CLINICAL

History:

• 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 Mycoplasma and Ureaplasma species:

• Urethritis

• Pyelonephritis

• Pelvic inflammatory disease

• Endometritis or chorioamnionitis

• Infectious arthritis

• Surgical wound infections

• Neonatal pneumonia

• Neonatal meningitis

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

Physical:

• Rather than listing the many nonspecific historical and clinical findings of various clinical 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 in order 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 that does not respond to antimicrobial treatment that is not likely to be effective against these organisms.

• 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 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 CNS.

• 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 and aminoglycoside 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.

Causes:

• The Ureaplasma genus now is subdivided into 2 species: U urealyticum and U parvum. For clinical purposes, separating infections caused by the different 2 species is not possible or necessary. In both the clinical setting and in the diagnostic laboratory, they are considered Ureaplasma species.

DIFFERENTIALS

Chlamydial Genitourinary Infections
Gonococcal Infections

Other Problems to be Considered:

Ureaplasma infections of the urogenital tract and systemic sites may be similar to infections caused by other bacteria and can only be distinguished by appropriate laboratory testing. Specifically, urogenital infections may mimic infections due to gonococci, chlamydiae, or other genital mycoplasmal species.

WORKUP

Lab Studies:

• 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.

• Obtain culture results.

• Both M hominis and U urealyticum can be detected in culture within 2-5 days. M genitalium requires a PCR assay.

• Specialized culture media and growth conditions are necessary, and most hospital-based laboratories do not offer these services on-site. 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 (Waites, 2001).

• Specimens can be collected in a specialized liquid transport system, a growth medium designed for mycoplasmal organisms (eg, SP4 broth), or some of the common transport systems for Chlamydia species or other bacteria and shipped frozen 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 calcium alginate swabs, 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 and if the number of organisms is quantitated. 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 more than 10 mL directly into liquid mycoplasmal growth medium in at least a 1:10 ratio. Smaller volumes can be used for neonates or children.

• 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 detecting these organisms in culture. Obtain specific instructions from the laboratory when testing is performed.

• Serologic studies are not useful for evaluating genital mycoplasmal infections.

• Molecular techniques are available on a limited basis from research or reference laboratories.

• Molecular techniques such as PCR are not needed when culture is available for M hominis and Ureaplasma species.

• 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. Their presence can be reliably detected only by molecular techniques such as the PCR assay. Seeking molecular techniques for diagnostic purposes is not usually practical because of the difficulty in their detection and the fact that their role in human disease is not well established. A few US laboratories are capable of testing for the presence of M genitalium and M fermentans. Obtain contact information from the author.

Imaging Studies:

• 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.

Procedures:

• 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
  • Blood collection to detect bacteremia

• 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.

TREATMENT

Medical Care:

• 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.

MEDICATION

An oral tetracycline administered for at least 7 days historically has been the DOC for urogenital infections due to M hominis, but resistance now occurs in 20-40% of isolates. A recent survey detected tetracycline resistance in 455 of Ureaplasma isolates, indicating that the susceptibility of these organisms can no longer be assumed (Waites, Clin Microbiol Rev, 2005). 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 species recovered from a normally sterile body site, from hosts who are immunocompromised, or from persons who have not responded to initial treatment.

Clindamycin is an alternative treatment for tetracycline-resistant M hominis but is much less effective against Ureaplasma species. Erythromycin or tetracyclines are the DOCs for Ureaplasma infections. Although tetracycline resistance is described in Ureaplasma species, high-level erythromycin resistance does not occur. 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 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. Newer agents (eg, levofloxacin and moxifloxacin) have the greatest in vitro potency, but scant clinical data are available. In general, M hominis is more susceptible to quinolones in vitro than Ureaplasma species based on minimal inhibitory concentrations. Recent reports have documented fluoroquinolone resistance among M hominis and Ureaplasma species in the United States, France, and China, but the extent to which this occurs is unknown (Bebear, 2000; Duffy, 2006).

Most clinical trials for treatment of genitourinary infections focus primarily on other pathogens, such as C trachomatis and Neisseria gonorrhoeae. Few studies include microbiologic data specific to genital Mycoplasma species, 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 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 contraindications. Erythromycin for Ureaplasma species, clindamycin for M hominis, or chloramphenicol for either species are alternatives. Treatment of ureaplasmal respiratory infections in neonates with erythromycin may be effective in eradicating the organisms from the lower airways, but treatment failures are known to occur (Waites, Clin Microbiol Rev, 2005; Waites, 1994). No single drug is successful in every instance for eradication of these organisms from the CSF of neonates. Little clinical experience is available with new-generation macrolides in the treatment of neonatal Ureaplasma infections, and no guidelines for their dosages or use in neonates are available.

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.

No clinical data are available for guidance of therapeutic interventions for infections when other mycoplasmal species may be involved; however, M fermentans has in vitro susceptibilities comparable to M hominis, demonstrating some degree of resistance to macrolides and susceptibility to clindamycin.

M genitalium is usually susceptible in vitro to macrolides, tetracyclines, and fluoroquinolones. Azithromycin has been recommended as a treatment alternative for M. genitalium urethritis in view of clinical failures with the tetracyclines. However, a recent case report of azithromycin treatment failure with documentation of elevated minimal inhibitory concentrations (MICs) to this drug in a clinical isolate that responded to a fluoroquinolone (moxifloxacin) indicates that these types of infections can be difficult to manage (Bradshaw, 2006).

Drug Category: Antimicrobial agents -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	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.
Adult Dose	250-500 mg PO/IV q6h
Pediatric Dose	20-50 mg/kg/d PO divided tid/qid 25-40 mg/kg/d IV divided qid
Contraindications	Documented hypersensitivity
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; adverse GI effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occurs

Drug Name	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.
Adult Dose	250-500 mg PO q12h
Pediatric Dose	15 mg/kg/d PO q12h
Contraindications	Documented hypersensitivity; coadministration of pimozide
Interactions	Toxicity increases with coadministration of fluconazole and pimozide; effects decrease and adverse GI effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, and HMG CoA-reductase inhibitors; serious cardiac arrhythmias may occur with coadministration of cisapride; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Coadministration with ranitidine or bismuth citrate not recommended with CrCl less than 25 mL/min; administer half dose or increase dosing interval if CrCl less than 30 mL/min; irritative diarrhea and superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Azithromycin (Zithromax) -- Treats mild-to-moderate microbial infections. IV formulation not recommended for children. Does not affect M hominis. No clinical data are available to support dosage or use in neonates.
Adult Dose	500 mg PO on d 1, then 250 mg PO qd days 2-5 500 mg/d IV for 2 d, then 500 mg PO qd; a single 1-g dose is used for urethritis
Pediatric Dose	10 mg/kg/d PO on d 1, then 5 mg/kg/d PO d 2-5
Contraindications	Documented hypersensitivity; hepatic impairment; coadministration with pimozide
Interactions	Effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine; nausea and vomiting or irritative diarrhea may occur

Drug Name	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.
Adult Dose	150-450 mg PO q6h 150-900 mg IV q6-8h
Pediatric Dose	Neonates: Not to exceed 15-20 mg/kg/d divided tid/qid 10-25 mg/kg/d PO divided tid/qid 10-40 mg/kg/d IV divided tid/qid
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; severe hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug Name	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.
Adult Dose	100 mg PO/IV q12h
Pediatric Dose	Not recommended for use in children; if no alternative, 2-4 mg/kg/d IV/PO or divided bid recommended
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases minimally with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Levofloxacin (Levaquin) -- Inhibits DNA gyrase and prevents DNA replication.
Adult Dose	500 mg/d PO/IV for 7-14 d
Pediatric Dose	less than 18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2 h before or 4 h after taking fluoroquinolones; cimetidine may interfere with metabolism; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal function impairment

Drug Name	Ofloxacin (Floxin) -- Inhibits DNA gyrase and topoisomerase IV and prevents bacterial DNA replication.
Adult Dose	200-400 mg PO/IV q12h
Pediatric Dose	less than 18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2 h before or 4 h after taking fluoroquinolones; cimetidine may interfere with metabolism; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment (if CrCl is less than 50 mL/min, dosage reduction may be necessary); superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Chloramphenicol (Chloromycetin) -- Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis.
Adult Dose	50-100 mg/kg/d IV divided qid
Pediatric Dose	Neonates less than 2 weeks: 25 mg/kg/d in 1 dose >2 weeks: 25-100 mg/kg/d IV divided qid
Contraindications	Documented hypersensitivity
Interactions	Concurrent administration with barbiturates may decrease serum levels, while barbiturate levels may increase (causing toxicity); manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity (chloramphenicol levels may be increased or decreased)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only for serious infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

Drug Name	Minocycline (Dynacin, Minocin) -- Treats infections caused by susceptible gram-negative and gram-positive organisms. Some M hominis strains and Ureaplasma species maybe resistant.
Adult Dose	100 mg PO bid
Pediatric Dose	less than 8 years: Not recommended >8 years: 4 mg/kg PO initially, followed with 2 mg/kg q12h
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Reduce dose in renal impairment; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth

FOLLOW-UP

Deterrence/Prevention:

• 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.

• 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.

MISCELLANEOUS

Medical/Legal Pitfalls:

• In general, infection with Mycoplasma and Ureaplasma species is limited to mucosal surfaces of the lower urogenital tract. In otherwise healthy persons, these infections are associated with relatively low morbidity rates. However, in individuals who are immunosuppressed, including preterm neonates, invasive infections of various organ systems can occur, including bones, joints, and the CNS. Failure to properly diagnose such systemic infections and to administer appropriate antimicrobial therapy can be associated with poor outcomes and chronic debilitation.