Ureaplasma Infection

Back

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 usually reside extracellularly in the respiratory and urogenital tracts and rarely penetrate the submucosa, except in the case of immunosuppression or instrumentation, when they may invade the bloodstream and disseminate to numerous organs and tissues. Some species also occur as intracellular pathogens.

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

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

Serologic studies and PCR have enhanced knowledge of several other fastidious and slow-growing mycoplasmal organisms, including Mycoplasma genitalium, Mycoplasma fermentans, Mycoplasma pirum, and Mycoplasma penetrans, 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.[5]

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.[6] 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. Respiratory infections caused primarily by M pneumoniae are usually transmitted through respiratory aerosols.

U urealyticum and M genitalium are causes of nonchlamydial nongonococcal urethritis in men.[1, 7] 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.[1]

Experimental infection studies using nonhuman primate models have shown that Ureaplasma in amniotic fluid causes up-regulation of proinflammatory cytokines, leukocytes, and prostaglandins, potentially contributing to premature delivery and fetal lung injury.[8]

Both M hominis and Ureaplasma species have been isolated from maternal blood, umbilical cord blood, and neonatal blood. Both organisms can invade the cerebrospinal fluid (CSF) and induce pleocytosis. While M fermentans has been detected in pure culture from placentae and amniotic fluid in the presence of inflammation, no studies confirm its occurrence and significance in neonates.[1]

Both Mycoplasma and Ureaplasma species can cause invasive disease of the joints and respiratory tract with bacteremic dissemination, particularly in persons with antibody deficiencies, indicating the importance of the humoral immune system in host defense against these organisms.[9] 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.[5] Production of urease by Ureaplasma species is a mechanism by which these organisms can produce struvite calculi in the urinary tract.[1]

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

Epidemiology

Frequency

United States

Ureaplasma species have been isolated from cervicovaginal specimens in 40-80% of women who are asymptomatic and sexually active. M hominis has been isolated from cervicovaginal specimens in 21-53% of women who are asymptomatic and sexually active.[1] These rates are somewhat lower in males. Only a subgroup of adults who are colonized in the lower urogenital tract develop symptomatic illness from these organisms. Nongonococcal urethritis is the most common sexually transmitted infection. Ureaplasma species and M genitalium may account for a significant portion of cases that are not due to chlamydiae. M genitalium is much less likely to be present in the urogenital tract of asymptomatic persons.

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

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

International

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

Mortality/Morbidity

Race

Sex

Age

History

Physical

Causes

Laboratory Studies

Imaging Studies

Procedures

Medical Care

Medication Summary

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

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

Clindamycin is an alternative treatment for tetracycline-resistant M hominis but is much less effective against Ureaplasma species. Macrolides, fluoroquinolones, or tetracyclines are the DOCs for Ureaplasma infections. Although tetracycline resistance is described in Ureaplasma species, high-level erythromycin resistance is uncommon, although it has been described in the United States and elsewhere due to ribosomal modification.[11, 12] A single 1-g dose of azithromycin is approved for treatment of urethritis due to Chlamydia trachomatis and works as well clinically as 7 days of doxycycline in persons with urethritis due to Ureaplasma species.

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

Fluoroquinolones are useful alternatives for treatment of certain infections caused by M hominis or Ureaplasma species within the urogenital tract and in some extragenital locations. Activity of quinolones is not affected by tetracycline resistance, making these drugs attractive alternatives for tetracycline-resistant M hominis or Ureaplasma infections. Levofloxacin and moxifloxacin have the greatest in vitro potency. In general, M hominis is more susceptible to quinolones in vitro than Ureaplasma species based on MICs. Fluoroquinolone resistance among M hominis and Ureaplasma species has been reported in several countries, often in patients with prior exposure to these drugs, but the extent to which this occurs in the general population is unknown.[13, 14]

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 are alternatives. Treatment of ureaplasmal respiratory infections in neonates with erythromycin or azithromycin may be effective in eradicating the organisms from the lower airways, but treatment failures are known to occur.[1, 15] 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 such as azithromycin in the treatment of neonatal Ureaplasma infections, and no guidelines for their dosages or use in neonates are available.

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

Overall treatment alternatives for neonates are the same as for urogenital and systemic mycoplasmal infections in adults, with appropriate dosage modifications based on weight, except that the intravenous route should be used for serious systemic infections. Duration of treatment and drug dosages for neonatal mycoplasmal infections have not been evaluated critically, but a minimum duration of 10-14 days is suggested based on experience in individual cases when microbiologic follow-up care has been assessed.[1, 16] M fermentans has in vitro susceptibilities comparable to M hominis, demonstrating some degree of resistance to macrolides and susceptibility to clindamycin, but little clinical data are available to guide therapeutic choices for this mycoplasma.

M genitalium is usually susceptible in vitro to tetracyclines, macrolides, and fluoroquinolones. Azithromycin has been recommended as a treatment for M genitalium urethritis in view of clinical failures with the tetracyclines, which appear to be less active overall. However, several reports of azithromycin treatment failure with documentation of elevated MICs to this drug have been reported.[17, 18] Treatment failure has also been described in patients with urethritis in whom M. genitalium was isolated following treatment with levofloxacin. Mutations in the gyrA and parC genes of M genitalium, and more recently in gyrB and parE, have been detected by molecular methods in M genitalium.[3]

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

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

Clarithromycin (Biaxin)

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

Azithromycin (Zithromax)

Clinical Context:  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.

Clindamycin (Cleocin)

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

Doxycycline (Vibramycin, Bio-Tab, Doryx)

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

Levofloxacin (Levaquin)

Clinical Context:  Inhibits DNA gyrase and prevents DNA replication.

Ofloxacin (Floxin)

Clinical Context:  Inhibits DNA gyrase and topoisomerase IV and prevents bacterial DNA replication.

Chloramphenicol (Chloromycetin)

Clinical Context:  Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis.

Minocycline (Dynacin, Minocin)

Clinical Context:  Treats infections caused by susceptible gram-negative and gram-positive organisms. Some M hominis strains and Ureaplasma species maybe resistant.

Class Summary

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

Deterrence/Prevention

Author

Ken B Waites, MD, Director, UAB Diagnostic Mycoplasma Laboratory, Professor, Department of Pathology, Division of Laboratory Medicine, University of Alabama at Birmingham

Disclosure: Nothing to disclose.

Specialty Editors

Gary L Gorby, MD, Associate Professor, Departments of Internal Medicine and Medical Microbiology and Immunology, Division of Infectious Diseases, Creighton University School of Medicine; Associate Professor of Medicine, University of Nebraska Medical Center; Associate Chair, Omaha Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Richard B Brown, MD, FACP, Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

References

  1. Waites KB, Katz B, Schelonka RL. Mycoplasmas and ureaplasmas as neonatal pathogens. Clin Microbiol Rev. Oct 2005;18(4):757-89. [View Abstract]
  2. Xiao L, Paralanov V, Glass JI, Duffy LB, Robertson JA, Cassell GH, et al. Extensive horizontal gene transfer in ureaplasmas from humans questions the utility of serotyping for diagnostic purposes. J Clin Microbiol. Aug 2011;49(8):2818-26. [View Abstract]
  3. Deguchi T, Maeda S, Tamaki M, Yoshida T, Ishiko H, Ito M. Analysis of the gyrA and parC genes of Mycoplasma genitalium detected in first-pass urine of men with non-gonococcal urethritis before and after fluoroquinolone treatment. J Antimicrob Chemother. Nov 2001;48(5):742-4. [View Abstract]
  4. Xiao L, Paralanov V, Glass JI, Duffy LB, Robertson JA, Cassell GH. Extensive horizontal gene transfer in ureaplasmas from humans questions the utility of serotyping for diagnostic purposes. J Clin Microbiol. Aug 2011;49(8):2818-26. [View Abstract]
  5. Waites KB, Talkington DF. New Developments in Human Diseases Due to Mycoplasmas. In: Blanchard A, Browning G, eds. Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control. Norwich, United Kingdom: Horizon Bioscience; 2005:Chapter 9, pages 289-354.
  6. Webster D, Windsor H, Ling C, Windsor D, Pitcher D. Chronic bronchitis in immunocompromised patients: association with a novel Mycoplasma species. Eur J Clin Microbiol Infect Dis. Sep 2003;22(9):530-4. [View Abstract]
  7. Jensen JS. Mycoplasma genitalium: the aetiological agent of urethritis and other sexually transmitted diseases. J Eur Acad Dermatol Venereol. Jan 2004;18(1):1-11. [View Abstract]
  8. Novy MJ, Duffy L, Axthelm MK, Sadowsky DW, Witkin SS, Gravett MG, et al. Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci. Jan 2009;16(1):56-70. [View Abstract]
  9. Furr PM, Taylor-Robinson D, Webster AD. Mycoplasmas and ureaplasmas in patients with hypogammaglobulinaemia and their role in arthritis: microbiological observations over twenty years. Ann Rheum Dis. Mar 1994;53(3):183-7. [View Abstract]
  10. Waites KB, Bebear CM, Robertson JA, et al. Laboratory Diagnosis of Mycoplasmal Infections. Cumulative Techniques and Procedures in Clinical Microbiology, ASM Press. 2001.
  11. Beeton ML, Chalker VJ, Maxwell NC, Kotecha S, Spiller OB. Concurrent titration and determination of antibiotic resistance in ureaplasma species with identification of novel point mutations in genes associated with resistance. Antimicrob Agents Chemother. May 2009;53(5):2020-7. [View Abstract]
  12. Xiao L, Crabb DM, Duffy LB, Paralanov V, Glass JI, Hamilos DL. Mutations in ribosomal proteins and ribosomal RNA confer macrolide resistance in human Ureaplasma spp. Int J Antimicrob Agents. Apr 2011;37(4):377-9. [View Abstract]
  13. Bebear CM, Renaudin H, Charron A, Gruson D, Lefrancois M, Bebear C. In vitro activity of trovafloxacin compared to those of five antimicrobials against mycoplasmas including Mycoplasma hominis and Ureaplasma urealyticum fluoroquinolone-resistant isolates that have been genetically characterized. Antimicrob Agents Chemother. Sep 2000;44(9):2557-60. [View Abstract]
  14. Duffy L, Glass J, Hall G, Avery R, Rackley R, Peterson S, et al. Fluoroquinolone resistance in Ureaplasma parvum in the United States. J Clin Microbiol. Apr 2006;44(4):1590-1. [View Abstract]
  15. Waites KB, Sims PJ, Crouse DT, Geerts MH, Shoup RE, Hamrick WB, et al. Serum concentrations of erythromycin after intravenous infusion in preterm neonates treated for Ureaplasma urealyticum infection. Pediatr Infect Dis J. Apr 1994;13(4):287-93. [View Abstract]
  16. Waites KB, Crouse DT, Cassell GH. Therapeutic considerations for Ureaplasma urealyticum infections in neonates. Clin Infect Dis. Aug 1993;17 Suppl 1:S208-14. [View Abstract]
  17. Jensen JS, Bradshaw CS, Tabrizi SN, Fairley CK, Hamasuna R. Azithromycin treatment failure in Mycoplasma genitalium-positive patients with nongonococcal urethritis is associated with induced macrolide resistance. Clin Infect Dis. Dec 15 2008;47(12):1546-53. [View Abstract]
  18. Bradshaw CS, Jensen JS, Tabrizi SN, Read TR, Garland SM, Hopkins CA, et al. Azithromycin failure in Mycoplasma genitalium urethritis. Emerg Infect Dis. Jul 2006;12(7):1149-52. [View Abstract]
  19. Schelonka RL, Katz B, Waites KB, Benjamin DK Jr. Critical appraisal of the role of Ureaplasma in the development of bronchopulmonary dysplasia with metaanalytic techniques. Pediatr Infect Dis J. Dec 2005;24(12):1033-9. [View Abstract]