ACP medicine, 3rd Edition

Infectious Disease

Mycoplasma Infections

1. Doug Hardy MD¹

¹Assistant Professor of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center at Dallas

The author participates in the speakers' bureau for Sanofi-Aventis.

Antimicrobial drugs discussed in this chapter have not been approved by the FDA for use in chronic respiratory Mycoplasma hominisinfection, M. genitalium infection, or M. hominis infection; azithromycin and levofloxacin have not been approved for use in Ureaplasma infection. The use of polymerase chain reaction for the diagnosis of Mycoplasma infection is investigational and is not approved by the FDA.

July 2005

Mycoplasmas are the smallest known free-living organisms. Their size—150 to 350 nm—is closer to that of viruses than of bacteria. Unlike viruses, however, mycoplasmas are able to grow in cell-free media and possess both RNA and DNA. Notably, they lack a cell wall and are bound by a cell membrane. The absence of a rigid cell wall explains many of the biologic properties of mycoplasmas, including resistance to b-lactam antibiotics and marked pleomorphism among individual cells.

Mycoplasmas are prokaryotes of the class Mollicutes. The entire genomes of many Mycoplasma species have been sequenced and have been found to be among the smallest of prokaryotic genomes. The characterization of M. genitalium, which has only 580,070 base pairs and 468 predicted proteins, has helped define the minimal set of genes necessary for cellular life.^1,2 The absence of genes related to the synthesis of amino acids, fatty acid metabolism, and cholesterol necessitates a parasitic or saprophytic dependence on the host for exogenous nutrients, such as nucleic acid precursors, amino acids, fatty acids, and sterols.

At least 13 Mycoplasma species, two Acholeplasma species, and one Ureaplasma species have been isolated from humans with varying frequency; most of these species are thought to be normal inhabitants of oral and urogenital mucous membranes.³ Only three species, M. pneumoniae, M. hominis, and U. urealyticum, have been shown conclusively to be pathogenic in humans. M. pneumoniae is the species that has been most clearly demonstrated to cause disease in humans. The respiratory tract is its primary site of involvement. M. hominis and U. urealyticum are associated with a variety of genitourinary tract disorders and neonatal infections. Evidence also implicates a fourth species,M. genitalium, as a cause of disease in humans. Rarely, other Mycoplasma species may cause disease in immunocompromised persons.

Mycoplasma pneumoniae

EPIDEMIOLOGY

1. pneumoniaeis a major cause of community-acquired respiratory illness in children and adults, both in terms of clinical severity and numbers affected. M. pneumoniaeis often grouped with Chlamydophila pneumoniae and Legionella species as being among the most important bacterial causes of so-called atypical community-acquired pneumonia. However, it is now known that atypical pneumonia caused by these pathogens cannot be reliably differentiated from pneumonia caused by typical community-acquired pathogens, such asStreptococcus pneumoniae, on the basis of clinical manifestations, general laboratory tests, or radiographic findings.^4,5 Hence, many experts believe that the term atypical is inappropriate and misleading. It is important to note, however, that the etiologic diagnosis of infection by these pathogens requires advanced methods of detection—methods that go beyond Gram stain or routine culture. Mycoplasma pneumonia has also been referred to as Eaton agent pneumonia, primary atypical pneumonia, and walking pneumonia.
2. pneumoniaewas first isolated in the early 1940s by Eaton from a patient with primary atypical pneumonia; it was proved to be a cause of clinical disease in humans in the 1960s.^5,6M. pneumoniae is the only Mycoplasma species that has clearly been established to be a cause of human respiratory tract disease, although M. genitalium has been isolated from the respiratory tract of patients with mixed infections involving M. pneumoniae, an organism with which M. genitalium can be confused.⁷ M. pneumoniae is known to cause many acute respiratory syndromes in humans, including pharyngitis, tracheobronchitis, reactive airway disease (wheezing), and community-acquired pneumonia. It is likely that the incidence of upper respiratory tract illness is 10 to 20 times that of pneumonia. Infection is spread from one person to another by respiratory droplets expectorated during coughing; infection results in clinically apparent disease in the majority of cases.⁵ The incubation period for M. pneumoniae is 2 to 4 weeks; hence, the course of infection in a specific population (e.g., within a family or an institution) may last several weeks [see Figure 1].⁸ Intrafamily attack rates may be as high as 84% in children and 41% in adults. Outbreaks of M. pneumoniae-related illness often occur in institutional settings such as military bases, boarding schools, and summer camps. Infections tend to be endemic, with sporadic epidemics every 4 to 7 years, without seasonal preponderance.⁵

The importance of M. pneumoniae as a cause of community-acquired pneumonia has become more evident with the development of advanced techniques for identifying this pathogen. For community-acquired pneumonia in adults, M. pneumoniae is the most frequently detected atypical organism. Analysis of 13 studies of community-acquired pneumonia published since 1995 (which included 6,207 ambulatory and hospitalized adults) showed that the overall prevalence of M. pneumoniae was 22.7%; by comparison, the prevalence of C. pneumoniae was 11.7%, and that of Legionella species was 4.6%.⁹ It must be acknowledged that these studies represent varying populations and used varying methods to establish the etiologies of community-acquired pneumonia.⁹

In community-acquired pneumonia, M. pneumoniae often occurs as part of a mixed infection. In a 1-year prospective study of 346 consecutive adults admitted with community-acquired pneumonia, 64% of those with M. pneumoniae infections were coinfected with other agents—most often with S. pneumoniae, followed by C. pneumoniae and Legionella species.¹⁰ In a study of C. pneumoniae community-acquired pneumonia in adults, 35.5% had a mixed infection; M. pneumoniae was the second most common copathogen, after S. pneumoniae.¹¹ Review of epidemiologic studies revealed the presence of at least one other pathogen in 33% to 64% of M. pneumoniaepneumonia.^9,11 S. pneumoniae with M. pneumoniae or C. pneumoniae appears to be the most common combinations of agents in mixed pneumonia, and these combinations have been given the most attention in clinical investigations.^9,12,13 Further study is required to define the clinical significance of M. pneumoniae coinfections, to determine whether infection with M. pneumoniae predisposes patients to invasion by other respiratory pathogens, and to establish whether the etiologic agents of mixed infections have an additive or synergistic clinical impact.

PATHOGENESIS, PATHOLOGY, AND IMMUNOLOGY

Classically, mycoplasmas act as extracellular parasites. The pathogenicity of M. pneumoniae depends on its extracellular attachment and the initiation of injury to the membrane of the host cell.¹⁴ M. pneumoniae penetrates mucociliary secretions by means of gliding motility and adheres firmly to the surface of respiratory epithelial cells.¹⁵ M. pneumoniae attaches to ciliated respiratory epithelial cells at the base of the cilia by means of a complex terminal organelle at one end of the elongated organism. This cytodherence is mediated by interactive adhesins and accessory proteins clustered at the tip organelle; it is not limited to epithelial cells or to human-derived tissues.^16,17 Multiple unlinked, incomplete copies of the genes that encode these adhesins constitute approximately 5% of the Mycoplasma genome; it has been proposed that recombination between gene copies generates antigenically variant proteins that avoid host immune recognition.¹⁷ One or more sialated glycoproteins act as one type of receptor on the surface of the epithelium.^18,19

1. pneumoniaecauses physiologic and cytolytic injury to the host cells (e.g., ciliated respiratory epithelium), in part by the production of hydrogen peroxide.^20,21Inhibition of host catalase by M. pneumoniae-derived hydrogen peroxide and superoxide anion, followed by oxidation of host membrane lipids and proteins, may then result in cumulative local cytotoxic effects.^22,23 Other mechanisms of physiologic and cytolytic injury are also under investigation. Lung biopsies from patients with M. pneumoniae community-acquired pneumonia reveal an inflammatory process involving the trachea, bronchioles, and peribronchial tissue with a monocytic infiltrate coinciding with a luminal exudate of polymorphonuclear leukocytes.^24,25

Although M. pneumoniae is classically thought of as an extracellular organism, it (as well as some other mycoplasmas, including M. penetrans, M. fermentans var. incognitos, and M. gallisepticum) can live and replicate intracellularly in human cells.^26,27,28,29 Residence ofM. pneumoniae in an intracellular reservoir, perhaps protected from the host's immunologic response and from antibiotics, might explain the organism's apparent ability to establish chronic infection, such as occurs in asthmatic patients.^30,31

Mycoplasmas have been shown to activate natural killer cells, macrophages, and complement; to stimulate the proliferation of B cells and T cells; and to induce expression of major histocompatibility complex class I and II molecules.³² Because mycoplasmas lack a cell wall, they also lack cell wall-derived stimulators of the innate immune system, such as lipopolysaccharide, lipotei choic acid, and murein (peptidoglycan) fragments. However, lipoproteins from various Mycoplasma species appear to have potent inflammatory properties. Three lipoproteins/lipopeptides of M. fermentans origin—macrophage-activating lipopeptide-2 (MALP-2), P48, and M161Ag (identical to MALP-404)—have been shown to have the ability to modulate the host immune system through a Toll-like receptor 2 (TLR2) and TLR6 pathway and through β2 integrin.^33,34,35 MALP-2 is a 2-kd lipopeptide from the cell membrane of M. fermentans that has been shown to induce cytokines and chemokines in human monocytes.³⁶ In M. pneumoniae, the genes for more than 30 different lipoproteins have been detected.¹Activation of TLR2 on macrophages by M. pneumoniae-derived lipoproteins with resultant production of tumor necrosis factor-α and nitric oxide has been reported.³⁷

Studies in mice with severe combined immunodeficiency support the hypotheses that innate immunity provides most of the defense againstMycoplasma infection in the lungs, that humoral immunity provides protection against dissemination of Mycoplasma infection, and that cellular immunity may play a role in exacerbating mycoplasmal lung disease.³⁸ Also supportive are the findings that patients with T cell deficiencies do not have more severe pneumonia from M. pneumoniae and that patients with humoral immunodeficiencies do not have more severe lung disease from M. pneumoniae than immunocompetent patients in the early stages of infection but do have more disseminated disease (e.g., arthritis, meningitis, and osteomyelitis).^39,40,41

1. pneumoniaeinfection in humans provokes a specific immune response that results in the production of secretory IgA and circulating IgG antibodies. Naturally acquired humoral immunity is associated with partial protection against reinfection; in particular, the immunity that follows more severe M. pneumoniaeinfections (e.g., pneumonia) is more protective and longer lasting than that which follows mild infection.⁴² Bona fide second attacks of M. pneumoniae pneumonia have been reported occasionally, however, both in immunocompetent and in immunodeficient patients. The ability of M. pneumoniae and other mycoplasmas to trigger autoimmune responses is an area of active research.⁴³

The role of cytokines and chemokines in M. pneumoniae infection has been investigated in vitro, in animal models, and in humans.^44,45,46,47Evidence indicates that various cytokines (including inflammatory, anti-inflammatory, T helper type 1, and T helper type 2 cytokines) as well as chemokines have pivotal roles in modulating M. pneumoniae disease. However, a concerted theory on the pathogenic and relative importance of these various modulators is lacking.

DIAGNOSIS

Acute Clinical Manifestations

1. pneumoniaeinfections have an incubation period of 2 to 4 weeks in naturally occurring cases, but the incubation period is shorter in experimental infection.⁵Approximately 20% of M. pneumoniae infections are asymptomatic.⁴⁸ Clinically apparent acute M. pneumoniaeinfections generally manifest as pharyngitis, tracheobronchitis, reactive airway disease (wheezing), or a nonspecific upper respiratory tract syndrome. Pneumonia, however, is the best-described clinical manifestation of M. pneumoniae infection and occurs in 3% to 13% of infected persons.⁴⁸

The onset of pneumonia is usually gradual (occurring over several days) but may be more abrupt.⁴⁹ Although Mycoplasma pneumonia may begin with a sore throat, the most common presenting symptom is cough. The cough is typically nonproductive, but some patients produce purulent sputum; in rare instances, the sputum is blood streaked.⁴⁸ Headache,° malaise, chills, and a temperature of 37.8° to 40.0° C (100 to 104° F) are present in the majority of patients. In a smaller percentage, nasal symptoms occur. Symptoms and signs of pneumonia are not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia.^4,48,50,51

Symptoms related to the ears or tympanic membrane findings on physical examination may be noted in approximately 6% of patients withM. pneumoniae pneumonia; 1% may have bullous myringitis. Because direct cultures rarely if ever grow M. pneumoniae, there is little evidence to support the old belief that this organism is an important cause of otitis media, with or without bullous myringitis.⁵²

Wheezes or rales are present in approximately 80% of patients with Mycoplasma pneumonia; bronchial breath sounds are noted less frequently. In many patients, however, pneumonia can be diagnosed only on chest x-ray. Pleural rubs are rare, as are pleural effusions of sufficient magnitude to be detected on physical examination.⁴⁸

Symptoms usually resolve within 2 to 3 weeks after the onset of illness. In about 20% of patients, symptoms and radiologic abnormalities persist for at least a month. Although M. pneumoniae pneumonia is generally self-limited, appropriate antimicrobial therapy can significantly shorten the duration of clinical illness.⁵³ In some patients, long-term recurrent wheezing may follow the resolution of acute pneumonia.^54,55Relapse and recurrence of pneumonia are infrequently reported.

Pulmonary complications of M. pneumoniae pneumonia may occur and, on rare occasions, result in death. Fulminant disease may be more common in young, previously healthy adults. Multilobar involvement, lung abscess, massive pleural effusion, acute respiratory distress syndrome, and diffuse interstitial fibrosis have been described. At particular risk for these complications are patients with Down syndrome, sickle cell disease, and other immunodeficient states.^56,57,58,59 M. pneumoniae does not seem to play an important role in lower respiratory tract infections in either children or adults with HIV infection.⁶⁰

Chronic Infection and Wheezing

In many patients, M. pneumoniae can be cultured from the respiratory tract for up to several months after clinical and radiologic resolution of acute pneumonia.⁷ There have been no controlled studies of such chronic infections using methods more sensitive than culture, such as polymerase chain reaction (PCR). M. pneumoniae apparently can be a long-term respiratory tract pathogen associated with recurrent wheezing, and it may contribute to the severity of chronic asthma.^54,55

Extrapulmonary Manifestations

A variety of extrapulmonary manifestations may develop during the course of acute M. pneumoniae respiratory tract infection. The most important of these are neurologic, dermatologic, cardiac, rheumatologic, and hematologic in nature.^3,56,61 Overall, these manifestations are uncommon, given the frequency of Mycoplasma infection. The mechanisms of these complications appear to include disseminated infection (especially in patients with humoral immunodeficiencies); autoimmune phenomena; and, pos sibly, toxin production.⁶² Notably, respiratory disease is absent in many patients with extrapulmonary M. pneumoniae disease.⁶³

Neurologic disease is reportedly the most common nonpulmonary manifestation of M. pneumoniae infection.^{63,64,65,66,67} A wide spectrum of neurologic manifestations has been reported. The most common ones are meningoencephalitis, encephalitis, poly radiculopathy (including Guillain-Barré syndrome), and aseptic meningitis; less common neurologic manifestations include cranial neuropathy, acute psychosis, cerebellar ataxia, acute demyelinating encephalomyelitis, cerebrovascular thromboembolic events, and transverse myelitis. In a prospective 5-year study of acute encephalitis in children, M. pneumoniae was determined to be the likely cause in 11 of 159 patients (6.9%). Findings on clinical examination, cerebrospinal fluid analysis, electroen ceph a lography, and neuroimaging in patients with M. pneumoniaeencephalitis are indistinguishable from those in patients with viral encephalitis. Long-term sequelae, such as seizure disorders, hemiparesis, expressive dysphasia, dysarthria, and truncal ataxia, have been described in 48% to 64% of patients after M. pneumoniae encephalitis. Preliminary evidence indicates that direct invasion of the central nervous system by M. pneumoniae may be the pathogenic mechanism in encephalitis cases in which prodromal symptoms are of short duration (< 5 days), whereas immunologic phenomena may be responsible for cases with a more prolonged prodrome.^63,65,66,67 The roles of antimicrobial therapy and immune-modulating therapy in the treatment of M. pneumoniae neurologic disease are unknown.

Skin eruptions described with M. pneumoniae infection include erythematous (macular or maculopapular), vesicular, bullous, petechial, and urticarial rashes; in one study, 17% of patients with M. pneumoniae pneumonia had an exanthem.⁶⁸ Erythema multiforme major (Stevens-Johnson syndrome) is the most clinically significant skin eruption associated with M. pneumoniae infection; it appears to occur more commonly with M. pneumoniae than with other infectious agents.⁶⁹

Hematologic manifestations of Mycoplasma infection include hemolytic anemia, aplastic anemia, disseminated intravascular coagulation, hypercoagulopathy, and perhaps thrombotic throm bocytopenic purpura.^70,71,72,73 Cold agglutinin-induced hemolytic ane mia is an uncommon manifestation of Mycoplasma pneumonia. Although up to 83% of patients with M. pneumoniae infection may have reticulocytosis and a positive direct Coombs test, clinically significant hemolysis is rare.⁷⁰ When anemia does occur, it begins suddenly in the second or third week of illness, and the agglutinin titer is high (> 1:512). The process is usually self-limited, lasting a few weeks.

Myocardial disease, pericardial disease, rhabdomyolysis, arthralgias, and arthritis (septic and reactive) have been attributed to M. pneumoniae.^3,74,75,76 Septic arthritis has been described most commonly in hypogammaglobulinemic patients.⁴¹ In addition, hepatitis and pancreatitis have been reported.

General Laboratory Tests and Radiologic Studies

As with clinical findings, general laboratory tests and chest radiography have not been found to be useful for differentiating Mycoplasmapneumonia from other types of community-acquired pneumonia.^4,48,50,77 The frequent occurrence of community-acquired pneumonia of mixed etiology may be partly responsible for this finding.^11,78 Measurement of cold agglutinin titers is no longer recommended for the diagnosis of Mycoplasma pneumonia, because they are nonspecific and because assays specific for M. pneumoniae are now available.

The radiologic abnormalities of Mycoplasma pneumonia are varied. The most common pattern on chest radiography is that of peribronchial pneumonia with thickened bronchial markings; streaks of interstitial infiltration; and areas of subsegmental atelectasis, often involving a single lower lobe. Other frequent patterns include platelike atelectasis, nodular infiltration, and hilar adenopathy.⁴⁸ Segmental or lobar consolidation is not uncommon. Clinically evident pleural effusions are uncommon in Mycoplasma pneumonia, but lateral decubitus views reveal that up to 20% of patients have pleural effusions.

Specific Laboratory Testing

Laboratory diagnosis of an acute M. pneumoniae infection can be established (1) by the isolation of M. pneumoniae from respiratory tract secretions (oropharyngeal, nasopharyngeal, or pulmonary) with PCR or culture (which requires special media) or (2) by the use of specific serologic tests, such as complement fixation, indirect immunofluorescence, and enzyme immunoassays (EIAs) for specific IgM and IgG antibodies in paired (acute and convalescent) serum samples [see Table 1]. Of these methods, EIAs are the most widely used and the most adaptable to the clinical laboratory setting.⁷⁹ Serum samples for M. pneumoniae serology taken only during the acute phase of illness may not be indicative of infection, because antibodies to M. pneumoniae may not develop for 2 weeks or more; therefore, it is important to test both acute and convalescent serum samples for accurate diagnosis. IgM antibodies against M. pneumoniae may not be produced during reinfection in older patients (i.e., persons older than 40 years with preexisting anti-M. pneumoniae IgG antibodies).⁸⁰ In addition, specific IgM can persist for up to a year after acute M. pneumoniae infection and so may indicate recent infection rather than acute infection.⁷⁹

1. pneumoniaeculture is not recommended for routine diagnosis, because the organism may take weeks to grow and is often difficult to isolate from clinical specimens, so sensitivity is low. PCR allows a rapid and specific diagnosis to be made early in the course of clinical illness. The combination of respiratory tract PCR testing and EIA has been recommended as the most sensitive and rapid approach to the diagnosis of M. pneumoniaeinfection.⁸¹ In children, PCR assays of nasopharyngeal or oropharyngeal samples appear equally effective for the diagnosis of serologically confirmed M. pneumoniae pneumonia; however, testing of specimens from both sites is optimal.⁸²

TREATMENT

Because the clinical manifestations of Mycoplasma pneumonia are not distinctive and laboratory diagnosis is often made retrospectively, treatment is usually empirical, as it is with community-acquired pneumonia in general. The possibility of M. pneumoniae infection deserves particular consideration in a patient with community-acquired pneumonia who has failed to respond to treatment with a penicillin or a cephalosporin, because β-lactam antibiotics are ineffective against mycoplasmas. Clinical trials ranging from observational reports to randomized, double-blind, placebo-controlled studies have demonstrated that appropriate antimicrobial therapy significantly decreases the duration of fever, cough, malaise, hospitalization, and radiologic abnormalities in Mycoplasma pneumonia.⁵³ In one study of military trainees with serologically confirmed M. pneumoniae pneumonia, treatment with oral erythromycin for 7 days reduced mean duration of fever from 4.2 days to 2.4 days; the duration of hospitalization was reduced from 14.1 days to 7.0 days; and the period in which radiologic abnormalities were present was reduced from 14.8 days to 7.2 days.⁸³

Treatment options for acute M. pneumoniae infection include macro lides, ketolides, tetracyclines, and most fluoroquinolones (cipro floxacin and ofloxacin are not recommended because of their high minimum inhibitory concentrations and poor performance in animal studies) [seeTable 2]. Antimicrobial resistance has not been clinically important in M. pneumoniae infections in North America. The optimal antibiotic choice, dosage, and duration are not clear; however, 14 days of therapy is generally recommended.

Even after therapy with appropriate antibiotics, M. pneumoniae can still be cultured from respiratory tract secretions.^8,84 The persistence ofM. pneumoniae in the nasopharynx of children after clarithromycin therapy (given for an acute exacerbation of wheezing accompanying M. pneumoniae infection) has been associated with recurrent wheezing.⁸⁵ In animal models of Mycoplasma pneumonia, treatment with antimycoplasmal agents such as ketolides, quino lones, clarithromycin, and azithromycin also has not eradicated this organism from the respiratory tract.⁵⁵ The efficacy of combination antimicrobial therapy for the eradication of M. pneumoniae has not been investigated.

In both animal and human studies, antimycoplasmal therapy significantly alleviated chronic respiratory disease caused by M. pneumoniae.^86,87 A randomized, double-blind, placebo-controlled trial in patients with stable chronic asthma showed that 6 weeks of treatment with clari th ro my cin produced significant improvement on respiratory function testing in those patients who tested positive forM. pneumoniae by PCR but not in those who tested negative; control subjects who received placebo also showed no improvement.⁸⁷Additional clinical studies are needed to strengthen this observation.

Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum

Because mycoplasmas and ureaplasmas often colonize the lower genitourinary tract of healthy adults (especially those who are sexually active), positive cultures for these organisms do not necessarily constitute proof of infection. Despite this difficulty, there is evidence thatM. hominis, M. genitalium, and U. urealyticum can cause several clinical syndromes.^3,88 The significance of isolating these organisms in a variety of other syndromes is investigational or unknown.

NONGONOCOCCAL URETHRITIS

About 40% of men who experience an initial episode of nongonococcal urethritis have infection caused by C. trachomatis [see 7:XIII Diseases Due to Chlamydia].⁸⁹ In many cases of Chlamydia-negative nongonococcal urethritis (negative culture and negative serology), U. urealyticum may be the causative agent, as judged by (1) the presence of larger numbers of U. urealyticum organisms in Chlamydia-negative cases than in Chlamydia-positive cases; (2) the production of urethritis in human volunteers and nonhuman primates by intraurethral inoculation of U. urealyticum clinical isolates; and (3) the differential response to sulfisoxazole therapy (in one study, all 13 patients with Chlamydia-positive, Ureaplasma-negative nongonococcal urethritis showed a response, compared with only 14 of 30Chlamydia-negative, Ureaplasma-positive patients).⁸⁹ C. trachomatis is susceptible to sulfonamides, but U. urealyticum is not. Such evidence suggests that U. urealyticum is the cause of at least some initial episodes of Chlamydia-negative nongonococcal urethritis in men—perhaps as many as 15% to 25% of these episodes.⁹⁰ Other studies have implicated U. urealyticum as a cause of acute urethral syndrome in some women; this organism may also cause chronic voiding symptoms in women, which may be mistaken for interstitial cystitis.⁹¹ It is possible that factors such as serotype, strain-specific virulence determinants, or host factors will explain why positive cultures for U. urealyticum are not better correlated with evidence of clinical infection. Alternatively, disease may develop only upon initial exposure to ureaplasmas. U. urealyticum also has been implicated in urethroprostatitis and epididymitis.³

1. genitaliumalso appears to cause acute and possibly chronic nongonococcal urethritis.^88,92One group of investi gators found M. genitalium DNA in C. trachomatis-negative samples from 22% of heterosexual men with nongonococcal urethritis but from only 4% of asymptomatic control subjects.⁹³ Other studies have confirmed the disproportionate detection rates of M. genitalium in patients with nongonococcal urethritis. M. genitalium does not have a known role in prostatitis or epididymitis.⁸⁸ M. hominis does not appear to have a primary etiologic role in nongonococcal urethritis.

Treatment

Doxycycline (100 mg orally two times daily for 7 days) or azithromycin (1 g orally as a single dose) is the recommended treatment for nongonococcal urethritis. Erythromycin base (500 mg orally four times daily for 7 days) or levofloxacin (500 mg once daily for 7 days) are alternatives. These treatment regimens apply to cases associated with U. urealyticum as well as M. genitalium.⁹⁴ Tetracycline resistance has increased in recent decades and has been reported in as many as one third of clinical U. urealyticum isolates.⁹⁵ Resistant strains are known to cause persistent urethritis that often does not respond to treatment with tetracyclines; however, they are usually sensitive to macrolides or quinolones.⁹⁶ Sexual contacts of an index case should be treated at the same time as the index case. Other causes of treatment failure include poor compliance with medications, reinfection, disease caused by Trichomonas vaginalis or herpes simplex virus, prostatitis, and noninfectious etiologies.

For M. genitalium, the treatment of choice seems to be azithromycin. Treatment failures have been reported with other macrolides and with quinolones.^88,92

UPPER URINARY TRACT INFECTION

1. hominiscauses approximately 5% of acute pye lon eph ritis cases, judging from culture and serologic data.⁹⁷How ever, the same association cannot be made for U. urealyticum.³ Treatment of acute pyelonephritis from M. hominis is the same as that for pelvic inflammatory disease (PID) from this organism (see below).
2. urealyticumhas a limited role in the production of urinary calculi. The frequency with which U. urealyticumreaches the kidney, the predisposing factors that allow this to occur, and the relative frequency of renal calculi induced by this organism as compared with other organisms is not known.³

PELVIC INFLAMMATORY DISEASE

1. hominismay cause some episodes of PID. In most of these cases, the organism occurs as part of a polymicrobial infection, but isolation of M. hominisfrom laparoscopic cultures of fallopian tubes in women with acute salpingitis has been reported, and the organism may be responsible for a few cases of PID on its own.⁹⁸ The prevalence of M. hominis involvement in PID may vary with global geographic location. It remains unclear how large a role M. hominis plays in the development of acute salpingitis and its sequelae. Some data also exist for an association of M. genitalium with PID.⁸⁸ In contrast, U. urealyticum is not considered to be a cause of PID.³

Treatment

1. hominisis resistant to the macrolides. Doxycycline is generally the drug of choice for M. hominisinfections, although resistance has been reported.⁹⁹ Clindamycin is also generally active against M. hominis. Quinolones and ketolides have been found to be active in vitro againstM. hominis; however, clinical experience is lacking.^96,100

POSTABORTION AND POSTPARTUM FEVER

Positive blood cultures and concurrent seroconversion have implicated M. hominis as the primary pathogen in approximately 10% of women who have fever after abortion.³ M. hominis is also responsible for 5% to 10% of fevers that arise more than 24 hours after vaginal delivery.¹⁰¹ Women with vaginal colonization by M. hominis who have low or absent antibody titers against Mycoplasma may be predisposed to postpartum fever, which is probably associated with endometritis. These infections are usually self-limited; if symptoms persist, however, specific antimicrobial therapy should be given as for M. hominis PID (see above).

OTHER CONDITIONS ASSOCIATED WITH MYCOPLASMAS

1. hominisrarely causes brain abscess, wound infection, poststernotomy mediastinitis,¹⁰²neonatal meningitis, and other nongenitourinary infections.^103,104 These infections are more common in immunocompromised or hypogammaglobulinemic persons. U. urealyticum and M. hominis can cause septic arthritis in immunodeficient patients,³ and U. urealyticum likely causes neonatal pneumonitis and contributes to neonatal chronic lung disease (including bronchopulmonary dysplasia).¹⁰⁵ It is unclear whether U. urealyticum and M. hominis can cause male and female infertility,¹⁰⁶ spontaneous abortion,¹⁰⁷ premature labor and low birth weight,¹⁰⁸ and chorioamnionitis.¹⁰⁵

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Editors: Dale, David C.; Federman, Daniel D.