Chapter 273. Mycoplasma Infections

Mycoplasma are bacteria that make up one genus of a special class called Mollicutes. The class contains both pathogenic and commensal species found in plants and animals. They are the smallest known microorganisms (0.2 μm) able to replicate in culture media. For instance, the Mycoplasmapneumoniae genome is 816,394 base pairs, approximately one sixth that of the common bacterium Escherichia coli. Precursor substances (eg, peptides, native proteins, cholesterol) are required for growth in vitro.

Unlike other bacteria, Mycoplasma lack rigid cell walls (Mollicute means soft skin); this feature precludes staining with organic dyes (such as those used in the Gram stain procedure) and renders the organisms insensitive to antibiotics that inhibit wall synthesis (such as the penicillins and polymyxins). There are 16 Mycoplasma species found in humans. Disease has been linked to four: M pneumoniae, M hominis, M genitalium, and M fermentans. Ureaplasma constitute another genus in the Mollicute class.

The best-characterized human Mycoplasma disease is respiratory tract infection due to M pneumoniae, a prominent cause of the atypical pneumonia syndrome. M hominis, another member of the genus, is associated with a variety of genitourinary and perinatal conditions, including postpartum maternal sepsis, neonatal skin infections and meningitis, and “sterile” pyelonephritis. Problems associated with M genitalium include pelvic inflammatory disease, salpingitis, and nongonococcal urethritis in sexually active individuals.

Epidemiology

Infections with M pneumoniae occur throughout life, but the respiratory disease syndrome, often called atypical pneumonia, is most common in school children, adolescents, and young adults. Epidemiologic studies have been conducted in various populations since the 1960s, but many of those studies relied on serologic determinations, the accuracy of which has been questioned as more advanced diagnostic techniques have been developed. It is estimated that M pneumoniae is responsible for about one fifth of all instances of pneumonia.1-3 Much more frequent than atypical pneumonia are several nonpneumonic respiratory syndromes; taken together, these conditions contribute about 6 episodes per 100 population annually to the burden of human respiratory infections. The prevalence of M pneumoniae disease varies greatly from year to year, with larger clusters of infections occurring in irregular 3- to 4-year cycles.4 Spread of infection is facilitated by prolonged close contact, such as within household units, childcare centers, college dormitories, and military barracks, and by the cough that is associated with respiratory infection. The incubation period can be as long as 3 to 4 weeks2,5 or as short as 4 days,6 and asymptomatic shedding can occur.1 Antimicrobial therapy may relieve symptoms without eradicating the organism. Natural protective immunity is apparently limited, because repeat episodes of infection and pneumonia have been documented.

Pathophysiology

M pneumoniae is transmitted from person to person by large droplet particles. The organism is shed from the nose, throat, and infected sputum of infected individuals. Upon reaching the respiratory tract epithelium, it attaches to the host cell using a specialized terminal tip structure. Attachment is thought to be dependent upon the P1 adhesin, a 170-kilodalton protein that is concentrated in the attachment tip. Damage to host cells is related to hydrogen peroxide and superoxide radicals interacting with host cell toxins leading to deterioration of epithelial cilia, cellular deterioration, and ultimately, exfoliation of epithelial cells.8

Infection of the lower respiratory tract by M pneumoniae provokes activation and migration of macrophages and formation of lymphocyte-laden alveolar fluid. There is evidence that cytokine release from activated and proliferating lymphocytes contributes to lower respiratory disease as well as to clinical manifestations of extrapulmonary infection.9-12

Clinical Features

The most frequent recognizable clinical presentation of M pneumoniae infection is tracheobronchitis, consisting of nonspecific systemic symptoms such as malaise, headache, low-grade fever, persistent cough, and increased respiratory secretions. Coughing may occur in paroxysms, is often worse at night, and may persist for several weeks if untreated. Patients with pneumonia present similarly but show evidence of progression to pulmonary involvement by physical examination or chest x-ray after as many as 7 days of generalized symptoms. Generally, pulmonary disease is not severe, leading to the term walking pneumonia. Untreated infections usually run their course in 1 to 3 weeks, but persistent coughing and malaise may extend several weeks into convalescence. Unusual pulmonary manifestations include perfusion defects, noncardiogenic pulmonary edema, massive pleural effusions, and lung abscesses.

Other syndromes that may be seen are upper respiratory infections, pharyngitis, and wheezing illness, particularly in children with a history of asthma. Because these clinical findings are nonspecific, M pneumoniae disease tends to be underdiagnosed.

The nonspecificity and usually mild symptoms of M pneumoniae infection are often coupled with a paucity of physical findings. The patient’s complaints often appear greater than is suggested by examination. The pharynx can be erythematous, with or without associated lymphadenopathy. Palpation of the trachea may stimulate a coughing paroxysm. If pneumonia is present, scattered crepitations or wheezes can be heard on inspiration, usually over one of the lower lobes. Rarely is there sufficient pulmonary consolidation or pleural effusion to be recognized by physical examination. It should be emphasized that symptoms and signs evolve gradually over several days to 1 week or more, and repeated examinations may be necessary to suggest the correct diagnosis. Other findings may include otitis media, evidence of sinusitis, and skin rashes (maculopapular, occasionally vesicular, rarely erythema multiforme). Children and adults with conditions known to be associated with impaired antibody production (sickle cell disease, Down syndrome, hypogammaglobulinemia syndromes) are known to be susceptible to severe respiratory disease due to M pneumoniae.13-16

The signs and symptoms of M pneumoniae respiratory disease are similar to those caused by multiple respiratory viruses, including rhinovirus, adenovirus, influenza, parainfluenza, respiratory syncytial virus, human metapneumovirus, and coronaviruses. Infection due to Chlamydia pneumoniae and Bordetella pertussis may also mimic disease due to M pneumoniae. Streptococcus pneumoniae infection typically is associated with a greater degree of pulmonary consolidation and an increase in the white blood cell count than is seen with M pneumoniae pneumonia. Concomitant infection with M pneumoniae and virtually any of the viral or bacterial pathogens listed has been noted in a variety of surveys.

The routine laboratory tests are chiefly used to exclude other conditions. Blood leukocyte levels and differential counts are usually within normal limits, but elevation of white blood cell (WBC) count can be seen in association with pneumonia. Erythrocyte sedimentation rate may be elevated during the course of the disease. Subclinical hemolysis is occasionally evident. Children with sickle cell disease often show marked polymorphonuclear leukocytosis, which complicates the interpretation of their laboratory findings.

Chest x-rays can document and detail the occurrence of pneumonia. Usually, infiltration appears in a bronchopneumonic pattern involving segments of one of the lower lobes, though bilateral involvement may occur. Frank consolidation (filling of alveolar spaces) is uncommon, although subsegmental areas of atelectasis are frequent. Pleural effusions are usually unilateral, small, and transient when they occur.

Extrapulmonary Disease

M pneumoniae infection has been associated with a variety of extrapulmonary sites, but uncertainty regarding definitive diagnostic testing has made it difficult to establish a causal role in every case. In the past, some nonrespiratory findings were thought to be manifestations of cross-reacting antibody and against human tissue and resulting inflammation, and there is evidence that this mechanism plays a role; but in recent years, identification of M pneumoniae in blood, cerebrospinal fluid (CSF), and synovial fluid using nucleic acid techniques has suggested that infection may also be involved outside the respiratory tract. (See Table 273-1.)

Subclinical hemolysis is probably the most common nonrespiratory condition associated with M pneumoniae infection. In a minority of cases Coombs-positive hemolytic anemia, thought to be caused by cross-reacting anti-I IgM antibody, is seen. 17-19

Dermatologic complications are commonly associated with M pneumoniae infections and may occur in up to 25% of patients. These include maculopapular and vesicular rashes, erythema multiforme, stomatitis, mucositis, and Stevens-Johnson syndrome.17,20 Neurologic conditions associated with M pneumoniae are varied and include meningoencephalitis,21 acute disseminated encephalitis, stroke22 aseptic meningitis, cerebellar syndromes, transverse myelitis,23 polyradiculitis, brachial plexus neuropathy, psychosis, Guillain-Barre syndrome and Bell palsy.24-30 Neurological complications are most often self-limited, but they may be severe, life-threatening, and associated with long-term sequelae. In most cases neurologic manifestations occur 1 to 2 weeks after respiratory signs and symptoms, but some patients have no evidence of recent or simultaneous respiratory tract involvement.

Arthritis is an uncommon complication of M pneumoniae infection in both adults and children, reported most often in patients with immune deficiencies. Identification of the organism from synovial fluid of such patients has been reported.31,32 Nonspecific musculoskeletal complaints, including myalgias and arthralgias, occur in a significant minority of infected patients.13,33,34

Nephritis is thought to be a rare complication of M pneumoniae infection and is likely antibody mediated, since efforts to identify the organism in renal tissue has been unsuccessful.35-37 Cardiac involvement associated with M pneumoniae infection has been reported. Pericarditis, myocarditis, congestive heart failure, myocardial infarction, and heart block have been described in individual patients,18,38-43 and identification of the organism from pericardial fluid in a 17-year-old bone marrow transplant recipient has been reported.44

Gastrointestinal involvement reported in association with M pneumoniae infection has included hepatic dysfunction, pancreatitis, and cholestatic hepatitis, but significant disease is unusual.45-47

Diagnosis

The diagnosis of M pneumoniae is suggested by the clinical picture, usual patient age (5–40 years), and exclusion of other entities. Helpful adjuncts are knowledge of other individuals in families, institutions, or communities with compatible respiratory infection. About 75% of adult patients with pneumonia due to M pneumoniae develop IgM antibodies against the I antigen on human erythrocytes (cold agglutinin antibody) within 7 to 10 days of initial symptoms. Data regarding the frequency with which cold agglutinin antibody develops in children and in nonpneumonic respiratory disease are lacking. The titer of cold agglutinin antibody, as determined by serial dilution of the patient’s serum, correlates roughly with the severity of disease. A titer of at least 1:64 in a patient with pneumonia is highly suggestive of M pneumoniae infection1,48 Although this test is not specific (other bacterial and viral causes of pneumonia are infrequently associated with a positive test for cold agglutinins), a strong positive reaction coupled with a compatible clinical picture can be useful in choosing initial therapy. Cultures, not available in most diagnostic laboratories, may require 2 to 6 weeks to complete. Serodiagnostic testing for the complement-fixing (CF) antibody against M pneumoniae depends upon a fourfold or greater titer change between an acute specimen and a second specimen collected 2 to 3 weeks later. Thus, both culture and CF antibody tests offer only retrospective diagnosis. Commercially available methods for detecting IgM against M pneumoniae have been developed and correlate well with CF antibody testing and with polymerase chain reaction (PCR) detection.49-51 IgM antibody develops within 7 days of the onset of illness, thus diagnosis can be made using 1 serum sample early in the course of infection. The PCR assay detects M pneumoniae even when only a small number of organisms is present in respiratory secretions and other body fluids. This assay has allowed a more complete understanding of the role of M pneumoniae in non-respiratory tract illness. However, because asymptomatic shedding of M pneumoniae is known to persist for weeks following initial infection, the significance of a positive PCR in the absence of an associated antibody response is not known. From a practical viewpoint, diagnosis most often is based on clinical and epidemiologic features and response to empirical therapy. Severe or unusual presentations may require attempted laboratory diagnosis using antibody testing and PCR.

Treatment

Clinical benefit from treatment of M pneumoniae respiratory infection with erythromycin and tetracycline was demonstrated in early adult-volunteer studies.2,52 Illness ascribed to M pneumoniae is generally self-resolving after 1 to 2 weeks, but persistent cough may resolve only after a considerably longer period. Antibiotics have been recommended and are widely used to shorten and ameliorate symptoms. There is, however, no randomized, controlled study that demonstrates effectiveness of antibiotics compared with placebo in individuals younger than 18 years old with respiratory infection documented to be due to M pneumoniae.53

Illness ascribed to M pneumoniae is generally self-resolving after 1 to 2 weeks, but persistent cough may resolve only after a considerably longer period. Antibiotics have been recommended and are widely used to shorten and ameliorate symptoms.2,52

Erythromycin has been the treatment of choice for suspected M pneumoniae infection in children because of its narrow antibacterial spectrum, its low toxicity, and its high level of in vitro activity against M pneumoniae. For preadolescent children an oral dose of 30 to 40 mg/kg/day divided into 4 evenly spaced administrations is usually effective. Therapy should be continued for 10 to 14 days to minimize symptomatic relapses. Several comparative studies in children with laboratory-documented M pneumoniae infection have demonstrated that clarithromycin (15 mg/kg/day divided into twice daily doses for 10 days)54 and azithromycin (10 mg/kg—maximum 500 mg—on day 1, followed by 5 mg/kg—maximum 250 mg—on days 2–5)55 are as effective as erythromycin in achieving clinical cure. Doxycycline is an effective alternative therapy for children older than 7 years. Adult doses of erythromycin (1–2 g per day divided into 4 doses) or doxycycline (100 mg twice daily) can be used in adolescents weighing more than 60 kg. Intravenous administration of erythromycin lactobionate can be used for severely ill patients. Fluoroquinolones are not recommended for use in children, but several antibiotics in this class, including moxifloxacin, gemifloxacin, ofloxacin, and levofloxacin have been studied in adults with atypical pneumonia and have been beneficial.56-58 A microbiologic diagnosis in some of those studies was not established, and in some cases the comparator antibiotic was a β-lactam, which would not be expected to be effective in treating M pneumoniae infections.

Macrolide-resistant M pneumoniae has not been recognized as a clinical problem in the United States, although resistance can be selected in the laboratory.59,60 Resistant organisms have been isolated from children with respiratory tract infection in Japan since 2000. Restriction fragment length polymorphism technique was used to demonstrate that a point mutation in domain V of 23S rRNA was present in 10 of 13 resistant clinical isolates from Japanese patients.61 There is some evidence that clinical benefit from treatment with macrolides is reduced in children infected with macrolide-resistant strains.62M pneumoniae is innately resistant to β-lactam antibiotics because it lacks a cell wall and sensitivity to the aminoglycosides and chloramphenicol is variable.

Natural M pneumoniae disease appears to confer only limited protective immunity; reinfections have been documented as soon as 13 months after the original infection in young children, and repeated episodes of pneumonia have been seen within 4 to 10 years in older children. Outbreaks of infection due to M pneumoniae in closed populations have been reported, and there is evidence that prophylactic azithromycin therapy is 60% to 75% effective in preventing transmission of infection in those settings.63,64

There is only anecdotal data regarding appropriate antimicrobial therapy for patients with severe M pneumoniae infection and for patients with involvement outside the respiratory tract. Antibiotics used to treat M pneumoniae inhibit its growth using doses that are safe in humans, but they do not actually kill the organism without aid from the host immune system. Prolonged therapy may be required for immunocompromised children. Because there is some evidence that extrapulmonary complications result from the host inflammatory response, rather than, or in addition to, damage from infection, both corticosteroids and immune globulin have been used in an attempt to ameliorate central nervous system disease.65,66

Despite limitations in our understanding of the importance of antimicrobials in treating M pneumoniae infections, antibiotic therapy should continue to be used for patients with community-acquired pneumonia when the differential diagnosis includes M pneumoniae, C pneumoniae, and S pneumoniae. It is impractical to establish a microbial cause for each patient, though reasonable efforts should be made to determine the cause of infection in hospitalized patients so that optimal antibiotic therapy can be provided. Antibiotic therapy aimed at treating M pneumoniae has limitations, however. Persistence of the organism despite antibiotics can confound diagnostic efforts, and relapsing infection can occur following appropriate therapy. In addition, emergence of multiresistant strains of S. pneumoniae limits the usefulness of macrolides in the treatment of pneumonia when that organism is a possible cause.

Six Mycoplasma species colonize the genitourinary tract in humans, but only two, M hominis and M genitalium, have been clearly linked to human disease. There is some evidence that M fermentans causes genitourinary disease, but infection due to that species will not be discussed here.

Epidemiology

M hominis is found in the genitourinary tract of 10% to 70% of apparently healthy women67 and is also thought to be a cause of salpingitis,68 endometritis and postpartum fever,69 and pyelonephritis.70,71 Colonization in men is less common. Not surprisingly, M hominis has also been detected on the skin and mucous membranes and in gastric aspirates of newborn infants whose mothers are colonized or infected, and a recent study demonstrated by culture the presence of M hominis in the cord blood of infants born prematurely.72

Infection in Pediatric Patients

During the 1980s and 1990s several prospective studies attempted to define a relationship between M hominis and low birth weight73 and premature delivery74,75 without consistent success. In addition, M hominis was isolated from the CSF of newborns in both prospective studies and individual case reports, most often without associated evidence of inflammation.76-78 In most cases, the infection had no apparent impact on the clinical course despite the fact that no specific antimycoplasma therapy was given. M hominis has, however, been the only reported pathogen associated with a variety of conditions in predominantly premature newborns, including chronic meningitis79 and ventriculitis,80,81 wound infection,82,83 scalp abscess,84 and pericardial effusion.85 In older children and adults, M hominis rarely causes infection outside the genitourinary tract. Bacteremia,86 arthritis,87-89 endocarditis,90 pneumonia,91 meningitis,92 infected subdural hematoma,93 and mediastinitis94 have been reported, primarily in postpartum or immunocompromised patients. Hypogammaglobulinemia appears to be an important risk factor.

Diagnosis

M hominis can be isolated on blood agar and in broth media used for the routine isolation of bacteria from blood. Pinpoint, translucent colonies are seen on blood agar, and confirmation is performed using special agar under anaerobic conditions. The laboratory should be requested to look specifically for M hominis when a localized purulent infection yields no pathogen using conventional methods, particularly if the patient is a newborn or immunocompromised.

Treatment

M hominis infection can be treated with tetracyclines, though resistance has been reported.95 Clindamycin and fluoroquinolones are effective alternatives. Unlike the other mycoplasmas that cause infection in humans, M hominis is not susceptible to erythromycin or to the newer macrolides, clarithromycin, or azithromycin. There are no prospective studies evaluating the benefit of immunoglobulin therapy, but the susceptibility of hypogammaglobulinemic patients to M hominis infection suggests that immune globulin might be of benefit for patients with invasive infection.

Isolation of M genitalium was first reported in 1981, and like M hominis, it is found in the genitourinary tract. Understanding of the epidemiology and clarification of the link between M genitalium and disease in humans has been made difficult by its fastidious growth requirements, but PCR identification has provided evidence that this organism causes pelvic inflammatory disease96 and nongonococcal urethritis. A recent study reported detection of M genitalium in 9.6% of men who experienced clinical failure after treatment with cephalosporin or spectinomycin treatment for urethritis.97 There is insufficient evidence to attribute pregnancy outcome or neonatal disease to M genitalium infection. M genitalium is susceptible to doxycycline, the macrolides, and to moxifloxacin. It is weakly sensitive to the other fluoroquinolones.