# 80 - 193 Infections Due to Mycoplasmas

### 193 Infections Due to Mycoplasmas

rifampin. Although antimicrobial susceptibility testing is not rou­
tinely performed and resistance to doxycycline does not appear to 
be a common problem in clinical practice, doxycycline-resistant 
isolates do exist.

Treatment of acute Q fever with doxycycline (100 mg twice daily 
for 14 days) is usually successful. Quinolones also are effective. 
When Q fever is diagnosed during pregnancy, treatment with TMPSMX is recommended for the duration of the pregnancy.
Treatment with doxycycline and hydroxychloroquine for 6−12 
months following acute infection should be considered in patients 
with valve abnormalities, a prosthetic heart valve, an aneurysm, 
or vascular prosthesis. This appeared to be effective in preventing 
progression to chronic Q fever in patients with valvulopathy. The 
exact indications and duration of prophylaxis should be based on a 
careful consideration of possible benefits and side effects.
Decisions on treatment of chronic Q fever are challenging, so 
consultation with an infectious diseases expert is recommended. 
There is no indication for antibiotic therapy in those with possible 
chronic Q fever (only elevated phase I IgG without symptoms or an 
infectious focus). Addition of hydroxychloroquine (to alkalinize the 
phagolysosome) renders doxycycline bactericidal against C. burnetii 
in vitro, and the combination of doxycycline 100 mg twice daily with 
200 mg hydroxychloroquine three times daily is the favored regi­
men. It is advised to determine serum levels of doxycycline aiming 
for concentrations between 5 and 10 mg/L, often requiring higher 
doses than 200 mg per day. Patients treated with this regimen must 
be advised about photosensitivity, but side effects should not lead to 
cessation of doxycycline too easily since it appears to be the most 
effective approach for this serious infection that has a high mortality 
despite treatment. Patients treated with hydroxychloroquine are at 
risk for developing retinopathy, so they should be evaluated by an 
ophthalmologist before starting treatment and every 6−12 months 
during the course of therapy. If doxycycline-hydroxychloroquine 
cannot be used, the regimen chosen should include at least two anti­
biotics active against C. burnetii. In a study including 322 patients 
with chronic Q fever, treatment with doxycycline combined with a 
quinolone appeared to be a safe alternative.
PART 5
Infectious Diseases
Minimum treatment duration is 18 months after PCR on blood 
had become negative (if positive before) and adequate doxycycline 
levels have been reached for native valve endocarditis and other 
manifestations without prosthetic material and 24 months for 
patients with prosthetic valve endocarditis or infected vascular 
prostheses. Many patients with vascular infection need prolonged 
treatment before the infection resolves, and surgical intervention is 
often necessary to remove an infected graft if the patient does not 
respond to antibiotic therapy. Abscesses need drainage for antibiotic 
therapy to be successful. Defining cure of chronic Q fever after the 
minimum treatment duration should be based on a combination of 
imaging (if abnormal at diagnosis), decline of serologic titers, nega­
tivity of PCR on blood or serum, and improvement of symptoms.
FOLLOW-UP
After acute Q fever, patients without risk factors for developing 
chronic Q fever should be evaluated clinically and serologically 
after 6 months. When IgG phase I is <1024 and clinical symptoms 
do not suggest chronic infection, follow-up can be stopped. For 
patients with a very high risk of developing chronic Q fever who 
have received antibiotics for 6−12 months, patients with immu­
nosuppression or other risk factors not treated with antibiotics for 
a prolonged period of time, or patients with possible chronic Q 
fever (only phase I IgG ≥1024), follow-up with serology and PCR 
every 3−6 months for 2 years is recommended. During treatment 
of chronic Q fever, patients should be followed every 3 months to 
evaluate symptoms, side effects, serology, and PCR. When new 
complications are suspected, imaging should be repeated. After the 
end of treatment, relapse has been described up to 5 years later. It is 
therefore recommended to continue monitoring with serology and 
PCR until a minimum of 5 years after end of treatment.

Prevention 
A whole-cell vaccine (Q-Vax) licensed in Australia 
effectively prevents Q fever in abattoir workers. Vaccine is given only 
to people without a history of Q fever and negative results in both 
serologic and skin testing that is performed with intradermal diluted 

C. burnetii vaccine to prevent side effects. Cases among abattoir work­
ers in Australia declined dramatically as a result of a vaccination pro­
gram, but the vaccine has not been approved outside Australia.
Good animal-husbandry practices are important in preventing 
widespread contamination of the environment by C. burnetii. These 
practices include isolating aborting animals for up to 14 days, raising 
feed bunks to prevent contamination of feed by excreta, destroying 
aborted materials (by burning and burying fetal membranes and still­
born animals), and wearing masks and gloves when handling aborted 
materials. Vaccination of sheep and goats and a culling program were 
effective in the Dutch outbreak.
During an outbreak of Q fever and for 4 weeks after it ceases, blood 
donations should not be accepted from individuals who live in the 
affected area.
Acknowledgment
The authors thank Thomas Marrie, MD, for his significant contributions 
to this chapter in the previous editions.
■
■FURTHER READING
Biggs HM et al: Diagnosis and management of tickborne rickettsial 
diseases: Rocky Mountain spotted fever and other spotted fever group 
rickettsioses, ehrlichioses, and anaplasmosis—United States. MMWR 
65:1, 2016.
Buijs SB et al: Still new chronic Q fever cases diagnosed 8 years after a 
large Q fever outbreak. Clin Infect Dis 73:1476, 2021.
Gillespie J, Salje J: Orientia and Rickettsia: Different flowers from the 
same garden. Curr Opin Microbiol 74:102318, 2023.
Ismail N, Mcbride JW: Tick-borne emerging infections: Ehrlichiosis 
and anaplasmosis. Clin Lab Med 37:317, 2017.
Varghese GM et al: Intravenous doxycycline, azithromycin, or both 
for severe scrub typhus. N Engl J Med 388:792, 2023.
R. Doug Hardy

Infections Due to 

Mycoplasmas
Mycoplasmas are prokaryotes of the class Mollicutes. Their size 
(150–350 nm) is closer to that of viruses than to that of typical bacteria. 
Unlike viruses, however, mycoplasmas grow in cell-free culture media; in 
fact, they are the smallest organisms capable of independent replication.
The entire genomes of many Mycoplasma species have been 
sequenced and have been found to be among the smallest of all 
prokaryotic genomes. Sequencing information for these genomes 
has helped define the minimal set of genes necessary for cellular life. 
The absence of genes related to the synthesis of amino acids, fatty acid 
metabolism, and cholesterol dictates the mycoplasmas’ parasitic or 
saprophytic dependence on a host for exogenous nutrients and neces­
sitates the use of complex fastidious media to culture these organisms. 
Mycoplasmas lack a cell wall and are bound only by a cell membrane. 
The absence of a cell wall explains the inactivity of β-lactam antibiotics 
(penicillins and cephalosporins) against infections caused by these 
organisms.
At least 13 Mycoplasma species, 2 Acholeplasma species, and 2 Urea­
plasma species have been isolated from humans. Most of these species 
are thought to be normal inhabitants of oral and urogenital mucous

membranes. M. pneumoniae, M. hominis, M. genitalium, U. urealyti­
cum, and U. parvum have been shown conclusively to be pathogenic 
in immunocompetent humans. M. pneumoniae primarily infects the 
respiratory tract, while M. hominis, M. genitalium, U. urealyticum, and 
U. parvum are associated with a variety of genitourinary tract disorders 
and neonatal infections. Other mycoplasmas may cause disease in 
immunocompromised persons.
MYCOPLASMA PNEUMONIAE
■
■PATHOGENESIS
M. pneumoniae is generally thought to act as an extracellular pathogen. 
Although the organism has been shown to exist and replicate within 
human cells, it is not known whether these intracellular events contrib­
ute to the pathogenesis of disease. M. pneumoniae attaches to ciliated 
respiratory epithelial cells by means of a complex terminal organelle 
at the tip of one end of the organism. Cytoadherence is mediated by 
interactive adhesins and accessory proteins clustered on this organelle. 
After extracellular attachment, M. pneumoniae causes injury to host 
respiratory tissue. The mechanism of injury is thought to be mediated 
by the production of hydrogen peroxide and of an ADP-ribosylating 
and vacuolating cytotoxin of M. pneumoniae that has many similarities 
to pertussis toxin. Because mycoplasmas lack a cell wall, they also lack 
cell wall–derived stimulators of the innate immune system, such as 
lipopolysaccharide, lipoteichoic acid, and murein (peptidoglycan) frag­
ments. However, lipoproteins from the mycoplasmal cell membrane 
appear to have inflammatory properties, probably acting through 
Toll-like receptors (primarily TLR2) on macrophages and other cells. 
Lung biopsy specimens from patients with M. pneumoniae respiratory 
tract infection reveal an inflammatory process involving the trachea, 
bronchioles, and peribronchial tissue, with a monocytic infiltrate that 
coincides with a luminal exudate of polymorphonuclear leukocytes.
Experimental evidence indicates that innate immunity provides most 
of the host’s defense against mycoplasmal infection in the lungs, whereas 
cellular immunity may actually play an immunopathogenic role, exacer­
bating mycoplasmal lung disease. Humoral immunity appears to provide 
protection against dissemination of M. pneumoniae infection; patients 
with humoral immunodeficiencies do not have more severe lung disease 
than do immunocompetent patients in the early stages of infection but 
more often develop disseminated infection resulting in syndromes such 
as arthritis, meningitis, and osteomyelitis. The immunity that follows 
severe M. pneumoniae infections is more protective and longer-lasting 
than that following mild infections. Genuine second attacks of M. pneu­
moniae pneumonia have been reported infrequently.
■
■EPIDEMIOLOGY
M. pneumoniae infection occurs worldwide. It is likely that the inci­
dence of upper respiratory illness due to M. pneumoniae is up to 20 
times that of pneumonia caused by this organism. Infection is spread 
from one person to another by respiratory droplets expectorated dur­
ing coughing and results in clinically apparent disease in an estimated 
80% of cases. The incubation period for M. pneumoniae is 2–4 weeks; 
therefore, the time-course of infection in a specific population may be 
several weeks long. Intrafamilial attack rates are as high as 84% among 
children and 41% among adults. Outbreaks of M. pneumoniae illness 
often occur in institutional settings such as military bases, boarding 
schools, and summer camps. Infections tend to be endemic, with spo­
radic epidemics every 4–7 years.
Most significantly, M. pneumoniae is a major cause of communityacquired respiratory illness in both children and adults and is often 
grouped with Chlamydia pneumoniae and Legionella species as one of 
the most important bacterial causes of “atypical” community-acquired 
pneumonia. For community-acquired pneumonia in adults, M. pneu­
moniae is the most frequently detected “atypical” organism. Analysis of 
13 studies of community-acquired pneumonia published between 1996 
and 2001 (which included 6207 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%. The summation of 26 more recent 

investigations of “atypical” organisms in community-acquired pneu­
monia in adults published between 2002 and 2015 found the overall 
prevalence of M. pneumoniae was 7.2%; by comparison, the prevalence 
of C. pneumoniae was 4.3%, and that of Legionella species was 2.8%. 

M. pneumoniae pneumonia is also referred to as Eaton agent pneumo­
nia (the organism having first been isolated in the early 1940s by Mon­
roe Eaton), primary atypical pneumonia, and “walking” pneumonia.

■
■CLINICAL MANIFESTATIONS
Upper Respiratory Tract Infections and Pneumonia 
Acute 

M. pneumoniae infections generally manifest as pharyngitis, tracheo­
bronchitis, reactive airway disease/wheezing, or a nonspecific upper 
respiratory syndrome. Little evidence supports the commonly held belief 
that this organism is an important cause of otitis media, with or without 
bullous myringitis. Pneumonia develops in 3–13% of infected individu­
als; its onset is usually gradual, occurring over several days, but may be 
more abrupt. 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 sputum. Headache, 
malaise, chills, and fever are noted in the majority of patients.
On physical examination, wheezes or rales are detected in ~80% of 
patients with M. pneumoniae pneumonia. In many patients, however, 
pneumonia can be diagnosed only by chest radiography. The most 
common radiographic pattern is that of peribronchial pneumonia with 
thickened bronchial markings, streaks of interstitial infiltration, and 
areas of subsegmental atelectasis. Segmental or lobar consolidation is 
not uncommon. While clinically evident pleural effusions are infre­
quent, lateral decubitus views reveal that up to 20% of patients have 
pleural effusions.
CHAPTER 193
Overall, the clinical presentation of pneumonia in an individual 
patient is not useful for differentiating M. pneumoniae pneumonia 
from other types of community-acquired pneumonia. The possibility 
of M. pneumoniae infection deserves particular consideration when 
community-acquired pneumonia fails to respond to treatment with a 
penicillin or a cephalosporin—antibiotics that are ineffective against 
mycoplasmas. Symptoms usually resolve within 2–3 weeks after the 
onset of illness. Although M. pneumoniae pneumonia is generally selflimited, appropriate antimicrobial therapy significantly shortens the 
duration of clinical illness. Infection uncommonly results in critical 
illness and only rarely in death. In some patients, long-term recur­
rent wheezing or reactive airway disease may follow the resolution of 
acute pneumonia. The significance of chronic infection, especially as it 
relates to asthma, is an area of active investigation.
Infections Due to Mycoplasmas 
Extrapulmonary Manifestations 
An array of extrapulmonary 
manifestations may develop during M. pneumoniae infection. The most 
significant are neurologic, dermatologic, cardiac, rheumatologic, and 
hematologic in nature. Extrapulmonary manifestations can be a result of 
disseminated infection, especially in patients with humoral immunode­
ficiencies (e.g., septic arthritis); postinfectious autoimmune phenomena 
(e.g., Guillain-Barré syndrome); or possibly ADP-ribosylating toxin. 
Overall, these manifestations are uncommon, given the frequency of 

M. pneumoniae infection. Notably, many patients with extrapulmonary 
M. pneumoniae disease do not have respiratory disease.
Skin eruptions described with M. pneumoniae infection include 
erythematous (macular or maculopapular), vesicular, bullous, petechial, 
and urticarial rashes. In some reports, 17% of patients with M. pneu­
moniae pneumonia have had an exanthem. Erythema multiforme major 
(Stevens-Johnson syndrome) is the most clinically significant skin erup­
tion associated with M. pneumoniae infection; it appears to occur more 
commonly with M. pneumoniae than with other infectious agents.
A wide spectrum of neurologic manifestations has been reported 
with M. pneumoniae infection. The most common are meningoen­
cephalitis, encephalitis, Guillain-Barré syndrome, and aseptic menin­
gitis. M. pneumoniae has been implicated as a likely etiologic agent in 
5–7% of cases of encephalitis. Other neurologic manifestations may 
include cranial neuropathy, acute psychosis, cerebellar ataxia, acute 
demyelinating encephalomyelitis, cerebrovascular thromboembolic 
events, and transverse myelitis.

TABLE 193-1  Diagnostic Tests for Respiratory Mycoplasma pneumoniae 
Infectiona
TEST
SENSITIVITY, %
SPECIFICITY, %
Respiratory culture
≤60

Respiratory PCR
65–90
90–100
Serologic studiesb
55–100
55–100
aA combination of PCR and serology is suggested for routine diagnosis. If macrolide 
resistance is suspected, resistance testing by culture and/or PCR is available. 
bAcute- and convalescent-phase serum samples are recommended.
Abbreviation: PCR, polymerase chain reaction.
aAntimicrobial resistance has been reported in mycoplasmas, as described in the text.
Hematologic manifestations of M. pneumoniae infection include 
hemolytic anemia, aplastic anemia, cold agglutinins, disseminated 
intravascular coagulation, and hypercoagulopathy. When anemia does 
occur, it generally develops in the second or third week of illness.
In addition, hepatitis, glomerulonephritis, pancreatitis, myocarditis, 
pericarditis, rhabdomyolysis, and arthritis (septic and reactive) have been 
convincingly ascribed to M. pneumoniae infection. Septic arthritis has 
been described most commonly in hypogammaglobulinemic patients.
■
■DIAGNOSIS
Clinical findings, nonmicrobiologic laboratory tests, and chest radi­
ography are not useful for differentiating M. pneumoniae pneumonia 
from other types of community-acquired pneumonia. In addition, 
since M. pneumoniae lacks a cell wall, it is not visible on Gram stain. 
Although of historical interest, the measurement of cold agglutinin 
titers is no longer recommended for the diagnosis of M. pneumoniae 
infection because the findings are nonspecific and assays specific for 
M. pneumoniae are now available.
PART 5
Infectious Diseases
Acute M. pneumoniae infection can be diagnosed by polymerase chain 
reaction (PCR) detection of the organism in respiratory tract secretions 
or by isolation of the organism in culture (Table 193-1). Oropharyngeal, 
nasopharyngeal, and pulmonary specimens are all acceptable for diag­
nosing M. pneumoniae pneumonia. Other bodily fluids, such as cerebro­
spinal fluid, are acceptable for extrapulmonary infection. M. pneumoniae 
culture (which requires special media) is not recommended for routine 
diagnosis because the organism may take weeks to grow and is often dif­
ficult to isolate from clinical specimens. In contrast, PCR allows rapid, 
specific diagnosis earlier in the course of clinical illness.
The diagnosis can also be established by serologic tests for IgM 
and IgG antibodies to M. pneumoniae in paired (acute- and conva­
lescent-phase) serum samples; enzyme-linked immunoassay is the 
recommended serologic method. An acute-phase sample alone is 
not adequate for diagnosis, as antibodies to M. pneumoniae may not 
develop until 2 weeks into the illness; therefore, it is important to 
test paired samples. In addition, IgM antibody to M. pneumoniae can 
persist for up to 1 year after acute infection. Thus, its presence may 
indicate recent rather than acute infection.
The combination of PCR of respiratory tract secretions and sero­
logic testing constitutes the most sensitive and rapid approach to the 
diagnosis of M. pneumoniae infection.
TREATMENT
Mycoplasma pneumoniae Infections
Although in the majority of untreated cases symptoms resolve 
within 2–3 weeks without significant associated morbidity, 

M. pneumoniae pneumonia can be a serious illness that responds 
to appropriate antimicrobial therapy (Table 193-2). Randomized, 
double-blind, placebo-controlled trials in adults have demonstrated 
that antimicrobial treatment significantly decreases the duration 
of fever, cough, malaise, hospitalization, and radiologic abnor­
malities in M. pneumoniae pneumonia. Treatment options for acute 

M. pneumoniae infection include macrolides (e.g., oral azithromy­
cin, 500 mg on day 1, then 250 mg/d on days 2–5), tetracyclines (e.g., 
oral doxycycline, 100 mg twice daily for 7–14 days), and respiratory 
fluoroquinolones. However, ciprofloxacin and ofloxacin are not rec­
ommended because of their high minimal inhibitory concentrations 

TABLE 193-2  Antimicrobial Agents of Choice for Mycoplasma 
Infectionsa
ORGANISM(S)
DRUGS
Mycoplasma pneumoniae Azithromycin, clarithromycin, erythromycin, 
doxycycline, levofloxacin, moxifloxacin, gemifloxacin 
(not ciprofloxacin or ofloxacin)
Ureaplasma urealyticum, 
Ureaplasma parvum
Azithromycin, clarithromycin, erythromycin, 
doxycycline
Mycoplasma hominis
Doxycycline, clindamycin
Mycoplasma genitalium
Azithromycin, moxifloxacin, doxycycline
against M. pneumoniae isolates and their poor performance in 
experimental studies. A 7- to 14-day course of quinolone therapy 
appears adequate. Even though appropriate antibiotic therapy signif­
icantly reduces the duration of respiratory illness, it does not appear 
to shorten the duration of detection of M. pneumoniae by culture or 
PCR; therefore, a test of cure for eradication is not suggested.
In Asian countries, a high prevalence (range 34–76%) of 

M. pneumoniae resistant to macrolides has been reported. In 
Europe and in the United States, macrolide-resistant M. pneu­
moniae is less common. In the United States, national surveillance 
from 2018 found that 10.2% of isolates demonstrated macrolide 
resistance. Furthermore, national surveillance from 2015–2018 
found macrolide resistance of 15.2–21.7% in the eastern United 
States and 1.9–2.8% in the western United States. Clinical studies 
have demonstrated that, when treated with macrolides, patients 
with community-acquired pneumonia due to macrolide-resistant 

M. pneumoniae experience a significantly longer duration of symp­
toms than do patients infected with macrolide-sensitive organisms; 
thus, macrolide resistance in M. pneumoniae does appear to have 
clinical significance. In addition, clinical investigations have indi­
cated that for macrolide-refractory M. pneumoniae pneumonia, 
tetracycline class therapy results in shorter duration of fever and 
hospital length of stay compared with macrolide therapy. If macro­
lide resistance is prominent in a particular geographic locale or is 
suspected, then a nonmacrolide antibiotic should be considered for 
treatment; in addition, in these instances, a respiratory sample may 
be sent to a Mycoplasma reference laboratory for the detection of 
macrolide resistance by culture or PCR.
While the 2019 Infectious Diseases Society of America and 
American Thoracic Society guidelines do not recommend routinely 
using corticosteroids in community-acquired pneumonia, growing 
clinical literature suggests that the addition of glucocorticoids to 
an antibiotic regimen may be of value for the treatment of severe 
or refractory M. pneumoniae pneumonia. A 2019 meta-analysis 
of 24 randomized controlled trials in children found that use of 
corticosteroids in macrolide-refractory M. pneumoniae pneumonia 
significantly reduced hospital days and duration of fever. Clinical 
literature in adults also shows benefit, but these data are limited and 
more observational in nature.
The roles of antimicrobial drugs, glucocorticoids, and IV 
immunoglobulin in the treatment of neurologic disease due to 

M. pneumoniae remain unknown.
UROGENITAL MYCOPLASMAS
■
■EPIDEMIOLOGY
M. hominis, M. genitalium, U. urealyticum, and U. parvum can cause 
urogenital tract disease. The significance of isolation of these organ­
isms in a variety of other syndromes is unknown and in some cases is 
being investigated. M. fermentans has not been shown convincingly to 
cause human disease.
While urogenital mycoplasmas may be transmitted to a fetus during 
passage through a colonized birth canal, sexual contact is the major 
mode of transmission, and the risk of colonization increases dra­
matically with increasing numbers of sexual partners. In asymptom­
atic women, these mycoplasmas may be found throughout the lower