Mycoplasma hominis, as well as many other mycoplasmas, is naturally resistant to erythromycin in vitro,

but susceptible to 16-membered macrolides (josamycin or miocamycin) and lincomycin, whereas this is
not true of U. urealyticum.

Genetic basis of natural resistance to

erythromycin in Mycoplasma hominis
Pio Maria Furneri Giancarlo Rappazzo Maria Pia Musumarra Gianna TemperaLucia
Silvana Roccasalva
Journal of Antimicrobial Chemotherapy, Volume 45, Issue 4, 1 April 2000, Pages 547–
548,
This study aimed to assess the colonization prevalence and antibiotic susceptibility of
genital Ureaplasma urealyticum and Mycoplasma hominis in a teaching hospital, in Turkey.
A total of 382 sexually active women with abnormal vaginal discharge were included in the
study. Samples that were obtained with cotton swabs were microbiologically analyzed for U.
urealyticum and M. hominis, together with antimicrobial susceptibility to doxycycline,
ciprofloxacin, ofloxacin, erythromycin, josamycin, pristinamycin, and tetracycline.
Ureaplasma urealyticum was detected in 185 (48.4%) cultures, and M. hominis in 17
(4.4%). Eight (2.1%) cultures were positive for both. Resistance of M. hominis to
doxycycline, ciprofloxacin, ofloxacin, erytromycin, josamycin, pristinamycin and tetrascycline
was 5.9%, 17.6%, 41.2%, 88.2%, 5.9%, 5.9% and 11.8%, respectively. Resistance to
doxycycline, ciprofloxacin, ofloxacin, erytromycin, josamycin, pristinamycin and tetrascycline
in U. urealyticum isolates was 1.6%, 40.5%, 58.4%, 54.0%, 1.6%, 8.1% and 13.5%,
respectively. Both U. urealyticum (94.1%) and M. hominis (96.2) were most sensitive to
josamycin, and most resistant to erytromycin (U. urealyticum 54.0%, M. hominis 88.2) and
ofloxacin (U. urealyticum 58.4%, M. hominis 41.2%). As a result, the rate of U. urealyticum
and M. hominis was found to be 48.4% and 4.4%, respectively. We conclude that
doxycycline may be used in empirical treatment of genital tract infections in sexually active
women.

Prevalence and antibiotic susceptibility of genital Mycoplasma hominis

and Ureaplasma urealyticum in a university hospital in Turkey.
Karabay O , Topcuoglu A, Kocoglu E , Gurel S , Gurel H , Ince NK

Ureaplasma spp. and Mycoplasma

45 hominis, which are fastidious bacteria that lack a cell wall. Lacking this structural component
46 causes Ureaplasma spp. and M. hominis to have intrinsic resistance to beta-lactam antibiotics
47 and vancomycin.
Further narrowing treatment options, Ureaplasma spp. and M. hominis also
48 possess intrinsic resistance to typical UTI treatment options including sulfonamides and
49 trimethoprim, as well as rifampin (9). Thus, antibiotic resistance in mycoplasmas poses even
50 further treatment challenges, due to the already limited spectrum of antibiotics capable of treating
51 them.
The Clinical and Laboratory Standards Institute (CLSI) has established breakpoints for
98 resistance only for levofloxacin (Ureaplasma, ≥ 4 μg/ml; M. hominis, ≥ 2 μg/ml), clindamycin (M.
99 hominis, ≥ 0.5 μg/ml), erythromycin (Ureaplasma, ≥ 16 μg/ml), and tetracycline (Ureaplasma, ≥ 2
100 μg/ml; M. hominis, ≥ 2 μg/ml).
Antibacterial Resistance 1 in Ureaplasma species and Mycoplasma hominis Isolates from
2 Urine Cultures in College-aged Females
Marissa A. Valentine-King,a Mary B. Brown

Resistance of M. hominis to fluoroquinolones, as for

other bacterial species, is associated with a gyrA mutation
at Ser83.34 Resistance of M. hominis to tetracyclines35,36
probably assumes more importance because of the
widespread use of these drugs for genital tract infections,
and in some areas the frequency of resistant strains has
increased to 30% or more.37 The reason for this, apparently,
is the acquisition of a streptococcal tetM gene.38
U. urealyticum strains may also become resistant to tetracyclines39
for the same reason.40 The tetM gene encodes a
protein which binds to ribosomes and in the case of U. urealyticum
it has been demonstrated to be associated on the chromosome, with Tn916, a conjugative transposon.4
Genitourinary infection
Some disease syndromes are caused not only by mycoplasmas
but also by various other microorganisms. Since
it is usually impossible to define rapidly which one is
responsible, the antibiotic sensitivity of all of them must be
taken into account when empirical therapy is prescribed.
Thus, for example, in the case of non-gonococcal urethritis,
patients should receive a tetracycline that inhibits
Chlamydia trachomatis, M. genitalium and U. urealyticum.
Doxycycline is often used, given in a dose of 100 mg twice
daily for 7 days. However, as mentioned before, at least 10%
of ureaplasmal strains isolated from patients attending
STD clinics in London are resistant to tetracyclines39 and
patients who fail to respond should be treated with
erythromycin (0.5 g daily for 7 days), to which most tetracycline-
resistant ureaplasmas are sensitive. A tetracycline
should also be included in the antibiotic regimen for pelvic
inflammatory disease, so that C. trachomatis and M. hominis
strains are covered. However, since the proportion of
M. hominis strains that are resistant to tetracyclines has
been increasing (_20%),37 other antibiotics such as lincomycin,
clindamycin or fluoroquinolones (often ofloxacin)
may sometimes need to be used. Azithromycin, which is
being used increasingly to treat non-gonococcal urethritis
and other infections in which C. trachomatis might be
involved, is also active against a wide range of mycoplasmas.
Antibiotic susceptibilities of mycoplasmas and treatment of
mycoplasmal infections
David Taylor-Robinsona and Christiane Bébéarb
A role for M. hominis in non-speci® c vaginitis, possibly in association with Gardnerella vaginalis or
other organisms, was ® rst proposed by Taylor-Robinson and McCormack2.
Carriage of M. hominis
Carriage of M. hominis by 9 (53%) of 17 women
with BV in comparison with none of 21 women
without BV was a highly signi® cant ® nding ((FET)
P=0.0001). It was not possible to calculate an odds
ratio because of the lack of M. hominis-positive
women in the control group. The difference in the
carriage of M. hominis by male partners of women
with or without BV was much less striking;
although the mycoplasma was detected more often
in male partners (8 (47%) of 17) of women with BV
than among those of control women (5 (24%) of 21),
the difference was not signi® cant (CAw2=1.342 (l df),
P=0.247). Among the 38 couples, both partners of 4
couples (10%) were positive for M. hominis, both
partners of 20 couples (53%) were M. hominisnegative
and 14 couples (37%) were discordant for
the carriage of M. hominis.
Carriage of U. urealyticum
Carriage of U. urealyticum was slightly greater in
women with BV (11 (65%) of 17) than in those
without BV (10 (48%) of 21), but the difference was
not signi® cant (CAw2=0.526 (l df), P=0.468). The rate
of detection of U. urealyticum in male partners of
women with BV (4 (24%) of 17) compared with
those of women without BV (6 (29%) of 21) was
unremarkable ((FET) P=1.000). Among the 38
couples, both partners of 9 couples (24%) were
positive for U. urealyticum, both partners of 16
couples (42%) were U. urealyticum-negative and 13
couples (34%) were discordant for the carriage of
U. urealyticum.

The association of Mycoplasma hominis,

Ureaplasma urealyticum and Mycoplasma
genitalium with bacterial vaginosis:
observations on heterosexual women and
their male partners
F E A Keane1, B J Thomas1, C B Gilroy1, A Renton2 and
D Taylor-Robinson

By
losing their cell walls, they have developed phenotypic plasticity through the ability to constantly
change the antigenic lipoproteins in their plasma membranes (reviewed in Razin et al., 1998;
Citti et al., 2010).
Mycoplasmas generally adhere to the host’s epithelial cells via a complex specialized
structure called the tip organelle. The tip organelle is mainly composed of adhesins and
cytadherence accessory proteins (Razin et al., 1998). Mycoplasmas adherence, has been reported
as a major factor, which triggers colonization and pathogenicity (Rottem, 2003). Once attached
to the epithelial cells, the mycoplasmas are able to persist and evade the host immune system
through variation of surface proteins (antigens) and cause chronic infection (Razin et al., 1998).
It has been documented that M. genitalium G37 can attach to the mucin component of the
epithelial mucus membrane via the glycolytic enzyme glyceraldehyde-3-phosphate
dehydrogenase. This glycolytic enzyme thus acts as an adhesin in some species of mycoplasmas
(Alvarez et al., 2003). Similarly, oligopeptide permease substrate-binding protein (OppA) of M.
hominis PG21, a multifunctional lipoprotein (Henrich et al., 1999; Hopfe et al., 2011) and OppF
of M. penetrans (Distelhorst et al., 2017) have been reported to be involved in cytadherence to
host cells.
With their small size, minimal genomes, phenotypic plasticity and their abilities to alter
shape, to invade host cells and to develop specialized attachment tip organelles, it seems
probable from an evolutionary point of view that the species of Mycoplasma are evolving
towards adapting to an intracellular habitat. M. hominis PG21 exist extracellularly, adhering to
the surface of
the host cells (Ladefoged et al., 1995). On the other hand, M. penetrans HF-2 and M. genitalium
G37 (under certain conditions) can exist intracellularly in non-phagocytic cells (Rottem, 2003).
M. hominis PG21 resides in the urogenital tract as a commensal. It is also opportunistically
pathogenic causing infection when the immune state of the host is compromised (Ladefoged et
al., 1995).
In order to evaluate the linkage between the adherence proteins and pathogenicity, a
compilation of virulence factors (adherence proteins, adhesins, cytadherence accessory proteins,
surface lipoproteins and other proteins) was conducted by review of literature for the four human
urogenital Mycoplasma species. A
comparative pathogenomic analysis on these adherence proteins indicated that each Mycoplasma
species has its own unique set of virulence factors.
Even though the virulence genes remain unique to each species, they can be grouped into
three categories: adhesins, cytadherence associated (adhesin-related accessory) proteins and
variable surface lipoproteins (Table 2). Adhesins involved in the cytadherence tip organelle have
been documented for M. genitalium G37 and M. hominis PG21
Some
of the surface membrane lipoproteins of the four Mycoplasma species show extensive sequence
variation as evidenced by the 45 homologs of the P35 lipoprotein of M. penetrans HF-2 and the
family of 6 Lmp related proteins in M. hominis PG21. The variable adherence-associated adhesin
(Vaa) in M. hominis PG21, like P35, is a surface membrane protein which exhibits
phasevariation
(Boesen et al., 2001). The variations in surface membrane proteins and adhesins are
vital for the survival of Mycoplasma species. The main virulence factor in the pathogenicity of
Mycoplasma species is cytadherence to molecular components of host epithelial cell membrane.
Inhibition of a single virulence factor doesn’t always lead to complete non-adherence as cell
adhesion appears to require the interplay of adhesins, adhesin-related proteins and some surface
membrane lipoproteins (Alvarez et al., 2003; Henrich et al., 1993; Yavlovich et al., 2004).
For M. hominis PG21 there were 3 minisatellite sequences (15, 21
and 29 bp) located in P120 (P120 adhesin), lmp3 (lmp3 adhesin) and MHO_3730 (lmp-related
protein). The fact that the mycoplasmas need to frequently readapt to their
environments by constant phenotypic reconstitution (through surface antigen variation) explains
why they have higher levels of minisatellites in their genomes than short tandem repeats as the
former yields greater variation.
Phylogenetically, the species of Mycoplasma have evolved to produce effective minimal
genomes that are extremely well adapted to their milieu. Our comparative genomic study with
the four Mycoplasma species indicates that this adaptation has been achieved by organizing the
genome into three functional categories, category I (genes involved in nuclear metabolism),
category II (genes responsible for protein and carbohydrate metabolic processes for energy
generation) and category III (genes coding for cytadherence and virulence) with categories I and
II forming the core genome. It is deduced that the main purpose of category II genes
(carbohydrate and protein metabolic processes) in mycoplasmas is for the production of energy
and proteins for a constant supply of variable surface membrane lipoproteins, whilst scavenging
the host for the reliable supply of needed nutrients. These surface proteins are engaged in
22
mycoplasmas’ phenotypic plasticity to avoid the host’s humoral defence system. The very
survival of mycoplasma depends on an adequate supply and variation of these lipoproteins.
The mycoplasmas can generate a wide range of homologous virulence genes
(lipoproteins) via DNA recombination by utilizing repeat sequences within their genomes. As
reflected in this study, they enhance the frequency of recombination via preferential
incorporation of minisatellites into their virulence genes instead of short tandem repeats as the
minisatellites are associated with a higher frequency of DNA recombination.
Mycoplasmas use phage-like proteins (PLPs) to contribute to their virulence by clustering
a substantial amount of PLPs in their genomes. This is indicated by the presence of phage-like
DNA gyrase/topoisomerases, the Mem protein of ɸMFV1 and the Ccs protein of M. penetrans
HF-2 that were found embedded in the Mycoplasma genomes.

Comparative genomics of four Mycoplasma species of

the human urogenital tract: analysis of their core genomes and
virulence genes
Authors: Orville St. E. Roachford, Karen E. Nelson, Bidyut R.
Mohapatra

Factors involved in Ureaplasma and M. hominis attachment have not been characterized to the same
extent as those involved in M. pneumoniae attachment, and Ureaplasma spp. and M. hominis do not
have prominent attachment organelles. Henrich et al. (46) demonstrated the presence of the variable
adherence-associated antigen (Vaa) that is believed to be a major adhesin of M. hominis and may also
assist in evasion of host immune responses through antigenic variation. Ureaplasmas also attach to a
variety of cell types, with attachment mediated by adhesin proteins expressed on the surface of the
bacterial cell. The multiplebanded (MB) antigen contains serotype-specific and crossreactive epitopes
and is a prominent antigen recognized during human ureaplasmal infections (116). Ureaplasmas are
known to produce immunoglobulin A (IgA) protease which may be associated with disease production,
and they release ammonia through urealytic activity (116).
Although mycoplasmas are generally considered to be extracellular organisms, intracellular localization
is now appreciated for M. fermentans, M. penetrans, M. genitalium, and M. pneumoniae (11, 28).
Intracellular localization may be responsible for protecting the organisms from antibodies and
antibiotics, as well as contributing to disease chronicity and difficulty in cultivation in some cases.
Variation in surface antigens of M. hominis and Ureaplasma spp. may be related to the persistence of
these organisms at invasive sites. In humans, mycoplasmas and ureaplasmas may be transmitted by
direct contact between hosts, e.g., venereally through genitalgenital or oral-genital contact and
vertically from mother to offspring either at birth or in utero.
Genitourinary Infections Ureaplasma spp. and M. hominis can be isolated from the lower genital tract in
many healthy, sexually active adults, but there is evidence that these organisms play etiologic roles in
some genital tract diseases. Results of human and animal inoculation studies and observations of
immunocompromised persons are supportive of ureaplasmas being a cause of nonchlamydial,
nongonococcal urethritis (NGU) in men, with further evidence supplied by therapeutic and serologic
studies (31, 69, 99, 101). Since the identification of two distinct biovars of Ureaplasma urealyticum,
biovar 2 (U. urealyticum) has been implicated in NGU whereas biovar 1 (U. parvum) has not been
implicated in this manner (31). Evidence that M. hominis causes NGU is lacking. M. genitalium has been
detected by PCR technology significantly more often in urethral specimens from men with acute NGU
than from those without urethritis (51–54) and is now considered to be one of the causes of the disease.
M. genitalium-positive men have been found to have symptomatic urethritis significantly more often
than those infected with Chlamydia trachomatis (43). Antibody responses have been detected in some
men with acute disease, and M. genitalium has also produced urethritis in nonhuman primates (101). M.
genitalium also may be a rare cause of conjunctivitis associated with urethritis (13). M. fermentans, M.
penetrans, and M. pirum were not detected in the urethras of men with urethritis by PCR assays,
suggesting that these organisms are unlikely to have a pathogenic role in this condition (30). In women,
there is no evidence that M. hominis is a cause of the urethral syndrome, but ureaplasmas may be
involved (96). M. hominis and Ureaplasma spp. have not been detected by culture of prostatic biopsy
samples from patients with chronic abacterial prostatitis (32), and M. genitalium has been found rarely
by using a PCR assay (61). In contrast, ureaplasmas have been recovered from an epididymal aspirate
from a patient suffering from nonchlamydial, nongonococcal acute epididymo-orchitis accompanied by
a specific antibody response (50) and may be an infrequent cause of the disease. Ureaplasma spp.
produce urease and induce crystallization of struvite and calcium phosphates in urine in vitro and calculi
in animal models (109). In addition, ureaplasmas have been found in urinary calculi of patients with
infection-type stones associated with disease. PCR assays have demonstrated the frequent occurrence
of M. genitalium in the urogenital tract in men with urethritis and in lower and upper genital tract sites
in women and of M. penetrans in urine of homosexual males with human immunodeficiency virus
infection (51, 116). Although mycoplasmas are generally considered to be extracellular organisms,
intracellular localization is now appreciated for M. fermentans, M. penetrans, M. genitalium, and M.
pneumoniae (11, 28). Intracellular localization may be responsible for protecting the organisms from
antibodies and antibiotics, as well as contributing to disease chronicity and difficulty in cultivation in
some cases. Variation in surface antigens of M. hominis and Ureaplasma spp. may be related to the
persistence of these organisms at invasive sites. In humans, mycoplasmas and ureaplasmas may be
transmitted by direct contact between hosts, e.g., venereally through genitalgenital or oral-genital
contact and vertically from mother to offspring either at birth or in utero; by respiratory aerosols or
fomites in the case of M. pneumoniae; or even by nosocomial acquisition through transplanted tissues.
CLINICAL SIGNIFICANCE Respiratory Infections M. pneumoniae was first identified and described in the
early 1960s. It causes approximately 20% of all communityacquired pneumonias in the general
population and up to 50% of pneumonias in certain confined groups (117). Although M. pneumoniae has
long been associated with pneumonias in school-aged children, adolescents, and young adults, in recent
years this organism has also been shown to occur endemically and occasionally epidemically in older
persons, as well as children under 5 years of age (117). The most typical clinical syndrome is
tracheobronchitis, often accompanied by upper respiratory tract manifestations such as acute
pharyngitis. Pneumonia develops in about one-third of persons who are infected. The incubation period
is generally 2 to 3 weeks, and spreading throughout households is common. The organism may persist in
the respiratory tract for several months after initial infection and sometimes for years in
hypogammaglobulinemic patients, possibly because the organism attaches strongly to and invades
epithelial cells. Disease tends not to be seasonal, subclinical infections are common, and the disease is
ordinarily mild. However, severe infections requiring hospitalization and even resulting in death are
known to occur (117). Extrapulmonary complications of M. pneumoniae infections may include
meningoencephalitis, ascending paralysis, transverse myelitis, Bell’s palsy, pericarditis, hemolytic
anemia, arthritis, and mucocutaneous lesions (98, 117). An autoimmune response is thought to play a
role in some extrapulmonary complications. However, M. pneumoniae has been isolated directly from
cerebrospinal, pericardial, and synovial fluids, as well as other extrapulmonary sites, and additional
evidence of direct invasion by this organism has been documented by the use of the PCR assay (98).
Clinical manifestations are not sufficiently unique to allow differentiation from infections caused by
other common bacteria, particularly Chlamydophila pneumoniae. Recent data from animal models as
well as clinical studies have suggested a potential role for M. pneumoniae and C. pneumoniae as
etiologic or exacerbating factors in bronchial asthma (73), but additional clinical studies are required to
determine the ultimate significance of these preliminary findings. 64. Mycoplasma and Ureaplasma ■
1007 more frequently than in those of patients with metabolic-type stones, suggesting a possible causal
association (45). M. hominis has been isolated from the upper urinary tract only in patients with
symptoms of acute pyelonephritis, often with an antibody response, and may cause about 5% of cases
of such disease (106). Obstruction or instrumentation of the urinary tract may be a predisposing factor.
Ureaplasmas have not been associated in the same way. Mollicutes do not cause vaginitis but are
among various microorganisms that proliferate in patients with bacterial vaginosis (BV). Some studies
suggest that M. hominis may contribute independently to BV, but evidence is lacking for an independent
association of ureaplasmas with BV (116). BV may lead to pelvic inflammatory disease, and M. hominis
has been isolated from the endometria and fallopian tubes of about 10% of women with salpingitis
diagnosed by laparoscopy and accompanied by a specific antibody response (109). The significance of
this mycoplasma is difficult to assess in an individual case when several microorganisms are present.
Nevertheless, serologic evidence suggests that M. hominis may be an independent factor in tubal-factor
infertility (7). Ureaplasma spp. have been isolated directly from affected fallopian tubes, but not alone.
This finding, together with the negative results of serologic tests, studies of inoculation of nonhuman
primates, and fallopian tube organ cultures (101), does not support a causal relationship for
ureaplasmas in pelvic inflammatory disease. M. genitalium, however, may play a role as indicated by its
significant association with cervicitis (42, 108) and endometritis (26). In addition, there is serologic
evidence that this mycoplasma causes some cases of tubal infertility (24). That ureaplasmas may cause
infertility remains speculative (99, 100). Ureaplasmas have been isolated from internal organs of
spontaneously aborted fetuses and from stillborn and premature infants more often than from fetuses
from induced abortions or normal full-term infants (116). The results from some serologic and
therapeutic studies have also supported a role for these organisms in fetal morbidity (21). BV is a
possible confounding factor which must be considered in the association between ureaplasmas in the
chorioamnion and low birth weight. Ureaplasmas at this site are directly associated with inflammation
(41) and may invade the amniotic sac early in pregnancy in the presence of intact fetal membranes,
causing persistent infection and adverse pregnancy outcome (19). The notion that M. hominis causes
fever in some women after abortion or after normal delivery is based on its isolation from the blood of
about 10% of such women but not from that of afebrile women who have had abortions or that of
healthy pregnant women (99). In addition, antibody responses have been detected in about half of
febrile aborting women but in few of those who remain afebrile (99). Similar observations have been
made for the isolation of Ureaplasma spp. which may be responsible for some cases of postpartum
endometritis (22). It is possible that ureaplasmas play a causal role in some cases of spontaneous
abortion and premature birth through elaboration of phospholipases and stimulation of cytokines which
are secreted in response to the presence of the microorganisms in amniotic fluid (116). There is no
evidence that M. genitalium is a cause of preterm labor or abortion (66, 78).

Susceptibility Testing and Treatment of Mycoplasmal Infections

Mollicutes are innately resistant to all beta-lactams. Sulfonamides, trimethoprim, and rifampicin are also
inactive. Resistance to macrolides and lincosamides is variable according to species, with M. hominis
being resistant to erythromycin but susceptible to clindamycin. For Ureaplasma spp., the reverse is true.
Tetracycline resistance has been well documented in recent years for both M. hominis and Ureaplasma
spp. and is mediated by the tet(M) determinant which codes for a protein that binds to the ribosomes,
protecting them from the actions of this type of drug. The extent to which tetracycline resistance occurs
in genital mycoplasmas varies geographically and according to prior antimicrobial exposure in different
populations but may approach 40 to 50%.

Manual of clinical microbiology 9th edition – Patrick Murray & colab. 2007 – 64. MYCOPLASMAS AND
OBLIGATE INTRACELLULAR BACTERIA Mycoplasma and Ureaplasma* KEN B. WAITES AND DAVID
TAYLOR-ROBINSON

De cautat: Henrich, B., R. C. Feldmann, and U. Hadding. 1993. Cytoadhesins of Mycoplasma hominis
Isolation of Mycoplasma species and Ureaplasma urealyticum from obstetrical and gynecological
patients by using commercially available medium formulations.
Morphology of the cells and colonies of Mycoplasma hominis
Waites, K., and D. Talkington. 2005. New developments in human diseases due to mycoplasmas, p. 289–
354. Blanchard and G. Browning (ed.), Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging
Strategies for Control
Waites, K. B., L. B. Duffy, S. Schwartz, and D. F. Talkington. 2004. Mycoplasma and Ureaplasma, p.
3.15.1– 3.15.17. In H. Isenberg (ed.), Clinical Microbiology Procedures Handbook, 2nd ed. ASM Press,
Washington, D.C.