Introduction
Mycoplasma and ureaplasma species, which are parasitic to humans, are the smallest
known cell-wall-free intra- and extracellular bacteria belonging to the class Mollicutes.
Their lack of a cell wall, extremely small genome and limited capacity for biosynthesis
together explain their parasitic or saprophytic life style, their sensitivity to environmental
factors, resistance to lactam antibiotics and high demands on living conditions.
These organisms can cause numerous often chronic conditions in humans. As parasites
or commensals they receive essential metabolites such as fatty acids, amino acids,
cholesterol and nucleic acid precursors from their host. Ureaplasma are defined and
differentiated from mycoplasma species by their characteristic lysis of urea. Sixteen
of the over 200 mycoplasma species known in the animal and plant kingdoms occur in
the human body, however only six of these appear to be of pathological importance
in immunocompetent human beings: mycoplasma pneumoniae, mycoplasma hominis, mycoplasma
genitalium, mycoplasma fermentans, ureaplasma parvum und ureaplasma urealyticum [1]. Only mycoplasma hominis, mycoplasma genitalium and ureaplasma urealyticum are important
pathogens in the human genital tract.
The prevalence of bacterial colonisation in women has been shown to correlate with
number of sexual partners in previous months [2], and prevalence differs according to geographic and socio-economic circumstances.
The pathogenic potential of these organisms is however not nearly as high as other
sexually transmitted pathogens (especially chlamydia trachomatis).
Because of the close topographical relationship between the female urethra and genital
tract it can be assumed that bacterial colonisation of the former from the latter
can affect the urinary tract. A lot is already known about mycoplasma-associated genital
tract infections, however there is still a lack of clarity on the influence and pathogenic
potential of mycoplasma and ureaplasma species in the context of urinary tract infections
and other urogynaecological symptoms such as irritable bladder and interstitial cystitis/bladder
pain syndrome.
The aim of this review is to summarise current knowledge on the prevalence and effects
of mycoplasma and ureaplasma infections, the best methods of pathogen detection and
best treatment options for the associated urogynaecological conditions (upper and
lower urinary tract infections, urethritis, overactive bladder [OAB], interstitial
cystitis [IC]/the bladder pain syndrome [BPS] [3]). The results presented are intended to be a practical treatment aid for clinicians.
Review
Literature search
A systematic literature search was performed in the data banks PubMed and MEDLINE
for publications between 1970 and 2017. Both “mycoplasma” and “ureaplasma” were used
as search terms coupled with the following: “cystitis, bladder infection, urinary
tract infection, LUTS, lower urinary tract, urethra, urethritis, pyelonephritis, upper
urinary tract infection, immune deficiency, overactive bladder, hyperactive bladder,
bladder irritation, interstitial cystitis, chronic pelvic pain, bladder pain, treatment,
laboratory analyses, detection and analysis”. For overall information on the topic
a further search using the following terms was performed: “sexually transmitted diseases
woman, reproductive tract, infertility, pregnancy, neonatal infection and delivery
transmission”. Both authors performed the research independently. Since very few publications
were found on overactive bladder and interstitial cystitis/the bladder pain syndrome
an additional search was conducted in the databases Scopus, Ovid and Science Direct.
[Table 1] summarises the relevant literature found.
Table 1 Search criteria coupled with the terms “mycoplasma” and “ureaplasma” and articles
found. Results are shown for the systematic literature search in Pubmed and Medline
using all relevant search criteria, and in Scopus, Ovid and Science Direct using search
terms “overactive bladder, hyperactive bladder, bladder irritation, interstitial cystitis,
chronic pelvic pain and bladder pain” with specification of subtopics.
|
Search criteria
|
No. articles found
|
|
Cystitis
|
17
|
|
Bladder infection
|
22
|
|
Urinary tract infection
|
100
|
|
LUTS
|
7
|
|
Lower urinary tract
|
22
|
|
Urethra
|
106
|
|
Urethritis
|
266
|
|
Pyelonephritis
|
14
|
|
Upper urinary tract infection
|
2
|
|
Immune deficiency
|
52
|
|
Overactive bladder
|
8
|
|
Hyperactive bladder
|
3
|
|
Bladder irritation
|
6
|
|
Interstitial cystitis
|
66
|
|
Chronic pelvic pain
|
116
|
|
Bladder pain
|
25
|
|
Treatment
|
483
|
|
Laboratory analysis
|
8
|
|
Detection and analysis
|
7
|
|
Sexually transmitted diseases woman
|
134
|
|
Reproduction tract
|
91
|
|
Infertility
|
178
|
|
Pregnancy
|
403
|
|
Neonate infection
|
123
|
|
Delivery transmission
|
10
|
The initial literature analysis yielded 2055 articles. Together with the extended
literature search a total of 2269 articles were identified. 54 publications were regarded
by both authors as relevant and served as the basis for this review ([Fig. 1]).
Fig. 1 Literature search flow diagram. The initial 2269 identified articles were analysed.
Original publications in German, English and French were included. Using objective
and subjective selection criteria all review articles, studies conducted only on men
or animals and in vitro studies were excluded from the analysis. Double references
and studies regarded as irrelevant were also eliminated. 377 articles remained for
final analysis. 54 of these publications were regarded as currently relevant and served
as the basis for this article.
Results
The role of mycoplasma and ureaplasma in urinary tract infections
The persistence of irritable bladder symptoms following a urinary tract infection
is a challenging situation for clinicians. Most uropathogenic organisms – especially
those originating from faeces – can be demonstrated on standard culture. Mycoplasma
and ureaplasma species on the other hand are not. When these organisms are specifically
sought they may be found in both asymptomatic [4] and symptomatic patients with sterile leukocyturia [5]. In women pathological significance is differentiated from harmless colonisation
by the presence of clinical symptoms. This is complicated in addition by the fact
that bacterial count in urine does not necessarily correlate with the amount of bacteria
in the bladder wall. A significant number of these intracellular organisms may occur
in the bladder wall in the absence of bacteriuria.
Mycoplasma hominis and ureaplasma urealyticum have also been demonstrated in patients
with pyelonephritis [6]. The pathogens are thought to have reached the renal pelvis exclusively by ascending
infection from the lower urinary tract. The detection of bacteria in catheter urine
from the bladder does not therefore prove bacterial colonisation of the upper urinary
tract [7].
We agree with the recommendation by Potts et al. that persistent lower urinary tract
infection symptoms or pyelonephritis with negative standard cultures and nonresponse
to routine antibiotics should prompt an active search for mycoplasma and ureaplasma,
with treatment according to antibiogram if findings are positive. Pathogen detection
should be undertaken before further expensive or invasive diagnostic measures are
resorted to [8].
Urethritis
Urethritis due to mycoplasma and ureaplasma infection, so-called “nonchlamydial nongonococcal
urethritis”, is extensively described in men. There is however very little data on
the topic in women: Moi et al., Falk et al. and Ross & Jensen have all described urethritis
in women caused by or associated with mycoplasma genitalium [9], [10], [11].
Although mycoplasma hominis and ureaplasma urealyticum have been found in women with
urethritis [12], clear evidence of causative effect is still lacking. Kyndel et al. recently published
a case-control study on the incidence of mycoplasma genitalium, ureaplasma urealyticum
and ureaplasma parvum in patients with chronic urethral pain. In contrast to Stamm
et al. [13], the authors found no difference between affected patients and the control group
[14].
In summary, data on this topic in women is sketchy. In the context of chronic urethral
symptoms with negative routine cultures we recommend a urethral swab with PCR analysis
for the three relevant mollicutes, and in case of positive findings appropriate treatment
according to resistogram.
Can mycoplasma and ureaplasma cause overactive bladder or interstitial cystitis?
The International Continence Society (ICS) defines OAB as urinary urgency with or
without urgency urinary incontinence in association with urinary frequency and/or
nocturia [15]. The symptoms thus match those of simple cystitis.
Interstitial cystitis – recently renamed the Bladder Pain Syndrome [3] – is defined by “chronic lower abdominal pain (continuous for at least six months)
with discomfort or pressure related to the bladder. In addition at least one further
symptom is present such as persistent urinary urgency or frequency” [15].
There is therefore overlap between the symptoms of OAB and BPS. OAB is more common
around menopause whereas BPS mostly affects premenopausal women. Both OAB [16] and BPS [17] occur more commonly in women than men. The diagnoses OAB and IC/BPS can only be
made after exclusion of possible infectious and other pathologies. The aetiology of
OAB is mostly, and that of BPS currently still always fully unexplained [18].
The theory that initial injury to the urothelium through acute or chronic infection,
causing persistent irritation of the bladder wall and subsequently OAB and IC/BPS,
has not been proven. Neither a particular microorganism nor any specific spectrum
of pathogens has been shown to be related to the two conditions.
In the late 1990s, using the laboratory methods of the day various investigators attempted
to ascribe an infectious aetiology to interstitial cystitis – without success [19], [20]. Despite controversial results [21] numerous studies however showed positive outcomes with empiric antibiotic treatment
(doxycycline) for OAB and IC/BPS [22], [23], [24], [25]. The question still remains whether OAB/IC/BPS can in fact be defined as idiopathic.
Chronic infection with one or more as yet undetected pathogens seems more likely.
Since mycoplasma and ureaplasma species are often eradicated by doxycycline and are
better detected with newer diagnostic methods, the question must be asked once again
whether the findings from the 1990s are still valid today, and whether there is in
fact a link between OAB/BPS and mollicutes.
Numerous recent studies have shown that ureaplasma and mycoplasma species can be detected
in the urine of women with OAB [26], [27] or IC [25]. Potts et al. showed that symptoms improved in patients with IC following targeted
antibiotic treatment [25]. A thorough search through the current available literature however brings us to
the conclusion that there is far too little data to provide an evidence-based answer
to this question. We therefore agree with the recommendation that all patients with
chronic unexplained urinary tract symptoms should be tested for mollicutes (mycoplasma
and ureaplasma) before invasive diagnostic measures and long-term treatments. Patients
with positive bacterial testing should be treated accordingly.
What are the best detection methods for mycoplasma and ureaplasma?
Mycoplasma genitalium is not detected on routine culture due to extremely slow growth.
Real-time polymerase chain reaction (PCR) is the diagnostic method of choice. In contrast,
ureaplasma urealyticum and mycoplasma hominis can be identified on culture or PCR
[28].
It is important for the clinician to know that correct sampling technique from the
appropriate site is at least as important for organism detection as the choice of
laboratory method [29]! Humburg et al. found that detection rates of mycoplasma and ureaplasma in women
with urinary tract symptoms were higher using urethral swabs than early morning urine
cultures or vaginal swabs [30], however in the presence of vaginal itch vaginal swabs provided the best results
[31]. Freezing of PCR specimens appears to reduce bacterial detection [32].
Treatment of infections
The most difficult question is left to the clinician, who must decide whether a given
bacterium, proven on laboratory tests, is pathogenically significant or not.
Ureaplasma and mycoplasma species do not have a cell wall. Beta-lactam antibiotics
and vancomycin are thus ineffective. Cyclines (doxycycline, monocycline), josamycin
and the fluoroquinolones are effective against the three species known to be pathogenic
in the urogenital tract. Tetracyclines and the fluoroquinolones are the first choice
antibiotics. In pregnant women in whom these drugs are contraindicated macrolides
such as erythromycin are often used.
In addition to the naturally occurring resistances there is increasing acquired antibiotic
resistance so that if possible treatment should only begin once the results of antibiotic
resistance testing are available.
Current treatment options include:
-
azithromycin 1 g as a single dose
-
azithromycin 1,5 g total dose given over 5 days
-
or doxycycline 100 mg 2 × daily for 7 days.
Treatment success should be tested three weeks after treatment at the earliest, especially
in the case of mycoplasma genitalium. In the presence of bacterial persistence common
antibiotic regimes are
-
metronidazole 500 mg 2 ×/day for 5 – 7 days plus azithromycin for 5 days
-
or doxycycline for 7 days
-
or moxifloxacin 400 mg per os 1 ×/day for 7 – 14 days [33].
Moxifloxacin should be used with caution and only in the context of treatment failure
since it can cause a rare but severe liver reaction. Mycoplasma genitalium infection
acquired in Southeast Asia is resistant to macrolides and quinolones in 10% of cases
and pristinamycin is the only effective antibiotic in these patients [34].
Treatment of the patientʼs partner with the same antibiotic shown to be effective
in the index patient is generally recommended. Condom use or abstinence from sexual
intercourse is recommended until symptoms have resolved.
Outlook for the future
New laboratory methods and gene analyses provide promise for the future: it has recently
become possible to determine the female microbiome in catheter urine using culture
and 16S RNA sequencing. This has already led to the finding that urine of symptom-free
patients contains bacteria and is not sterile as previously assumed [35], [36]. Urine appears to constitute its own microbiological niche that is extremely diverse
and may include typical uropathogens such as mycoplasma and ureaplasma species [26], [36].
Limitations of this review
There is little factual knowledge regarding women in this field. Studies on men, which
are far more numerous, were deliberately excluded from this analysis in order to focus
and provide clarity on the evidence in women. Preclinical studies would expand on
these findings.
The heterogeneity of definitions e.g. interstitial cystitis, the painful bladder syndrome
and OAB is a further limitation since they were not used according to the international
criteria of the IUGA or ICS in all articles and are thus of limited informative value.
Larger, high evidence level, randomised studies of treatment are lacking.
