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 he also been demonstrated in patients with pyelonephritis 6 . The pathogens are thought to he 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 .
UrethritisUrethritis 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 he all described urethritis in women caused by or associated with mycoplasma genitalium 9 , 10 , 11 .
Although mycoplasma hominis and ureaplasma urealyticum he 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 he 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 ailable 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 infectionsThe 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 he 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 ailable.
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 he resolved.
Outlook for the futureNew 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 reviewThere 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.