Culture facilities for identifying Mycoplasma genitalis, M. hominis and Ureaplasma urealyticum should be introduced as a matter of urgency writes Dr Fred Lim.
“When we omit these cultures we are increasing a reservoir of sexually transmissible bacteria, resulting in a further increase in reported cases of NSU and its complications.”
We have all seen patients with genital infections. After examination and investigations no offending organisms are cultured. Is there a parallel between male patients who attend with classical symptoms of non-specific urethritis (NSU), and female patients presenting with cystitis, or who have been diagnosed as cases of non-specific vaginitis (NSV). Add those patients with interstitial cystitis, pelvic inflammatory disease (PID), Bartholinitis, subfertile patients, cases of epididymo-orchitis, prostatitis and sexually acquired reactive arthritis, then we have a large group of patients and frustrated colleagues.
When the physician is unsure of the cause the patient becomes concerned and the use of a broad spectrum antibiotic, although given with reason, hinders the establishment of a definite diagnosis. Furthermore, contact tracing is made more difficult when the partner cannot relay a diagnosis to their physician.
Although much has been written about chlamydia, how many times has it been absent despite the availability and relative ease of its identification by ELISA or polymerase chain reaction (PCR)? We often receive reports stating that bacterial vaginitis (BV) is the cause of vaginal discharge – we are advised to prescribe metronidazole, then to extend the course to 400mg bd for 7 days, and to treat the male partner if there is a recurrence. Is this not an all too familiar tale?
Patients might be treated in primary care or referred to a genito-urinary (GU) department, and the more chronic cases await a gynaecological or a urological opinion. The GU departments admit their workload has greatly increased with more than 1.5 million attendances in 2002. In the 6 years previously there was a 457% increase in uncomplicated chlamydia and 105% increase in uncomplicated gonococcal infections (GP; 30 Aug 2004:31). The clinics rely on the presence of leucocytes in the male urethral swab as an indication of urethritis with threads in the first urine sample voided. A Gram-stained vaginal sample is used to identify Gardnerella vaginalis and mixed anaerobes, and a wet film is examined for T vaginalis. Urine samples from both sexes and a high vaginal swab (HVS) would give greater clarity.
There are recent papers detailing the causes of vaginal discharge (BMJ 2004;328:1306) and infection screening in routine antenatal care (BMJ 2004;329:371). There are, however, few papers on Ureaplasma urealyticum, Mycoplasma genitalis, Mycoplasma hominis and their role as causes of NSU, NSV, cystitis and PID, (Lancet 1998;351 (Suppl III):1215), (Sex. Transm. Inf. 2001;77:22), (Sex. Transm. Inf. 2002;79:154). There are presently no routine culture facilities for identification of these bacteria in the NHS GU departments, yet I have received and confirmed reports from Croatia and France.
Mycoplasma have been known to be pathogenic for mammals since 1898. The first human mycoplasma isolated was M. hominis from an inflamed Bartholin’s gland in 1937.
Mycoplasmas are the smallest self-replicating organisms with the smallest genomes (total 500-1000 genes). These are therefore nutritionally fastidious and difficult to culture. Ureaplasma require urea for growth too and were isolated in 1954. They have fulfilled Koch’s postulates and been identified in venereal – associated arthritis (Arthr. Rheum. 1996; 39:905). Mycoplasma genitalium was isolated in 1980 (Lancet 1981;1:1298) and there is a strong association with acute NSU (Sex. Transm. Int. 2001;77:229). It has many characteristics with M. pneumoniae, a recognised pathogenic bacteria. They have been considered a surface parasite of the human respiratory and urogenital tracts and are able to attach to eukaryotic cell surfaces. I therefore think the term that these bacteria are “potentially pathogenic” should be adopted. It would explain why there is reluctance to accept their role when they are isolated without apparent harm to the patient. I anticipate that future research further will support that they are pathogenic in the urogenital tract.
Chlamydial intervention has not, and is unlikely to eradicate PID. Antibiotics given to treat chlamydia infection may be less effective in the treatment of mycoplasma and ureaplasma. There is an association between M genitalium and PID (Sex. Transm. Inf. 2003;79:154) and it was shown that this relationship was independent of C. trachomatis. The causes of PID should include these elusive bacteria and those associated with BV.
Gardnerella vaginalis is not the sole cause of BV. M. hominis has been found in two-thirds of woman with BV. Its exact role is not known, but it has been isolated from endometrium and fallopian tubes of 10% of women with salpingitis diagnosed at laparoscopy (BJVD 1970; 46:179). Women who have BV have a five-fold increased risk of premature labour or late miscarriage (Br. J. Obstet Gynaecol 1994;101:1048). I suggest that uncomplicated cases of BV should be given intravaginal metronidazole, with prophylactic Gyno-Daktarin pessaries on alternate nights. Recurrent cases should be prescribed a course of doxycycline, 100mg bd for 7 days, reducing to 100mg daily for a further 7 days. Add again Gyno-Daktarin pessaries, which the patient omits if she has a period. A possible alternative to doxycycline is a 5-day course of azithromycin 500mg on day 1 and 250mg for the following 4 days (Int. J. of STD & AIDS 2002; 13:145) but information is sparse and contradictory when fluoroquinolones and clindamycin have been recommended in Singapore (Diag, Micro. And Int. Dis. 2004; 48:207).
When investigating a case of cystitis I take an HVS. This swab may yield ureaplasma or mycoplasma when the urine sample, a more difficult medium to utilise, is negative. This is advantageous when patients have already taken multiple antibiotics.
Another problem has arisen because chlamydia became so well recognised and there has been a concerted effort by the NHS to reduce it’s incidence. Whilst the GU departments favoured tetracycline, especially doxycycline, as the preferred therapy for patients with NSU and their partners, chlamydia, ureaplasma and mycoplasma could be eradicated simultaneously, if the course was given for long enough. Patient compliance was a problem and studies on azithromycin (Zithromax) indicated its use as a single dose of 1g was as effective as a 7-day course of doxycycline 100mg bd, so prescriptions were altered.
I believe that time taken to explain to patients why a lengthy course of antibiotics is necessary results in compliance. I illustrate that these bacteria are unusual and unlike other bacteria, they have no cell wall that the antibiotic can split and destroy. Imagine a sponge with pores. To kill it, it has to be suffocated by filling up all the pores, a process which tetracyclines (which are bacteriostatic by action) are ideal. It therefore takes time, perhaps 2 to 3 weeks or longer. Patients then understand why I do not favour short courses unless the condition is acute. Epithelial cells can be invaded by M. genitalium and thus protected, might result in apparent clinical failure of treatment (Int. J. Exp. Pathol. 1994;75:91). This is similar to the lifecycle of C.trachomatis, which includes an intracellular phase.
Culture facilities for identifying M. genitalis, M. hominis and U. urealyticum should be introduced as a matter of urgency. DNA probes and amplification of specific genome mycoplasma sequences by PCR have been developed (in December 2007) and have increased our knowledge. When we omit these cultures we are increasing a reservoir of sexually transmissible bacteria, resulting in a further increase in reported cases of NSU and its complications.