Clinical outcome of routine treatment of patients with Pelvic Inflammatory Disease and/or Tubo Ovarial Abcess in the presence or absence of Mycoplasma genitalium (MG)

One of the most common and serious infections of nonpregnant women of
reproductive age is pelvic inflammatory disease (PID). PID is caused by
ascending bacteria and can be complicated by tubo-ovarian abscesses (TOA).
These TOA*s can rupture and cause sepsis, resulting in life-threatening
situations.

In the Netherlands, pelvic inflammatory disease (PID) is empirically treated
with ofloxacin/levofloxacin and metronidazole after exclusion of Chlamydia
trachomatis (CT) and Neisseria gonorrhoeae (NG) as causative pathogens.
Numerous studies implicate a role for Mycoplasma genitalium (MG) in the
development of PID. A pooled estimate relative risk for PID if MG is present is
2.14 (95% CI 1.31-3.49). However, some studies indicate that there is no major
role of MG in the development of PID. In addition, whether specific treatment
for MG improves short-term and long-term outcome is unsure. A recent review
recommends that prospective studies evaluate whether screening programs and
targeted treatment of MG improve reproductive outcomes in women are necessary
to guide public health policy for this emerging pathogen. Nonetheless, recent
British (BASHH) as well as international (IUSTI) guidelines recommend MG
testing, molecular determination of antimicrobial resistance and specific
treatment, including partner treatment (6, 7). In contrast, neither the US CDC
guideline, nor the Dutch NHG, NVOG and multidisciplinary STD guidelines for PID
treatment do recommend MG testing in case of PID (2, 9). Patients with non-NG,
non-CT PID are routinely treated with ofloxacin (2 dd 400 mg po) or
levofloxacin (2 dd 500 mg iv), in combination with metronidazole (oral 500mg 2
dd) for 14 days; or the alternative regimen consisting of a single dose
ceftriaxon (500 mg im) for the treatment of a possible NG infection, followed
by doxycyclin (oral 2 dd 100 mg) in combination with metronidazole (oral 500 mg
2dd) for 14 days.

Treatment of MG with the fluoroquinolones ofloxacin or levofloxacin is probably
suboptimal, since both antibiotics are only moderately active against MG. Both
ofloxacin and levofloxacin have higher Minimal Inhibatory Concentrations (MIC)
values than the fluoroquinolone moxifloxacin. However, clinical effectivity of
these antibiotics for MG has so far only been tested for male patients with
urethritis, using a lower dosage and a shorter treatment duration in comparison
to schedules mentioned above. The European guidelines on MG infections
recommend to treat uncomplicated MG infections with azithromycin (po 500 mg on
day one, then 250 mg on days 2-5) or josamycin (po 500 mg 3 dd for 10 days).
Resistance against azithromycin is increasing and is in many countries higher
than 30%. The European guidelines recommend to treat uncomplicated
azithromycin-resistant MG infections with moxifloxacin (po 400 mg for 7-10
days). Unfortunately, resistance against the second line treatment is also
already reported. Advised third-line treatment consists of doxycycline (po 100
mg 2 dd for 14 days), however this will only eradicate MG in 30% of the
patients. Alternatively pristinamycin (po 1g 4 dd for 10 days) can be used, of
which the cure rate of macrolide resistance MG is around 75%. Neither josamycin
nor pristinamycin is registered in the Netherlands. The recommended treatment
for complicated MG infections, such as PID and epididymitis, is moxifloxacin
(po 400 mg dd for 14 days).

If MG is a causative organism in PID, an optimal treatment of MG in PID will
improve final outcome, possibly also with regard to long-term consequences in
fertility. It could also decrease the number of reinfections after treatment of
PID if partners are appropriately treated. However, widespread use of MG
testing will increase costs for diagnostic testing. In addition, it can be
expected that as soon as MG is recognized as an important pathogen in PID,
efforts will be started to test and treat also MG in asymptomatic patients
(both male and female) with a risk of STD. The number of tests for MG might in
that case become equal to the number of tests for CT, at least for the
heterosexual population. In 2017, 105,000 CT tests were performed for the
heterosexual population in STI clinics, and probably the same number of tests
at GP offices and other settings. Moreover, since resistance to azithromycin
(preferred treatment outside of PID for susceptible MG strains) occurs in
30-50% of MG positive patients, additional antimicrobial susceptibility testing
will be required at additional costs. In addition, in case of MG infection a
test of cure is recommended, increasing diagnostic costs even more. Finally, if
10% of all tested patients will be MG-positive and 50% of them will need
treatment with moxifloxacin, 11,000 patients might require a 10-14 day
treatment. Moreover, extensive treatment of MG potentially induces
antimicrobial resistance in other pathogens. We therefore aim to study how
relevant MG testing and treatment is for clinical sequelae.

An additional question is the effectiveness of treatment in patients in whom no
MG has been detected. In some of them CT or NG is demonstrated, but in a large
proportion of patients the causative agent is unclear. The collected data makes
it possible to compare the clinical effectiveness of therapy between groups
with different causative agents.

The primary aim of the present study is to investigate whether current standard
treatment for PID is clinically effective in patients in whom Mycoplasma
genitalium (MG) is present. A secondary aim of the study is to asses whether
this treatment is microbiologically effective.
Research questions involved in this study are the following:
1. What is the prevalence of MG in patients with PID and/or TOA?
2. What is the effectivity of PID treatment according to NHG/NVOG guidelines on
persistence of MG?
3. Does persistence of MG in PID correlate with worse clinical outcome in PID
on day 14 and 28?
4. What is the relation of treatment effectiveness and antibiotic resistance in
MG?

Addititional question added May2024:
5. What is the clinical efficacy of PID-treatment according to NHG/NVOG
guidelines, in relation to the causative agent of PID?

This prospective cohort study will take approximately 1 year. The study will
include patients diagnosed with PID and/or TOA at the hospitals OLVG (both
locations East and West), Meander Medical Centre (MC) and Flevo Hospital, and
at the STI clinic in Amsterdam.

All patients diagnosed with PID and/or TOA will be asked to participate in this
study. Patients at the hospitalswill be routinely treated with ofloxacin po (or
levofloxacin iv) and metronidazol po treatment according to present NHG/NVOG
guidelines. Patients at the STI clinic will be treated with doxycyclin (1 dd
200 mg) and metronidazol, according to local guidelines. Ceftriaxone (one
single dose 500 mg im) is added to the antibiotic regimen in the hospitals when
patients are hospitalized and antibiotics are intravenously administrated; and
will be added in case of NG infection at the STI clinic. Treatment will be
evaluated clinically. Vaginal swabs, routinely obtained for testing of CT and
NG, will also be tested for MG. Patients will be asked to keep a diary in which
they report fever, pain and other clinical symptoms. Results of MG testing will
not be communicated with the clinician and the patient until the end of
follow-up at day 28.

At day 14 patients are asked to take a swab for a self-sampling test and send
it to the research laboratory to test for microbes including CT, NG and MG. At
day 28 the patient is asked for a control visit to evaluate clinical treatment
efficacy and microbiological MG treatment efficacy.

All specimens that are positive for MG will be additionally tested for
resistance to azithromycin and fluoroquinolones. Specimens and clinical data
collected during the study will also be anonymously stored in a Biobank and a
clinical database, respectively, for possible later studies regarding causative
organisms in PID, such as bacterial vaginosis related pathogens and Trichomonas
vaginalis.

If MG persists at day 28, it will be decided by the clinician whether
additional antibiotic treatment, including partner treatment, is deemed
necessary. Patients are asked for extra control visits (day 42 and 56) to
evaluate the alternative MG clinical and microbiological treatment efficacy.

At day 1, 3, 5, 7, 14 and 28 (and in case of persistent MG with start of
another antibiotic treatment at day 29, 31, 33, 35, 42 and 56) patients will be
asked to report pain, fever and other clinical symptoms in a diary. In
addition, MG will be tested for at the start of inclusion, at day 14 and 28
(and in case of persistent MG at day 42 and 56) after the diagnosis PID.
C-reactive protein (CRP) will also be determined at inclusion and at day 28.

In case the patient detoriates under standard clinical care, the clinician can
decide to change the treatment regimen. If deemed necessary in these cases, the
clinician can ask for the result of the MG test. Before switching treatment, a
new vaginal swab will be taken for routine diagnostics as well as for MG
testing. Clinicians should report this change in regimen clearly. In all other
cases, the initial MG test result will be disclosed at day 28 after the
clinical evaluation of the patient.

Burden associated with participation:
- collection of an additional vaginal self-swab at day 14
- completion of diary
- test of cure visit at day 28 (if patient does not participate, this could be
done by telephone)
- additional vaginal swab and blood specimen collection at day 28.

Risks associated with participation:
- not applicable

Benefits associated with participation:
- test of cure visit at physician's office
- if persistent presence of MG and persisting complaints: possibility of guided
treatment