Pilot study: Fosfomycin levels in prostate tissue after oral and iv administration

Infections of the prostate caused by multidrug-resistant gram-negative bacteria
are a growing problem. In particular resistance to fluoroquinolones and
cephalosporines is problematic, as these drugs are widely used as treatment for
prostatitis and as profylaxis prior to prostate biopsy and transurethral
resection of the prostate (TURP). The increase of resistance is prompting the
re-assessment of *older* agents. Fosfomycin is such an agent, and particularly
interesting as many of the multidrug-resistant bacteria remain susceptible to
this antibiotic.

To prevent and to treat infections, adequate tissue concentrations of
fosfomycin need to be achieved. Until now, little is known about the
penetration of fosfomycin in prostate tissue.

To measure intraprostatic concentrations and serum levels of fosfomycine after
a single oral or intravenous dose prior to TURP. This is done to achieve more
insight in whether fosfomycin is a suitable antibiotic to use as profylaxis or
treatment of prostatitis

There will be no randomization or blinding. The first 15 subjects included in
the study will receive 3 gr fosfomycin tromethamine 2 hours before TURP (group
A), the second 15 subjects will receive 2 gr fosfomycin disodium directly prior
to TURP (group B).
In addition, intravenous cefazolin 1 hour before surgery will be used as
standard antibiotic prophylaxis (1 gram in patients <80 kg, 2 grams in patients
>80 kg)
At the start of the TURP procedure a plasma sample of 4-6 ml will be drawn.
Peak serum concentrations of intravenous fosfomycin occur immediately after the
administration. Peak serum concentrations of oral fosfomycin occur two hours
after a 3 g dose. At the end of the procedure, a second blood sample will be
drawn. A third blood sample will be drawn the morning after the operation (as a
standard procedure, a blood sample is drawn the morning after the operation to
determine creatinine en hemoglobin levels in every patient undergoing a TURP)

Currently all tissue removed during transurethral resection of the prostate is
brought to the pathology department. For this study the 2cc prostate tissue
first acquired will be separated and the 2cc prostate tissue last acquired as
well, and these samples will be sent to the department of pharmacy for further
processing. Times of first removed tissue and of last removed tissue will be
accurately recorded.

For pathological investigation, in any TUR-P, a maximum of 10 cc tissue will be
included for microscopical analysis. Any material exceeding this 10 cc will be
discarded. That*s why a cut-off of 15 grams of resected tissue is chosen as a
exclusion criterion, so that there will be no tissue processed for this study
that would otherwise be analyzed for pathological investigation.

Prostate samples will be carefully washed to remove all blood contamination and
will be weighed prior to being frozen. This is necessary to make sure the
measured tissue concentration is not affected by fosfomycin present in any
blood left behind in the tissue.
Antibiotic concentration in plasma and prostate tissue samples will be
determined by a validated liquid-chromatography-tandem mass spectrometry
analysis method.

administration of 2 grams iv fosfomycin at the start of the procedure, or 3
grams orally 2 ours prior to surgery

The burden for patients included in this study consists of 2 venipunctures
during the TURP. Part of these patients will undergo this procedure under
general aenthesia, en therefore will not notice it.
Patients in this study risk experiencing side effects of the administered
medication. As it consist of only one gift, chances that this will happen are
considered low.