Pneumonia treated with rifampicine attenuates inflammation

Community acquired pneumonia (CAP) is diagnosed by the general practitioner in
approximately six of thousand patients a year. This incidence is much higher in
the elderly.
CAP associated mortality is about six thousand patients in the Netherlands a
year.
With current economic depression and cutback in funding for health care, we
need to reduce expenses without compromising quality.
The costs for pneumonia and influenza each year are approximately 500 million
Euros in the Netherlands. In patients with CAP, better treatment can result in
reduction of costs. This study will contribute to better care in the future for
patients with community acquired pneumonia.

In order to reduce mortality and length of hospital stay in the future, we want
to do a pilot study to find out if we can reduce inflammation (inflammatory
parameters/biomarkers) in patients with community acquired pneumonia. Later, in
a future study we can compare if treatment with rifampicin is better than
treatment without rifampicin in community acquired pneumonia.

An important source of inflammation in pneumonia is the release of bacterial
cell wall products. The amount of immune-active compounds from bacteria is an
important determinant of the severity of inflammation.
Lipoteichoid acid is released from the bacterial cell wall in gram positive
bacteria. This occurs when bacteria are killed by autolysis or host immune
cells. An acute, excessive break down of bacterial cell wall occurs with
exposure to antibiotics.
This lipoteichoid acid (LTA) can act on macrophages and can induce a cascade of
proinflammatory reactions in the host. Since morbidity and mortality have been
attributed to the inflammatory respons in infection, reduction of release of
lipoteichoid acid might decrease inflammation and morbidity and mortality.

One potential solution for this is killing the bacteria without immediately
lysing them. Less bacterial cell wall products, like lipoteichoic acid, will
then be released directly after start of treatment.
Penicillin and cephalosporin, and to a lesser extent ciprofloxacine/quinolone,
disrupt the bacterial cell wall causing acute lysis of the bacterium. Non-lytic
antibiotic might cause less inflammation.
In vitro studies showed that rifampicin releases less lipoteichoic acid and
pro-inflammatory compounds from Streptococcus pneumoniae than ceftriaxon or
meropenem.
Herman Mattie et al. showed that rifamycins were most effective in killing S.
pneumoniae while causing the least LTA released per killed bacterial cell. When
beta lactam antibiotics are started 6 hours after initiating treatment with
rifampicin, no substantial release of LTA/TA (and pneumolysin) is observed in
vitro. A second immunomodulatory substance is pneumolysin. It also possesses
cytolytic effects. This thiol-activated membrane-damaging toxin pneumolysin is
one of the important virulence factors of Streptococcus pneumoniae. It is a
cytoplasmic protein and is released during bacterial growth and autolysis:
e.g., due to antibiotic treatment.
There is difference between outcome in patients with severe pneumonia admitted
to the ICU early (< the first 24 hour of admission) or late (>= 1 day to of
admission). Patient referred to the ICU late, have higher 30-day mortality. The
initial screening tools for the severity of community acquired pneumonia may be
insufficient for predicting the course of disease in the first few days of
admission, especially after start of antimicrobial therapy.
Release of lipoteichoid acid and other proinflammatory compounds of bacteria
(pneumolysin) can be the cause of initial clinical deterioration after start of
antibiotic treatment.
Prospective in vivo studies with a sufficient number of patients on this
subject do not exist.
This study can provide clues that a larger study to compare treatment with and
without rifampicin, can be valuable. In the future, clinical end points can be
compared.

See for reference list chapter 12 in the protocol

To primary objective is to demonstrate a reduction in lipoteichoic acid release
in patients with pneumococcal pneumonia treated with rifampicin. This will be
done by measuring lipoteichoic acid in serum and urine.
Evaluable patients for Intention-to-Treat analysis are those who met the
following criteria: (1) the inclusion criteria, (2) Streptococcus pneumonia is
identified as the cause of pneumonia, (3) received at least one dose of study
drugs and (4) outcome is measured at 30 days.

Evaluable patients for Per-Protocol analysis are those who meet the following
criteria: (1)the inclusion criteria, (2) Streptococcus pneumonia is identified
as the cause of pneumonia, (3) received the study drug for 48 hours and (4)
outcome is measured at 30 days.


Secondary Objectives:
The secondary objectives of this study are to determine:
• Duration of symptoms
• Length of hospital stay
• 30 Day all cause mortality
• Length of ICU stay
• (Multiple) organ failure on ICU
• Adverse events
• Serum biomarkers: C-reactive protein (CRP), Procalcitonin (PCT), Plasma
secretory leukocyte protease inhibitor (SLPI), Soluble triggering receptor
expressed on myeloid cells (sTREM)-1, IP-10, vitamin D and antimicrobial
peptides like Cathelicidin and Beta-defensin-2,
• Microbiological diagnosis
• Evaluation of empirical coverage of the microbiological diagnosis (with this,
we can determine whether the empirical treatment was appropriate or not)
• Emerging of resistant microorganism carriage.

The PRISTINE Study is a randomized, non-therapeutic controlled study that will
evaluate the response of rifampicin treatment added to penicillin with or
without ciprofloxacin in patients with pneumonia (CURB65 score >=2, or high
clinical suspicion of pneumococcus as causal microorganism) presenting at the
emergency department.
After informed consent, patients will be randomized (2:1) on the emergency
department.

All patients get treatment according to the latest guideline of the SWAB
(Stichting Werkgroep Antibioticabeleid), see chapter 5.
The same samples will be drawn in the rifampicin treatment group as in the
group which gets no treatment with rifampicin.
Total treatment duration will be assigned according to the latest Dutch
guideline of community acquired pneumonia.
Treatment of pneumococcal pneumonia will be 5-7 days.

Assessments of clinical response will be performed continuously during the
treatment period by the attending physician, 1-3 days after admission by the
clinical researchers, 30 days after start of therapy by a visit of the clinical
researchers and 90 days posttherapy by a telephone call.

Besides normal diagnostic procedures (sputum culture, blood culture, routine
laboratory tests), extra samples are taken:
• At inclusion: 2 throat swabs, 1 rectum swabs, a urine sample and 8 ml of EDTA
blood for biomarker assay en LTA measurement and 2 ml of blood (in PAXgene RNA
tubes).
• At 2, 4, 8, 16, 24, and 48 hours after inclusion: 8 ml blood and a urine
sample (10ml)
• At day 30: 8 ml of blood, a urine sample (10 ml) and a rectum swab

All subjects will receive standard antibiotic treatment defined by the 2011
SWAB guidelines. Patients with moderately severe CAP (CURB-65 score = 2) will
be treated with monotherapy benzylpenicillin, 4 times a day 0,5 million IU
intravenously. If patients in this group have risk factors for legionella
(recently travelled abroad, legionella epidemic or failure of β-lactam
antibiotic), ciprofloxacin, 2 times a day 400 mg intravenously, will be added.
All patients with severe CAP will be treated with benzylpenicillin, 4 times a
day 0,5 million IU intravenously and ciprofloxacin, 2 times a day 400 mg
intravenously.

Subjects will be randomized to receive, besides standard antibiotic treatment,
either:
• Rifampicin 2 times a day 600 mg iv for 48 hours intravenously.

OR

• No extra treatment

The study treatment will be open-label.

The total duration of antibiotic therapy in pneumococcal pneumonia is 7 days.

burden and risk are limited since this is an open-label trial with a well known
drug
Benefit will be limited, we'll expect a biochemical benefit in the treatment
group. Clinical benefit will probably be limited.