Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT04925388 |
| Other study ID # |
APHP191112 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 30, 2022 |
| Est. completion date |
March 5, 2024 |
Study information
| Verified date |
May 2024 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hospitals, and more specifically Intensive Care Units (ICU), face the challenging issue of
emergence and rapid spread of multi-drug resistant bacteria (MDR). In some cases, the
therapeutic choice is extremely limited. Prevention and adequacy of antibiotic therapy (AB)
are the key responses applied toward these threats. A delayed adequate AB is a known factor
of poor prognosis. Intra-abdominal infections (IAI) are frequent, polymicrobial and life
threatening diseases. Source control and adequate AB are instrumental issues in this setting.
Despite technical advances, susceptibility testing of the microorganisms collected from
peritoneal samples is not usually available before day two or three after surgery. In this
time lapse, empiric AB might be inadequate (not targeting all the pathogens, which leads to a
prolonged duration of AB and potential increased morbidity/mortality risk) or too broad (with
the two issues of ecology with an increased risk of selection of MDR bacteria and additional
costs). In a pilot study evaluating the potential benefit of a direct culture of peritoneal
samples from resuscitation patients treated for peritonitis, we observed that conventional
treatment made it possible to obtain microbiological results within a median of 3 [extremes
2-7] days whereas a direct microbiological technique by E-test gave results in 1 [1-2] days
(p <0.0001). With this technique close to conventional microbiological, a change in
antibiotic therapy could have been achieved within an average of 1 [1-2] days versus 4 [1-11]
days with conventional management (p = 0, 0006).
The development of modern molecular techniques suggests that a large margin of improvement
for the rendering and the precision of the results is possible.
Description:
BACKGROUND
Antiinfective agents are aimed at eradicating microorganisms, or at least significantly
reducing the size of inoculum to facilitate the natural activity of host defence mechanisms.
One of the most challenging issues faced by prescribers is the emergence of multidrug
resistant bacteria (MDR) and fungi, especially in the ICU setting. In some instances, the
therapeutic options are extremely limited or even totally inadequate.
The responses to this threat are improvements in prevention of nosocomial infection,
antiinfective stewardship policy, and a better use of available resources including
optimization of antibiotic therapy from the empiric phase of treatment. The optimization of
antibiotic and antifungal therapy is a key issue. In a recent paper analysing the antibiotic
prescription in a tertiary care hospital over a 9 to 10 weeks period, the authors reported an
inappropriateness in 37% of the cases involving indication of therapy (17.5%), choice of the
spectrum (7.6%) and application of the treatment (dosage, timing, duration…)(9.3%).
Delayed adequacy for antibiotic therapy is a known factor of prolonged duration of
anti-infective therapy and consequently of selection pressure. Adequacy is defined as the
microbiologically effective antimicrobial treatment against the causative pathogens. A
decreased duration of antibiotic therapy is an easy to implement strategy to decrease the
emergence of resistance both at individual and community levels. This strategy of a reduced
duration of therapy has additional potential advantages such decreased incidence of adverse
effects and reduced costs.
The selection of an empiric antibiotic (AB) therapy is often a difficult challenge. Despite
advances in conventional microbiologic techniques, identification and susceptibility testing
of the microorganisms collected from a suspected infectious site are not usually available
before day two or three after sampling. In this time lapse, empiric AB therapy might not
target all the pathogens, which leads to a prolonged duration of AB and potential increased
morbidity/mortality rates. To overcome this uncertainty, physicians frequently prescribe very
broad-spectrum empiric regimens to target a maximum number of potential pathogens. This is
specifically the case in ICUs where life-threatening infections justify this policy. However,
as mentioned above, the consequences in terms of selection pressure, cost and adverse effects
are of major importance.
To overcome the disadvantage of delayed microbiologic results, some authors in ICU medicine
tried to shorten the delay of results of susceptibility testing in using direct E-test. The
E-test antimicrobial susceptibility procedure is a quantitative method for antimicrobial
susceptibility testing that consists of a reagent strip with a predefined gradient of AB. The
stable gradient provides an inoculum tolerant system that allows its application directly to
clinical specimens. This method has been shown to be reliable for predicting the
susceptibility of microorganisms directly from positive blood cultures. It has also been
applied directly to sputum samples from patients with cystic fibrosis. However, the
physicians in charge of the patient still have to wait for at least 24 hours before having
the first results of bacterial growth and susceptibility. However, in case of slow-growth
this delay could be enlarged. In addition, this technique is inaccurate for antifungal
therapy.
Major advances in molecular biology over the last decade led to the development of rapid
diagnosis and identification techniques. Techniques of genomic analyses bring important
information on pathogen identification and on presence of certain resistance genes in hours
rather than days and allow an early adaptation of antibiotic treatment,allowing the physician
to choose the most accurate therapeutic strategies. Promising results have been obtained in
the field of pneumonia. On the opposite, few data are available in intra-abdominal
infections.
The Unyvero (Curetis) platform is a turnkey rapid diagnostic system that can be used to
diagnose severe infections in 4 to 5 hours. The Unyvero IAI panel (Intra-Abdominal Infection)
covers the bacteria involved in IAI, such as Gram negative bacilli (Enterobacteriaceae,
Pseudomonas aeruginosa, Acinetobacter baumannii), Gram positive bacteria (Streptococcus spp.,
Staphylococcus spp., Enterococcus spp.), anaerobic bacteria (Bacteroides spp., B fragilis,
Prevotella spp.) and fungi (Candida albicans, C glabrata, C tropicalis, Candida spp.), as
well as some antibiotic resistance genes such as certain ESBL (CTX-M) and carbapenemases.
These infections are among the most frequent complications in surgical patients and are
marked by a severe prognosis. They are characterized by high proportions of MDR isolates,
reaching 85% of all the cultured organisms. In addition, the characteristics of bowel flora
with mixed Gram positive, Gram negative and anaerobes bacteria lead to the constant threat of
inadequate empiric antibiotic therapy. These IAI need an early efficient antibiotic therapy
combined to source control, especially in the most severe cases admitted in ICU.
Postoperative IAI are the cases where the needs for an adequate antibiotic treatment from the
empiric phase are the most significant. In community-acquired infections, guidelines have
been published that give satisfactory results in a vast majority of the cases. On the
opposite in postoperative cases, many unsolved questions remain depending of the case mix and
local epidemiology, leading to high proportion of inadequate empiric antibiotic therapy, and
consequently increased duration of treatment, delayed adequacy and increased mortality and
morbidity rates.
Fungal infections, especially candidas are another issue in these cases of IAI. These
microorganisms are reported in up to 30% of the operative samples in postoperative
intraabdominal infections. However, due to the lack of relevant clinical criteria and the
slow growth of these microorganisms, more than 70% of all antifungal empiric therapies given
for these patients are inappropriate, and not necessary in most of them. In line with the
French recommendations, in patients at risk of fungal infections an empiric antifungal
therapy will be started.
Every approach aimed at improving the empiric antiinfective therapy in postoperative IAI is
welcomed. To our knowledge, few data are available addressing this issue. Techniques derived
from conventional cultures are of interest but the delay to reach bacterial growth remains
high and obviously >24 hours. Due to the capacities of the rapid molecular diagnostic test,
therapeutic decisions (initiation of empirical therapy, interruption of unnecessary empirical
therapy or adjunction of specific additional regimens such as antifungal agents) could be
performed in a few hours. The potential benefit of these techniques and gain of time could be
illustrated in an experimental pilot study performed in our unit analysing peritoneal samples
of ICU patients with secondary peritonitis when these new molecular techniques were not yet
available. The conventional approach brought results in a median delay of 3 [extremes 2-7]
days while the use of direct antibiotic-enriched agar plates were available in 1 [1-2] days
(p<0.0001). A change in AB regimens would have been made in a median delay of 4 [1-11] days
versus 1 [1-2] days if direct cultures were applied, respectively (p=0.0006).
Recently, an external evaluation of a multiplex PRC rapid test for detection of
intra-abdominal infections was assessed in 4 laboratories of microbiology. Three hundred
clinical samples were evaluated including 107 peritoneal fluids, 47 ascites, 36 peritoneal
cavity drain fluids, 32 swabs (eswab fluid as well as charcoal swabs), 27 pus, 29 bile, 7
tissue samples, 7 aspirates, 5 pancreatic fluids, and 3 samples were from blood culture
bottles inoculated with peritoneal fluid. Microbiology results were negative for 86 samples.
Of these, 62 samples (72%) were also negative with the Unyvero IAI test while pathogens were
detected in the remaining 24. In 16/24 samples, the pathogens detected by Unyvero IAI were
confirmed by sequencing. Overall Sensitivity was 91.2% and Specificity 99.5%. Most pathogens
detected by the Unyvero IAI test achieved a sensitivity of at least 80.0% while 12/27 panel
targets achieved a sensitivity of 100%. Specificity ranges from 97.3% to 100% over all panel
targets.The Unyvero IAI cartridge was able to detect additional microorganisms in particular
anaerobes with most detections confirmed by sequencing. Time to identification was reduced by
an average of about 17h (39:06 ± 16:09 h for microbiology vs 22:02 ±4:12 h Unyvero IAI (ID
+resistance markers)) and time to full microbiological results was reduced by an average of
about 41h (64.19 ± 12.10 h for microbiology vs. 23.44 ± 3. 58 for Unyvero IAI). The most
frequent resistance markers detected were mecA/mecC (n=25), aacA4 (n=20), blaCTX-M (n=17) and
nine instances of carbapenemase were identified. PPV range from 62.5 to 93.8% while NPV range
from 70.2 to 100%.
HYPOTHESIS
The use of a rapid molecular diagnostic test by multiplex PCR on the peritoneal samples from
ICU patients admitted for an intra-abdominal infection is feasible and makes it possible to
obtain the identification of the germs present in the clinical sample and detect the presence
of certain resistance genes in the first 24 hours after surgery, making it possible to reduce
exposure to antibiotics and antifungals without increasing the frequency of clinical or
microbiological failures
