Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream – results of the first in human study

doi:10.21203/rs.3.rs-1494222/v1

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Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream – results of the first in human study

https://doi.org/10.21203/rs.3.rs-1494222/v1

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Background: The outcome of patients with bacteremia depends on both, the bacterial burden as well as the duration of bacteremia. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with Seraph^® 100 Microbind^® Affinity Blood Filter (Seraph^® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in Seraph^® 100 as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph^® 100 could help to decrease bacterial burden in vivo.

Methods: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for renal replacement therapy as an adjunctive treatment for bloodstream infection. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days.

Results: Fifteen hemodialysis patients (3F/12M, age 74.0 [68.0 - 78.5] years, dialysis vintage 28.0 [11.0 - 45.0] months) were enrolled. Seraph^® 100 treatment started 66.4 [45.7 - 80.6] hours after the positive initial blood culture was drawn. During the treatment with the Seraph^® 100 with a median blood flow of 285 [225 - 300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5 - 98.0] to 99.0 [98.0 - 99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph^® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was reduced between inflow and outflow blood cultures by 36 [-7.2 – 96.3] minutes. However, overall TTP reduction was not significant.

Conclusions: Seraph^® 100 treatment was well tolerated. Adding Seraph^® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies.

Trail registration: ClinicalTrials.gov Identifier: NCT02914132

Extracorporeal devices

bloodstream infections

haemodialysis

bacteraemia

Clinical outcome in bacteremia depends on both, the bacterial burden as well as the duration of bacteremia. This has been first shown in a preclinical model of pneumonia in which all rabbits receiving small doses of Streptococcus pneumoniae survived, while dose escalation of bacterial count increased mortality stepwise up to 100% (1). In men this correlation between bacterial load and outcome has been shown in E. coli and Staphylococcus aureus bacteremia where the amount of bacterial DNA in the blood correlated with mortality (2). The time to positivity (TTP) of blood cultures can be used as an indicator of pathogen load. In 742 adult hospital patients a positive blood culture within 48 to 96 hours after initial diagnosis was the strongest predictor of complicated Staphylococcus aureus bacteremia (3). In children with Staphylococcus aureus bacteremia a time to positivity of ≤ 17 hours correlated with adverse outcomes (4). The relationship between high bacterial burden and adverse clinical outcome has also been shown for Neisseria meningitides (5), Streptococcus pneumoniae pneumonia in adults (6) and in children (7). Aside from surgical intervention, only the timely administration of an empiric, broad-spectrum antibiotic therapy is so far able to improve outcome in critically ill patient with an infection (8). However empiric broad spectrum antibiotic treatment increasingly fails due to a rising frequency of resistance among most human pathogens (9) rendering even antibiotics of last resort ineffective (10).

To quickly reduce the blood pathogen load and to be effective in removing even multi-resistant bacteria, extracorporeal methods capturing bacteria are developed by several companies. A fast decrease of blood pathogen content, irrespective of the infectious agent, would not even require the microbiological identification of bacteria and viruses. After failed attempts of such a strategy in the 1980s (11) many different technologies such as filtration (12), use of human opsonin Mannose Binding Lectin (13), magnetic nanoparticle separation (14) bendable polycrystalline nanowires/carbon foam (15) and polyethylene beads with endpoint-attached heparin (16) have been developed. The latter uses covalently end-point attached heparin-coated ultrahigh molecular weight polyethylene (UHMWPE) that mimics heparan sulfate on cell surfaces so that bacteria and viruses bind to it in vitro (17).

The aim of the current first in human study was to investigate safety as well as efficacy of the Seraph® 100 Microbind® Affinity Blood Filter in the setting of blood stream infections in hemodialysis patients.

Patients and study design:

This first in human, prospective, multicenter, non-randomized interventional study included patients with bloodstream infections diagnosed with positive blood cultures and the preexisting need for renal replacement therapy. All patients had an already existing hemodialysis dialysis access at study enrollment, so no dialysis catheters had to be placed. Patients between 18 and 90 years of age were eligible when they showed signs of dialysis catheter related infection (redness, tenderness or purulence at the exit site or a lower TTP of at least two hours at the catheter than in the peripheral blood culture) or a suspected high bacterial burden (TTP less than 14 hours or blood culture positivity in at least two blood cultures). Detailed inclusion and exclusion criteria are shown in Supplemental table 1.

Medical device and treatment characteristics

The Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100) was manufactured by ExThera Medical Corporation, Martinez, CA, USA. The Seraph® 100 is a whole blood sorbent hemoperfusion device packed with polymer beads whose surface is modified with covalent end-point attached heparin (17). This bound heparin mimics cell-surface heparan sulfate in the body, a binding target for pathogens, toxins and Antithrombin III. This gives the Seraph® 100 the ability to remove pathogens while presenting a blood compatible surface to the blood being treated. The Seraph® 100 was placed upstream of the dialyzer on a regular dialysis machine. The treatment was intended to last between three to four hours with an established blood flow of 250–350 mL/min.

Outcome measures:

The primary endpoint measure of the study was to demonstrate the safety of the Seraph® 100 in a hemodialysis circuit assessed by rate of adverse events during procedure, clinically significant changes in hematology and chemistry indices and device complications during the procedure and 14 days thereafter. The secondary endpoint measure was the reduction of bacteria in blood passed through the Seraph® 100 over the four-hour treatment, indicated by a pathogen reduction of > 40% measured as colony forming units (CFU) or an increase in time to positivity (TTP) of > 22 minutes in blood passed through the Seraph® 100 cartridge in those blood cultures with a pre cartridge detectable bacterial count (as measured by CFU or TTP).

Blood sampling during the treatment:

Blood cultures were drawn upstream (inflow) and downstream (outflow) of the Seraph® 100 at 5, 30, 60, 120, 180 and 240 minutes after treatment initiation. The bacterial burden was assessed by the time to positivity (TTP), defined by the time between collection of the blood culture and the first signal of bacterial growth. The relationship between TTP and colony forming unit (CFU) as reported by Idelevich et al (18) is linear over the range of 1 to 100 CFU/mL. Therefore a TTP increase of 22 minutes is estimated to indicate a CFU reduction of about 22%. Additionally, a panel of routine laboratory test was performed before and after the Seraph® 100 treatment.

Statistical analysis

Quantitative variables were expressed as median [Q1 - Q3], categorical variables as counts (proportions). Continuous data was compared with the use of Wilcoxon paired signed rank test. For all test used a significance level of p < 0.05 was considered significant.

GraphPad Prism 9 (San Diego, CA, USA) and R Statistical Software (version 4.0.4; R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analysis.

We enrolled fifteen chronic hemodialysis patients (three female and twelve male) with a median age of 74.0 [68.0–78.5] years and a dialysis vintage of 28.0 [11.0–45.0] months. The vascular access comprised of tunneled dialysis catheter (n = 9), acute dialysis catheters (n = 4) and native AV-fistulas (n = 3) as some patients had more than one access. Patients were treated 66.4 [45.7–80.6] hours after initial positive blood culture. Detailed patient characteristics are given in Table 1.

Table 1

Baseline and treatment characteristics of the enrolled patients (data shown as median IQR).
Sex (F/M)	Age (years)	BMI (kg)	Dialysis vintage (months)	Blood flow (ml/min)	Dialysate flow (ml/min)	Ultrafiltration volume (ml)	Time enrolment to treatment (h)	Pathogen
F	72	42.5	86	250	250	0	89.25	Staph. aureus
M	74	24.0	39	285	500	1000	138.75	E. coli
M	69	24.3	15	81	81	0	45.0	Staph. aureus
M	57	33.3	28	300	500	2500	70.47	Staph. aureus
M	82	26.3	3	300	500	1600	66.4	Staph. aureus
M	67	27.2	29	300	500	3500	86.12	Staph. aureus
M	81	13.7	7	300	500	400	46.45	Staph. epidermidis
M	78	23.9	3	300	500	600	65.39	Staph. aureus
M	51	37.9	0.75	300	500	600	44.23	E. faecalis
F	75	36.0	75	250	500	3200	75.14	S. epidermidis
M	79	20.7	202	150	500	-1500	65.35	Staph. aureus
F	89	25.6	28	300	500	1300	99.25	Staph. aureus
M	70	33.1	51	250	250	320	23.5	E. faecalis
M	66	16.2	38	150	500	-1500	40.5	Klebsiella pneumoniae
M	78	28.0	20	200	500	1000	72.25	Staph. aureus
3/12	74.0 [68.0-78.5]	26.3 [24.0- 33.2]	28.0 [11.0–45.0]	285 [225–300]	500 [500–500]	600 [160–1450]	66.4 [45.7–80.6]

Primary outcome:

All patients tolerated the treatment well. None of the procedures had to be terminated prematurely. There were no visible clots or blood remnants reported in the Seraph® 100 after the rinse back with normal saline at the end of treatment. All patients survived the follow up period. A pre- and post- treatment overview of all vital signs and routine serum tests is given in Figs. 1 & 2.

During the treatment with the Seraph® 100 we did not observe any adverse effect on vital signs. Blood pressure and heart rate remained stable, peripheral oxygen saturation did increase from a median of 98.0 [92.5–98.0] before the treatment to 99.0 [98.0–99.5] %; p = 0.0184 (Fig. 1D). Antithrombin activity declined from 90.0 [84.5–103.0] to 85.0 [74.25–91.25] %; p = 0.0076 during the combined dialysis and Seraph® 100 treatment (Fig. 2E). As expected in a hemodialysis session, we detected a decrease for serum creatinine from 6.31 [4.54–6.94] mg/dl to 2.82 [1.83–3.46] mg/dl; p < 0.0017 and for urea from 100.0 [74.5–127.5] mg/dl to 46.5 [29.4–57.6] mg/dl; p = 0.0023 (Fig. 2Q and 2R). Serum total bilirubin levels increased during the procedure from 0.35 [0.20–0.40] mg/dl to 0.4 [0.28–0.52] mg/dl; p = 0.0168) (Fig. 2M). A single adverse event was reported during the procedures, but was not related to the device or the procedure according to the reporting clinician. Reported adverse events (AE) during the 14 day observation period are listed in Supplemental table 2. No AE was supposedly related to the procedure.

Secondary outcome:

The secondary outcome measure was the reduction of bacteria in blood passed through the Seraph® 100 over the four-hour treatment. We show inflow and outflow TTP values in Fig. 3. A total of four out of fifteen patients (26.7%) still showed bacteremia at the beginning of the treatment. Over the Seraph® 100 treatment, a total of 52 (54.2%) blood cultures showed bacterial growth with a measurable time to positivity, resulting in 20 inflow and outflow pairs for a paired analysis. Overall, the blood cultures showed a median TTP of 18.96 [14.04–22.38] hours inflow to the device and 19.44 [14.36–23.78] hours outflow from the Seraph® 100 (p = 0.2) (Fig. 3B). The median TTP reduction between positive inflow and outflow blood cultures was 36 [-7.2–96.3] minutes.

One patient with Klebsiella pneumoniae infection who still had positive blood cultures 30 min into the Seraph® 100 treatment turned to be blood culture negative in the subsequent sampling points. A patient by patient overview of the inflow and outflow TTP in the blood culture positive patients is given in supplemental Fig. 1.

Our first in human study could show that an extracorporeal biomimetic device can safely and easily be used in conjunction with standard dialysis equipment. Even in acutely infected patients the treatment does not lead to cardiovascular instability. Just a few patients showed positive blood cultures at the beginning of the treatment, so significant pathogen reduction based on changes in TTP could not be proven in this study. However, the secondary efficacy endpoint (medium TTP increase of > 22 minutes) was met.

Currently, the only FDA approved therapy for targeting pathogens in sepsis are anti-infective drugs, but slow pathogen identification and therefore improper empirical use of antibiotics can lead to poor outcome and antibiotic resistance. Extracorporeal treatment approaches in bacteremia or sepsis have failed thus far to improve clinically relevant patient centered outcomes. However, those treatment strategies have so far concentrated at later stages of sepsis and were mainly aimed to modify mediators that were increased in response to a fulminant infection, were treatment success is difficult to achieve (19, 20). However, recent reports concerning the effect of plasma exchange are encouraging (21). Seraph® 100 is not designed for the late stage of sepsis but for early usage in serious infections that can trigger sepsis.

Safety – vital signs

Even during routine outpatient dialysis procedures, hypotension occurs in almost 50% of the treatments (22). On this background it is remarkable that the additional placement of the Seraph® 100 in series, upstream of the dialyzer, did not result in drop in blood pressure. An additional finding from the study was a significant increase in peripheral oxygen saturation during the treatment with Seraph® 100 treatment. This data point was not included in the clinical research file but was recorded during the normal hemodialysis procedure. Although we do not provide arterial blood gas analysis we consider this finding as significant as the peripheral O₂ saturation typically decreases during hemodialysis (23, 24).

Safety – laboratory data

With regard to the clinical laboratory changes over the four hour of treatment we did not see any negative safety signal. Creatinine and urea showed the typical drop of small molecules during hemodialysis (25). The significant increase in bilirubin levels within the normal range is not clear. As that higher bilirubin levels are associated with beneficial effects in hemodialysis patients, we do not consider this as a point of concern (26). Direct bilirubin and liver function were not affected by the Seraph® 100 treatment. None of the three blood cell lines was significantly altered by the Seraph® 100 treatment. The same holds true for fibrinogen, albumin and immunoglobulins, not to mention the electrolytes. The finding that the antithrombin activity is slightly but significantly decreasing is comforting as free heparin can greatly increase antithrombin activity. This suggests that the endpoint attached heparin in the Seraph® 100 is indeed not released into the circulation.

Reduction of bacterial load

The Seraph® 100 is aimed to rapidly remove heparin-binding pathogens from circulating blood. Indeed, in vitro studies have demonstrated that many bacteria, including all of those present in our patients are bound to the Seraph® 100 adsorption media as blood passes over it, allowing the concentration of bacteria to be reduced by up to 85 percent in just a single pass of contaminated blood (17). As the design of this study required a confirmation of a bloodstream infection by a positive blood culture before patient enrolment, up to 138 hours passed until the Seraph® 100 treatment was started. However, four out of 15 patients (26.7%) continued to have positive blood cultures despite appropriate antibiotic therapy. In one patient, blood cultures identified a pathogen at the beginning of the treatment and were negative after the Seraph® 100 treatment. The secondary efficacy endpoint (TTP increase of > 22 minutes) was met in our study. However, TTP reduction of the Seraph® 100 was ultimately not significant.

Study limitations

We want to point out several limitations of this study. This study was designed to investigate primarily the safety and performance of the Seraph® 100. Due to the delay between initial diagnosis of bacteremia and the start of the adsorber treatment less than half of the measured blood cultures showed positive results and could be analyzed. Therefore, our results regarding the pathogen reduction of the device are limited.

Outlook

Future studies are needed to assess the efficacy of the device. Such studies should aim to reduce the time between clinical diagnosis of a blood stream infection and the Seraph® 100 treatment. Shortening the time between diagnosis and start of treatment seems to be crucial, as it is for any therapy against bacteria. Larger clinical trials assessing end-points like incidence of endocarditis, sepsis, hospital length of stay and mortality are currently underway.

This is the first in human study of hemodialysis patients with proven bacteremia treated with the Seraph® 100. Serial use of the device on a non-modified dialysis machine was technically easy to implement and well tolerated. Although the efficacy endpoint for pathogen reduction was met, further studies are needed to evaluate the clinical efficacy of the device.

AE – adverse event

CFU – colonizing blood units

FDA – federal drug agency

SAE – severe adverse event

TTP – time to positivity

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki, registered under www.clinicaltrials.gov (NCT02914132, registered 26 September 2016) and approved by the German competent authority (Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM]) under the reference number 94.1.01 - 5660 - 9496. Ethical approval was obtained from all responsible internal review boards of the four participating institutions.

Consent for publication

All patients or their legal guardian provided written informed consent.

Availability of data and materials

The data that support the findings of this study are available from ExThera Medical but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of ExThera Medical.

Competing interests

JJS, SB and JTK received research support from ExThera Medical.

Funding

This study was funded by ExThera Medical, Martinez, CA, USA

Authors' contributions

All authors participated in patient screening and enrolment for the study as well as documentation of clinical data. GE, JJS and JTK analyzed the data and wrote the initial draft of the manuscript. All authors reviewed the manuscript.

Acknowledgements

Not applicable

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Competing interest reported. JJS, SB and JTK received research support from ExThera Medical.

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You are reading this latest preprint version

Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream – results of the first in human study

Status:

Version 1

Abstract

Figures

Background:

Methods:

Patients and study design:

Medical device and treatment characteristics

Outcome measures:

Blood sampling during the treatment:

Statistical analysis

Results:

Primary outcome:

Secondary outcome:

Discussion:

Safety – vital signs

Safety – laboratory data

Reduction of bacterial load

Study limitations

Outlook

Conclusions:

Abbreviations:

Declarations:

References:

Additional Declarations

Supplementary Files

Status:

Version 1