# A Prospective Pilot Clinical Study reveals a promising non-toxic anti-biofilm activity of gentamicin-EDTA-Na Central Venous Catheter Lock Solution

David Lebeaux, Bérénice Souhail, Tan-Phuc Bui-Van, Lénaig Le Fouler, Matthieu Lafaurie, Raphael Lepeule, Etienne Canoui, Victoire de Lastours, Antoine Froissart, Damien Blez, et al.

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David Lebeaux, Bérénice Souhail, Tan-Phuc Bui-Van, Lénaig Le Fouler, Matthieu Lafaurie, et al. A Prospective Pilot Clinical Study reveals a promising non-toxic anti-biofilm activity of gentamicin-EDTA-Na Central Venous Catheter Lock Solution. International Journal of Infectious Diseases, 2025, 157, pp.107933. 10.1016/j.ijid.2025.107933. pasteur-05382880

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Short Communication

# A Prospective Pilot Clinical Study reveals a promising non-toxic anti-biofilm activity of gentamicin-EDTA-Na₂ Central Venous Catheter Lock Solution

<figure><img src="image_2.png" /></figure>

David Lebeaux<sup>1,2,*</sup>, Bérénice Souhail<sup>3</sup>, Tan-Phuc Bui-Van<sup>4</sup>, Lénaig Le-Fouler<sup>4,5</sup>, Matthieu Lafaurie<sup>2</sup>, Raphael Lepeule<sup>3</sup>, Etienne Canoui<sup>6</sup>, Victoire de Lastours<sup>7,8</sup>, Antoine Froissart<sup>9</sup>, Damien Blez<sup>10,11</sup>, Christophe Beloin<sup>1</sup>, Jean-Marc Ghigo<sup>1</sup>, Fabrice Pirot<sup>12</sup>, Carole Dhelens<sup>12</sup>, Sandrine Fernandes-Pellerin<sup>4</sup>

ARTICLE INFO

Article history:
Received 6 March 2025
Revised 29 April 2025
Accepted 10 May 2025

Keywords:
Biofilm
conservative treatment
Totally implantable venous access port
Antibiotic lock therapy

A B S T R A C T

**Objectives:** The treatment of long-term intravenous catheter-related bloodstream infections (LTIVC-related BSI) often requires catheter removal or conservative treatment using intra-catheter locks, with a 50-60% success rate. We previously demonstrated the synergistic effect of a combination of gentamicin and ethylenediaminetetraacetic acid disodium salt (EDTA-Na₂) against bacterial biofilms. We conducted a phase 1/2 clinical trial to assess the tolerance and efficacy of genta-EDTA-Na₂ locks for the conservative treatment of LTIVC-related BSI.

**Methods:** Prospective study including adult patients with monomicrobial, uncomplicated LTIVC-related BSI caused by gentamicin-susceptible coagulase-negative staphylococci, *Enterobacterales*, or *Pseudomonas aeruginosa*. Primary objective: assess the safety and efficacy at genta-EDTA-Na₂ locks at day 40 (D40) by evaluating the frequency of clinical and microbiological cure 30 days after the end of treatment (D40).

**Results:** Eight patients were included. Complete follow-up was obtained for seven patients, six of whom met the criteria for cure. The single patient with incomplete follow-up met all criteria for cure at D23. A single microbiological failure occurred (relapse of *P. aeruginosa* LTIVC-related BSI). Two patients experienced at least one serious adverse event; none were attributed to the genta-EDTA-Na₂ locks.

**Conclusions:** Genta-EDTA-Na₂, used as intra-catheter locks, may be a promising anti-biofilm candidate for evaluation in a randomized controlled trial.

© 2025 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

Introduction

Long-term intravenous catheters (LTIVC) are crucial for millions of patients dependent on hemodialysis, parenteral nutrition, or antineoplastic chemotherapy, but their use can be complicated by catheter-related bloodstream infections (LTIVC-related BSI) [1].

<footnote n="1"><sup>1</sup> Institut Pasteur, Université Paris Cité, CNRS UMR6047, Genetics of Biofilms Laboratory, Paris, France</footnote>

<footnote n="2"><sup>2</sup> AP-HP, Département de Maladies Infectieuses et Tropicales, Hôpital Saint-Louis, Lariboisière, Paris, France</footnote>

<footnote n="3"><sup>3</sup> AP-HP, Unité Transversale de Traitement des Infections, Département Prévention Diagnostic et Traitement des Infections, Hôpital Henri Mondor, Créteil, France</footnote>

<footnote n="4"><sup>4</sup> Institut Pasteur, Clinical Research Coordination Office, Paris, France</footnote>

<footnote n="5"><sup>5</sup> Institut Pasteur, Data Management Core facility, Paris, France</footnote>

<footnote n="6"><sup>6</sup> Équipe Mobile d'Infectiologie, AP-HP, APHP.CUP, Hôpital Cochin Port Royal, 27 rue du faubourg Saint-Jacques, Paris, France</footnote>

<footnote n="7"><sup>7</sup> AP-HP, Service de Médecine Interne, Hôpital Beaujon, Clichy, France</footnote>

<footnote n="8"><sup>8</sup> Université Paris Cité, Inserm, IAME research Group, Paris, France</footnote>

<footnote n="9"><sup>9</sup> Service de médecine interne, CHI de Créteil, Créteil, France</footnote>

<footnote n="10"><sup>10</sup> Service de Microbiologie, Unité Mobile d'Infectiologie, AP-HP, Hôpital Européen Georges Pompidou, Leblanc, Paris, France</footnote>

<footnote n="11"><sup>11</sup> Université Paris Cité, Faculté de Santé, UFR de Médecine, Paris, France</footnote>

<footnote n="12"><sup>12</sup> Hospices Civils de Lyon, FRIPHARM®, Service Pharmacie, Hôpital Edouard Herriot, Lyon, France</footnote>

<footnote>* Corresponding author.
E-mail address: david.lebeaux@aphp.fr (D. Lebeaux).</footnote>
Treatment of LTIVC-related BSI relies on catheter removal or, al-
ternatively, a conservative strategy combining systemic antibiotics
and intra-catheter locks, which use a small volume (2–3 mL) of
highly concentrated antibiotic (100 to 1,000 times the minimum
inhibitory concentration) to eradicate bacterial biofilms colonizing
the catheter [1]. However, the success rate of the currently used
antibiotic locks is limited to 50–60% at 3 months [2,3].

We demonstrated that the combination of ethylenediaminetetraacetic acid disodium salt (EDTA-Na₂) and the aminoglycoside antibiotic gentamicin eradicated *in vivo* biofilms in a rat model of LTIVC-related infections and was synergistic against a broad range of bacterial isolates responsible for LTIVC-related infections [4,5]. Subsequently, a study using commercial gentamicin sulfate and EDTA-Na₂ assessed the long-term stability of genta-EDTA-Na₂ lock solutions for 12 months [6].

Here, we conducted a pilot phase 1/2 clinical trial to assess the
tolerance and efficacy of genta-EDTA-Na₂ used as an intra-catheter
lock for the curative and conservative treatment of LTIVC-related
BSI.

Material and methods

Study setting and inclusion criteria

We performed a prospective interventional study (CATH-GE)
between April 2021 and November 2023 in five tertiary hospi-
tals in the Ile-de-France region, France (Supplementary Table 1)
(ClinicalTrials.gov Identifier: NCT04789928). Adult patients were
included if they had a monomicrobial uncomplicated LTIVC-related
BSI, defined as the absence of any systemic complication (sepsis
or septic shock) or local complication (tunnel or port-pocket infec-
tion, thrombophlebitis, endocarditis, bone and joint infections re-
lated to the LTIVC-related BSI), caused by gentamicin-susceptible
coagulase-negative staphylococci, *Enterobacterales*, or *Pseudomonas
aeruginosa*. The indication for conservative treatment had to be
confirmed by the physician in charge of the patient (Supplemen-
tary Methods).

Objectives and endpoints

The primary objective was to assess the efficacy and safety at
day 40 (D40) of genta-EDTA-Na₂ used as an intra-catheter lock for
the conservative treatment of uncomplicated LTIVC-related BSI. Ef-
ficacy was assessed by the frequency of clinical and microbiologi-
cal cure 30 days after the end of treatment (D40) (Supplementary
Methods). The safety of genta-EDTA-Na₂ locks was assessed by the
frequency of any suspected related adverse event (Supplementary
Methods).

The secondary objective was to assess the long-term clinical
efficacy at day 100 (D100) of genta-EDTA-Na₂ used as an intra-
catheter lock for the conservative treatment of uncomplicated
LTIVC-related BSI.

Study design and follow-up

This was a pilot-phase, non-comparative, non-randomized, mul-
ticentric study. We initially planned to include 35 patients, as we
expected a 90% clinical and microbiological cure rate at D40 with
a 10% precision and an alpha-risk of 0.05. However, due to major
inclusion limitations, we stopped inclusion in November 2023.

The study design included: (i) a screening and inclusion visit within 72 hours after the first positive blood culture drawn from the LTIVC; (ii) 7 to 10 days of genta-EDTA-Na₂ lock treatment (D6-D9), depending on the prescription of a prior treatment lock (see Supplementary Figure 1); (iii) daily clinical and biological follow-up during the genta-EDTA-Na₂ lock treatment; (iv) an efficacy and

safety follow-up visit at D40 (± 7 days); and (v) an end-of-study
visit at D100 (± 7 days).

Day 0 (D0) was defined as the initiation of genta-EDTA-Na₂ lock therapy. On D1, D2, and D6-D9, blood samples (blood ionized calcium level, gentamicin concentration, and serum creatinine) were taken from a peripheral vein to avoid contamination from the previous lock.

Control blood cultures were sampled from a peripheral vein and from the LTIVC on D3-D5, D6-D9, and on D40. Venous ultrasound was performed between D2 and D5, and transthoracic echocardiography was performed between D2 and D7.

Microbiological relapse was defined as a BSI with the same mi-
crobial pathogen, i.e., the same species and the same antibiotic
susceptibility pattern.

End of treatment was defined as the completion of at least 10
days of local treatment, including at least 7 days of genta-EDTA-
Na² lock if the patient had previously received an active lock be-
fore inclusion, regardless of the identified bacteria.

The choice and duration of systemic antimicrobials were left to
the physician in charge of the patient, but a total systemic treat-
ment duration of 10 days was required.

Clinical and microbiological cure were assessed at D40 (± 7
days) (primary objective) and D100 (± 7 days) (secondary objec-
tive). The comprehensive definition of cure is provided in Supple-
mentary Methods.

Production of genta-EDTA-N<sub>2</sub> vials and description of the use of the
intra-catheter lock solution

The production and labeling of the genta-EDTA-N<sub>2</sub> solution
were carried out by the Edouard Herriot Hospital Pharmacy,
on the FRIPHARM® platform, Hospices Civils de Lyon, as pre-
viously described. Genta-EDTA-N<sub>2</sub> lock solutions were prepared
by compounding commercial gentamicin sulfate (Gentamicin PAN-
PHARM® 80 mg, solution for injection) and EDTA-N<sub>2</sub> under asep-
tic conditions in sterile, and non-pyrogenic, amber glass type I
pharmaceutical vials, followed by sterilizing filtration and termi-
nal sterilization by autoclaving. Final concentrations were: gen-
tamicin 5 mg/mL, EDTA-N<sub>2</sub> 30 mg/mL [6] (Supplementary Meth-
ods). Intra-catheter locks were performed as part of routine care
(Supplementary Methods). Briefly, the catheter dead space was
measured for first use. Each lock was performed with the dead
space volume plus 0.5 mL. Each lock was maintained for 24 hours.
Twenty-four hours later, the previous lock (at least 3 mL) was as-
pirated and replaced by a new genta-EDTA-N<sub>2</sub> lock. After the first
48 hours, if the patient was afebrile, locks could be changed every
12 hours, allowing intravenous injections of antibiotics (or other
treatments) twice a day through the LTIVC.

Collected data: see Supplementary Methods

Statistical analysis

The proportions of clinical and microbiological cure at D40 and D100 and the proportion of suspected related adverse events were assessed. Due to the low number of included patients, no statistical analysis was performed.

Ethics

The trial was conducted in accordance with the principles of
Good Clinical Practice and the Declaration of Helsinki for biomed-
ical research involving human subjects. It was approved by the
French National Ethics Committee (Comité de Protection des Per-
sonnes, CPP Île-de-France XI) and authorized by the Agence na-
tionale de sécurité du médicament et des produits de santé.
<table><caption>**Table 1**
Clinical characteristics and outcome of eight patients receiving genta-EDTA-Na₂ as intra-catheter locks.</caption><thead><tr><th>Patient number</th><th>Gender</th><th>Age, year</th><th>Reason for LTIVC implantation</th><th>Charlson comorbidity index</th><th>Karnofsky score</th><th>Microbial pathogen</th><th>Initial eGFR</th><th>Total duration of lock (days)</th><th>Total duration of genta-EDTA-Na2 lock (days)</th><th>Clinical and microbiological cure at D40</th><th>Clinical and microbiological cure at D100</th></tr></thead><tbody><tr><td>Patient #1</td><td>Male</td><td>36</td><td>Cancer</td><td>6</td><td>80%</td><td>P. aeruginosa</td><td>73</td><td>10</td><td>10</td><td>NA<sup>a</sup></td><td>NA<sup>a</sup></td></tr><tr><td>Patient #2</td><td>Female</td><td>83</td><td>Cancer</td><td>9</td><td>100%</td><td>E. coli</td><td>33</td><td>9</td><td>9</td><td>Yes</td><td>Yes</td></tr><tr><td>Patient #3</td><td>Female</td><td>71</td><td>Parenteral nutrition</td><td>5</td><td>70%</td><td>E. cloacae</td><td>98</td><td>9</td><td>9</td><td>Yes</td><td>Yes</td></tr><tr><td>Patient #4</td><td>Female</td><td>80</td><td>Cancer</td><td>10</td><td>60%</td><td>S. epidermidis</td><td>83</td><td>10</td><td>8</td><td>Yes</td><td>Yes</td></tr><tr><td>Patient #5</td><td>Female</td><td>61</td><td>Cancer</td><td>8</td><td>70%</td><td>S. hominis</td><td>80</td><td>10</td><td>8</td><td>Yes</td><td>Yes</td></tr><tr><td>Patient #6</td><td>Male</td><td>48</td><td>Cancer</td><td>6</td><td>80%</td><td>P. aeruginosa</td><td>130</td><td>10</td><td>7</td><td>No<sup>b</sup></td><td>No<sup>b</sup></td></tr><tr><td>Patient #7</td><td>Female</td><td>76</td><td>Cancer</td><td>11</td><td>70%</td><td>P. aeruginosa</td><td>66</td><td>10</td><td>7</td><td>Yes</td><td>Yes</td></tr><tr><td>Patient #8</td><td>Male</td><td>62</td><td>Cancer</td><td>5</td><td>70%</td><td>S. haemolyticus</td><td>128</td><td>10</td><td>9</td><td>Yes</td><td>Yes</td></tr></tbody></table>

NOTE: D, day; EDTA-Na₂, ethylenediaminetetraacetic acid disodium salt; eGFR: estimated glomerular filtration rate, in ml/min/1.73 m²; LTIVC-related BSI, long-term intra-venous catheter-related bloodstream infections; NA: not available.

Written informed consent was obtained from all patients enrolled in the trial. The trial was registered at ClinicalTrials.gov (NCT04789928).

## Results

### Characteristics of patients

Eight patients were included, with a median age of 66 years (range, 36–83) (Table 1). All patients had totally implantable venous access port (TIVAP), mostly for antineoplastic chemotherapy (7/8). Three infections were caused by *P. aeruginosa*, three by coagulase-negative staphylococci, and two by *Enterobacteriales*.

### Efficacy of genta-EDTA-Na₂ intra-catheter locks

A complete follow-up was obtained at D40 for seven patients, six of whom met the clinical and microbiological cure criteria, with negative blood cultures at D40 (± 7 days) (Table 1). The single patient with incomplete follow-up (Patient #1) had negative paired blood cultures performed at D3, D7, and D14. His last clinical follow-up was on D23, at which time he met all criteria for clinical and microbiological cure. All patients who met the clinical and microbiological cure criteria at D40 also met these criteria at D100. A single microbiological failure occurred (Patient #6), who experienced a relapse of his LTIVC-related BSI (*P. aeruginosa*) with no local or systemic complications.

### Tolerance of genta-EDTA-Na₂ intra-catheter locks

Between D0 and D40, 2/8 patients experienced at least one serious adverse event (Supplementary Table 2). None were attributed to the genta-EDTA-Na₂ intra-catheter lock. Follow-up blood ionized calcium and serum creatinine levels are depicted in Figure 1a and 1b. All gentamicin dosages were negative.

## Discussion

In this pilot phase 1/2 clinical trial using genta-EDTA-Na₂ as an intra-catheter lock, we observed no treatment-related adverse event, a favorable tolerance profile, and high efficacy for the conservative treatment of LTIVC-related BSI (seven treatment successes among eight treated patients).

Recent data have reported success rates for conservative treatment ranging between 50% and 60% [2,3]. Our pilot study showed that seven out of eight patients achieved clinical and microbiological cure using genta-EDTA-Na₂ as an intra-catheter lock, with one

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /><figcaption>**Figure 1.** Evolution of blood ionized calcium (mmol/L) and serum creatinine (μmol/L) levels among eight patients receiving a genta-ethylenediaminetetraacetic acid disodium salt intra-catheter lock. Patient #1 never had a blood ionized calcium level measurement. His blood calcium levels remained stable throughout the treatment duration. Patient #2 experienced an increase in her creatinine level after the introduction of cotrimoxazole. Patient #7 experienced an acute functional kidney failure secondary to cancer-induced diarrhea. D, day.</figcaption></figure>

patient having a limited follow-up of D23. In this context, the main limitation of our study is the small sample size, which precludes drawing any definite conclusions regarding the efficacy of genta-EDTA-Na₂ as an intra-catheter lock.

Regarding the safety profile of genta-EDTA-Na₂ locks, we observed no adverse events related to the experimental treatment. No patient experienced a significant reduction in ionized calcium levels, and all gentamicin dosages were negative. Two patients experienced an increase in their serum creatinine levels, none of

<footnote><sup>a</sup> Patient #1 had negative paired blood cultures performed at D3, D7, and D14. His last clinical follow-up was on D23 when he met all criteria for clinical and microbiological cure. He was then transferred to his native country for palliative care.</footnote>

<footnote><sup>b</sup> Patient #6 experienced a relapse of his LTIVC-related BSI with the same bacterial species (*P. aeruginosa*).</footnote>
which were related to the genta-EDTA-Na₂ lock. Additionally, the tolerance profile of EDTA used as an intra-catheter lock was favorable among 190 patients who received EDTA-minocycline as a preventive lock in previously published studies [7–10].

In conclusion, the use of genta-EDTA-Na₂ as intra-catheter locks for the conservative treatment of LTIVC-related BSI appears to be a promising candidate for study in a randomized controlled trial.

## Declarations of competing interest

The authors have no competing interests to declare.

## Funding

The CATH-GE study has been funded as follows: Fonds de Dotation Patrick de Brou de Lauriere; Sauver la vie Grant (Paris Descartes); A.R.C.A.D (Aide à la Recherche en CAncérologie Digestive); Ligue contre le cancer; mécénat Air France, ANR-10-LABX-62-IBEID, Agence Nationale de la Recherche, Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases". We also would like to thank all our friends, family, and colleagues who supported this project through a Thellie Crowdfunding.

## Acknowledgments

The authors would like to thank Cécile Artaud, Simon Amador Paz, and Charles-Henry Bourlier for their help in preparing the study protocol.

## Author contributions

**David Lebeaux:** Study design, Data collection, Data analysis, Writing. **Bérénice Souhail:** Data collection, Writing. **Tan-Phuc Bui Van:** Study design, Data collection, Data analysis, Writing. **Lénaig Le Fouler:** Study design, Data collection, Data analysis, Writing. **Matthieu Lafaurie:** Data collection, Writing. **Raphael Lepeule:** Data collection, Writing. **Etienne Canoui:** Data collection, Writing. **Victoire de Lastours:** Data collection, Writing. **Antoine Froissart:** Data collection, Writing. **Damien Blez:** Data collection, Writing. **Christophe Beloin:** Study design, Data analysis, Writing. **Jean-Marc Ghigo:** Study design, Data analysis, Writing. **Fabrice Pirot:** Study

design, Writing. **Carole Dhelens:** Study design, Data analysis, Writing. **Sandrine Fernandes-Pellerin:** Study design, Data collection, Data analysis, Writing.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ijid.2025.107933.

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