Continuous Local Antibiotic Perfusion (CLAP): A Treatment Strategy that Allows Implant Retention in Fracture-Related Infections

doi:10.21203/rs.3.rs-1495493/v1

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Continuous Local Antibiotic Perfusion (CLAP): A Treatment Strategy that Allows Implant Retention in Fracture-Related Infections

https://doi.org/10.21203/rs.3.rs-1495493/v1

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Background

Fracture-related infections (FRI) are challenging to treat because of the formation of biofilms around implants. Systemic antibiotics are notoriously ineffective against biofilms due to insufficient penetration of tissues with poor vascularity. The treatment of Fracture-related infections aims to achieve bone union while retaining the implant. As proposed by us, continuous local antibiotic perfusion (CLAP) refers to the continuous local delivery system of sufficient antibiotics to bone and soft tissue infection sites. This allows for continuous administration of antibiotics to bone marrow via needles as intra-medullary antibiotics perfusion (iMAP) and to soft-tissue via double-lumen sub tubes as intra-soft tissue perfusion (iSAP).

Methods

We examined the outcomes of FRI patients treated based on the concept of CLAP at the first author’s hospital. Forty patients treated with CLAP for FRI between 2015 and 2021 were included. CLAP was initiated as urgently as possible after the infection was diagnosed. Patient/treatment background and efficacy/safety evaluation were analyzed. Gentamicin was used in CLAP in all cases.

Results

The mean patients’ age was 60.5 years, and the mean follow-up was 696.4 days. The affected bones were the tibia (n=17), humerus (n=6), patella (n=3), pelvis (n=3), radius (n=2), femur (n=2), calcaneus (n=2), metatarsals (n=2), ulna (n=1), proximal phalanx (n=1), and vertebra (n=1). Twelve cases were treated with iMAP alone, 11 were treated with iSAP alone, and 17 were treated with a combination of both. Implant removal was required in five patients. Two of them required toe amputation and knee arthrodesis, while fracture union was achieved in the remaining 38 patients. Only one case of transient acute renal injury was observed as a systemic side effect; however, the patient’s condition improved soon. No eighth cranial nerve neuropathy of concern was observed, and the blood concentration of gentamicin could be adjusted to an appropriate level through the combined use of iMAP and iSAP.

Conclusion

CLAP is a novel local drug delivery system that can potentially deliver sufficient concentrations of antibiotics with few systemic side effects and is a valuable option for FRI treatment.

local antibiotic perfusion

fracture-related infection

gentamicin

intramedullary antibiotic perfusion

intrasoft tissue antibiotic perfusion

Fracture-related infections (FRIs) following osteosynthesis are usually challenging to treat because the goals of infection control and fracture healing must be pursued concurrently. [1] This is because there are dead cavities around the fracture site and hematoma where intravenous antibiotics cannot achieve sufficient concentrations. Bacteria also form biofilms, which are highly resistant to antibiotics, [2–4] around implants and tissues with poor blood flow, making it very difficult to control infections without removing such tissue. Generally, the treatment priority is to eliminate the infection through cleaning and complete debridement of the affected bone, muscles, and soft tissue, including implant removal. [5, 6] Removing implants, however, reduces the stability at the fracture site. Therefore, it would be ideal to retain the implant while treating FRIs. However, the antibiotic concentration required to eradicate biofilms, defined as the minimum biofilm eradication concentration (MBEC), is much higher than the minimum inhibitory concentration (MIC). [7–9] Achieving MBEC locally via intravenous infusion is impossible due to systemic complications. In addition, in most FRIs, the infection spreads to the bone marrow and surrounding soft tissue, necessitating parallel treatment of the soft tissue infection.

We have proposed continuous local antibiotics perfusion (CLAP) as a therapeutic concept for the sustained local drug delivery of antibiotics to bone and soft-tissue infections; local administration procedures were termed "intra-medullary antibiotic perfusion” (iMAP) for bone marrow and “intra-soft tissue antibiotic perfusion” (iSAP) for soft-tissues. In iMAP, a daily dose of antibiotics was diluted with a small amount of saline and continuously infused at a low rate using a bone marrow needle placed near the infected site, allowing the delivery of a sufficient local concentration of the agent. [10] In iSAP, double-lumen tubes for injection and drainage are placed in the soft tissue surrounding the focus of infection; the antibiotic is administered at the same dose as iMAP via one of the tubes, and constant negative pressure is applied by the other tube to create a perfusion route for the antibiotic. In combination with iMAP and iSAP, the antibiotic infiltrates both the affected bone and surrounding soft tissue due to the assistance of negative pressure. It is then drained via the iSAP drainage tube.

We believe that the combined use of iMAP and iSAP creates a continuous antibiotic perfusion pathway in which antibiotics administered via bone marrow needles or double-lumen tubes infiltrate infected areas and are promptly drained via the drainage tube. This pathway enables targeted antibiotic delivery while preventing the unnecessary infiltration of the agent into the systemic blood flow.

Aminoglycosides have been reported to reduce the infection rate in open fractures when administered locally and in combination with systemic antibiotics. [11] We opted for gentamicin as the standard antibiotic in CLAP for the following reasons: Firstly, gentamicin is a bactericidal antibiotic that is also effective against drug-resistant microbes, including methicillin-resistant Staphylococcus aureus (MRSA). [12, 13] Secondly, gentamicin has a better anti-biofilm efficacy compared to most antibiotics. [7] Thirdly, gentamicin blood concentrations are easy to monitor during CLAP and clinical practice.

The purpose of this study was to examine the utility of CLAP by reporting the outcomes of patients with FRIs who were treated by CLAP.

Subjects

Patients with FRIs were diagnosed using the following criteria: purulent drainage from a fistula, or clinical signs of deep infection confirmed by the presence of pus that excluded superficial infection in isolation. [1] Cases of FRIs treated using CLAP from 2015 to 2021 that met the following criteria were included in this study: 1) the availability of the blood antibiotic concentration as a safety indicator and local antibiotic concentration as an indicator of whether antibiotics were properly administered, and 2) a postoperative follow-up period of at least 6 months.

Data collection

Data collected include patient characteristics such as the age, sex, location of injury, date of injury, presence of open fracture, type of fixation, the time of onset of infection [early (< 2 weeks), delayed (2–10 weeks), and late onset (> 10 weeks)], [14] date of CLAP initiation, presence of steroids medication, presence of diabetes, presence of renal dysfunction [glomerular filtration rate (GFR) of < 60 mL/min per 1.73 m² for more than three months (GFR category G3a–G5)], [15] American Society of Anesthesiologists (ASA) classification, [16] and time to latest follow-up.

The following treatment-related factors were also investigated: duration of systemic antibiotics use, duration and number of iMAP and iSAP implantations, respectively, and whether negative pressure wound therapy (NPWT) was used. The efficacy endpoints of CLAP were the local concentration, time to normalization of biochemical signs of infection (raised white blood cell [WBC] count and C-reactive protein [CRP] level in the blood), presence of unscheduled surgical treatment such as amputation, recurrence of deep infection, and whether the implant could be retained. The drainage tube fluid was collected and the antibiotics concentration was measured for 12 h as a reference for the local antibiotics concentration. The safety endpoints were the fracture union rate, time to fracture union, maximum serum concentration of gentamicin, presence of acute kidney injury (AKI) after initiation of CLAP based on the KDIGO classification, [15] presence of eighth cranial nerve neuropathy, and presence of an allergic reaction. Fracture union was assessed using radiographs. In cases with AKI, the time to recovery of renal function (the time until no longer classifiable by KDIGO) was also investigated.

Intra-medullary antibiotic perfusion (iMAP)

The iMAP technique, as previously reported, [10] is depicted in Fig. 1A. In the case of plate fixation, the needle was inserted 2–3 cm away from the edge of the plate; in the case of intramedullary nail fixation, it was inserted into the diaphysis of the bone, along the nail. Next, we visually checked that the saline solution flushed from the needle flowed out of the fracture site (flow test). If this circulation pathway was not confirmed, we repeated the flow test until the pathway was established, by changing insertion positions and needle depths or by creating perfusion routes using K-wires or drills. After verification of the flow test, an iSAP tube was placed at the affected lesion.

Previously, the Tohoku University-style bone marrow puncture needle (Senko Medical Instrument Manufacturing, Tokyo) was used to inject antibiotics into the bone marrow. Due to the structure of this device, which consists of an inner and outer tube, antibiotics leaked from the injection site due to loosening, or the needle was dislodged in some cases. In addition, there was insufficient anchoring strength owing to the nature of the needle attachment. It is detrimental to the mental health of patients to have them constantly lie in bed, and it affects their daily activities. We developed the iMAP pin (Cubex Medical, Tokyo, Japan) to address these issues (Fig. 1B). After pre-drilling into the contralateral cortical bone, the iMAP pin is inserted using a screwdriver. This pin has a threaded tip, allowing fixation to the contralateral cortex, thus increasing the anchoring stability. The iMAP pin is designed to allow antibiotics from the syringe pump to pass through its hollow core and enter the bone marrow via holes in both sides of the threaded part (Fig. 1C). This custom pin solves the problems of leakage and dropout, as well as patient discomfort. The three vailable sizes of iMAP pins (i.e., 3 mm, 4 mm, and 5 mm diameter with 9 cm, 10 cm, and 11 cm lengths, respectively) should be selected depending on the bone size.

Intra-soft tissue antibiotics perfusion (iSAP)

The iSAP technique, depicted in Fig. 2, is a method for the continuous infusion of antibiotics to soft tissues and the aspiration of the infused antibiotic solution, blood, and effusion fluid via drainage tubes, to establish a perfusion pathway at the infection focus. Prior to inserting the drainage tube, dead cavities are identified. Then, an entry hole is made 5 cm from the margin of the dead cavity, and the drainage tube is introduced through this hole to infuse the dead space. If a single tube is not sufficient to drain the dead space, other tubes are added for complete drainage. Gentamicin is administered via the infusion tube and continuous negative pressure is applied via the drainage tube (Fig. 2A).

Initially, one injection tube and one drainage tube were used; however, due to the distance between the two tubes, the infused fluid was not collected by the drainage tube, and they were often blocked by hematomas or soft tissues. Therefore, we started using a double-lumen Salem sump tube (Japan Covidien, Tokyo) with a > 20Fr diameter as the iSAP tube. Infusion was performed via the outer lumen and aspiration via the main lumen. (Fig. 2B), which reduced the incidence of obstructions. [17] When a wound was difficult to close, NPWT was applied using a RENASYS (Smith and Nephew Japan, Tokyo, Japan) device. This facilitated efficient effusion fluid collection due to the negative pressure generated in the iSAP tube by the NPWT. This was achieved by connecting the drainage circuits with a Y-shaped connector (Fig. 2C). NPWT was used continuously, with a negative pressure of 60 mmHg.

Antibiotic Regimen

For the local antibiotic administration, gentamicin was administered through the iMAP pin and double-lumen Salem sump tube, with the dose strictly controlled by a syringe pump. The treatment protocol began with 1.2 mg/ml as a standard dose and infused the solution at a rate of 2 ml/h continuously. During this period, the blood and leachate concentrations of gentamicin was measured twice a week. It has been reported that the rate of nephrotoxicity increases when the serum trough concentration of gentamicin is > 2 µg/ml and the maximal serum concentration is > 10 µg/ml. [18] Thus, the target gentamicin concentration was < 2 µg/ml; if the concentration exceeded 1 µg/ml, the dose was lowered accordingly. If the concentration of the leachate fluid was low, the circuit was checked for abnormalities such as blockages and leaks.

CLAP is always used in combination with intravenous administration of systemic antibiotics. The antibiotic choice and duration were based on the recommendations of a group of FRI experts. Antibiotics were chosen based on the susceptibility when the pathogen was known; otherwise, empirical therapy was initiated, consisting of sulbactam/ampicillin or cefazolin. As soon as the pathogen was identified, the antibiotic was switched as per the susceptibility. In parallel with CLAP, systemic antibiotics were continued for 4–6 weeks and then switched to oral antibiotics for several months. [14, 19, 20]

Treatment of FRIs with a combination of iMAP and iSAP using CLAP

FRIs were treated with a combination of iMAP and iSAP, based on CLAP. Once an FRI was diagnosed using the aforementioned criteria, [1] to prevent deep infections, surgery to set up iMAP and iSAP was performed as soon as possible. It was postulated that fracture stability by internal fixation was essential for infection eradication; therefore, implants that were in place were retained. Loosened implants and an inadequate reduction of the fracture or adjustment of the implant were addressed using single- or double-stage surgery. As shown in Fig. 3, the combination of iMAP and iSAP completed the perfusion pathway, in which the administered agent was infused throughout the infected lesion and then discharged via the tubes. The iMAP pin and double-lumen tube were withdrawn when local and hematological findings suggested the resolution of the infection; a decrease in the blood CRP level was used as the first indicator, which was confirmed using local findings).

Patient background

Data from 40 patients (28 males, 12 females) were included in this study. The mean age at the time of operation for the fracture was 60.5 (range, 17–98) years, and the mean follow-up period was 696.4 (range, 190–2231) days. Locations of injury were the tibia (n = 17), humerus (n = 6), patella (n = 3), pelvis (n = 3), radius (n = 2), femur (n = 2), calcaneus (n = 2), metatarsals (n = 2), ulna (n = 1), proximal phalanx (n = 1), and vertebra (n = 1) (Fig. 4A). Open fractures were present in 11 cases (Gustilo Anderson classification Type I: one case, Type Ⅱ: one case, Type Ⅲa: eight cases, and Type Ⅲb: one case). The method of osteosynthesis used was plating in 18 cases, intramedullary nailing in 7 cases, screwing in 8 cases, and other methods in 7 cases (Fig. 4B). Deep infections developed an average of 172.1 (range, 4-2042) days after the first internal fixation procedure, and CLAP was initiated upon diagnosis. Of the infections, 4 cases (10%) were early, 15 (37.5%) were delayed, and 21 (52.5%) were late. The causative organisms were methicillin-susceptible Staphylococcus aureus (MSSA) (n = 12), MRSA (n = 7), methicillin-resistant coagulase negative staphylococci (MRCNS) (n = 4), Escherichia coli (n = 3), Corynebacterium sp (n = 2), Klebsiella pneumoniae (n = 2), others (n = 4), and unknown (n = 6) (Fig. 4C). Of the 40 cases, one patient was treated with steroids, nine patients had diabetes mellitus, and 11 patients had renal dysfunction. The ASA-PS classification was class 1 in 19 cases, class 2 in 20 cases, and class 3 in one case (Fig. 4D).

Treatment background

Of the cases, 12 were treated with iMAP alone, 11 were treated with iSAP alone, and 17 were treated with a combination of both. Gentamicin was used as the antibiotic in all cases. An average of 1.41 iMAP pins (range, 1–2) and 1.25 tubes for iSAP (range, 1–2) were used. The mean CLAP treatment periods were 13.9 (range, 7–20) days and 14.1 (range, 10–20) days, respectively. NPWT was used concomitantly in 30 cases. Systemic antibiotics were given intravenously for an average of 3.1 (range, 1–13) weeks and then orally for an average of 12 additional (range, 1–52) weeks.

Efficacy evaluation

The mean local concentration of gentamicin was 1634 (range, 125-14080) µg/ml. In blood examinations, the CRP level decreased to less than 0.3 mg/dL by an average of 15.4 (range, 3-109) days after CLAP initiation. Of the 40 cases, 5 required implant removal to control the infection, and the implant retention rate after a single CLAP surgery was 87.5%. During the follow-up period, the recurrence of deep infection was observed in six cases, and CLAP was re-initiated. The infection was controlled in four cases, but one of the remaining two cases required toe amputation, and one case required knee arthrodesis.

Safety evaluation

Fracture union was achieved in 95% (38 of 40) of cases, and 2 cases required unscheduled surgical procedures. The mean time required for fracture union was 7.5 (range, 2–24) months. The mean maximum blood concentration of gentamicin was 1.7 (range, 0.3–4.9) µg/ml in cases treated with iMAP alone, 0.4 (range, 0.3–0.6) µg/ml in cases treated with iSAP alone, and 1.1 (range, 0.3-2) µg/ml in cases treated with a combination of both (Fig. 5). Complications of AKI classified as KDIGO stage I during CLAP were observed in one patient, but the renal function recovered within 6 weeks. There were no cases of eighth cranial nerve neuropathy or local allergic reactions after the initiation of CLAP.

Case presentation

An 87-year-old woman with untreated diabetes mellitus (HbA1c: 9.0%) fell and injured her left hand. She presented with left, closed, highly comminuted transcondylar distal humeral fractures (Fig. 6A). She was hospitalized on the same day and appropriate glycemic control was achieved prior to surgery. We performed open reduction and internal fixation (ORIF) using dual locking plates and transplanted a bone graft to fill the defect on the 11th day after injury (Fig. 6B). On the 14th postoperative day, symptoms such as fever, swelling, and heat around the surgical wound were noted, along with purulent drainage from the wound and an increase in blood CRP levels. FRI was diagnosed according to the two major criteria, and surgery was performed the same day. A large amount of purulent discharge was noticed when pressure was applied around the open wound. Intraoperative findings included a partial rupture of the triceps fascia and purulent drainage from the deep elbow joint area, suggesting the infection had spread to the inside of the joint (Fig. 6C). After thorough lavage with a large amount of saline, an iMAP pin was percutaneously inserted at the distal lateral aspect of the humerus. The flow test confirmed proper infiltration, including the bone graft and intra-joint space. The subcutaneous dead space was confirmed, and the margins were marked with a surgical pen. A 22 Fr double-lumen tube was inserted into the joint as an iSAP from a position 5 cm from the margin of the dead cavity via the infected lesion. It was then confirmed that the iMAP fluids were drained by the iSAP tube. Using this system, a large amount of saline was used to irrigate the lesion. Another double-lumen tube was also introduced into the subcutaneous area of the forearm. As per the standard CLAP protocol, 1.2 mg/mL gentamicin was continuously perfused via one iMAP pin and 2 iSAP tubes at 2 mL/h. The dual plates and bone graft were retained (Fig. 6D). The causative organism was identified as MSSA based on several intraoperative samples. Local findings improved promptly after the initiation of CLAP. The CLAP systems were removed 13 days after insertion. During CLAP, there were no findings suggestive of AKI, eighth cranial nerve neuropathy, or allergic reactions. The maximum blood concentration of gentamicin was 0.5 µg/ml, and the average local concentration was 1427 µg/ml (1040–1700 µg/ml). Gentamicin concentrations recorded in the blood and leachate are shown in Fig. 6E. Intravenous antibiotics were administered for 4 weeks and replaced by oral antibiotics, which were then continued for 4 weeks. CRP and WBC levels and details of the antibiotics used are shown in Fig. 6F. CRP levels normalized 9 days after the initiation of CLAP. Fracture union was achieved 6 months after surgery. (Fig. 6G). No signs of infection recurrence have been observed in the two years following the surgery. The patient’s elbow range of motion was 30 to 120 degrees, and there were no limitations to their daily activities.

Implant-associated infections, including prosthetic joint infections (PJIs) and FRIs, are major postoperative complications. However, their treatment strategies differ significantly due to their fundamental characteristics. [20] The goal with PJIs is complete "eradication" of the infection and stable implant retention, without recurrence until the end of life. Conversely, the goal with FRIs is bone union, with the infection being “controlled” until the fracture union is complete, following which the implants can be removed. Implant retention is amenable to the goal of fracture union in FRIs; biofilm suppression is essential in enabling this. CLAP is a novel local drug delivery system, developed to achieve the goal of retaining implants while controlling infection.

Based on the concept of CLAP, we had previously devised iMAP. [10] Initially, we treated FRIs with iMAP combined with a simple drainage tube; however, in many cases, the tube was often occluded, leading to an increase in the serum concentration of gentamicin. Thereafter, we combined iMAP with a suction system, which also delivered antibiotics to the surrounding soft tissue, to create a comprehensive antibiotic perfusion pathway. In addition, during the typical clinical course of FRIs, superficial surgical site infections progress to deeper layers and cavities surrounding the fracture, which then spread into the bone marrow. [15] Thus, we thought it necessary to have a means of applying suction and administering antibiotics to the surrounding soft tissue and developed iSAP. In early infection, the application of iSAP to the superficial layer is enough to control the infection; however, in delayed or later infections, when the infection is assumed to have spread into the bone marrow, the additional application of iMAP is required. After initiating concurrent use of iSAP and iMAP, there were virtually zero cases where the blood concentration of gentamicin crossed the safety threshold. Thus, the combination of iMAP with iSAP is an effective and ideal therapeutic modality in FRIs and the perfect perfusion system for CLAP.

NPWT is an effective tool for treating open or difficult-to-close wounds. [21–23] The combination of NPWT with the continuous instillation of physiologic saline or antiseptic solution has been reported to be effective in the treatment of infected ulcers and bone and soft tissue infections. [24–27] The principle behind these treatments is the comprehensive irrigation of the contaminated area followed by the collection of the washing solution using continuous negative pressure. These systems are similar to the iSAP model and effective in treating superficial open wounds but not in treating deep, closed wounds surrounded by vascular dead spaces. In contrast, in most FRIs, the infected area is significant at the superficial level and in the muscular layers and bone marrow. We discovered that connecting the suction circuits of the iSAP tube and an NPWT system created a more efficient perfusion pathway for the antibiotic solution, resulting in a more sustainable method of CLAP. If pressure was not maintained due to a leak or obstruction of the CLAP route, the NPWT system alerted us. It also crimps and reduces the dead cavity where the antibiotic has difficulty reaching, by concurrently suctioning the superficial and deep layers. Thus, we have treated FRIs with a combination of NPWT and CLAP, to optimize the local delivery of antibiotics and better manage the surrounding vascular dead space.

AKI and eighth cranial nerve palsy have been reported as systemic side effects of gentamicin. [28, 29] The trough concentration of gentamicin is 2 µg/ml for intra-venous administration; therefore, theoretically, for continuous administration, keeping under this level should prevent systemic side effects. [18] In this study, there were almost no cases of systemic side effects, which we attribute to continuous monitoring and dosage adjustments based on serum gentamicin levels.

It is also important to maintain an appropriate local concentration of the antibiotic. It has been reported that exposure to high concentrations of gentamicin does not inhibit the activity or proliferation of osteoblasts and endothelial cells, both of which are essential for fracture union. [30] However, the same aminoglycoside in the other study, tobramycin, is reported to cause cell death at extremely high concentrations, such as at ≥10,000 µg/ml. [31] The MBEC of gentamicin against Staphylococcus aureus has been reported to be 64–512 µg/ml, [12, 30, 32] and we believe that it can be safely used by adjusting the local concentrations to a range that exceeds the MBEC and is below the threshold that results in cytotoxicity. In this study, fracture union was achieved in 95% of the cases, which suggests that the local concentration was maintained within an appropriate range. The major advantage of this method is that the blood and local concentrations can be adjusted by altering the dosage of the drug being administered.

There are two major methods for the local administration of antibiotics, roughly classified as methods using a carrier and methods not using carriers. Indwelling a bone cement, such as polymenthyl methacrylate (PMMA) and calcium sulfate, containing antibiotics is a well-known example of a carrier method. This method requires debridement to place a carrier and eventually to remove it. [33–35] However, with this method, local antibiotic concentrations have been reported to be one to several times higher than the MIC at 4–6 weeks postoperatively, [36–38] and this is far below the concentration required to inhibit biofilm formation. In addition, this range is hypothesized to be the “mutant selection window,” which promotes the growth of resistant bacteria. [39–42] Therefore, these methods have limited local antibiotic elution areas and durations. As a no-carrier method, the local intra-operative injection of antibiotic solutions lowered postoperative infection rates. [11, 43] However, the duration of the antibiotic elution is poor in this method. [44] Another method of local antibiotic administration, the suction irrigation method, requires a large amount of washing solution, in which it is practically difficult to mix high concentrations of antibiotics. [18] Therefore, these methods have limitations in terms of the duration and concentration of antibiotics. CLAP, in contrast, uses a syringe pump that allows the continuous administration of antibiotics at any rate against the intramedullary pressure. In addition, using the pressure gradient created by the combined use of CLAP and NPWT make it possible to transfer and expand the infiltration range of antibiotics beyond previous limits. These points suggest that CLAP may be more useful than conventional methods for the treatment of FRIs. We are considering the application of this treatment method in PJIs, and we hope to continue research in this avenue.

The limitation of this study is that there were no cases treated by other methods as a comparison group. We understand the importance of having a comparative group with other methods for treating FRIs, and we consider this to be a subject for the future.

In conclusion, CLAP, which can safely deliver antibiotics locally at concentrations unachievable by systemic administration, is an effective treatment for difficult-to-treat cases of FRIs, due to its lack of side effects and proven efficacy.

AKI, acute kidney injury; ASA, American Society of Anesthesiologists; CLAP, continuous local antibiotics perfusion; CRP, C-reactive protein; FRI, fracture-related infection; GFR, glomerular filtration rate; iMAP, intra-medullary antibiotic perfusion; iSAP, intra-soft tissue antibiotic perfusion; MBEC, minimum biofilm eradication concentration; MIC, minimum inhibitory concentrations; MRCNS, methicillin-resistant coagulase negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; NPWT, negative pressure wound therapy; ORIF, open reduction and internal fixation; PJI, prosthetic joint infection; PMMA, polymenthyl methacrylate; WBC, white blood cell

Ethics approval and consent to participate

This study was approved by the institutional review board of the Steel Memorial Hirohata Hospital (approval number: H27-0311). Informed written consent was obtained from all patients whose clinical course or images have been presented in this manuscript.

Consent for publication

Patients provided signed informed consent forms regarding the publication of their data and photographs.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The corresponding author received consultant fees to develop the CLAP system from Cubex Medical. The remaining authors have no conflicts of interest to declare.

Funding

Not applicable.

Authors’ contributions

AM and TO were the major contributors to writing the manuscript. RM, HM1, HM2, TF, KO, RK, and TN conceived the study and were involved in the study design and coordination. All authors read and approved the final version of the manuscript. AM is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgments

Not applicable.

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Competing interest reported. The corresponding author received consultant fees to develop the CLAP system from Cubex Medical. The remaining authors have no conflicts of interest to declare.

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Continuous Local Antibiotic Perfusion (CLAP): A Treatment Strategy that Allows Implant Retention in Fracture-Related Infections

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Abstract

Figures

Background

Methods

Subjects

Data collection

Intra-medullary antibiotic perfusion (iMAP)

Intra-soft tissue antibiotics perfusion (iSAP)

Antibiotic Regimen

Treatment of FRIs with a combination of iMAP and iSAP using CLAP

Results

Patient background

Treatment background

Efficacy evaluation

Safety evaluation

Case presentation

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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