Surgical Wound Infection, Neck Infection, Nasal Reconstruction
Conditions
Keywords
Microdialysis, Pharmacokinetics, Antibiotic tissue penetration, Inferior turbinate flap, Beta-lactam antibiotics, Tissue ischemia
Brief summary
The goal of this study is to measure how well commonly used antibiotics reach the tissue in the head and neck region in adults with a postoperative neck infection or undergoing reconstructive nasal surgery with an inferior turbinate flap. The study also describes markers of ischemia and inflammation in the newly created flap during the first days after surgery. The main question it aims to answer is: For how long do the free concentrations of cefuroxime, cloxacillin, dicloxacillin, and amoxicillin/clavulanic acid stay above the minimal inhibitory concentration (T\>MIC) in infected tissue, non-infected tissue, the flap, and plasma? Participants will receive the antibiotics on a fixed, protocol-defined schedule for about two days. Small microdialysis catheters will be placed in the tissue to collect fluid continuously, and serial blood samples will be drawn. Participation ends when the last sample is collected and the catheters are removed.
Detailed description
Infections in the head and neck region and reconstructive surgery in the nasal and sinus area are associated with considerable morbidity and require effective antibiotic treatment. Treatment is based mainly on systemic antibiotic concentrations, but little is known about actual tissue penetration in infected tissue and in reconstructed flaps, where perfusion, edema, ischemia, and inflammation may alter drug distribution. Microdialysis is a minimally invasive method for continuous sampling of free, pharmacologically active drug concentrations and metabolic and inflammatory markers in the extracellular fluid. This is a prospective, non-randomized, open-label, exploratory interventional study with two sub-studies and a total of 16 participants. All study drugs are marketed antibiotics used in routine clinical practice; they are administered in a protocol-defined regimen to allow pharmacokinetic sampling. Sub-study 1 (n=8): Adults admitted with a postoperative infection in the neck. Treatment is started on day 1 with cefuroxime 750 mg IV four times daily and dicloxacillin 1000 mg orally four times daily. On day 2, microdialysis catheters are placed in infected and non-infected subcutaneous tissue of the neck, and sampling is performed over two consecutive dosing intervals: (1) cefuroxime 750 mg IV plus dicloxacillin 1000 mg orally, sampled for 6 hours; and (2) cefuroxime 1500 mg IV plus cloxacillin 1000 mg IV, sampled for 8 hours. This allows comparison of two cefuroxime doses and of oral dicloxacillin versus intravenous cloxacillin. Sub-study 2 (n=8): Adults undergoing reconstructive surgery with an inferior turbinate flap (IFT flap). Postoperatively, amoxicillin/clavulanic acid 500/125 mg and dicloxacillin 1000 mg are given orally three times daily. Microdialysis catheters are placed in the flap and in the nasal septal mucosa (reference tissue). Ischemia markers (glucose, lactate, pyruvate, glycerol) and inflammatory proteins are sampled hourly during the first 6 postoperative hours and in the morning and evening of day 2. Antibiotic concentrations are measured over one dosing interval after the morning dose on day 2. In both sub-studies, dialysate is collected in 30-60 minute intervals and serial blood samples are drawn for plasma concentrations. Catheters are calibrated in vivo at the end of sampling. Drug concentrations are analysed by LC-MS. Clinically indicated treatment can be changed by the treating physician at any time.
Interventions
DRUGCefuroxime
Sub-study 1: Cefuroxime 750 mg intravenously four times daily from day 1. On day 2, one dosing interval of cefuroxime 750 mg IV (sampled over 6 hours) followed by one dosing interval of cefuroxime 1500 mg IV (sampled over 8 hours), to compare tissue penetration of the two doses.
DRUGDicloxacillin
Dicloxacillin 1000 mg orally. Sub-study 1: four times daily from day 1, with tissue and plasma sampling during the first dosing interval on day 2 (6 hours). Sub-study 2: three times daily postoperatively from day 1, with tissue and plasma sampling over one dosing interval after the morning dose on day 2.
DRUGCloxacillin
Sub-study 1: Cloxacillin 1000 mg intravenously as a single dose in the second dosing interval on day 2 (given together with cefuroxime 1500 mg IV), with tissue and plasma sampling over 8 hours, to compare with oral dicloxacillin.
Sub-study 2: Amoxicillin/clavulanic acid 500/125 mg orally three times daily postoperatively from day 1 (together with dicloxacillin), with tissue and plasma sampling of amoxicillin over one dosing interval after the morning dose on day 2.
PROCEDUREMicrodialysis and serial blood sampling
CE-marked microdialysis catheters perfused with isotonic saline (0.5-1 microL/min) are placed in the target tissues: infected and non-infected subcutaneous neck tissue (sub-study 1), or the inferior turbinate flap and nasal septal mucosa as reference tissue (sub-study 2). Dialysate is collected in 30-60 minute intervals, with serial blood samples drawn for plasma concentrations. Catheters are calibrated in vivo at the end of sampling and then removed.
Sponsors
Tejs Ehlers Klug
Danish Cancer Society
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Two independent, non-randomized sub-studies in different patient populations: (1) patients with postoperative neck infection, and (2) patients undergoing reconstruction with an inferior turbinate flap. Within each sub-study, all participants receive the same protocol-defined antibiotic regimen, allowing within-patient comparison of tissue and plasma concentrations.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * Either a postoperative infection in the neck (sub-study 1) or planned reconstruction with an inferior turbinate flap (sub-study 2) * Age 18 years or older
Exclusion criteria
* Known allergy or hypersensitivity to any of the study antibiotics (cefuroxime, cloxacillin, dicloxacillin, or amoxicillin/clavulanic acid) * eGFR below 30 mL/min/1.73 m2 * Pregnancy or planned pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time Above the Minimal Inhibitory Concentration (T>MIC) in Tissue and Plasma | Sub-study 1: two consecutive dosing intervals on day 2 (0-6 hours and 0-8 hours after dosing). Sub-study 2: one dosing interval (approximately 8 hours) after the morning dose on postoperative day 2. | Time during which the free concentration of each study antibiotic (cefuroxime, cloxacillin, dicloxacillin, and amoxicillin/clavulanic acid) exceeds the minimal inhibitory concentration in each measured tissue (microdialysis) and in plasma (serial blood samples), calculated from concentration-time profiles. Pre-specified MIC targets: cefuroxime 4 mg/L; cloxacillin 2 mg/L; dicloxacillin 2 mg/L; amoxicillin/clavulanic acid 2 mg/L (amoxicillin component). Reported as time (hours) and as percentage of the dosing interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve (AUC) in Tissue and Plasma | Sub-study 1: two consecutive dosing intervals on day 2 (0-6 hours and 0-8 hours after dosing). Sub-study 2: one dosing interval (approximately 8 hours) after the morning dose on postoperative day 2. | AUC of the free concentration of each study antibiotic in each measured tissue compartment (microdialysis) and in plasma. |
| Tissue Penetration Ratio (AUC Tissue / AUC Plasma) | Sub-study 1: two consecutive dosing intervals on day 2 (0-6 hours and 0-8 hours after dosing). Sub-study 2: one dosing interval (approximately 8 hours) after the morning dose on postoperative day 2. | Ratio of the AUC of the free antibiotic concentration in each tissue compartment to the AUC in plasma, for each study antibiotic. |
| Maximum Concentration (Cmax) in Tissue and Plasma | Sub-study 1: two consecutive dosing intervals on day 2 (0-6 hours and 0-8 hours after dosing). Sub-study 2: one dosing interval (approximately 8 hours) after the morning dose on postoperative day 2. | Peak free concentration of each study antibiotic in each measured tissue compartment and in plasma. |
| Time to Maximum Concentration (Tmax) in Tissue and Plasma | Sub-study 1: two consecutive dosing intervals on day 2 (0-6 hours and 0-8 hours after dosing). Sub-study 2: one dosing interval (approximately 8 hours) after the morning dose on postoperative day 2. | Time from dose administration to peak free concentration of each study antibiotic in each measured tissue compartment and in plasma. |
| Elimination Half-Life (T1/2) in Tissue and Plasma | Sub-study 1: two consecutive dosing intervals on day 2 (0-6 hours and 0-8 hours after dosing). Sub-study 2: one dosing interval (approximately 8 hours) after the morning dose on postoperative day 2. | Elimination half-life of each study antibiotic in each measured tissue compartment and in plasma, derived from the concentration-time profiles. |
| Lactate/Pyruvate Ratio in the Inferior Turbinate Flap | Hourly during the first 6 postoperative hours (day 1), and in the morning and evening of postoperative day 2. | Lactate/pyruvate ratio measured in microdialysate from the inferior turbinate flap and the nasal septal reference tissue, as a marker of tissue ischemia (sub-study 2). |
| Tissue Ischemia Markers (Glucose, Lactate, Pyruvate, and Glycerol) | Sub-study 2: hourly during the first 6 postoperative hours (day 1), and in the morning and evening of postoperative day 2. Sub-study 1: during the sampling period on day 2 (up to approximately 14 hours). | Concentrations of glucose, lactate, pyruvate, and glycerol in microdialysate from the measured tissue compartments. |
| Inflammatory Proteins in Microdialysate | Hourly during the first 6 postoperative hours (day 1), and in the morning and evening of postoperative day 2. | Levels of inflammatory proteins measured in microdialysate from the inferior turbinate flap and the nasal septal reference tissue, to characterize the early postoperative inflammatory tissue response (sub-study 2). |
Countries
Denmark
Contacts
CONTACTPelle Hanberg, MD, PhD
CONTACTTejs Ehlers Klug, MD, DMSc
PRINCIPAL_INVESTIGATORTejs Ehlers Klug, MD, DMSc
Aarhus University Hospital
Outcome results
None listed