Tumescent Antibiotic Delivery Pharmacokinetics
Condition: Prevention of Surgical Site Infections
MeSH terms: Infections; Surgical Wound Infection
Study type: Interventional
Phase: Phase 1

Summary: 
      Tumescent Antibiotic Delivery (TAD) is a technique for improving the prevention of surgical
      site infections (SSI). TAD involves the subcutaneous infiltration of tumescent local
      anesthesia (TLA) containing water soluble antibiotic(s) such as cefazolin and metronidazole.
      TLA consists of the subcutaneous infiltration of very dilute lidocaine (≤ 1 gram/liter) and
      epinephrine (≤ 1 milligram/liter) with sodium bicarbonate (10 milliequivalents/liter) in a
      physiologic solution of sodium chloride which produces intense local anesthesia associated
      with profound wide-spread vasoconstriction lasting for more than 12 hours. Compared to
      intravenous antibiotic delivery (IVAD), TAD is expected to produce higher local tissue
      concentrations of the antibiotic(s) for longer periods of time and lower systemic/serum
      antibiotic concentrations. This clinical trial will compare TAD to IVAD with respect to
      pharmacokinetic evidence for possible improved SSI prevention.
    

Detailed description: 
      The protocol entitled Absorption Kinetics of Subcutaneous Tumescent Cefazolin and
      Metronidazole is a Phase I dose ranging clinical study designed to document the
      concentration-time profile of cefazolin and lidocaine after subcutaneous infiltration of
      cefazolin in tumescent local anesthesia (TLA). The antibiotic cefazolin is routinely given
      intravenously (IV) for the prophylaxis of surgical site infections (SSI).

      Tumescent local anesthesia (TLA) consists of the subcutaneous infiltration of very dilute
      lidocaine (≤ 1 gram/liter) and epinephrine (≤ 1 milligram/liter) with sodium bicarbonate (10
      milliequivalents/liter) in a physiologic solution of sodium chloride. Clinically TLA produces
      intense local anesthesia associated with profound wide-spread vasoconstriction lasting for
      more than 12 hours. Tumescent delivery of a cefazolin refers to the subcutaneous infiltration
      of cefazolin dissolved in a dilute solution of tumescent local anesthesia.

      For a number of surgical procedures the current standard of care for prophylaxis of surgical
      site infection (SSI) is IV antibiotics (e.g. cefazolin) administered within 30 to 60 minutes
      before a surgical incision. We hypothesize that tumescent delivery of cefazolin may be more
      effective in preventing SSI and possibly safer with fewer side effects compared to IV
      delivery of cefazolin.

      This protocol is a preliminary step in exploring the possibility that tumescent delivery of
      cefazolin is better than standard IV delivery for the prevention of SSI. The present protocol
      is a phase I study that will document and compare serum and tissue cefazolin levels after IV
      and subcutaneous tumescent delivery. A finding that tumescent delivery provides prolonged
      tissue levels of cefazolin will justify a phase II study of tumescent cefazolin at the site
      of an anticipated surgical incision for SSI prevention.

      • Summary of Experimental Design of Clinical Trial Protocol The tumescent cefazolin study
      protocol is organized as follows. The tumescent cefazolin clinical study protocol will
      involve four adult volunteer subjects/participants. Each subject will participate in up to
      four (4) separate 12 to 24-hour investigative procedures at least one to two weeks apart.
      Concentrations of drugs in the solution of tumescent local anesthesia will be: lidocaine ≤
      1000 mg/L, epinephrine ≤ 1.0 mg/L, sodium bicarbonate 10 meq/L, cefazolin ≤ 1 gm/L with or
      without metronidazole 500mg/L . Maximum total cefazolin dose will be 1 gm. The maximum total
      metronidazole dose will be 500 mg. The maximum tumescent lidocaine dosage will be 20 mg/kg.
      TLA will be delivered into subcutaneous fat by peristaltic infiltration pump using
      blunt-tipped infiltration cannulas.

      Procedures 1 & 2: Subcutaneous infiltration of tumescent cefazolin: Two of the four
      investigative procedures will begin with infiltration of a solution of tumescent local
      anesthesia containing cefazolin. Following infiltration of subcutaneous tumescent local
      anesthesia containing cefazolin approximately 9 sequential blood and tissue samples are taken
      over 12 to 24 hours. In these two studies a minimal volume of liposuction (10 ml to 12 ml
      using a hand held syringe) will be done in order to obtain samples of subcutaneous fat and
      tumescent subcutaneous interstitial tissue-fluid for measurement of cefazolin and
      metronidazole concentration.

      Procedure 3: IV infusion of cefazolin or metronidazole: In the control study the patient is
      given 1 gm of IV cefazolin with or without 500 mg of metronidazole and subsequent sequential
      serum samples for antibiotic concentration will be obtained over 12 hours.

      Serum Samples: Sequential sampling of serum and fat will be obtained at 0, 1, 3, 6, 9, 12,
      18, and 24 hour (T0, T1, T3, T6, T9, T12, T15, T18 and T24), where T0 = time of completion of
      tumescent infiltration or IV infusion. Serum samples will be obtained from a peripheral vein
      via an indwelling catheter and analyzed for cefazolin concentration by HPLC.

      Tissue Fluid Samples: Samples of subcutaneous tissue fluid will be obtained by liposuction of
      approximately 10 ml of subcutaneous fat and tumescent anesthetic solution using a hand-held
      syringe, the aspirate being centrifuged to obtain an aqueous infranate from which cefazolin,
      metronidazole and lidocaine concentration will be measured by HPLC. Clinical experience has
      shown that tumescent local anesthesia persists for at least 12 hours. If the patient
      experiences any significant discomfort during the aspiration of subcutaneous fat using a
      hand-held syringe, then no further subcutaneous tissue samples will be taken for the duration
      of that clinical procedure.
    

Intervention name(s): Tumescent Antibiotic Delivery of cefazolin with or without metronidazole; Intravenous Antibiotic Delivery
Intervention type(s): Procedure; Procedure
Intervention description(s): TAD of cefazolin with or without metronidazole followed by sequential serum and interstitial fluid samples over 14 to 24 hours for antibiotic concentrations; Intravenous antibiotic delivery of cefazolin with or without metronidazole followed by sequential serum sampling for antibiotic concentration of subsequent 12 to 24 hours.
Other intervention name(s): Cefazolin; Metronidazole
Intervention MeSH terms: Anti-Bacterial Agents; Metronidazole; Cefazolin; Antibiotics, Antitubercular
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Surgical site infections; Prevention; Prophylaxis; Tumescent; Intravenous; Antibiotic; Absorption; Pharmacokinetics; Bioavailability