Tumescent Antibiotic Delivery Pharmacokinetics
Tumescent Antibiotic Delivery Pharmacokinetics
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.
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.
Inclusion Criteria:

 -  Healthy adult

 -  No allergies to cefazolin, metronidazole or lidocaine

 Exclusion Criteria:

 -  HIV

 -  Hepatitis C

 -  Diabetes