Prevention of Surgical Site Infections Clinical Trial
Official title:
Tumescent Antibiotic Delivery: Pharmacokinetic Evidence for Improved Surgical Site Infection Prevention
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.
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Allocation: Non-Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
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