Dose Escalation Trial of Intrasite Vancomycin Pharmacokinetics
| Status: | Terminated |
|---|---|
| Conditions: | Infectious Disease, Hospital |
| Therapuetic Areas: | Immunology / Infectious Diseases, Other |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 5/12/2018 |
| Start Date: | January 2013 |
| End Date: | December 2013 |
A Prospective Dose-Escalation Trial of the Pharmacokinetics and Preliminary Safety of Intrasite Lyophilized Vancomycin to Prevent Wound Infections in Instrumented Spinal Surgery
Surgical wound infections remain a serious problem despite aseptic techniques and the use of
prophylactic systemic antibiotics. Such infections can occur at rates up to ~20% in high-risk
patients receiving long segment instrumented spinal fusions for deformity correction and
present potentially catastrophic consequences. Given this, the high cost of treatment, and a
payer system unable to support such expenses, investigators must make every effort to find
new cost-effective ways to prevent these complications.
Increasingly surgeons have sought to address this problem by placing lyophilized Vancomycin
into spinal surgery wounds immediately prior to wound closure. This method, known as
"intrasite" application, is adapted from techniques used to prevent infection in joint
replacement surgeries. The motivation for this practice is to maximize antibiotic
concentration within the wound while minimizing systemic concentration and toxicity, (the
inverse of the situation when using IV antibiotics). While the popularity of intrasite
delivery has grown rapidly, this has occurred without prospective scientific evidence.
Recently, three retrospective papers including nearly 2,500 treated patients, indicated that
intrasite Vancomycin reduces wound infections without increasing adverse events[1-3].
However, there are no published data on the dosing or pharmacokinetics of intrasite
Vancomycin, let alone prospective trials of its efficacy and safety.
The investigators propose to perform the first prospective trial of intrasite Vancomycin
pharmacokinetics and safety. Study objectives will include standardizing application and
dosing, defining peak/trough concentrations and clearance parameters, verifying bactericidal
potency, and dose selection for use in future studies. This will be accomplished by enrolling
groups of patients (n=10) to receive one of three doses of intrasite lyophilized Vancomycin
(3, 6 or 12 mg/cm2), prior to wound closure. Vancomycin concentrations in venous blood and
wound seroma fluid will be measured at regular intervals after surgery to establish
pharmacokinetic parameters. Preliminary data regarding local and systemic adverse events
including wound healing, fusion rate, and toxicity will be prospectively collected. The
ultimate goal of this learning-phase study is to gather sufficient information regarding
application, dosing, pharmacokinetics, measurement strategies, and adverse events to prepare
for a Phase III efficacy trial.
prophylactic systemic antibiotics. Such infections can occur at rates up to ~20% in high-risk
patients receiving long segment instrumented spinal fusions for deformity correction and
present potentially catastrophic consequences. Given this, the high cost of treatment, and a
payer system unable to support such expenses, investigators must make every effort to find
new cost-effective ways to prevent these complications.
Increasingly surgeons have sought to address this problem by placing lyophilized Vancomycin
into spinal surgery wounds immediately prior to wound closure. This method, known as
"intrasite" application, is adapted from techniques used to prevent infection in joint
replacement surgeries. The motivation for this practice is to maximize antibiotic
concentration within the wound while minimizing systemic concentration and toxicity, (the
inverse of the situation when using IV antibiotics). While the popularity of intrasite
delivery has grown rapidly, this has occurred without prospective scientific evidence.
Recently, three retrospective papers including nearly 2,500 treated patients, indicated that
intrasite Vancomycin reduces wound infections without increasing adverse events[1-3].
However, there are no published data on the dosing or pharmacokinetics of intrasite
Vancomycin, let alone prospective trials of its efficacy and safety.
The investigators propose to perform the first prospective trial of intrasite Vancomycin
pharmacokinetics and safety. Study objectives will include standardizing application and
dosing, defining peak/trough concentrations and clearance parameters, verifying bactericidal
potency, and dose selection for use in future studies. This will be accomplished by enrolling
groups of patients (n=10) to receive one of three doses of intrasite lyophilized Vancomycin
(3, 6 or 12 mg/cm2), prior to wound closure. Vancomycin concentrations in venous blood and
wound seroma fluid will be measured at regular intervals after surgery to establish
pharmacokinetic parameters. Preliminary data regarding local and systemic adverse events
including wound healing, fusion rate, and toxicity will be prospectively collected. The
ultimate goal of this learning-phase study is to gather sufficient information regarding
application, dosing, pharmacokinetics, measurement strategies, and adverse events to prepare
for a Phase III efficacy trial.
Despite extremely close attention to aseptic technique and the use of prophylactic IV
antibiotics, wound infection rates for posterior instrumented spinal surgery have been as
high as ~20% in published studies[4-13]. Such infections can be devastating for patients,
frequently requiring multiple re-operations to remove and then replace spinal implants,
lengthy hospital stays, prolonged courses of intravenous antibiotics, pain, immobility, and
increased risk of other complications. While the cost of the initial surgical episode can be
upwards of $250,000, the total cost of care can increase to more than quadruple this number
when complications like wound infection occur[14, 15]. Given the impetus to decrease
healthcare costs and a federal reimbursement policy denying payment for any care surrounding
a wound infection, it is critical to search for cost-effective ways of preventing surgical
wound infections[14, 16].
For several decades the standard of care in North America for surgical wound infection
prophylaxis has been IV cephalosporin administration within one hour of incision, followed by
interval IV dosing for 24 to 48hrs post-procedure[5, 13]. In some settings these antibiotics
now effectively treat less than half of identified infection-causing organisms[17, 18]. In
response, some groups of surgeons, including at the investigators' own institution, have
begun placing lyophilized Vancomycin into the surgical wound bed at the conclusion of the
procedure in an effort to further reduce wound infection rates[1-3]. The rationale behind
this intrasite antibiotic application is to increase local concentrations of antibiotic to
many times the minimally inhibitory concentration (MIC) for even moderately-resistant
gram-positive organisms, thereby increasing the bacterial kill rate[3]. It is also thought
that local antibiotic application should minimize blood concentrations of the drug, thereby
minimizing systemic complications like renal toxicity. Additionally, it is hypothesized that
intrasite antibiotic therapy could be less inclined to generate resistant organisms due to a
steep concentration gradient from the wound to the systemic circulation. The site of
potential infection (the wound) receives a dose of antibiotic vastly exceeding the saturation
concentration for bactericidal effect while the systemic concentration remains extremely low.
Bacteria should therefore be completely exterminated in the area of the wound or elsewhere
exposed to such a minimal concentration of Vancomycin that selection for resistant organisms
is avoided.
While none of these hypotheses have been rigorously or prospectively tested, three
retrospective studies have recently published a total of 2,479 spinal fusion patients treated
with intrasite Vancomycin for wound infection prophylaxis[1-3]. The largest of these studies
demonstrated a 0.99% infection rate in the treatment group, among the lowest rates ever
published[1]. Two of the studies showed large and statistically significant decreases in the
wound infection rate, compared to historical controls, when using intrasite Vancomycin in
addition to standard of care IV cephalosporins. Preliminary evidence in one study also
indicated high levels of Vancomycin within the wound and low or undetectable levels within
the blood following surgery[3]. All of these studies specifically cited that no adverse
events had been observed related to the treatment[1-3].
If intrasite Vancomycin proves to be safe and effective for preventing spinal fusion surgical
site infections, the treatment will offer great clinical value both for reducing morbidity
and also for decreasing large unsupported costs. A future large prospective efficacy trial
would be required to provide high-level evidence for this new mode of antibiotic therapy in
order to justify wide-spread adoption of the practice in spine surgery. Such data in any
population might also be generalizable to surgical wounds at large and prompt a paradigm
shift in infection prophylaxis for all types of surgical wounds. The proposed study addresses
necessary prerequisites for such a large-scale efficacy trial, including basic
pharmacokinetic and preliminary prospective safety data.
antibiotics, wound infection rates for posterior instrumented spinal surgery have been as
high as ~20% in published studies[4-13]. Such infections can be devastating for patients,
frequently requiring multiple re-operations to remove and then replace spinal implants,
lengthy hospital stays, prolonged courses of intravenous antibiotics, pain, immobility, and
increased risk of other complications. While the cost of the initial surgical episode can be
upwards of $250,000, the total cost of care can increase to more than quadruple this number
when complications like wound infection occur[14, 15]. Given the impetus to decrease
healthcare costs and a federal reimbursement policy denying payment for any care surrounding
a wound infection, it is critical to search for cost-effective ways of preventing surgical
wound infections[14, 16].
For several decades the standard of care in North America for surgical wound infection
prophylaxis has been IV cephalosporin administration within one hour of incision, followed by
interval IV dosing for 24 to 48hrs post-procedure[5, 13]. In some settings these antibiotics
now effectively treat less than half of identified infection-causing organisms[17, 18]. In
response, some groups of surgeons, including at the investigators' own institution, have
begun placing lyophilized Vancomycin into the surgical wound bed at the conclusion of the
procedure in an effort to further reduce wound infection rates[1-3]. The rationale behind
this intrasite antibiotic application is to increase local concentrations of antibiotic to
many times the minimally inhibitory concentration (MIC) for even moderately-resistant
gram-positive organisms, thereby increasing the bacterial kill rate[3]. It is also thought
that local antibiotic application should minimize blood concentrations of the drug, thereby
minimizing systemic complications like renal toxicity. Additionally, it is hypothesized that
intrasite antibiotic therapy could be less inclined to generate resistant organisms due to a
steep concentration gradient from the wound to the systemic circulation. The site of
potential infection (the wound) receives a dose of antibiotic vastly exceeding the saturation
concentration for bactericidal effect while the systemic concentration remains extremely low.
Bacteria should therefore be completely exterminated in the area of the wound or elsewhere
exposed to such a minimal concentration of Vancomycin that selection for resistant organisms
is avoided.
While none of these hypotheses have been rigorously or prospectively tested, three
retrospective studies have recently published a total of 2,479 spinal fusion patients treated
with intrasite Vancomycin for wound infection prophylaxis[1-3]. The largest of these studies
demonstrated a 0.99% infection rate in the treatment group, among the lowest rates ever
published[1]. Two of the studies showed large and statistically significant decreases in the
wound infection rate, compared to historical controls, when using intrasite Vancomycin in
addition to standard of care IV cephalosporins. Preliminary evidence in one study also
indicated high levels of Vancomycin within the wound and low or undetectable levels within
the blood following surgery[3]. All of these studies specifically cited that no adverse
events had been observed related to the treatment[1-3].
If intrasite Vancomycin proves to be safe and effective for preventing spinal fusion surgical
site infections, the treatment will offer great clinical value both for reducing morbidity
and also for decreasing large unsupported costs. A future large prospective efficacy trial
would be required to provide high-level evidence for this new mode of antibiotic therapy in
order to justify wide-spread adoption of the practice in spine surgery. Such data in any
population might also be generalizable to surgical wounds at large and prompt a paradigm
shift in infection prophylaxis for all types of surgical wounds. The proposed study addresses
necessary prerequisites for such a large-scale efficacy trial, including basic
pharmacokinetic and preliminary prospective safety data.
Inclusion Criteria:
1. Posterior instrumented spinal surgery patients 18 years of age and older with
instrumented fusion of at least three vertebral levels
1. Revision, elderly, obese, and diabetic patients will not be excluded since these
patients are known to be at higher risk of wound infection and represent an
important fraction of the elective surgical patient population.
2. Patients requiring IV Vancomycin for infection prophylaxis (i.e. due to cephalosporin
allergy) will be eligible for participation in the IV Vancomycin group.
Exclusion Criteria:
Intrasite Vancomycin Study Arm Exclusion Criteria
1. Children under 18 years old
2. Patients not receiving instrumentation or having less than three segment surgery
- therefore having small wound bed surface areas, close operative quarters, and lower
infection risk.
3. Patients not receiving wound drains
- drains provide the conduit for seroma fluid collection
4. Patients with known or suspected current infection
5. Use of systemic or topical antibiotics within 72 hours prior to surgery
- other than standard pre-op dose of ancef
6. Use of drugs or medications known to significantly increase the risk of renal toxicity
within the perioperative period.
7. Patients with known significant allergy to Vancomycin
- Redman Syndrome patients will not be excluded
8. Use of IV Vancomycin for perioperative infection prophylaxis (for example, in cases of
penicillin/cephalosporin allergy) will exclude patients from participation in the
intrasite Vancomycin groups of the study.
- IV Vancomycin Study Arm Exclusion Criteria
1. Children under 18 years old
2. Patients not receiving instrumentation or having less than three segment surgery -
therefore having small wound bed surface areas, close operative quarters, and lower
infection risk.
3. Patients not receiving wound drains
- drains provide the conduit for seroma fluid collection
4. Patients with known or suspected current infection
5. Use of systemic or topical antibiotics within 72 hours prior to surgery
- other than study related IV Vancomycin
6. Use of drugs or medications known to significantly increase the risk of renal toxicity
within the perioperative period.
7. Patients with known significant allergy to Vancomycin
- Redman Syndrome patients will not be excluded
8. Use of intrasite Vancomycin for infection prophylaxis will exclude patients from
participation in the IV Vancomycin study group.
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