Surgical Site Infection

Prophylaxis - Optimizing
Antibiotic Use
William R. Mikesell, PharmD
Brandon J. Speakman, PharmD
Learning Objectives
• Explain the reasoning behind the use of
prophylactic antibiotics
• Review recommendations on dosing,
administration, and redosing antibiotics
• Formulate a guideline-directed prophylactic
antibiotic regimen for orthopedic procedures
• Discern whether an allergy should exclude a
patient from receiving cefazolin
• Evaluate current literature on the use of
prophylactic antibiotics for orthopedic
surgeries
Background
Why do we give antibiotics prior to surgery?
• Antimicrobial prophylaxis plays an important
role in reducing the rate of surgical site
infections (SSI).
Common Organisms:
• Predominantly gram-positive organisms
• Staphylococcus aureus
• Staphylococcus epidermidis
• 40% LHN isolates were gram positive
(2022-2023 TOH knee and hip SSI)
• 27% of patients had polymicrobial infections
Antibiotic Selection
Common Principles:
• Prevent SSI, morbidity and mortality
• Reduce duration and cost of health care
• Minimize adverse effects
• Minimize adverse consequences to microbial
flora
To achieve these goals, antimicrobial agent(s)
should be:
• Active against most likely pathogens
• Appropriate dosage and administration time
• Safe
• Administered for shortest effective period
 Antibiotic Selection

Gram-positive Gram-negative Gram-negative

Anaerobes

MSSA MRSA/MRSE

Cefazolin

Vancomycin

Clindamycin Caution: Caution:

Increasing Increasing
resistance resistance
Antibiotic Selection: Cefazolin
Coverage:
• Excellent activity against gram-positive cocci,
some activity against gram-negative bacilli
Advantages:
• Drug of choice for methicillin sensitive
Staphylococcus aureus (MSSA)
Disadvantages:
• No methicillin resistant Staphylococcus aureus
(MRSA) coverage
• Shortest half-life
Pharmacodynamic Properties:
• Time > MIC
Antibiotic Selection: Vancomycin
Coverage:
• Staphylococci (Including MRSA), Streptococci,
Enterococci (NOT vancomycin resistant enterococcus)
Advantages:
• MRSA coverage
• Alternative for patient allergies
• Longest half-life
Disadvantages:
• Requires long administration time
• Higher rates of SSI compared to cefazolin
• No gram-negative coverage
• Weight-based dosing
• Less activity against MSSA compared to cefazolin
• Nephrotoxicity
• Poor tissue penetration
• Reduced bactericidal rates
Pharmacodynamic Properties:
• AUC/MIC
Antibiotic Selection: Clindamycin
Coverage:
• Activity against most gram-positive bacteria
Advantages:
• MRSA coverage
• Alternative for patient allergies
Disadvantages:
• Boxed Warning: C. difficile
• Higher rates of SSI compared to cefazolin
• Increasing resistance rates
• No gram-negative coverage
Pharmacodynamic Properties:
• AUC/MIC
 Compare the rate of SSI between the 3 drugs

A study by Norvell, et al. compared cefazolin to

vancomycin or clindamycin for SSI after total hip
or knee arthroplasty.
Cefazolin Vancomycin or
Clindamycin
Rate of SSI 7 (0.9%) 12 (3.8%)
Periprosthetic Joint 1 (0.1%) 6 (1.9%)
Infection

Norvell MR, Porter M, Ricco MH, Koonce RC, Hogan CA, Basler E, Wong M, Jeffres MN.
Cefazolin vs Second-line Antibiotics for Surgical Site Infection Prevention After Total
Joint Arthroplasty Among Patients With a Beta-lactam Allergy. Open Forum Infect Dis.
2023 Apr 24;10(6):ofad224. doi: 10.1093/ofid/ofad224. PMID: 37363051; PMCID:
PMC10289809.
Patient Case: 1
LD is a 56 y.o. patient presenting for a right total
knee arthroplasty (TKA). While reviewing his chart,
you note that he has a “mild” allergy to ampicillin
listed with an unknown reaction. He is negative for
MRSA colonization. Which of the following options
would be the most appropriate choice for surgical
site infection prophylaxis preoperatively?
a. Cefazolin
b. Vancomycin
c. Clindamycin
d. Cefazolin + Vancomycin
Antibiotic Selection: Allergies
Patient Case: 1
LD is a 56 y.o. patient presenting for a right TKA.
While reviewing his chart, you note that he has an
“mild” allergy to ampicillin listed with an unknown
reaction. He is negative for MRSA colonization.
Which of the following options would be the most
appropriate choice for surgical site infection
prophylaxis preoperatively?

a. Cefazolin ←
b. Vancomycin
c. Clindamycin
d. Cefazolin + Vancomycin
Patient Case: 2
TR is a 73 year old male presenting for a total hip
arthroplasty. While reviewing his chart, you note
that he has a “severe” allergy to cephalexin listed
with an Stevens-Johnson Syndrome (SJS). He is
negative for MRSA colonization. Which of the
following options would be the most appropriate
choice for surgical site infection prophylaxis
preoperatively?

a. Cefazolin
b. Vancomycin
c. Clindamycin
d. Cefazolin + Vancomycin
Patient Case: 2
TR is a 73 year old male presenting for a total hip
arthroplasty. While reviewing his chart, you note
that he has a “severe” allergy to cephalexin listed
with an Stevens-Johnson Syndrome (SJS). He is
negative for MRSA colonization. Which of the
following options would be the most appropriate
choice for surgical site infection prophylaxis
preoperatively?

a. Cefazolin
b. Vancomycin←
c. Clindamycin
d. Cefazolin + Vancomycin
 Dosing
IDSA/ASHP CDC WHO AAOS
Cefazolin 80-120 kg = 2 g >60-80 kg = 2 g Refer 2-3 g

≥ 120 kg = 3 g ≥120 kg = 3 g

Vancomycin 15 mg/kg based on 15 mg/kg Refer 15 mg/kg

total body weight
Clindamycin 900 mg N/A Refer 900 mg

● Dale W. Bratzler, E. Patchen Dellinger, Keith M. Olsen, Trish M. Perl, Paul G. Auwaerter, Maureen K. Bolon, Douglas N. Fish,
Lena M. Napolitano, Robert G. Sawyer, Douglas Slain, James P. Steinberg, Robert A. Weinstein, Clinical practice guidelines for
antimicrobial prophylaxis in surgery, American Journal of Health-System Pharmacy, Volume 70, Issue 3, 1 February 2013,
Pages 195–283, https://doi.org/10.2146/ajhp120568
● Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention
of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784–791. doi:10.1001/jamasurg.2017.0904
● Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK536404/
● American Academy of Orthopaedic Surgeons. Diagnosis and Prevention of Periprosthetic Joint Infections Clinical Practice
Guideline. https://www.aaos.org/pjiguideline. Published March 11, 2019.
Administration:
Administration Time
IDSA/ Within 60 minutes prior to incision (Vancomycin 60-120
ASHP minutes)
CDC Within 60 minutes prior to incision (Vancomycin 60-120
minutes)
WHO Within 120 minutes before incision, but take half-life into
consideration
AAOS Within 60 minutes prior to surgical incision, with most
surgeons opting for within 30 minutes of incision.

Vancomycin may be infused up to 2 hours before surgery due

to extended infusion times and long half-lives

● Dale W. Bratzler, E. Patchen Dellinger, Keith M. Olsen, Trish M. Perl, Paul G. Auwaerter, Maureen K. Bolon, Douglas N. Fish,
Lena M. Napolitano, Robert G. Sawyer, Douglas Slain, James P. Steinberg, Robert A. Weinstein, Clinical practice guidelines for
antimicrobial prophylaxis in surgery, American Journal of Health-System Pharmacy, Volume 70, Issue 3, 1 February 2013,
Pages 195–283, https://doi.org/10.2146/ajhp120568
● Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention
of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784–791. doi:10.1001/jamasurg.2017.0904
● Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK536404/
● American Academy of Orthopaedic Surgeons. Diagnosis and Prevention of Periprosthetic Joint Infections Clinical Practice
Guideline. https://www.aaos.org/pjiguideline. Published March 11, 2019.
Intraoperative Redosing
IDSA/ CDC WHO AAOS
ASHP
Cefazolin 4 hrs 1-2 t½ Refer 4 hrs
(2-4 hrs)
Vancomycin N/A 1-2 t½ Refer N/A
(8-16 hrs)
Clindamycin 6 hrs 1-2 t½ Refer N/A
(2-8 hrs)

American Society of Health-System Pharmacists (ASHP) (4)

recommend that intraoperative redosing is needed if the duration of
the procedure exceeds 2 half-lives of the drug or if there is excessive
blood loss during the procedure. (>1500 mL)

● Dale W. Bratzler, E. Patchen Dellinger, Keith M. Olsen, Trish M. Perl, Paul G. Auwaerter, Maureen K. Bolon, Douglas N. Fish,
Lena M. Napolitano, Robert G. Sawyer, Douglas Slain, James P. Steinberg, Robert A. Weinstein, Clinical practice guidelines for
antimicrobial prophylaxis in surgery, American Journal of Health-System Pharmacy, Volume 70, Issue 3, 1 February 2013,
Pages 195–283, https://doi.org/10.2146/ajhp120568
● Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention
of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784–791. doi:10.1001/jamasurg.2017.0904
● Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK536404/
● American Academy of Orthopaedic Surgeons. Diagnosis and Prevention of Periprosthetic Joint Infections Clinical Practice
Guideline. https://www.aaos.org/pjiguideline. Published March 11, 2019.
 Duration: Extended Prophylaxis
IDSA/ Single dose or continuation for less than 24 hours.
ASHP

CDC High-quality evidence suggested no benefit of continuing

antibiotics after intraoperative closure of the surgical
incisions.

WHO Administration should NOT be prolonged after completion of

the operation

AAOS Discontinue within 24 hours post end of surgery

● Dale W. Bratzler, E. Patchen Dellinger, Keith M. Olsen, Trish M. Perl, Paul G. Auwaerter, Maureen K. Bolon, Douglas N. Fish,
Lena M. Napolitano, Robert G. Sawyer, Douglas Slain, James P. Steinberg, Robert A. Weinstein, Clinical practice guidelines for
antimicrobial prophylaxis in surgery, American Journal of Health-System Pharmacy, Volume 70, Issue 3, 1 February 2013,
Pages 195–283, https://doi.org/10.2146/ajhp120568
● Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention
of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784–791. doi:10.1001/jamasurg.2017.0904
● Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK536404/
● American Academy of Orthopaedic Surgeons. Diagnosis and Prevention of Periprosthetic Joint Infections Clinical Practice
Guideline. https://www.aaos.org/pjiguideline. Published March 11, 2019.
 Extended Oral Antibiotic Prophylaxis in
High-Risk Patients Substantially
Reduces Primary Total Hip and Knee
Arthroplasty 90-Day Infection Rate

Inabathula A, Dilley JE, Ziemba-Davis M, et al.

Inabathula A, Dilley JE, Ziemba-Davis M, et al. Extended Oral Antibiotic Prophylaxis in High-Risk Patients
Substantially Reduces Primary Total Hip and Knee Arthroplasty 90-Day Infection Rate. J Bone Surg Am.
2018;100:2103-9. doi: 10.2106/JBJS.17.01485
Inabathula et al.
Methodology
• Retrospective cohort study
• Group A vs. Group B vs. Group C
• Group A: low risk, no prolonged antibiotics
• Group B: high risk, no prolonged antibiotics
• Group C: high risk, prolonged antibiotics
• “High-Risk” Factors
• BMI ≥35 kg/m2
• Diabetes mellitus
• Smoker
• Chronic kidney disease
• Autoimmune disease
• Nasal colonization w/ MRSA or MSSA
Inabathula et al.
Methodology cont’d.
• Antibiotic selection
• Cefadroxil 500mg PO BID x7days
• MRSA positive: Bactrim DS 1 tablet PO BID x7days
• True cephalosporin allergy: Clindamycin 300mg PO
TID x7days
• 2181 patients with primary total knee
arthroplasty (TKA) or total hip arthroplasty
(THA) analyzed
• Primary Outcome: number of prosthetic joint
infections (PJI) within 90 days
Inabathula et al.
Results
• 90-day PJI Rate ≥ 1 risk factor
Group B Group C p-value
TKA 2.1% 0.5% 0.038*
THA 4.3% 1.1% 0.034*
• Male patients were 7.2 times more likely to develop
PJI than female patients (CI 2.0-26.2)
Author’s Conclusion
• “Extended postoperative oral antibiotic
prophylaxis for 7 days results in a statistically
significant and clinically meaningful reduction in
the 90-day infection rate.”
Inabathula et al.
Limitations
• Potential for confounding variables
• Retrospective design
• Changes in hospital infection-prevention protocols
not controlled for
• Statistically significant differences in baseline
demographics
• Median age, Median BMI, Use of tranexamic acid (TXA)
• 9 patients were included in treatment group
that did not have protocol “high-risk” factors
• Study protocol amended to include nasal
colonization as risk factor in July 2016
 The AAHKS Clinical Research Award:
Extended Oral Antibiotics Prevent
Periprosthetic Joint Infection in
High-Risk Cases: 3855 Patients With
1-Year Follow-Up

Kheir MM, Dilley JE, Ziemba-Davis M,

Meneghini RM

Kheir MM, Dilley JE, Ziemba-Davis M, Meneghini RM. The AAHKS Clinical Research Award: Extended Oral
Antibiotics Prevent Periprosthetic Joint Infection in High-Risk Cases: 3855 Patients With 1-Year Follow-Up.
J Arthroplasty. 2021;36:S18-25. doi:10.1016/j.arth.2021.01.051
Kheir MM, et al.
Builds on Inabathula et al.
• Primary outcome extended to 1 year
• Sample size increased to 3855 patients
Results consistent with previous trial
• 1.40% overall infection rate
• 2.64% Group B vs. 0.89% Group C (p<0.001)
• Number needed to treat (NNT) = 57 patients
Author’s Conclusion
• “Extended oral antibiotic prophylaxis may be a
simple, safe, and cost-effective measure [...] to
reduce PJI rates at 1 year postoperatively”
Kheir MM, et al.
Limitations
• Resistant PJI rates
Group A Group B Group C NNH
0% 11.8% 8
7.1% 11.8% 21

• NNT was 57
• TKA Results
• ≥ 1 risk factor: P=0.016 (significant)
• ≥ 2 risk factors: P=0.228 (not significant)
Association of Duration and Type of
Surgical Prophylaxis With
Antimicrobial-Associated Adverse
Events

Branch-Elliman W, O’Brien W, Strymish J, et al.

● Branch-Elliman W, O’Brien W, Strymish J, et al. Association of Duration and Type of Surgical

Prophylaxis With Antimicrobial-Associated Adverse Events. JAMA Surg.
2019;154(7):590-598. doi: 10.1001/jamasurg.2019.0569
Branch-Elliman W, et al.
Methodology
• Retrospective cohort study
• VA patients
• Stratified by surgery type
• Cardiac
• Orthopedic total joint replacement (TJR)
• Colorectal
• Vascular
• Variety of antibiotics were examined
• Examined adverse effects (AE) related to
postoperative antibiotic use
• <24 hours
• ≥24-<48 hours
• ≥48-<72 hours
• ≥72 hours
Branch-Elliman W, et al.
Results
• Surgical Site Infection (SSI)
• Adjusted for a priori SSI risk factors, antibiotic
courses >24hr did not reduce SSI in any surgery type
• Orthopedic TJR (adjusted odds ratio [aOR]
referenced to <24hr)
• No statistical differences between groups

aOR
≥24-<48 hr 1.11 (0.82-1.51)
≥48-<72 hr 2.04 (1.00-4.16)
≥72 hr 1.63 (0.22-12.07)
Branch-Elliman W, et al.
Results contd.
• Acute Kidney Injury (AKI)
• Duration-dependent increase in AKI
• Non-Cardiac Surgeries (aOR referenced to <24hr)

aOR NNH
≥24-<48 hr 1.31 (1.21-1.42) 9
≥48-<72 hr 1.72 (1.47-2.01) 6
≥72 hr 1.79 (1.27-2.53) 4
Branch-Elliman W, et al.
Results contd.
• C. difficile Infection (CDI)
• Duration-dependent increase observed
• All surgery types (aOR referenced to <24hr)

aOR NNH
≥24-<48 hr 1.08 (0.89-1.31) 2000
≥48-<72 hr 2.43 (1.80-3.27) 90
≥72 hr 3.65 (2.40-5.55) 50
Branch-Elliman W, et al.
Limitations
• Retrospective, observational study
• Limited generalizability
• Predominantly male (96.3%)
• AKI/CDI not stratified by orthopedic surgeries
specifically
Author’s Conclusion
• “Longer durations of prophylaxis did not lead to
additional SSI reduction but were associated
with increases in preventable adverse events…”
Summary
• Prophylactic antibiotics given prior to surgery
reduce the rate of SSI
• Antibiotics commonly used for orthopedic
surgery prophylaxis include cefazolin,
vancomycin, and clindamycin
• Proper dose timing and redosing is crucial for
prevention of SSI
• Cefazolin may often be safely administered to
most patients with a listed penicillin allergy
• Literature regarding postoperative antibiotic
prophylaxis is mixed
 Surgical Site Infection
Prophylaxis - Optimizing
Antibiotic Use
William R. Mikesell, PharmD
Brandon J. Speakman, PharmD