Cefazolin Dosing for Surgical Prophylaxis

(MorphAbxPKSurg Trial)

Overseen By June Sullivan, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Michigan

Must be taking: Cefazolin

Disqualifiers: Penicillin allergy, Pregnancy

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

104 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical study is to compare the dosing of an antibiotic in overweight patients having surgery. The main question\[s\] it aims to answer are: * Are the antibiotic concentrations in blood and fat tissue in patients that are overweight sufficient to prevent the chance of infection? * Can dosing using body composition rather than body weight improve the chance of achieving good antibiotic concentrations in overweight patients? Participants will allow us to collect small amounts of blood and fat tissue during their regularly scheduled surgery. Researchers will compare differences in antibiotic concentrations based on dosing by standard of care (body weight based) versus body composition.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Cefazolin for surgical prophylaxis?

Research shows that Cefazolin, when given in the right dose and timing before surgery, helps reduce the risk of infections at the surgical site. Studies have found that maintaining adequate levels of Cefazolin during surgery is important for preventing infections, and it has been effective in both human and animal studies. ^{1 2 3 4 5}

Is cefazolin generally safe for use in humans?

Cefazolin is widely used and recommended for preventing infections during surgeries, and studies have shown it to be safe for various patient groups, including those who are obese or have kidney issues. Adjustments in dosing may be needed based on individual factors like body weight and kidney function, but overall, it is considered safe for human use. ^{1 3 6 7 8}

How is the drug Cefazolin unique for surgical prophylaxis?

Cefazolin is unique for surgical prophylaxis because it can be administered as a continuous infusion, which may provide better drug levels in the body compared to traditional intermittent dosing. This approach is particularly beneficial in ensuring adequate drug concentration during surgery, especially in patients with specific needs like those undergoing cardiac surgery or obese patients. ^{1 9 10 11 12}

Eligibility Criteria

This trial is for adults over 18 with a BMI of ≥25 kg/m^2 who are scheduled for surgery and expected to receive cefazolin. They must have had an abdominal CT scan before surgery and a creatinine clearance ≥90 mL/min, indicating good kidney function. Pregnant individuals or those with allergies to penicillin or cephalosporins cannot participate.

Inclusion Criteria

I am over 18 years old.

Body Mass Index ≥ 25 kg/m^2

I will be given cefazolin before my surgery starts.

Exclusion Criteria

History of a hypersensitivity reaction to penicillin or cephalosporin

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cefazolin doses based on either body weight or morphomic measures during their scheduled surgery

1 day

1 visit (in-person, during surgery)

Follow-up

Participants are monitored for antibiotic concentrations in blood and fat tissue post-surgery

4 hours

Long-term follow-up

Participants are monitored for any surgical site infections and overall recovery

4 weeks

Treatment Details

Interventions

• Cefazolin

Trial Overview The study tests if dosing the antibiotic cefazolin based on body composition rather than just weight can better prevent infections in overweight patients during surgery. It will compare blood and fat tissue concentrations of the drug when dosed by standard care versus morphomic analysis.

Participant Groups

Group I: Standard of Care Active Control 1 Intervention

The patients assigned to this group have cefazolin dose assignments based on body weight, which is the standard of care.

Group II: Morphomic-based Active Control 1 Intervention

The patients assigned to this group have cefazolin dose assignments based on body depth and kidney function.

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

Agency for Healthcare Research and Quality (AHRQ)

Collaborator

Trials

415

Recruited

6,777,000+

Findings from Research

A quality improvement initiative successfully increased compliance with the recommended preoperative dose of cefazolin from 40% to 93% among 9086 patients, significantly reducing the risk of surgical site infections.

Cefazolin doses ordered electronically were administered correctly 94% of the time, compared to only 76% for verbal orders, highlighting the importance of electronic ordering in ensuring accurate dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A quality improvement initiative to optimize dosing of surgical antimicrobial prophylaxis. Caruso, TJ., Wang, E., Schwenk, HT., et al.[2018]

Intraoperative continuous-infusion (CI) cefazolin significantly reduced the incidence of superficial surgical site infections (SSIs) compared to intermittent (INT) dosing in patients undergoing coronary artery bypass grafting (CABG), with rates of 0.4% in the CI cohort versus 2.8% in the INT cohort.

While the overall incidence of SSIs was lower in the CI group (1.7% vs 4.6%), this difference did not reach statistical significance, indicating the need for larger studies to confirm the findings; importantly, CI cefazolin did not increase the risk of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Intraoperative Continuous-Infusion Versus Intermittent Dosing of Cefazolin Therapy on the Incidence of Surgical Site Infections After Coronary Artery Bypass Grafting. Shoulders, BR., Crow, JR., Davis, SL., et al.[2016]

In a study of 57 patients undergoing elective surgery, 26% did not comply with national guidelines for cefazolin administration, which is used to prevent surgical-site infections (SSI).

Among those who did not follow the guidelines, 67% had low cefazolin levels at the end of the procedure, indicating a significant risk for inadequate infection prevention, while compliance with guidelines resulted in better outcomes, though it did not guarantee sufficient antibiotic levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

End-of-procedure cefazolin concentrations after administration for prevention of surgical-site infection. Koopman, E., Nix, DE., Erstad, BL., et al.[2019]

In a study of 24 cardiac surgery patients, administering 2 grams of cefazolin during anesthesia induction and again after starting cardiopulmonary bypass (CPB) maintained effective drug levels to combat over 90% of bacteria found on sternal skin, which were sensitive to cefazolin.

Pharmacokinetic modeling revealed that CPB significantly altered the drug's volume of distribution and clearance, indicating that patient-specific factors like albumin levels and kidney function also play a crucial role in cefazolin's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic characteristics and microbiologic appropriateness of cefazolin for perioperative antibiotic prophylaxis in elective cardiac surgery. Lanckohr, C., Horn, D., Voeller, S., et al.[2018]

Cefazolin is an effective choice for surgical antimicrobial prophylaxis in small animal surgeries, as it maintains effective concentrations in surgical wounds for over 12 hours after administration.

A bolus dose of 20 mg/kg given intravenously at the start of surgery, followed by subcutaneous doses, ensures that cefazolin concentrations remain above the effective level needed to inhibit common pathogens like staphylococci and E. coli.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefazolin antibacterial activity and concentrations in serum and the surgical wound in dogs. Rosin, E., Uphoff, TS., Schultz-Darken, NJ., et al.[2013]

A successful intervention program reduced the prophylactic dose of cefazolin from 2 g to 1 g for cesarean sections, leading to a 45% decrease in the average number of vials used per surgery.

Despite the reduced dosage, the rate of surgical site infections (SSIs) decreased from 3.34% to 2.42%, demonstrating that the lower dose was both effective and safe, while also saving over $4,000 in medication costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful control program to implement the appropriate antibiotic prophylaxis for Cesarean section. Fonseca, SN., Sofia, MH., Quintana, S., et al.[2019]

The recommended dosing protocol of cefazolin for antimicrobial prophylaxis during liver surgery is generally suitable for various patient populations, including obese individuals, as it maintains effective drug concentrations in tissues.

However, if the minimum inhibitory concentration (MIC) for bacteria is set at 3 microg/ml, the standard dosing regimen may not provide adequate cefazolin levels during surgery for most patients, except those with renal insufficiency (GFR < 50 ml/min), suggesting a need for adjusted dosing in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiological modeling for indirect evaluation of drug tissular pharmacokinetics under non-steady-state conditions: an example of antimicrobial prophylaxis during liver surgery. Lagneau, F., Marty, J., Beyne, P., et al.[2018]

In a study of 58 colorectal surgery patients, morphomic measurements and kidney function were found to be better predictors of cefazolin exposure than standard body weight, suggesting a need for more personalized dosing strategies in obese patients.

The research indicated that maintaining effective cefazolin levels in subcutaneous fat during surgery is challenging, particularly in patients with high creatinine clearance and significant body depth, highlighting the importance of tailored dosing based on individual body composition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Morphomics-informed population pharmacokinetic and physiologically-based pharmacokinetic modeling to optimize cefazolin surgical prophylaxis. Liu, S., Matvekas, A., Naimi, T., et al.[2023]

A study comparing two dosing methods of cefazolin in cardiac surgery found that continuous infusion resulted in more stable and higher drug levels in the blood and heart tissue compared to intermittent dosing.

90% of patients receiving continuous infusion met the pharmacokinetic goals for effective antibiotic levels, while only 30% of those on intermittent dosing achieved the same, highlighting the superiority of continuous administration for effective infection prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefazolin bolus and continuous administration for elective cardiac surgery: improved pharmacokinetic and pharmacodynamic parameters. Adembri, C., Ristori, R., Chelazzi, C., et al.[2014]

A single intravenous dose of cefazolin administered shortly before minimally invasive gynecologic surgery effectively achieves serum concentrations above the minimum inhibitory concentrations (MIC) for susceptible pathogens, ensuring adequate antimicrobial coverage.

The study involved 21 women and demonstrated that the timing of cefazolin administration did not significantly affect serum levels, indicating that cefazolin is a reliable prophylactic agent for preventing infections in these surgical procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cefazolin prophylaxis in minimally invasive gynecologic surgery - are dosage and timing appropriate? Prospective study using resampling simulation. Lavie, M., Lavie, I., Cohen, A., et al.[2021]

In a study of 20 obese patients undergoing cesarean delivery, a 4-g dose of cefazolin resulted in significantly higher tissue and plasma concentrations compared to the traditional 2-g dose, indicating better potential for effective antibacterial prophylaxis.

All tissue samples from both dosage groups exceeded the target concentration of 4 mcg/g, and no adverse effects or infections were reported, suggesting that the higher dose is safe but its impact on infection prevention remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma and tissue cefazolin concentrations in obese patients undergoing cesarean delivery and receiving differing pre-operative doses of drug. Stitely, M., Sweet, M., Slain, D., et al.[2013]

Intraoperative continuous infusions of cefazolin provide better drug exposure and higher probabilities of target attainment compared to intermittent bolus dosing, even at lower doses, which is crucial for preventing infections during major surgery.

The study highlights the importance of considering patient factors like body weight and renal function when determining cefazolin dosing regimens, as these factors significantly influence drug clearance and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial. Naik, BI., Roger, C., Ikeda, K., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

A quality improvement initiative to optimize dosing of surgical antimicrobial prophylaxis. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Impact of Intraoperative Continuous-Infusion Versus Intermittent Dosing of Cefazolin Therapy on the Incidence of Surgical Site Infections After Coronary Artery Bypass Grafting. [2016]

3. England pubmed.ncbi.nlm.nih.gov

End-of-procedure cefazolin concentrations after administration for prevention of surgical-site infection. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetic characteristics and microbiologic appropriateness of cefazolin for perioperative antibiotic prophylaxis in elective cardiac surgery. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Cefazolin antibacterial activity and concentrations in serum and the surgical wound in dogs. [2013]

6. Brazil pubmed.ncbi.nlm.nih.gov

Successful control program to implement the appropriate antibiotic prophylaxis for Cesarean section. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Physiological modeling for indirect evaluation of drug tissular pharmacokinetics under non-steady-state conditions: an example of antimicrobial prophylaxis during liver surgery. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Morphomics-informed population pharmacokinetic and physiologically-based pharmacokinetic modeling to optimize cefazolin surgical prophylaxis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Cefazolin bolus and continuous administration for elective cardiac surgery: improved pharmacokinetic and pharmacodynamic parameters. [2014]

10. France pubmed.ncbi.nlm.nih.gov

Cefazolin prophylaxis in minimally invasive gynecologic surgery - are dosage and timing appropriate? Prospective study using resampling simulation. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Plasma and tissue cefazolin concentrations in obese patients undergoing cesarean delivery and receiving differing pre-operative doses of drug. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial. [2022]