Prospective quasi-experimental design

N= 238

IVPB cefazolin (n= 118)

IVP cefazolin (n= 120)

Cefazolin dosage

          1000 mg

          2000 mg

34%

66%

33%

67% 

Cefazolin Dosing for Surgical Prophylaxis in Morbidly Obese Patients

Prospective pharmacokinetic study

N= 25

To determine an optimal dosing regimen for cefazolin as a prophylactic antibiotic in surgery in patients with morbid obesity (MO)

MO2-IVP (2 g via IVP; n= 10)

MO2-INF (2 g via 30-min infusion; n= 5)

Super morbid obesity (SMO) 2-INF (2 g via 30-min infusion; n= 5)

SMO3-INF (3 g via 30-min infusion; n= 5)

Patients undergoing surgical procedures for morbid obesity with BMI > 40 kg/m2

Allergy to penicillins or cephalosporins, current pregnancy or lactation, chronic kidney disease, or chronic hepatic insufficiency

Patients were given a single dose of cefazolin: 2 g via IVP or 30-min infusion for MO, and 2 g or 3 g via infusion for SMO. Serum cefazolin concentrations were measured at 5, 30, 120, and 360 min post-dose. The half-life and time above MIC were calculated using 8 mcg/mL as the breakpoint.

Lab measures: up to 360 min post dose

Protective duration of cefazolin dose, mean cefazolin concentrations at various time points, and half-life of cefazolin

Mean concentration, mcg/mL

The mean cefazolin concentrations after 30 min were similar in all groups; the mean concentrations at 120 and 360 min were 67.1–84.8 mcg/mL and 22.9–40.8 mcg/mL, respectively. The half-life ranged from 2.3 to 3.6 h and was unaffected by administration method. The protective duration was 5.1 h for MO2-IVP, 4.8 h for MO2-INF, 5.8 h for SMO2-INF, and 6.8 h for SMO3-INF.

No adverse events reported

A single 2-g dose of cefazolin appears to provide antibiotic exposures sufficient for most common general surgical procedures of < 5-h duration, regardless of BMI

Retrospective cohort study within a single large health system

N= 431

Infusion (n= 80)

IV Push (n= 351)

Race

White

Black or African American

70 (87.5%)

2 (2.5%)

298 (84.9%)

22 (6.3%)

368 (85.4%)

24 (5.6%)

Baseline ANC, ×103 cells/µL; median (IQR)

Low: 1.6-3.9 cells×1000/µL

Normal: 4-6.9 cells×1000/µL

Elevated: >7 cells×1000/µL

8.0 (7.5)

10 (12.5)

20 (25.0)

50 (62.5)

7.3 (6.9)

52 (14.8)

110 (31.3)

189 (53.8)

7.4 (6.9)

62 (14.4)

130 (30.2)

239 (55.5)

OPAT Duration, days; median (IQR)

0-4 weeks

4-6 weeks

>6 weeks

Indeterminate

36 (16.0)

22 (27.5)

25 (31.2)

20 (25.0)

13 (16.3)

28 (22.0)

158 (45.0)

83 (23.6)

64 (18.2)

46 (13.1)

29 (21.0)

180 (41.8)

108 (25.1)

84 (19.5)

59 (13.6)

Preoperative Cefazolin Push Injection in Awake or Sedated Patients: A Direct Observational Study in Two Hospitals

Preliminary direct observational study

N= 60

To quantify the total administration time of cefazolin and assess adherence to the manufacturer’s recommendations, and to record any adverse reactions

Prince of Wales Hospital (POW) (n= 21)

Sydney Hospital and Sydney Eye Hospital (SSEH) (n= 39)

Patients undergoing surgery awake or under conscious sedation who received intravenous cefazolin as the sole antibiotic

Patients who did not receive cefazolin or were administered additional antibiotics

A convenience sample was observed in the operating theaters of 2 Sydney metropolitan hospitals. Cases were selected according to the availability of 4 observers, with 1 observer assigned to each case. At POW, operations from all specialties except cardiothoracic surgery were eligible for observation; at SSEH, only hand surgery was observed because intravenous cefazolin was rarely used during ophthalmic procedures. Observers recorded cefazolin injection start and completion times and associated adverse reactions; pain was identified by spontaneous patient reporting or behavioral signs such as facial grimacing or arm withdrawal. Age, sex, surgery type, and sedation medications were also recorded, although these characteristics were not reported in the results. Data were analyzed using descriptive statistics. Cefazolin dose, dilution, and administration technique were not reported.

5 months to September 2024

Primary: Total administration time of cefazolin, adherence to manufacturer’s recommendations

Secondary: Incidence of adverse reactions

The study did not report baseline patient characteristics, including age, sex, race, surgery type, or sedation medications, either overall or by hospital.

Median injection time (IQR), seconds

Injection time, range, seconds

Injection duration ≥180 seconds

Injection duration <180 seconds

Patients with pain on injection

Abbreviations: IQR, interquartile range.

All cases of pain occurred when cefazolin was administered in less than 180 seconds; no pain occurred with injection times longer than 180 seconds. The authors stated that the small sample precluded conclusions regarding this association.

*The article contains internal numerical inconsistencies. The table prints SSEH administration <180 seconds as 33 (8.4%), whereas the narrative reports 84.6%. The overall count of 39 for administration <180 seconds is inconsistent with both the reported hospital counts (16+33=49) and N= 60. Additionally, the hospital-specific pain counts and percentages do not correspond mathematically to the respective group denominators and conflict with the percentages stated in the narrative.

Pain at the injection site was the only adverse reaction, occurring in 18.3% of patients. No other side effects such as nausea, vomiting, or phlebitis were observed.

We found low adherence with the recommended cefazolin injection rate across both hospitals along with a notable incidence of pain during injection. Future larger-scale studies could offer greater insight into adherence with the recommended rate of cefazolin push in awake or consciously sedated patients. Additionally, the relationship between the time to complete injection and the incidence of pain at injection site could be further explored.

Direct observation under routine clinical conditions and inclusion of awake or consciously sedated patients allowed administration time and injection-related pain to be captured; however, the small convenience sample, descriptive analysis, and internally inconsistent results limit interpretation. Most importantly, this study evaluated cefazolin push administration speed and tolerability without an infusion comparator or surgical-site infection outcomes; therefore, it does not establish comparative safety or effectiveness between cefazolin IV push and infusion for surgical prophylaxis.

Dosing Cefazolin for Surgical Site Infection Prophylaxis in Adolescent Idiopathic Scoliosis Surgery: Intermittent Bolus or Continuous Infusion?—A Pilot Study

Randomized, controlled, prospective pharmacokinetic pilot study

N= 12

To study how cefazolin dosing affects cefazolin tissue concentrations during the operative phase of care and to compare the efficacy of intermittent bolus versus continuous infusion dosing in achieving bactericidal concentrations in subcutaneous and muscle tissues

Intermittent Bolus (n= 6)

Continuous Infusion (n= 6)

Diagnosis of idiopathic scoliosis with planned fusion of at least 6 vertebral levels; age between 12 and 20 years

Known allergy to cefazolin, known renal or hepatic insufficiency or failure, abnormalities precluding insertion of microdialysis catheters into paraspinal muscles, or American Society of Anesthesiologists Physical Status 3 or higher

Patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis at the University of Florida were screened and randomly assigned using simple randomization to intermittent bolus or continuous-infusion cefazolin. Group A received cefazolin 30 mg/kg IV before surgical incision and every 3 hours throughout surgery; Group B received the same 30-mg/kg IV dose before incision, followed by a continuous infusion of 10 mg/kg/hour until surgery ended. The rate or duration of administration of the initial IV bolus was not reported.

Serial plasma samples were collected before cefazolin administration; at 5, 15, 30, 60, 90, and 180 minutes afterward; and every 60 minutes thereafter. Microdialysis samples were collected from paraspinal muscle and adjacent subcutaneous adipose tissue at 30-minute intervals throughout surgery. Three randomized patients had unusable tissue concentration data because of sample-processing problems, leaving 9 patients in the pharmacokinetic analysis.

Not specified

Total drug exposure (AUC) in plasma, muscle, and subcutaneous adipose tissue; time spent above minimal inhibitory concentration (MIC)

Bolus Group (n= 4)

16 ± 1 (13–17)

25%

20 ± 2

284 ± 64

124 ± 44

Fluid Balance, ml (mean)

Blood Loss

Urine Output

Crystalloid

Colloid

Autologous Blood

825 ± 263

1050 ± 897

3400 ± 860

563 ± 427

306 ± 240

640 ± 230

1274 ± 747

3237 ± 1039

500 ± 177

40 ± 89

Surgical Details

Cobb Angle, degrees (mean)

Levels Fused

58 ± 10

9 ± 3

74 ± 10

12 ± 1

The continuous-infusion group received a higher total cefazolin dose than the intermittent-bolus group.

After dose normalization, total and unbound plasma cefazolin AUCs were similar between groups, whereas muscle and subcutaneous adipose tissue AUCs were greater with continuous infusion; however, no between-group differences were statistically significant.

Bolus dosing produced more variable and typically lower tissue concentrations, with median cefazolin concentrations below 32 µg/mL for approximately one-fifth and one-third of the operative period in subcutaneous adipose and muscle tissue, respectively.

No wound complications or surgical site infections occurred in either group.

None reported

Our study demonstrates that the administration of cefazolin by continuous infusion intraoperatively results in higher plasma, subcutaneous adipose tissue, and muscle concentrations of cefazolin in healthy patients undergoing PSF for AIS than cefazolin administration by intermittent bolus. Continuous infusion is more likely to result in antibiotic concentrations that are bactericidal and should reduce the likelihood of surgical site infections in this population. Our technique of combining microdialysis with simultaneous retro-dialysis of a calibrator molecule with similar chemical structure integrates relatively easily into the logistics of a complex surgical procedure.

Randomization and direct serial measurement of unbound cefazolin in clinically relevant tissue compartments strengthen the pharmacokinetic comparison. However, the analysis included only 9 patients, the infusion group received a higher total cefazolin dose, no significant between-group differences or SSI benefit were demonstrated, and the bolus administration rate was not reported; therefore, this is not a definitive comparison of rapid IV push versus infusion administration.

Comparative Total And Unbound Pharmacokinetics Of Cefazolin Administered By Bolus Versus Continuous Infusion In Patients Undergoing Major Surgery: A Randomized Controlled Trial

Prospective open-label observational randomized controlled pharmacokinetic trial

N= 20

To determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing

Intermittent bolus (n= 10)

Continuous infusion (n= 10)

Patients undergoing major urological or multilevel spine surgery, aged 18-80 years, weight <120 kg, with an arterial line

Allergy to b-lactams, pregnant females, creatinine clearance <30 ml/min, received cefazolin within 72 hours before surgery

All patients received cefazolin 2 g in 50 mL of 5% dextrose intravenously over 5 minutes between 15 and 60 minutes before surgical incision. Using a block design stratified by sex, patients were randomized to intermittent cefazolin 2 g every 4 hours until skin closure or a continuous infusion of 500 mg/hour beginning immediately after the preincision dose and continuing until skin closure. Blood was collected before cefazolin administration; at 2.5, 5, 10, 15, 20, 30, 45, and 60 minutes after the initial dose; and every 30 minutes thereafter until skin closure. Total and unbound plasma cefazolin concentrations were measured using a validated ultra-high-pressure liquid chromatography–tandem mass spectrometry method; unbound concentrations were measured at 5, 30, and 120 minutes.

Population pharmacokinetic modeling was performed using total plasma concentrations. Monte Carlo simulations (n= 1,000) evaluated PTA for achieving 100% free-drug time above the minimum inhibitory concentration (100% fT>MIC) during the first 4 hours of surgery. Simulations evaluated intermittent 2-g doses every 2, 3, or 4 hours and continuous doses totaling 0.5, 1, or 2 g over 4 hours following a 2-g loading dose across body weights of 60, 80, and 100 kg and creatinine clearances of 50, 80, and 120 mL/min. FTA was calculated against MIC distributions for methicillin-susceptible Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli. A regimen was considered successful when the PTA of 100% fT>MIC was achieved against ≥90% of isolates.

Not specified

PTA and FTA for cefazolin; total and unbound cefazolin concentrations, pharmacokinetic parameters

Intermittent bolus (n= 10)

62 (40–78)

30%

171 (9)

80 (15)

27 (5)

2725 (1102)

600 (391)

0 (0–2)

0 (0–650)

665 (403)

298 (100–850)

77 (17)

248 (97)

3000 (2000–4000)

A total of 318 total and 60 unbound cefazolin concentrations were obtained from 20 patients.

Mean cefazolin protein binding was 69% (range, 44%–80%), mean central volume of distribution was 5.73 ± 2.42 L, and mean total clearance was 4.72 ± 1.1 L/hour; body weight and creatinine clearance were retained as covariates for central volume of distribution and clearance, respectively.

Monte Carlo simulations evaluated the PTA of maintaining 100% fT>MIC during the first 4 hours of surgery; although exact PTA values were not reported in the main article, the authors reported that continuous infusion produced better target attainment than intermittent dosing, particularly at higher MICs.

Corresponding FTA ranges across body weights of 60 to 100 kg and creatinine clearances of 50 to 120 mL/min with cefazolin 2 g every 4 hours were 86% to 91% for S aureus, 59% to 81% for S epidermidis, and 77% to 96% for E coli, compared with 92% to 99%, 83% to 100%, and 97% to 99%, respectively, with a continuous dose of 2 g over 4 hours following a 2-g loading dose.

Intermittent dosing every 2 or 3 hours produced FTA values more comparable to continuous infusion, while FTA for S epidermidis was generally below the prespecified 90% target with both administration strategies.

Not specified

Based on plasma concentrations of cefazolin, our study demonstrates that intraoperative continuous infusions provide better FTA with lower infusion doses. Renal function and body weight are important covariates for optimizing the doses and method of delivery of cefazolin required to achieve ideal PK/PD targets.

Strengths include randomized allocation, frequent intraoperative sampling, measurement of total and unbound cefazolin, and pharmacokinetic simulations accounting for body weight and renal function. However, this small plasma pharmacokinetic study did not measure tissue concentrations, surgical-site infections, or other postoperative clinical outcomes; therefore, it supports improved modeled target attainment with continuous infusion but does not establish superior clinical prophylactic efficacy or direct equivalence between administration strategies.