Is there any stability data for using cefoxitin 8g/24h (or up to 12g/24h) as a continuous infusion in an OPAT setting?

Comment by InpharmD Researcher

There is a paucity of data regarding the stability of cefoxitin 8g/24h administered as a continuous infusion in an outpatient parenteral ­antimicrobial therapy (OPAT) setting. However, available evidence provides insights on the stability of reconstituted solutions of cefoxitin under various temperature conditions. For comprehensive data on the stability of 20 mg/mL and 40 mg/mL of cefoxitin, please refer to Tables 1-3.
Background

A 2008 retrospective pilot study (N= 116) evaluated 30-day postoperative surgical site infections (SSIs) and antibiotic discontinuation post-colorectal surgery in patients receiving continuous infusion (n= 58) versus intermittent infusion (n= 58) cefoxitin prophylactically. Patients who received intermittent cefoxitin utilized weight-based doses (1 g if ≤ 80 kg; 2 g if > 80 kg) q8h for 3 doses, starting 3 hours after surgery and finished within 24 hours. The continuous-infusion patients similarly received weight-based doses (3 g if ≤ 80 kg; 6 g if > 80 kg), started immediately after surgery, and infused over 20 hours. The preparations consisted of cefoxitin 3 g in 250 mL of normal saline or 6 g in 500 mL of normal saline (both 12 mg/mL) for the continuous infusions. This concentration was used because stability studies have shown little to no decomposition of cefoxitin over 24 hours at a concentration of 20 mg/mL. All patients were stratified according to risk; medium-risk patients receiving continuous infusion had lower, albeit non-significant, 30-day postoperative SSI rates versus intermittent infusion (4% versus 8%, p= 0.55), while low-risk patients had equal risk regardless of infusion (3%). All continuous infusion patients were able to discontinue antibiotic prophylaxis within 24 hours after surgery versus 47 (83.9%) intermittent infusion patients (p= 0.0015). These results support the use of continuous infusion prophylactic cefoxitin, although caution should be used when extrapolating data due to use in a limited sample size and observational study design. [1]

References:

[1] Suffoletta TJ, Jennings HR, Oh JJ, Stephens D, Poe KL. Continuous versus intermittent infusion of prophylactic cefoxitin after colorectal surgery: a pilot study. Pharmacotherapy. 2008;28(9):1133-1139. doi:10.1592/phco.28.9.1133

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any stability data for using cefoxitin 8g/24h (or up to 12g/24h) as a continuous infusion in an OPAT setting?

Level of evidence

X - No data  Read more→



Please see Tables 1-3 for your response.


 

Stability of Cefamandole Nafate and Cefoxitin Sodium Solutions

Design

Stability study

Objective

To develop high-pressure liquid chromatographic (HPLC) procedures for the analyses of cefamandole nafate, cefamandole, and cefoxitin sodium, using the available microphenyl columin, and to investigate the stabilities of reconstituted solutions as found in actual practice

Methods

Preparation of Antibiotic Solutions: 2% solutions of cefoxitin sodium were prepared in 0.9% sodium chloride injection and 5% dextrose injection. The solutions were divided into two portions and transferred back to the original containers, plastic Viaflex PL 146 bags, from which the sterile solvents were withdrawn to prepare them. One set of solutions was stored at room temperature (24 ± 1°C), while the other set was refrigerated (5 ± 1°C). The solutions were assayed after 1, 2, 5, 7, and 10 days of storage at 24°C, and after 4, 7, 13, and 44 days of storage at 5 °C.

To prepare a 500 mcg/mL solution of cefoxitin sodium, the stock solutions were diluted with water to contain 60 mcg/mL of cefoxitin sodium (internal standard). The 2% antibiotic solutions were further diluted with water to achieve identical concentrations of either cefamandole nafate and cephalothin sodium or cefoxitin sodium and cefazolin sodium. A 20.0 microliter aliquot of the assay solution was injected into the chromatograph using specified conditions. For comparison, an equal volume of the appropriate standard solution was injected following elution of the assay solution.

Chromatographic Conditions: The mobile phase for cefoxitin contained 15% v/v methanol and 0.01 M ammonium acetate in water, with a flow rate of 2.5 ml/min.

Duration

10 days storage at room temperature, 44 days in a refrigerator

Outcome Measures

Assay results for solutions stored at 24 ± 1°C and at 5 ± 1°C

Results

HPLC assay results for solutions stored at 24 ± 1°C

Cefoxitin sodium 2 g/100 mL in NS

% retained after 1 day

% retained after 2 days

% retained after 5 days

% retained after 7 days

% retained after 10 days

 

100.0 ± 1.8 

87.9 ± 1.9

73.7 ± 1.7

62.2 ± 1.6*

56.6 ± 1.8

Cefoxitin sodium 2 g/100 mL in D5W

% retained after 1 day

% retained after 2 days

% retained after 5 days

% retained after 7 days

% retained after 10 days

 

99.8 ± 1.7

89.1 ± 1.7

74.9 ± 1.8

69.5 ± 1.8*

56.4 ± 2.0

HPLC assay results for solutions stored at 5 ± 1°C

Cefoxitin sodium 2 g/100 mL in NS

% retained after 4 days

% retained after 7 days

% retained after 13 days

% retained after 44 days

 

97.3 ± 1.6

96.9 ± 1.7

96.6 ± 1.6

89.8 ± 1.8**

Cefoxitin sodium 2 g/100 mL in D5W

% retained after 4 days

% retained after 7 days

% retained after 13 days

% retained after 44 days

 

97.5 ± 1.4

97.2 ± 1.8

97.1 ± 1.6

89.8 ± 1.9**

* The solutions had turned yellow in colour. 

** Solutions had turned to a very light greenish yellow color.

NS= 0.9% sodium chloride injection, D5W= 5% dextrose injection

Study Author Conclusions

The stability studies of 2% solutions of cefamandole nafate and cefoxitin sodium in 0.9% sodium chloride injection and in 5% dextrose injection, using HPLC procedures, indicate that the shelf-lives of these products under refrigeration may be longer than recommended by the manufacturer.

InpharmD Researcher Critique

The limitations of the study include the relatively short duration of some stability testing, limited assessment of temperature conditions (24°C and 5°C), potential variability in real-world storage conditions, lack of comprehensive degradation pathway analysis, and minimal discussion on clinical implications.

References:

Das Gupta V, Stewart KR. Stability of cefamandole nafate and cefoxitin sodium solutions. Am J Hosp Pharm. 1981;38(6):875-879.

 

Stability of ciindamycin phosphate and ceftizoxime sodium, cefoxitin sodium, cefamandole nafate, or cefazoiin sodium in two intravenous solutions

Design

Stability study 

Objective

To determine the stability and compatibility of clindamycin phosphate with four cephalosporins—ceftizoxime sodium, cefoxitin sodium, cefamandole nafate, and cefazolin sodium—in either 5% dextrose injection or 0.9% sodium chloride injection, and also to determine the stability of each cephalosporin alone

Methods

Sterile powder was reconstituted with either 5% dextrose or 0.9% sodium chloride injection and added to a 100-mL glass container, followed by agitation. Antibiotic concentration, pH, and visual appearance were assessed at mixing and at 1, 4, 8, 12, 24, and 48 hours, with all solutions stored at room temperature under fluorescent lighting.

High-performance liquid chromatography (HPLC) was used for antibiotic assays, with drug-specific assays separating the target antibiotic from others and breakdown products. Cefoxitin sodium samples were prepared by adding 200 μL of the test solution to 100 μL of internal standard (cefotaxime sodium 20 mg/mL), vortexing for 15 seconds, and injecting 2 μL onto a C18 reverse-phase column. Elution used a mobile phase of 14% acetonitrile in 0.02M KH2PO4 buffer (pH adjusted to 2.7 with H3PO4), with detection at 254 nm and a flow rate of 1.5 mL/min.

The initial antibiotic concentration was set at 100%, with subsequent concentrations expressed as a percentage of the initial concentration. The analysis involved comparing antibiotic concentrations at each sampling time with those at admixture, noting the time of a 10% or greater decrease in concentration.

Duration

48 hours

Outcome Measures

Stability of single antibiotic solutions, stability of clindamycin in combination with cefoxitin, stability of cefoxitin in combination with clindamycin

Results

Endpoint

Mean % of initial concentration

pH change over 48 hours

Cefoxitin in D5W

1 hr

4 hr

8 hr

12 hr

24 hr

48 hr

 

100.0 ± 0.3

101.5 ± 1.4

99.9 ± 2.1

96.9 ± 1.7

100.9 ± 0.8

94.0 ± 4.5 

4.6-6.6 

Cefoxitin in NS

1 hr

4 hr

8 hr

12 hr

24 hr

48 hr

 

101.2 ± 0.7

106.8 ± 0.7

100.8 ± 0.8

99.9 ± 1.7 

103.7 ± 3.2

94.1 ± 0.06

4.4-6.4

Stability of clindamycin in combination with cefoxitin

Admixture Mean % of initial concentration pH change over 48 hours

Clindamycin plus cefoxitin in D5W

1 hr

4 hr

8 hr

12 hr

24 hr

48 hr

 

103.2 ± 0.0

100.7 ± 3.2

100.9 ± 3.9

100.7 ± 0.6

105.4 ±3.5

103.8 ± 0.4 

6.2-6.2

Clindamycin plus cefoxitin in NS

1 hr

4 hr

8 hr

12 hr

24 hr

48 hr

 

104.7 ± 0.3

100.9 ± 0.2

101.7 ± 3.1

102.6 ± 1.3

104.3 ± 5.6

107.2 ± 0.3 

5.9-6.0

Stability of cefoxitin in combination with clindamycin

Admixture Mean % of initial cefoxitin concentration  

Cefoxitin and clindamycin in D5W

1 hr

4 hr

8 hr

12 hr

24 hr

48 hr

 

99.5 ± 0.4

100.9 ± 0.7

98.5 ± 2.2 

99.3 ± 0.9

98.2 ± 2.6

98.8 ± 1.2

 

Cefoxitin and clindamycin in NS

1 hr

4 hr

8 hr

12 hr

24 hr

48 hr

 

99.9 ± 4.3

97.6 ± 1.6

96.9 ± 3.3

94.7 ± 1.1

99.4 ± 1.7

92.8 ± 0.9

 

D5W = 5% dextrose injection and NS = 0.9% sodium chloride injection

Study Author Conclusions

Clindamycin is stable for at least 48 hours when mixed with cefoxitin sodium, cefamandole nafate, or cefazolin sodium in either 5% dextrose or 0.9% sodium chloride injections and for at least 24 hours when mixed with ceftizoxime sodium in 0.9% sodium chloride injection. All of the cephalosporins tested are stable alone and in combination with clindamycin for at least 48 hours in the two fluids tested. Administration of clindamycin with any of these antibiotics in the same container could result in considerable cost savings for the hospital. 

InpharmD Researcher Critique

The study had a relatively short observation period of 48 hours, a small sample size, and an absence of clinical outcome data. Additionally, the potential for interactions over longer durations was not assessed. Furthermore, the criteria used to define stability may not fully reflect clinical significance.

References:

Bosso JA, Townsend RJ. Stability of clindamycin phosphate and ceftizoxime sodium, cefoxitin sodium, cefamandole nafate, or cefazolin sodium in two intravenous solutions. Am J Hosp Pharm. 1985;42(10):2211-2214.

 

Stability of cefazolin sodium, cefoxitin sodium, ceftazidime, and peniciliin G sodium in portabie pump reservoirs

Design

Stability study

Objective

To determine the stability of cefazolin sodium, cefoxitin sodium, ceftazidime, and penicillin G sodium stored in prefilled drug reservoirs

Methods

Sufficient quantities of commercially available cefoxitin sodium were reconstituted or diluted to fill drug reservoirs and provide 10 mL for a control sample. Each admixture was placed in 20-mL glass scintillation vials for controls, and 100 mL of cefoxitin sodium was loaded into drug reservoirs. Triplicate reservoirs were prepared for each drug. These were stored at -20°C for 30 days, then thawed at 5°C for four days before a one-day pumping cycle at 37°C. Samples were collected at various intervals over 35 days and stored at -20°C until analysis. Prior to analysis, samples were thawed, equilibrated to room temperature, mixed, and diluted with distilled water for HPLC analysis. The stability of the assays was confirmed by degrading samples at 45°C for 72 hours.

Duration

35 days 

Outcome Measures

Stability of cefoxitin sodium in the cycle of freezing, thawing, and administration 

Baseline Characteristics

 

Cefoxitin sodium

Infusion concentration, mg/mL

40

Infusion volume, mL

23

Pump setting infusion period, hr

1
Infusion cycle, hr

6

Keep vein open rate, mL/hr

0.2

Actual initial concentration, mg/mL

Medication cassette reservoir

Glass vial

 

40.0 ± 1.0

40.0 ± 0.6

Results

Endpoint

% of Initial Concentration Remaining on Days 30-35

Medication cassette reservoir

Day 30

Day 31

Day 32

Day 33

Day 34

Day 34.5

Day 35

 

100.2 ± 4.2 

97.5 ± 3.2

100.9 ± 5.6

101.8 ± 1.8

99.7 ± 1.6

103.4 ± 6 5

97.4 ± 4.2

Glass vial

Day 30

Day 31

Day 32

Day 33

Day 34

Day 34.5

Day 35

 

97.2 ± 3.4

99.1 ± 2.0

97.0 ± 3.0

96.9 ± 1.0

97.0 ± 2.2

94.4 ± 5.9

93.3 ± 3.2 

Freezing = -20 °C, days 0-30; thawing = 5 °C, days 31-34; administration = 37 °C, day 35

No color change or precipitation was observed for any of the admixtures under any of the storage conditions. 

Less than 1 ppm of diethylhexyl phthalate (DEHP) was determined to have leached from the drug reservoir or extension tubing during the 35-day period. 

Study Author Conclusions

Cefazolin sodium, cefoxitin sodium, ceftazidime, and penicillin G sodium in admixtures with sterile water for injection were found to be stable in the concentrations studied when stored in drug reservoirs and frozen at -20 °C for 30 days and then refrigerated for four days at 5 °C in prefilled drug reservoirs. With the exception of penicillin G sodium, no significant loss of activity was observed after the drugs were pumped at body temperature for one day.

InpharmD Researcher Critique

The limitations include a brief 35-day observation period and lack of specified total sample size. Moreover, the absence of comprehensive investigation into factors affecting cefoxitin sodium's stability, coupled with the lack of real-time monitoring and comparative analysis, emphasizes the need for further research to elucidate its stability profile and inform clinical practice effectively. 

References:

Stiles ML, Tu YH, Allen LV Jr. Stability of cefazolin sodium, cefoxitin sodium, ceftazidime, and penicillin G sodium in portable pump reservoirs. Am J Hosp Pharm. 1989;46(7):1408-1412.