Can ampicillin be administered as 12 grams over 24h at room temperature?

Comment by InpharmD Researcher

Clinical literature on 24-hour infusions of ampicillin is primarily presented in case reports. Pharmacokinetic studies show that ampicillin, depending on the concentration, maintains just above 90% concentration after 24 hours at room temperature, suggesting a 24-hour infusion is viable. Buffered solutions may have better stability, and solutions that are refrigerated before infusion may be more stable during a 24-hour infusion period.

Background

The Infectious Diseases Society of America (IDSA) published guidelines for the diagnosis and treatment of prosthetic joint infections and native vertebral osteomyelitis in 2013 and 2015, respectively. Both guidelines discuss pathogen-specific intravenous antimicrobial therapy. For the management of penicillin-susceptible Enterococcus species, the expert panel recommends penicillin G 20–24 million units IV every 24 hours continuously or in 6 divided doses or ampicillin sodium 12 g IV every 24 hours continuously or in 6 divided doses as preferred treatment options. These recommendations offer clear guidance for managing these challenging infections. [1], [2]

A 2023 stability assessment investigated ampicillin sodium at two concentrations (15 mg/mL and 50 mg/mL) in 250 mL polyisoprene elastomeric infusion pumps (EIPs), with the goal of informing their suitability for outpatient parenteral antimicrobial therapy (OPAT). Ampicillin diluted in 0.9% sodium chloride was analyzed under refrigerated storage (4 ± 1 °C) and under simulated real-life conditions using two ambient temperatures (25 °C and 32 °C), both with and without a cooling device. The analytical method employed was a validated ultra-high-performance liquid chromatography (UHPLC) assay with photodiode array detection at 225 nm, utilizing a BEH C18 column and a methanol/acetonitrile-based mobile phase. At each time point, ampicillin samples were diluted and injected in triplicate, with stability defined as ≥90% of baseline concentration. Physical stability was concurrently assessed through pH and visual appearance parameters. Results demonstrated that at 15 mg/mL, ampicillin remained chemically stable (>90% of baseline) for up to 72 hours under refrigeration, and for an additional 24 hours at 25 °C regardless of cooling device use. In contrast, the 50 mg/mL solution degraded rapidly, falling below 90% after 24 hours even under refrigerated conditions, and below 85% at 25 °C after 8 hours of ambient exposure, despite the use of a cooling device. At 32 °C, only the 15 mg/mL formulation preserved ≥90% concentration for up to 20 hours when combined with temperature modulation through the cooling system. Continuous temperature monitoring confirmed that the cooling device had limited effectiveness beyond the initial few hours of ambient storage. Throughout all conditions tested, no significant pH shifts or visible precipitation occurred. These results provide compelling evidence that low-concentration (15 mg/mL) ampicillin in elastomeric pumps is a viable candidate for OPAT implementation, while higher concentrations may be unsuitable due to subtherapeutic degradation profiles. [3]

References:

[1] Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clin Infect Dis. 2015;61(6):e26-e46. doi:10.1093/cid/civ482
[2] Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25. doi:10.1093/cid/cis803
[3] Rodríguez-Martínez L, Castro-Balado A, Hermelo-Vidal G, et al. Ampicillin Stability in a Portable Elastomeric Infusion Pump: A Step Forward in Outpatient Parenteral Antimicrobial Therapy. Pharmaceutics. 2023;15(8):2099. Published 2023 Aug 8. doi:10.3390/pharmaceutics15082099
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

Can ampicillin be administered as 12 grams over 24h at room temperature?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-5 for your response.

 

Continuous Infusion Ampicillin for the Outpatient Management of Enterococcal Endocarditis

Design

Case report
Case Presentation

A 30-year-old male originally presented with cough, fever, and shortness of breath. A transthoracic echocardiogram demonstrated vegetations on both tricuspid valve leaflets measuring 1.86 x 0.66 cm and 1.9 x 0.66 cm, consistent with tricuspid valve endocarditis. On day 4, organism identification and sensitivities returned from the blood cultures demonstrating E. faecalis sensitive to ampicillin, daptomycin, gentamicin, penicillin, and vancomycin. 

The regimen was changed from vancomycin and piperacillin-tazobactam to ampicillin 2 g IV every 4 hours plus gentamicin 80 mg (1 mg/kg) IV every 8 hours. Gentamicin was adjusted to 1 mg/kg IV every 24 hours based on drug levels targeting a peak of 3 to 4 mg/L and a trough of < 1 mg/L. Renal and hepatic function remained stable throughout treatment. The patient was ready for discharge, but the local home health agency was unable to take the patient due to compliance, stability, and delivery with ampicillin.

The patient was set up with an outpatient infusion center to receive gentamicin on-site daily, then sent home to receive ampicillin via continuous infusion with an ambulatory pump. 

The gentamicin was prepared prior to the arrival of the patient and administered in the outpatient infusion center, while the ampicillin infusion was being freshly prepared. Ampicillin was then set to infuse over 22 hours, allowing time to administer gentamicin in the infusion clinic the following day. The ambulatory infusion pump required 3 to 4 hours of battery charging per day, usually performed at night while the patient slept. The patient completed 42 days of therapy without a missed dose and was deemed clinically cured. Of note, 81% (34/42 days) of treatment was performed in the outpatient setting, sparing 34 days of hospital stay. He has remained without relapse or readmission to the hospital for over 1 year.
Study Author Conclusion

Combination with either gentamicin or ceftriaxone plus continuous infusion over 24 hours or pump programmed pulse-dosed ampicillin are all viable options and alleviate concerns of compliance. Given the 10% loss seen at 24 hours, a reasonable approach involves compounding a daily bag and administering it to the patient immediately, ideally at a facility open and available for delivery 7 days a week.

Based on the rate of drug loss, studies show buffered ampicillin 12 g/L could be refrigerated for up to 48 hours, then used at room temperature within 24 hours with an acceptable drug loss of 10% over a 3-day period

 

References:

Lewis PO, Jones A, Amodei RJ, Youssef D. Continuous Infusion Ampicillin for the Outpatient Management of Enterococcal Endocarditis: A Case Report and Literature Review. J Pharm Pract. 2020;33(3):392-394. doi:10.1177/0897190018804964

 

Stability of ampicillin sodium, nafcillin sodium, and oxacillin sodium in autodose infusion system bags

Design

 Stability study

Objective

To evaluate the physical and chemical stability of ampicillin sodium 1 g/100 mL, nafcillin sodium 1 g/100 mL, and oxacillin sodium 1 g/100 mL, each of which admixed in 0.9% sodium chloride and packaged in AutoDose Infusion System bags

Methods

 Ampicillin sodium, nafcillin sodium, and oxacillin sodium were reconstituted in normal saline to a strength of 1 g/100 mL. They were packaged in AutoDose bags, which are ethylene vinyl acetate plastic containers designed for use in the AutoDose Infusion System. Samples were stored protected from light and were evaluated at appropriate intervals for up to 7 days at 23°C and up to 30 days at 4°C.

Results

 

Ampicillin

Nafcillin

Oxacillin
  23°C 4°C 23°C 4°C 23°C 4°C

Percentage of initial concentration remaining

After 1 day

After 3 days

After 5 days

After 7 days

After 14 days

After 21 days

After 30 days

 

90.7±0.8%

79.6±0.3

-

-

-

-

-

 

97.2±1.1%

94.2±0.9%

89.1±1.2%

-

-

-

-

 

99.0±1.3%

96.7±1.7%

30.3±1.8%

85.5±0.8%

-

-

-

 

99.5±1.2%

98.8±1.3%

-

98.5±1.3%

97.8±1.9%

Precipitation

Precepitation

 

96.9±0.7%

95.8±0.7%

93.3±0.7%

90.7±0.2%

-

-

-

 

98.4±1.1%

99.0±0.9%

-

98.7±0.9%

96.1±1.2%

95.6±1.0%

95.5±0.7%

Study Author Conclusions

Ampicillin sodium, nafcillin sodium, and oxacillin sodium exhibited physical and chemical stability consistent with previous studies on these drugs. The AutoDose Infusion System bags did not adversely affect the physical and chemical stability of those three penicillin antibiotics.
References:

Zhang Y, Trissel LA. Stability of ampicillin sodium, nafcillin sodium, and oxacillin sodium in autodose infusion system bags. Int J Pharm Compd. 2002;6(3):226-229.

 

Stability of Ampicillin in Normal Saline Following Refrigerated Storage and 24-Hour Pump Recirculation

Design

Stability study

Objective

To evaluate the stability of ampicillin using high-pressure liquid chromatography (HPLC) in an outpatient parenteral antimicrobial therapy (OPAT) dosing model using continuous infusion at room temperature over 24 hours immediately following preparation compared with batches stored under refrigeration for 24 hours, 72 hours, and 7 days.

Methods

Four ampicillin 24 mg/mL batches were prepared for each experimental condition (immediate use and refrigerated storage for 24 hours, 72 hours, and 7 days). A pump was used to recirculate the solutions through medical-grade tubing for 24 hours. Triplicate 1-mL aliquots were removed from each batch at time 0, 4, 8, 12, and 24 hours and analyzed for ampicillin concentration.

Duration

7 days

Results

 Ampicillin  Immediate use

After 24-hour refrigeration 

After 72-hour refrigeration 

After 7-day refrigeration
Initial concentration

21.50 ± 0.512

 20.34 ± 0.672 21.17 ± 0.718 20.98 ± 0.644
After 4 hour infusion

20.91 ± 0.84 (97.22%)

 19.69 ± 0.72 (96.81%) 20.23 ± 0.69 (95.55%) 19.11 ± 0.47 (91.11%)
After  8 hour infusion

20.94 ± 1.03 (97.33%)

 19.53 ± 0.64 (96.03%) 20.04 ± 0.70 (94.78%)  18.98 ± 0.49 (90.47%)
After 12 hour infusion

20.88 ± 1.07 (97.06%)

 19.45 ± 0.60 (95.62%) 19.91 ± 0.70 (94.06) 18.88 ± 0.49 (90.00%)
After 24 hours infusion 20.23 ± 0.77 (94.09%) 19.27 ± 0.71 (94.77%) 19.61 ± 0.61 (92.63) 18.51 ± 0.45 (88.24%)

Study Author Conclusions

Ampicillin can be prepared and stored in a refrigerator for up to 72 hours prior to continuously infusing at room temperature over 24 hours with less than a 10% loss of potency over the dosing period.
References:

Huskey M, Lewis P, Brown SD. Stability of Ampicillin in Normal Saline Following Refrigerated Storage and 24-Hour Pump Recirculation. Hosp Pharm. 2020:001857872092538.

 

Ampicillin and ceftriaxone solution stability at different temperatures in outpatient parenteral antimicrobial therapy

Design

Stability study

Objective

To determine the stability of ampicillin and ampicillin plus ceftriaxone solutions in a simulated outpatient setting conditions

Study Groups

Ampicillin 24 g/L in 0.9% sodium chloride

Ampicillin 24 g/L + Ceftriaxone 8 g/L in 0.9% sodium chloride

Methods

Both antibiotics were reconstituted with water for injection (10 mL per gram of antibiotic) resulting in a concentration of 100 g/L. The solutions were further diluted in 0.9% sodium chloride polypropylene infusion bags, to obtain the following concentrations: Ampicillin 24 g/L and ceftriaxone 8 g/L. The solutions were stored at three different temperatures (25, 30, and 37°C) for 48 hours.

Chemical and physical stability was evaluated at 20, 24, 30, and 48 hours after manufacturing. Polypropylene infusion bags were utilized to host antimicrobial mixtures.

Results

 Time Temperature Ampicillin 24 g/L Ampicillin 24 g/L + Ceftriaxone 8 g/L
20 hours

25°C

30°C

37°C

≥90%

≥90%

≥90%

≥90%

≥90%

<90%
24 hours

25°C

30°C

37°C

≥90%

≥90%

≥90%

≥90%

≥90%

<90%
30 hours

25°C

30°C

37°C

101.11% ± 2.19

96.43% ± 2.71

88.95% ± 4.22

≥90%

≥90%

<90%
48 hours

25°C

30°C

37°C

<90%

<90%

<90%

<90%

<90%

<90%

Ampicillin: Throughout sampling, solutions were clear and colorless

Ampicillin + Ceftriaxone: Regarding ceftriaxone stability in a combined solution plus ampicillin, after 30-hour storage at 25 ºC and 48-hour storage at 30 ºC the solutions attained the stability criterion of 90% original concentration. At 37ºC, the concentration decreased to 81.96±1.00% within the first 20 hours. No changes in color or clearness were observed

Study Author Conclusions

This study offers solid evidence supporting that the concentration of both drugs at two of the tested temperatures (25 and 30 ºC) demonstrated stability for up to 30 hours. Therefore, both ampicillin alone or plus ceftriaxone solutions would be appropriate candidates for inclusion in outpatient parenteral antimicrobial therapy programs (OPAT) programs.
References:

Herrera-Hidalgo L, López-Cortes LE, Luque-Márquez R, et al. Ampicillin and ceftriaxone solution stability at different temperatures in outpatient parenteral antimicrobial therapy. Antimicrob Agents Chemother. 2020;64(7).

 

Stability of ampicillin in normal saline and buffered normal saline

Design

 Stability study

Objective

To evaluate if the stability of ampicillin in 0.9% sodium chloride could be extended by adding sodium phosphate for injection using modern high-performance liquid chromatography (HPLC)

Methods

Ampicillin 12 g/L was prepared with and without 10 mM sodium phosphate for injection and diluted to 1 L with 0.9% sodium chloride. Aliquots of the solutions were stored at room temperature (~25°C) or refrigeration (2°C to 8°C). Samples were collected at 0, 8, 24, 30, 48, and 72 hours and analyzed via HPLC.

Duration

Up to 72 hours

Results

Ampicillin 12 g/L

 Percent of initial concentration remaining Time to 90% concentration
8 hours 24 hours 30 hours 48 hours 72 hours

25°C with buffer

 101 ± 0.56% 99.4 ± 0.50% 87.7 ± 0.19% 86.2 ± 0.27% 80.2 ± 0.30% 32.0 hours

25°C with buffer (repeat)

 97.2 ± 0.12% 91.0 ± 0.07% 94.8 ± 0.46% 85.3 ± 0.13% 83.4 ± 0.91% 41.7 hours

25°C without buffer

 100 ± 0.13% 96.4 ± 0.34% 95.5 ± 0.46% 924 ± 0.21% 88.2 ± 0.15% 57.6 hours

4°C with buffer

 117 ± 0.13% 95.6 ± 0.35% 103 ± 1.1% 95.4 ± 0.18 92.6 ± 0.17% N/A

25°C with buffer after storing at 4°C

 105 ± 0.25% 95.2 ± 0.15% N/A 92 ± 0.15% N/A N/A

Study Author Conclusions

Using a stability-indicating high-performance liquid chromatographic assay, ampicillin 12 g/L in 0.9% sodium chloride is stable for at least 24 hours at room temperature. The addition of 10 mM sodium phosphate for injection extends the stability to at least 48 hours at room temperature.
References:

Maher M, Jensen KJ, Lee D, Nix DE. Stability of ampicillin in normal saline and buffered normal saline. Int J Pharm Compd. 2016;20(4):338-342.