Parenteral antimicrobial stability and preparation in ambulatory antimicrobial therapy

Antimicrobial preparations for infusion can be made either on-site or by a specialist compounding pharmacy, or purchased from a licensed manufacturer. Antimicrobials given as an intravenous injection or intermittent infusion are usually prepared immediately before administration. To ensure sterility, preparations made in advance of administration (more than 24 hours) must be prepared by trained staff, under aseptic conditions in an appropriately maintained clean room using suitable equipment (eg laminar flow hood, clean room garments). Quality control measures, such as appropriate environmental monitoring, are essential. Australian guidelines on compounding of medicines can be found on the Pharmacy Board of Australia website.

The antimicrobial drug preparation should be sufficiently stable for the duration of the infusion, and for extended periods if prepared in advance. Stability is usually defined as more than 90% of the original concentration remaining at the end of the infusion, and is dependent on drug concentration, temperature of the preparation, and, in some cases, the buffer, diluent fluid and final container used. Some health services also use therapeutic drug monitoring for continuous intravenous infusions of antimicrobials (eg meropenem) to optimise dosing. However, this requires specialist guidance and is not always available, particularly in rural areas.

Infusions prepared in advance should generally be stored at 2 to 8°C (if physically and chemically stable at this temperature) until use. Patients should be advised how to store the infusions both before and during use (see Information for patients receiving ambulatory antimicrobial therapy).

Usual method of administration of drugs used for ambulatory parenteral antimicrobial therapy in adults contains information about the usual method of administration of drugs used for ambulatory parenteral antimicrobial therapy in adults. It also includes a list of drugs not recommended for use in ambulatory parenteral antimicrobial therapy because of inadequate stability. The information presented in Usual method of administration of drugs used for ambulatory parenteral antimicrobial therapy in adults is a conservative interpretation of the available data to minimise the risk of patients receiving substandard care. Other antimicrobials may be appropriate if a lower concentration or a less frequent dose is required. For advice about the usual method of administration of drugs used for ambulatory parenteral antimicrobial therapy in children, seek expert advice.

Stability of drugs commonly administered by continuous intravenous infusion over 12 or 24 hours for ambulatory parenteral antimicrobial therapy in adults lists the stability of drugs commonly used in ambulatory parenteral antimicrobial therapy in adults on refrigeration and at elevated temperatures. However, there are limitations in the available data. Most of the stability data are based on studies performed at fixed temperatures (usually refrigerated and room temperature [typically less than 25°C]), whereas research shows there is significant temperature fluctuation in practice, and that infusions placed close to the patient’s body often reach higher temperatures (up to 35°C)Docherty, 2017 Jenkins, 2022 Voumard, 2017. The information presented in the table therefore represents a conservative interpretation of the available data, to minimise the risk of patients receiving substandard care. The table is not intended to replace local protocols. Drug administration practices in ambulatory parenteral antimicrobial therapy programs vary across Australia, largely because of the way each program is delivered (eg once- or twice-daily visits) and local experience. Local patient outcome data is sometimes used to inform protocols, but is usually unpublished. Seek expert advice for information about the stability of antimicrobial drugs for children.

Some antimicrobials (eg many beta lactams) are pharmacokinetically and pharmacodynamically suited to continuous infusion via delivery devices.

In some cases, antimicrobials not stable in solution for 24 hours out of the fridge can be given by continuous infusion provided the daily dose is split into 2 preparations that are changed every 12 hours.

The rate of drug delivery through elastomeric infusors may be affected by temperature (low temperatures can reduce the flow rate and high temperatures can increase it), viscosity of the solution and placement of the infusorDocherty, 2024 Kawabata, 2012. Consider these factors if the flow rate is unexpectedly low or high.

Further information on antimicrobial stability and administration for ambulatory parenteral antimicrobial therapy can be found in the Australian Injectable Drugs Handbook¹.

Table 1. Usual method of administration of drugs used for ambulatory parenteral antimicrobial therapy in adults
[NB1] [NB2] [NB3]
Method of administration	Drugs
Continuous intravenous infusion over 24 hours	benzylpenicillin, cefazolin, ceftolozane+tazobactam, flucloxacillin (buffered solution), flucloxacillin (unbuffered solution), piperacillin+tazobactam, vancomycin
Continuous intravenous infusion over 12 hours	ceftazidime, meropenem
Once-daily intermittent infusion [NB4]	liposomal amphotericin, anidulafungin, caspofungin, cefazolin (when used in combination with oral probenecid), ceftriaxone, daptomycin, ertapenem, gentamicin, teicoplanin
Twice-daily intermittent infusions [NB4]	ceftriaxone, tigecycline
Not recommended for ambulatory parenteral antimicrobial therapy [NB5]	amoxicillin, amoxicillin+clavulanate, ampicillin, benzylpenicillin (unbuffered solution)
Note: NB1: This table is provided as an overview of the method of administration of antimicrobials and is not intended to replace local protocols. Stability data for antimicrobial infusions are limited and difficult to translate to community settings. The information in this table is a conservative interpretation of the available data to minimise the risk of patients receiving substandard care. NB2: The data in this table are based on commonly used adult antimicrobial dosages. In certain patient groups (eg patients with hepatic or kidney impairment) lower antimicrobial concentrations may be used – seek expert advice as stability data may differ. NB3: This table should not be extrapolated to paediatric patients – seek expert advice. NB4: Drugs that are administered by intravenous injection or intermittent infusion for ambulatory antimicrobial therapy are usually given at the same dosage, and are prepared and administered, as for inpatient management. Refer to local hospital protocols or the Australian Injectable Drugs Handbook for further information. The handbook is available for purchase from the Advanced Pharmacy Australia website. NB5: These antimicrobials are not recommended because appropriate alternatives with better stability are available.

Table 2. Stability of drugs commonly administered by continuous intravenous infusion over 12 or 24 hours for ambulatory parenteral antimicrobial therapy in adults
[NB1] [NB2] [NB3] [NB4] [NB5]
benzylpenicillin (buffered solution) cefazolin ceftazidime ceftolozane+tazobactam flucloxacillin (buffered solution) flucloxacillin (unbuffered solution)	meropenem piperacillin+tazobactam piperacillin+tazobactam (Tazocin EF) vancomycin
benzylpenicillin (buffered solution)
Stability on refrigeration at 2 to 8°C [NB6]	7 daysMcDougall, 2014
Stability ‘in use’ at room temperature [NB7] [NB8]	24 hours at 37°CMcDougall, 2014 Smith, 2021
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	7.2 to 14.4 g by 24-hour continuous infusion
cefazolin
Stability on refrigeration at 2 to 8°C [NB6]	3 days at 12.5 mg/mL and 25 mg/mL in 0.9% sodium chloride in elastomeric infusor devicePatel, 2018
Stability ‘in use’ at room temperature [NB7] [NB8]	24 hours for 12.5 mg/mL and 25 mg/mL in 0.9% sodium chloride in elastomeric infusor device at room temperature (12 hours at 35°C then 12 hours at 25°C)Patel, 2018
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	4 to 6 g by 24-hour continuous infusion
ceftazidime
Stability on refrigeration at 2 to 8°C [NB6]	48 hoursJamieson, 2020
Stability ‘in use’ at elevated temperature [NB7] [NB8]	12 hours 32°CJamieson, 2020
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	1.5 to 3 g given as continuous infusion over 12 hours twice daily (total maximum daily dose 3 to 6 g)
Note	Ceftazidime continuous intravenous infusions are used in some hospitals, particularly tropical regions where melioidosis is being treated. Check local guidelines or seek specialist advice
ceftolozane+tazobactam
Stability on refrigeration at 2 to 8°C [NB6]	8 daysJamieson, 2021
Stability ‘in use’ at room temperature [NB7] [NB8]	24 hours 32°CJamieson, 2021
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	3 to 6 g by 24-hour continuous infusion
flucloxacillin (buffered solution)
Stability on refrigeration at 2 to 8°C [NB6]	13 days at 10 mg/mL and 50 mg/mL diluted in 0.3% w/v citrate-buffered saline (pH 7) in elastomeric infusor device 6 days at 5 mg/mL and 60 mg/mL in elastomeric infusor device (buffered by reconstituting vials with sodium citrate 4%)Jamieson, Allwood, 2020
Stability ‘in use’ at elevated temperature [NB7] [NB8]	24 hours at 32°CAllwood, 2020 Smith, 2021
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	4 to 12 g by 24-hour continuous infusion
flucloxacillin (unbuffered solution)
Stability on refrigeration at 2 to 8°C [NB6]	6 daysCarroll, 2005
Stability at elevated temperature [NB7] [NB8]	24 hours at 31°CCarroll, 2005
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	4 to 12 g by 24-hour continuous infusion
meropenem
Stability on refrigeration at 2 to 8°C [NB6]	consult local protocols and manufacturer advice
Stability at elevated temperature [NB7] [NB8]	consult local protocols and manufacturer advice
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	3 to 6 g daily
Notes	Meropenem continuous intravenous infusions are used in some hospitals where meropenem therapeutic drug monitoring is available to guide dosing, and where the infusion can be prepared immediately before administrationLegg, 2020. Check local guidelines or seek specialist advice. Consider using an alternative antimicrobial with better stability.
piperacillin+tazobactam
Stability on refrigeration at 2 to 8°C [NB6]	5 days (or 13 days when prepared in a citrate-buffered solution)
Stability ‘in use’ at elevated temperature [NB7] [NB8]	24 hours at 32°C
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	9 to 18 g by 24-hour continuous infusion
piperacillin+tazobactam (Tazocin EF)
Stability on refrigeration at 2 to 8°C [NB6]	more than 7 daysJamieson, 2022
Stability at elevated temperature [NB7] [NB8]	24 hours at 37°CJamieson, 2022
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	13.5 to 18 g by 24-hour continuous infusion or intermittent intravenous injection via programmable pump
Note	Tazocin EF contains disodium edetate (EDTA) and citrate to reduce the formation of subvisible particulate matter and to meet Food and Drug Administration (FDA) criteria on limits of subvisible particulate matter. If prepared in advance, Tazocin EF is recommended.
vancomycin
Stability on refrigeration at 2 to 8°C [NB6]	more than 7 daysWalker, 2010
Stability at elevated temperature [NB7] [NB8]	48 hours at 37°CLoeuille, 2022
Usual maximum adult total daily dose and intravenous dosing schedule for ambulatory parenteral antimicrobial therapy [NB9] [NB10]	initial dosage as for inpatient management maintenance dosage varies based on blood concentration monitoring
Note: NB1: This table is provided as an overview and is not intended to replace local protocols. Drug administration practices in ambulatory parenteral antimicrobial therapy programs vary across Australia, largely because of the way each program is delivered (eg once- or twice-daily visits) and local experience. Local patient outcome data are sometimes used to inform protocols, but are usually unpublished. NB2: Stability data for antimicrobial infusions are limited and difficult to translate to community settings. The information in this table is a conservative interpretation of the available data to minimise the risk of patients receiving substandard care. NB3: Commercially produced antimicrobial preparations may have stability information that differs from the recommendations in this table. Seek product information from the manufacturer to determine stability. NB4: Stability is usually defined as more than 90% of the original concentration remaining at the end of the infusion, and is dependent on drug concentration, temperature of the preparation, and, in some cases, the buffer and diluent used. For infusions, data given are generally applicable to standard doses in 240 to 500 mL sodium chloride 0.9%. NB5: Most antimicrobial stability studies evaluate the stability of the antimicrobial on refrigeration followed by the stability at elevated temperatures. NB6: Temperature in stability studies varies between 2 to 8°C. NB7: Preparations left out of the fridge in hot climates or placed close to the patient’s body during infusion often reach high temperatures (up to 35°C). NB8: A maximum shelf life of 24 hours is applied for microbiological stability at elevated temperatures for products not prepared under aseptic conditions. When a period longer than 24 hours is given, this only applies if the product is prepared in a high-grade clean room. NB9: Check the recommended dose for the indication being treated – see the clinical topics in these guidelines. NB10: Clinical trials using continuous infusions for most indications are lacking. The total daily dose for 24-hour continuous infusion is the sum of intermittent doses given over 24 hours.

¹ The Australian Injectable Drugs Handbook is available for purchase from the Advanced Pharmacy Australia website.Return