A review of evidence,antimicrobial stability,and feasibility considerations for OPAT continuous infusion

Abstract

Outpatient parenteral antimicrobial therapy (OPAT) has been widely used in clinical practice for many decades because of its associated cost savings, reductions in inpatient hospital days, and decreases in hospital-associated infections. Despite this long history, evolving practice patterns and new drug delivery devices continue to present challenges as well as opportunities for clinicians when designing appropriate outpatient antimicrobial regimens. One such change is the increasing use of extended and continuous infusion (CI) of antimicrobials to optimize the achievement of pharmacokinetic and pharmacodynamic targets. Elastomeric devices are also becoming increasingly popular in OPAT, including for the delivery of CI. In this article, we review the clinical evidence for CI in OPAT, as well as practical considerations of patient preferences, cost, and antimicrobial stability.

Keywords

anti-infective agents continuous infusion elastomeric OPAT outpatient parenteral antimicrobial therapy outpatients patient satisfaction stability

Introduction

Outpatient parenteral antimicrobial therapy (OPAT) is the administration of parenteral antimicrobial therapy in at least two doses on different days outside of an acute hospital setting.¹ For OPAT in the home, administration is usually undertaken by the patient or a caregiver. Therefore, a simpler, less frequently administered antimicrobial regimen is most likely to garner adherence.^1,2 However, several antimicrobials that may be selected for a patient requiring OPAT are traditionally dosed multiple times a day to meet the required pharmacokinetic and pharmacodynamic (PK-PD) targets to treat pathogens. One possible option to leverage less-frequent administration and maximize the chances of meeting PK-PD targets is continuous infusion (CI). In this article, we review the evidence supporting the use of antimicrobial agents often given by CI in OPAT, their stability in available delivery devices, patient satisfaction, and cost considerations. We also discuss clinical controversies in CI and evidence for CI use with newer antimicrobial agents.

Practical considerations

Patient/caregiver acceptance

In some cases, CI may be less burdensome than intermittent infusions for OPAT. This is particularly true for medications that are traditionally administered 4–6 times daily and cannot be administered via intravenous (IV) push. CI may allow for a dose administration just once daily, and medication delivery devices can allow patients to be fully ambulatory during the infusion. CI does require patients to be connected to an infusion all day, however, and may introduce compatibility concerns if other concomitant medications need to be administered.

Common delivery devices used for CI include ambulatory electronic infusion pumps and elastomeric devices. Ambulatory electronic infusion pumps (Figure 1), or continuous ambulatory delivery devices, are battery-powered pumps that are connected to a compounded or commercially prepared medication bag or cassette. They are programed to deliver the medication for intermittent, continuous, bolus, or tapered infusions. They are small enough to be worn in a small carrying case or backpack, which allows the patient to be ambulatory during the medication infusion.³ Advantages of ambulatory infusion pumps include a lower margin of error (5%),⁴ alarms that alert the patient of infusion interruption or pump malfunction, and the ability to accommodate large and varying infusion volumes. These electronic pumps are, however, more difficult for patients to use and require home care staff to be available to assist with alarms and other mechanical malfunctions.

Figure 1.

Ambulatory pump: (a) pump door for installation of tubing, (b) display screen, (c) LED light indicators, and (d) battery compartment on back (two size C batteries).

Elastomeric devices (Figure 2) are medication containers made of polyvinyl chloride, and when filled with medication they resemble a ‘ball’ or ‘grenade’. These devices use a patented membrane technology that creates a positive pressure system, which allows for consistent and uniform drug delivery. The tubing is already attached and there is no need for gravity, which makes these devices relatively easy to use.³ Use of elastomeric devices has been shown to be preferred by patients,⁵ but this may come at the expense of a higher margin of error (15%) because flow rates depend on fluid viscosity and temperature.⁴

Figure 2.

Elastomeric device: (a) filling port, (b) medication container with elastomeric membrane (deflated), (c) clamp, (d) tubing, (e) particulate- and air-eliminating filter with infusion rate indicator, (f) flow restrictor, and (g) Luer-Lok tip.

Cost

Multiple studies have demonstrated the cost-effectiveness of OPAT compared with inpatient treatment. One study showed the cost-effectiveness of antimicrobials (including nafcillin for 32% of the cohort; penicillin G, 34%; piperacillin/tazobactam, 13%; cefazolin, 17%; and cefepime, 4%) administered via disposable elastomeric CI pumps for 91 patients treated in the outpatient setting.⁶ The use of self-administered elastomeric CI pumps for a total of 1925 OPAT days resulted in cost avoidance of $2.3 to $3.5 million relative to an inpatient-only treatment course.⁶ A study in Spain among patients receiving CI OPAT via elastomeric devices (with piperacillin/tazobactam, 43%; meropenem, 20%; ceftazidime, 25%; ceftolozane/tazobactam, 3%; and cloxacillin, 2%) showed a similar cost avoidance of €745,290.55 associated with 1409 OPAT days compared with inpatient days.⁷

Data are limited regarding cost comparisons among various OPAT delivery methods. A recent cost-minimization analysis based on OPAT practice models in the United Kingdom showed similar costs associated with CI via elastomeric devices compared with bolus dosing via elastomeric devices.⁸ However, the use of elastomeric devices had higher costs than bolus dosing via gravity infusion.⁸ The CHID (Comparing Home Infusion Devices) study protocol included pump operating costs of electronic versus elastomeric pumps for CI as a secondary outcome measure,⁹ but the results of this trial are not yet published. In the United States, insurance coverage for these elastomeric devices and ambulatory electronic infusion pumps varies, which may create disparities in patient access. In some cases the cost of the medication may be covered by insurance, but patients may incur additional out-of-pocket costs for each elastomeric device or may incur a daily rental fee for the use of an ambulatory electronic infusion pump.

Stability

The stability of sterile antimicrobial preparations is typically determined under controlled conditions at room temperature (25°C) or with refrigeration (5°C). The actual conditions encountered in a patient’s home environment may vary substantially, particularly in warm climates and with prolonged infusions during which elastomeric devices may be kept close to the body and reach temperatures between 30°C and 37°C.^10,11 In a study that examined temperature variations associated with the use of CI antimicrobials via elastomeric devices, the use of a white carrying pouch prevented excessive temperature increases.¹¹

Data on the stability of medications under these warmer conditions (30°C–37°C) are currently limited, but some suggest that ceftazidime and meropenem may be physically or chemically unstable at these warmer temperatures during prolonged infusion.^12,13 Although some data support the safety and efficacy of ceftazidime via CI, as described below, it does degrade to a potentially toxic by-product, pyridine, which requires careful safety consideration to limit its accumulation. Jones et al.¹² suggest that this degradation may be limited by keeping the ceftazidime concentration to 3% or lower, maintaining temperatures between 15°C and 25°C while connected to the patient, and using normal saline (NS; 0.9% sodium chloride) as a diluent rather than 5% dextrose in water (D5W). Other data show that ceftazidime diluted to 36.6 mg/mL in sterile water for injection is stable for up to 24 h at 37°C in a polyvinyl chloride container.¹⁴ In contrast, meropenem diluted in sterile water to 50 mg/mL has been reported to be physically instable after only 1 h at 37°C¹³ In addition to reviewing published stability data, some facilities may have access to reference laboratories that can perform individualized stability testing to support local practice.

Available stability data for agents included in this review are summarized in Table 1 (plastic containers) and Table 2 (elastomeric devices). Medications being considered for CI should ideally have data to support stability at 25°C or higher for no less than 24 h. Preparations that do not meet these criteria are highlighted in gray in the tables.

Table 1.

Stability in plastic containers.^a

Medication	Container	Diluent	Concentration	Stability
Medication	Container	Diluent	Concentration	5°C	25°C	⩾30°C
Ampicillin	EVA	NS	5 mg/mL	4 d¹⁴	24 h¹⁴	NA
			10 mg/mL	3 d¹⁵	24 h¹⁵	NA
Ampicillin/sulbactam	PVC	NS	20 mg/mL (20/10)	68 h¹⁴	32 h¹⁴	NA
			30 mg/mL (15/15)	3 d¹⁴	32 h¹⁴	NA
Cefazolin	EVA	NS	10 mg/mL	30 d¹⁴	7 d¹⁴	NA
	PVC	NS	5 mg/mL	7 d¹⁴	4 d¹⁴	NA
			10 mg/mL	30 d¹⁵	7 d¹⁵	NA
			20 mg/mL	15 d¹⁴	7 d¹⁴	NA
		D5W	5 mg/mL	7 d¹⁴	4 d¹⁴	NA
			10 mg/mL	30 d¹⁴	NA	NA
			20 mg/mL	24 d¹⁴	5 d¹⁵	NA
		SWFI	73.2 mg/mL	4 d¹⁴	NA	24 h at 37°C¹⁴
Cefepime	EVA	NS	10 mg/mL	30 d¹⁴	2 d¹⁴	NA
			40 mg/mL	7 d¹⁴	24 h¹⁴	NA
	PVC	NS	1 mg/mL10 mg/mL40 mg/mL	7 d¹⁴	24 h¹⁴	NA
			2.5 mg/mL	7 d¹⁴	5 d¹⁴	NA
			5 mg/mL	7 d¹⁴	3 d¹⁴	NA
			20 mg/mL	23 d¹⁴	2 d¹⁴	NA
		D5W	1 mg/mL5 mg/mL40 mg/mL	7 d¹⁴	24 h¹⁴	NA
			10 mg/mL	7 d¹⁴	2 d¹⁴	NA
			2.5 mg/mL20 mg/mL	7 d¹⁴	3 d¹⁴	NA
Ceftazidime^b	EVA	NS	20 mg/mL	7 d¹⁴	24 h¹⁴	NA
	PVC	NS	40 mg/mL	14 d¹⁴	24 h¹⁴	NA
		D5W	40 mg/mL	10 d¹⁴	24 h¹⁴	NA
		SWFI	36.6 mg/mL	NA	NA	24 h at 37 °C¹⁴
			95–280 mg/mL	7 d	24 h	NA
Ceftazidime/avibactam	PVC	NS, D5W	8–40 ceftazidime + 2–10 mg/mL mg/mL avibactam	24 h¹⁵	12 h¹⁵	NA
Ceftolozane/tazobactam	PVC	NS, D5W	15 mg/mL (10/5)1.5 mg/mL (1/0.5)	10 d ¹⁰	24 h¹⁰	NA
Meropenem^b	PVC	NS	1 mg/mL	10 d¹⁴	22 h¹⁴	NA
		D5W	1 mg/mL	1 d¹⁴	4 h¹⁴	NA
		NS	22 mg/mL	4 d¹⁴	17 h¹⁴	NA
		D5W	22 mg/mL	1 d¹⁴	8 h¹⁴	NA
Nafcillin	EVA	NS	10 mg/mL	7 d¹⁵	14 d¹⁴	NA
	PVC	NS	20 mg/mL	4 d¹⁴	24 h	NA
		D5W	20 mg/mL	7 d¹⁵	15 d¹⁵	NA
		SWFI	20 mg/mL120 mg/mL	14 d¹⁴	3 d¹⁴	NA
Oxacillin	EVA	NS	10 mg/mL	30 d¹⁴	7 d¹⁴	NA
	PVC	D5W, NS	1 mg/mL	24 h¹⁴	24 h¹⁴	NA
Piperacillin/tazobactam	EVA	NS	30, 40 mg/mL	21 d¹⁴	5 d¹⁴	NA
	PVC	D5W, NS	20 mg/mL80 mg/mL	28 d¹⁵	3 d¹⁵	NA
			40 mg/mL	7 d¹⁴	24 h¹⁴	NA
			60 mg/mL	28 d¹⁵	14 d¹⁵	NA
Vancomycin	EVA	NS	10 mg/mL	30 d¹⁴	7 d¹⁴	NA
	PVC	NS	4, 5 mg/mL	30 d¹⁵	24 d¹⁵	NA
		D5W	4, 5 mg/mL	30 d¹⁵	17 d¹⁵	NA

Shading indicates preparations that do not have data to support stability at 25°C or higher for ⩾24 h.

Theoretical or established risk of instability at temperatures ⩾30°C.^12,13

d, day; D5W, dextrose 5% in water; EVA, ethylvinyl acetate; h, hour; NA, not available; NS, normal saline; PVC, polyvinyl chloride; SWFI, sterile water for injection.

Table 2.

Stability in elastomeric devices.^a

Medication	Device^b	Diluent	Concentration	Stability
Medication	Device^b	Diluent	Concentration	5°C	25°C	⩾30°C
Ampicillin	AutoDose	NS	10 mg/mL	3 d¹⁴	24 h¹⁴	NA
	Homepump Eclipse/C-series, Intermate, MedFlo, Easypump II, SMARTeZ, and MEDI-FLO	NS	20 mg/mL	3 d¹⁴	8 h¹⁴	NA
Ampicillin/sulbactam	Homepump Eclipse/C-series	NS	45 mg/mL (30/15)	3 d¹⁴	NA	NA
	Intermate	NS	15 mg/mL (10/5)45 mg/mL (30/15)	3 d¹⁴	2 h¹⁴	NA
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	45 mg/mL (30/15)	2 d^16–18	6 h^16–18	NA
Cefazolin	AutoDose	NS	10 mg/mL	30 d¹⁴	7 d¹⁴	NA
	Homepump Eclipse/C-series	NS	20 mg/mL	7 d¹⁴	24 h¹⁴	NA
	Intermate	D5W	10–40 mg/mL	14 d¹⁴	96 h¹⁴	NA
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	16.7 mg/mL	14 d^16–18	2 d^16–18	NA
	MedFlo	NS	20 mg/mL	7 d¹⁹	24 h¹⁹	NA
	ReadyMED	NS	20 mg/mL	14 d¹⁴	48 h¹⁴	NA
			5 mg/mL	14 d¹⁴	4 d¹⁴	NA
	FOLfusor	NS, D5W	20 mg/mL	7 d¹⁴	24 h¹⁴	NA
			25 mg/mL	NA	NA	24 h at 31.1°C¹⁹
			50 mg/mL	NA	NA	6 h at 37°C¹⁹
	Accufuser	NS, D5W	40 mg/mL	28 d¹⁹	68 h¹⁹	NA
Cefepime	AutoDose	NS	10 mg/mL	30 d¹⁴	2 d¹⁴	NA
			40 mg/mL	7 d¹⁴	24 h¹⁴	NA
	Homepump Eclipse/C-series	NS	20 mg/mL	14 d¹⁴	24 h¹⁴	NA
	Intermate	NS, D5W	1–5 mg/mL	14 d¹⁴	2 d¹⁴	NA
	Easypump II, AccuFlo MEDI-FLO, or SMARTeZ	NS	20 mg/mL	14 d^16–18	24 h^16–18	NA
			12.5 mg/mL	NA	NA	24 h at 30.9°C²⁰
	FOLfusor	NS	50 mg/mL	NA	NA	6 h at 37°C²¹
Ceftazidime^c	AutoDose	NS	20 mg/mL	7 d¹⁴	24 h¹⁴	NA
	Homepump Eclipse/C-Series	NS	5–40 mg/mL	14 d¹⁴	24 h¹⁴	NA
	Intermate	NS	5–40 mg/mL	7 d¹⁴	24 h¹⁴	NA
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	40 mg/mL	14 d^15,16,18	24 h^15,16,18	NA
	MedFlo	NS, D5W	20 mg/mL	7 d¹⁴	18 h¹⁴	NA
	ReadyMED	NS	20 mg/mL	14 d¹⁴	24 h¹⁴	NA
	Accufuser	NS	5 mg/mL	14 d¹⁹	48 h¹⁹	NA
		D5 W	5 mg/mL	4 d¹⁹	48 h¹⁹	NA
		D5W	40 mg/mL	2 d¹⁹	24 h¹⁹	NA
		NS	60 mg/mL	4 d¹⁹	24 h¹⁹	NA
	FOLfusor	NS, D5 W	25 mg/mL	NA	NA	8 h at 37°C²¹
Ceftazidime/avibactam	FOLfusor	NS	25 mg/mL + 6.25 mg/mL	NA	NA	12 h at 37°C²¹
Ceftolozane/tazobactam	Easypump II and FOLfusor	NS	5 mg/mL(3.33 mg/mL + 1.67 mg/mL)20 mg/mL(13.33 mg/mL + 6.67 mg/mL)	8 d²²	NA	18 h at 32°C²²
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	1 mg/mL + 0.5 mg/mL2 mg/mL + 1 mg/mL30 mg/mL + 15 mg/mL	14 d^16–18	24 h^16–18	NA
	Accuflo, Homepump Eclipse	NS or D5W	10 mg/mL + 5 mg/mL1 mg/mL + 0.5 mg/mL	10 d²³	24 h²³	NA
	FOLfusor	NS	25 mg/mL + 12.5 mg/mL	NA	NA	12 h at 37°C²¹
		D5W	25 mg/mL + 12.5 mg/mL	NA	NA	8 h at 37°C²¹
Meropenem^c	Homepump Eclipse/C-series	NS	5 mg/mL	4 d¹⁴	26 h¹⁴	NA
			10 mg/mL	4 d¹⁴	20 h¹⁴	NA
	Intermate SV	NS	5 mg/mL	96 h¹⁴	34 h¹⁴	NA
			10 mg/mL	96 h¹⁴	20 h¹⁴	NA
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	5 mg/mL	10 d^16–18	24 h^16–18	NA
			20 mg/mL	4 d^16–18	24 h^16–18	NA
Nafcillin	AutoDose	NS	10 mg/mL	14 d¹⁴	3 d¹⁴	NA
	Homepump Eclipse/C-Series	NS	10 mg/mL	3 d¹⁴	24 h¹⁴	NA
	Intermate	D5W	10–40 mg/mL	14 d¹⁴	48 h¹⁴	NA
	MedFlo	D5W, NS	10–20 mg/mL	4 d¹⁴	24 h¹⁴	NA
	ReadyMED	D5W, NS, SWFI	250 mg/mL	7 d¹⁴	72 h¹⁴	NA
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	5 mg/mL50 mg/mL	14 d^16–18	30 h^16–18	NA
Oxacillin	AutoDose	NS	10 mg/mL	30 d¹⁴	7 d¹⁴	NA
	Homepump Eclipse/C-series	NS	10–100 mg/mL	8 d¹⁴	7 d¹⁴	NA
		D5W	10–100 mg/mL	8 d¹⁴	2 d¹⁴	NA
	Intermate	D5W, NS	10–80 mg/mL	10 d¹⁴	24 h¹⁴	NA
	MedFlo	NS	20 mg/mL	8 d¹⁴	3 d¹⁴	NA
		D5W	20 mg/mL	3 d¹⁴	24 h¹⁴	NA
	ReadyMED	NS, SWFI	10–50 mg/mL	8 d¹⁴	7 d¹⁴	NA
		D5W, LR	10–50 mg/mL	8 d¹⁴	2 d¹⁴	NA
	Easypump II, AccuFlo, MEDI-FLO, or SMARTeZ	NS	10 mg/mL100 mg/mL	8 d^16–18	4 d^16–18	NA
Piperacillin/tazobactam	AutoDose	NS	30,40 mg/mL	21 d¹⁴	5 d¹⁴	NA
	Intermate	D5W, NS	10–80 mg/mL	7 d¹⁴	24 h¹⁴	NA
	Easypump II^d, AccuFlo, MEDI-FLO, or SMARTeZ^d	NS	10 mg/mL + 1.25 mg/mL80 mg/mL + 10 mg/mL	21 d^16–18	48 h^16–18	NA
	Easypump II and FOLfusor	NS	9 mg/mL + 1.1 mg/mL50 mg/mL + 6.2 mg/mL90 mg/mL + 11.25 mg/mL	NA	NA	24 h at 35°C²⁰
	FOLfusor	D5W, NS	67 mg/mL + 8 mg/mL50 mg/mL + 6.25 mg/mL	NA	NA	24 h at 31.1°C²⁰
	FOLfusor	NS	67.7 mg/mL + 8.3 mg/mL	NA	NA	8 h at 37°C²¹
	FOLfusor	D5W	67.7 mg/mL + 8.3 mg/mL	NA	NA	24 h at 37°C²¹
Vancomycin	AutoDose	NS	10 mg/mL	30 d¹⁴	7 d¹⁴	NA
	Homepump Eclipse/C-series	D5W	5 mg/mL	63 d¹⁴	17 h¹⁴	NA
		NS	5, 10, 15 mg/mL	28 d¹⁴	24 h¹⁴	NA
	Intermate	D5W, NS	5–10 mg/mL	10 d¹⁴	24 h¹⁴	NA
	Intermate/LV	D5W	10–20 mg/mL	14 d¹⁴	3 d¹⁴	NA
	MedFlo	D5W, NS	5 mg/mL	14 d¹⁴	7 d¹⁴	NA
	ReadyMED	D5W	5 mg/mL	63 d¹⁴	17 d¹⁴	NA
	Easypump II^d, AccuFlo, MEDI-FLO, or SMARTeZ^d	D5W, NS	4 mg/mL	21 d^16–18	14 d^16–18	NA
		D5W, NS	15 mg/mL	14 d^16–18	2 d^16–18	NA
	FOLfusor	D5W, NS	37.5 mg/mL	NA	NA	48 h at 37°C²¹

Shading indicates preparations that do not have data to support stability at 25°C or higher for ⩾24 h.

Device manufacturers are as follows: AccuFlo (B. Braun); Accufuser (Woo Young Medical); AutoDose (Tandem Medical); Easypump II (B. Braun); FOLfusor (Baxter); Homepump Eclipse C-series (Avanos Medical); Intermate (Baxter); MedFlo (Secure Medical); MEDI-FLO (Wolf-pak); ReadyMED (Alaris); and SMARTeZ (Epic Medical).

Theoretical or established risk of instability at temperatures ⩾30°C.^12,13

Combined - tested refrigerated + room temperature.

d, day; D5W, dextrose 5% in water; h, hour; LR, lactated ringers solution; NA, not available; NS, normal saline; SWFI, sterile water for injection.

Outcomes associated with CI antimicrobial use

Penicillins

CI penicillins have been used for serious invasive diseases such as central nervous system infections and enterococcal endocarditis.^24–26 In one study of patients with central nervous system infections (meningitis, brain abscesses, and neurosyphilis), cure was noted all for patients with penicillin delivered as CI via ambulatory electronic infusion pump.²⁶ More recently, penicillin was shown to be frequently prescribed and administered via elastomeric systems for neurosyphilis and other diseases, which resulted in substantial institutional cost savings.⁶

Ampicillin, which has more limited stability than penicillin, has been less frequently used in elastomeric systems and may require the use of ambulatory electronic pump systems. Some stability data are available for ampicillin in an elastomeric device as well as in a plastic container (72 h refrigerated; 20 mg/mL concentration).^27,28 The ability to achieve large desired daily ampicillin doses (8–12 g/day), however, is hindered by available elastomeric device sizes and the need to provide more frequent home deliveries. In contrast, IV amoxicillin (although unavailable in the US) has been shown to be stable in such devices and has successfully treated Enterococcus faecalis endocarditis and osteomyelitis.²⁹

Data indicate that ampicillin-sulbactam also possesses limited stability with elastomeric systems. The limited stability of both ampicillin and ampicillin-sulbactam formulations must be considered when making treatment-related decisions, given that it takes extra time for compounding and delivery of OPAT medications. This compounding issue has limited their routine inclusion in the OPAT home infusion models and formularies.¹ However, data on the extended stability of ampicillin with and without sulbactam may support its use with ambulatory electronic pump-based CIs.³⁰ This method, although currently lacking published efficacy data, may allow for the provision of OPAT to treat deep-seated enterococcal infections and multidrug-resistant (MDR) Acinetobacter baumannii, for which large daily doses may be required.³¹

Historically, antistaphylococcal penicillins such as nafcillin, as well as isoxazolyl penicillins (e.g. oxacillin, cloxacillin, and flucloxacillin), have been used for deep-seated methicillin-susceptible Staphylococcus aureus (MSSA) infections. High rates of clinical success have been established with CI penicillins because their frequency of dosing necessitated the use of CI to facilitate OPAT.^6,32 Penicillin-based regimens for deep-seated enterococcal infections have other clinically relevant issues independent of stability, which are discussed later.

Piperacillin-Tazobactam

The short interval of traditional piperacillin-tazobactam dosing makes this agent less desirable for routine use in OPAT other than with CI. Piperacillin-tazobactam has been widely included in published reviews of the efficacy and safety of elastomeric pump systems in OPAT programs.^6,7,32 It is important to note that rates of use of piperacillin-tazobactam varied throughout these reports (8−43%), but clinical success rates were high, with these investigations demonstrating approximately 84–95% cure rates. One study demonstrated mean (SD) serum piperacillin concentrations of 25.8 (15) mg/L. This resulted in advantageous serum concentration ratios of piperacillin relative to the epidemiologic cutoff values of the identified bacteria, which were one or greater in 12 of 14 assessments (86%).³² The specific antimicrobial doses and tazobactam concentrations were not reported.

The safety and efficacy of CI piperacillin-tazobactam has been reported for Pseudomonas aeruginosa OPAT, including in 35 patients during a 3-year time frame.³³ This study demonstrated a high clinical cure rate (93%), with one patient dying during therapy, although unrelated to P. aeruginosa infection. Only one patient (3%) had a reinfection within 30 days. In a large, longitudinal evaluation of the safety of prolonged antimicrobial therapy, piperacillin-tazobactam had a 2.5-fold increased risk of non-Clostridioides difficile diarrhea compared with benzylpenicillin.³⁴ Administration modality was not specified, but approximately half the patients performed daily elastomeric device changes.³⁴

Cephalosporins

Cefazolin, a first-generation cephalosporin, has recently become more prevalently used in lieu of traditional nafcillin or oxacillin-based therapies for the treatment of invasive MSSA infections, which has prompted multiple reviews and meta-analyses.^35–39 Traditionally, cefazolin has been administered as an every-8-h infusion with dose adjustment for kidney dysfunction. It has demonstrated stability in both elastomeric and electronic pump-based systems (Tables 1 and 2). Given the favorable results of clinical studies, as well as OPAT-related data demonstrating reduced tolerability of nafcillin-based regimens, CI cefazolin may present clinicians with an evidence-based, better-tolerated treatment alternative. Cefazolin has comparable, if not improved, clinical outcomes regarding patient tolerability compared with nafcillin-based therapy.^40–42 These clinical data are supported by PK data in 100 patients with difficult-to-treat bone and joint infections.⁴³ Cefazolin demonstrated excellent median (range) serum cefazolin concentrations [60.75 (13–203) mg/L] when compared with the 90% minimum inhibitory concentration (MIC) in this study (1 mg/L). The median bone-to-serum concentration ratio of cefazolin was 0.25 (range, 0.06–0.41) in eight patients.

Later-generation cephalosporins, specifically ceftazidime and cefepime, have also been used as CI in acute care settings, mostly to optimize PK-PD target attainment. Efficacy and safety data with ceftazidime when administered as CI have been available since the late 1980s for patients with cystic fibrosis and P. aeruginosa infection.^44–46 Ceftazidime was included in a recent large study of CI in OPAT patients, demonstrating high success rates.⁷ Of note, however, more recent guidance documents from the Infectious Diseases Society of America (IDSA) have recommended avoiding ceftazidime with AmpC β-lactamase-producing Enterobacterales.³¹ In these situations, cefepime or alternative therapies should be recommended.

Substantial effort has been expended toward optimizing the PK-PD parameters of cefepime, often with extended or CI regimens.⁴⁷ In the OPAT setting, CI cefepime has limited but promising efficacy data. In a study by Voumard et al.,³² cefepime was used in 36 of 150 episodes of OPAT, with treatment failure occurring in only one patient. One case of neutropenia occurred in the cefepime cohort, and no patients treated with cefepime had neurotoxicity. Therapeutic drug monitoring (TDM) of cefepime showed mean (SD) serum concentrations of 21.3 (12.1) mg/L. Antibiotic-free plasma concentration-to-epidemiologic cutoff ratios were also calculated, and 36 of 40 cefepime measurements (90%) yielded a desirable ratio of 1 or greater. Neutropenia has been reported with prolonged courses of cefepime (⩾2 weeks) in OPAT studies but is potentially associated with rapid IV push administration methods, compared with standard 30- to 60-min infusions.^48,49 Given the paucity of comparative data with cefepime CI, clinicians should remain vigilant and adhere to standard OPAT monitoring recommendations.⁵⁰

Clinical controversies in CI

Management of staphylococcal infections

In recent years, increasing reports of intolerance and adverse events with nafcillin, when compared with agents such as oxacillin or cefazolin, have prompted debate regarding preferred therapies for OPAT. One 5-year study showed significantly increased rates of premature antimicrobial discontinuation with nafcillin versus cefazolin (33.8% versus 6.7%; p < 0.001).⁴² Patients were more likely to have development of rash (13.9% versus 4.2%; p = 0.002), kidney dysfunction (11.4 versus 3.3%; p = 0.006), and abnormal liver function (8.1% versus 1.6%; p = 0.01) with nafcillin versus cefazolin therapy.

Subsequently published studies, in both admitted patients with MSSA endocarditis and OPAT-treated patients, have reported similar findings.^40,41 Interestingly, nafcillin had increased rates of nephrotoxicity, with nearly a threefold increased rate of acute kidney injury compared with oxacillin-based treatments (18% versus 6%; p = 0.03).⁵¹ This study also identified increased rates of hypokalemia (potassium ⩽3.3 mmol/L) for nafcillin-treated patients compared with oxacillin-treated patients (51% versus 20%). This is unlikely to be an institution-specific result, given a recent evaluation of the US Food and Drug Administration Adverse Event Reporting System demonstrating similarly lower rates of acute kidney failure and hypokalemia with oxacillin than with nafcillin.⁵²

Management of enterococcal endocarditis

The 2015 IDSA guidelines recommend ampicillin plus either gentamicin or ceftriaxone for up to 6 weeks for enterococcal endocarditis.⁵³ However, the frequency of administration and short stability at room temperature have presented challenges for the transition of ampicillin into the outpatient setting.

Ampicillin is a β-lactam antibiotic that exhibits time-dependent PD activity, and because β-lactams lack bactericidal activity for Enterococcus, combination therapy is required for the treatment of deep-seated infections.^53,54 Given the short half-life of ampicillin, CI administration can maximize time above the MIC, which may improve clinical outcomes.^54,55 In an experimental animal model of enterococcal endocarditis, CI ampicillin, compared with high-dose intermittent infusion, significantly improved survival rate and sterilization of blood cultures and cardiac vegetations after 5 days of treatment.⁵⁶

Clinical data evaluating CI ampicillin for enterococcal infections are limited. In one study, patients with enterococcal endocarditis were treated with ceftriaxone 4 g administered via short infusion over 30 min in combination with ampicillin 12 g daily in 500 mL of NS solution delivered as 2 g over every 4 h via programmable pump.⁵⁷ For the four patients who met the inclusion criteria, with a median of 22.5 days of outpatient therapy, all patients achieved clinical and microbiologic cure without recurrence or complications in the subsequent year.⁵⁷ Although guidelines recommend a dosage of ceftriaxone 2 g every 12 h for the treatment of enterococcal endocarditis, the dosing strategy that best optimizes synergy with ampicillin CI remains unknown, which demonstrates the need for additional prospective studies.⁵³ When using ceftriaxone and CI ampicillin in combination, the ampicillin infusion may be paused for administration of ceftriaxone due to potential concerns of physical incompatibility.

Although the combination of ampicillin and ceftriaxone has emerged as an effective and possibly safer regimen for specific patient populations, a recent case report described successful administration of CI ampicillin in conjunction with once-daily gentamicin for the treatment of enterococcal endocarditis.⁵⁸ Ampicillin and gentamicin were compounded daily and administered in an infusion therapy center. After gentamicin administration, ampicillin was set to infuse over the next 22 h via ambulatory infusion pump with battery charging completed overnight. As a result, the patient achieved clinical cure and was without relapse or readmission in the subsequent year. Of 42 days of therapy, 34 days were administered in the ambulatory setting.⁵⁸

The utility of TDM for optimization of CI ampicillin has also been investigated. In a study by Gatti et al.,⁵⁵ patients with enterococcal infections were administered an ampicillin-based regimen with a loading dose of 2 g over 1 h, followed by CI. Real-time TDM was used, and optimal free fraction:MIC ratios were obtained for all 10 patients with documented infections. Dose reduction by more than 50% was recommended in 92% of the cohort within 48 h and in 56% of all interventions. This suggests that ampicillin doses required to maintain optimal PK-PD targets are likely lower with CI than intermittent infusion. Patients in the cohort received a median of 13.5 days of treatment with no persistent bloodstream infections or ampicillin-related adverse drug reactions observed. A 90-day mortality rate of 25% (3/12) was reported, however, occurring in patients with severe underlying disease.⁵⁵ Larger studies are warranted to better understand the relationship between PK-PD targets and clinical outcomes in enterococcal endocarditis.

Vancomycin

The first case reports of CI vancomycin were published in the early 1990s.^59,60 Since then, interest has increased regarding the use of CI vancomycin to maximize its PK-PD properties, including a potentially faster time to a therapeutic steady state and less variation in levels. The 2019 IDSA update to the vancomycin dosing and monitoring guidelines specifically identified CI vancomycin as an appropriate modality to reach the area under the curve (AUC)-to-MIC targets.⁶¹ Interestingly, for methicillin-resistant S. aureus isolates with a MIC of 1 mg/L, the guidelines recommend an AUC:MIC ratio for vancomycin of 400–600 for intermittent infusion but 480–600, or a random level of 20–25 mg/L, for CI. Justification for this higher AUC target appears related to previous trials of CI vancomycin in the intensive care unit setting.⁶¹ If the intermittent infusion AUC:MIC range was applied to CI, the random level range would be 16.67–25 mg/L. The clinical risks and/or benefits of a more aggressive AUC:MIC ratio must be further investigated. A resultant MIC of 2 mg/L generally indicates a change to an alternative antimicrobial. Furthermore, the appropriate AUC:MIC ratio for isolates with MICs less than 1 mg/L is not well established.

Previous studies assessed CI vancomycin in various patient populations such as critically ill, pediatric, and outpatient populations. Improved clinical efficacy of CI compared with intermittent vancomycin regimens has not been demonstrated, which is expected because the two modalities obtain a similar AUC. The possible benefit of CI vancomycin is largely believed to be a reduced risk of nephrotoxicity. Multiple meta-analyses have evaluated the nephrotoxicity of intermittent infusion versus CI vancomycin with diverging results.^62–64 Notably, most included studies are retrospective, with only two randomized clinical trials being included in all three meta-analyses.^65,66

The use of CI vancomycin has many practical aspects that are of value to the clinician. Historically, substantial coordination has been needed between the patient, treating clinician, outside facilities, home healthcare nurses, and infusion pharmacies to ensure that blood samples are collected at an appropriate time for measurement of vancomycin levels. Several factors could potentially create scenarios in which vancomycin trough levels are not captured or are not clinically valid. With CI vancomycin, any random level obtained after 24 h of initiation is assumed to be equivalent to steady-state concentration and can be measured whenever it is most convenient for the patient.

Several studies of CI vancomycin in the adult outpatient population have been performed. In a randomized clinical trial of the outpatient treatment of osteomyelitis in France, CI vancomycin regimens were associated with more predictable serum concentrations and were less likely than intermittent infusions to require dose adjustment. Additionally, patients were less likely to discontinue CI vancomycin because of adverse drug reactions versus intermittent infusion vancomycin (8.7% versus 42.9%).⁶⁷ Discontinuations were related largely to adverse drug events, most commonly kidney adverse events.⁶⁷ Several retrospective reviews of CI vancomycin in the outpatient setting have demonstrated no difference in clinical failure rates compared with intermittent infusion, despite the potentially improved monitoring capabilities of CI vancomycin.^68,69 Several studies identified lower incidence and/or slower development of kidney impairment with CI versus intermittent infusion.^67,68,70

The increased safety and practicality benefits of CI vancomycin should be weighed against the potential work for the patient or caregiver. Patients receiving OPAT vancomycin in one study stated that receipt of vancomycin moderately affected their daily routines, which was not observed with receipt of daptomycin.⁷¹ Of note, that study did not use CI vancomycin, and patient preference may have differed for CI versus intermittent infusion vancomycin when compared with daptomycin. A recent study in Belgium reported that all respondents in a home CI OPAT program were satisfied with their care, and 71.4% were ‘very satisfied’.⁷² This contrast in responses may be related to various factors, but patients in the Belgian study received vancomycin CI via an elastomeric pump and not a traditional mechanical ambulatory infusion pump.⁷² Further studies are warranted to compare patient preferences between CI and intermittent infusion modalities in OPAT.

Meropenem

The appropriateness of using meropenem for CI has been a clinical challenge given the variable stability data at different concentrations, particularly at the higher concentrations potentially used to achieve typical daily doses.^73,74 Data regarding use of CI meropenem demonstrate its stability in both polyvinyl chloride and elastomeric systems, at concentrations up to 20 mg/mL, which would allow for compounding and delivery for in-home administration.⁷⁵ Similar to the situation with ampicillin, the lack of sufficiently sized elastomeric systems can hinder the use of larger daily doses (e.g. 6 g/day). Recently, a case series described meropenem compounded as 1% and 1.25% solutions (w/v) used in four patients transitioning from intermittent infusions to CI for OPAT.⁷⁶ CIs were coupled with TDM, and all four patients achieved serum drug concentration at least two times the measured or presumed MIC of the pathogen. Meropenem CI is promising and may become increasingly needed in OPAT for MDR organisms, but more research is needed.

CI OPAT experience with select newer antimicrobials

Ceftolozane/Tazobactam

Ceftolozane/tazobactam (C/T), a combination cephalosporin/β-lactamase inhibitor, is an option for certain MDR P. aeruginosa infections; however, the every-8-h infusions may be perceived as a barrier for OPAT. The C/T product label reports a stability after dilution in NS or D5W of 24 h at room temperature or up to 7 days when refrigerated; this generated early interest in converting the standard regimen to 24-h CI as an off-label use for OPAT.^77,78

PK analyses, case reports, and case series support that C/T can be safe and effective when given as CI. A multicenter prospective cohort study evaluated the percentage of patients reaching PK-PD targets of 100% time-free drug concentration maintained above the MIC (ƒT_>MIC) or 100% ƒT_>4×MIC. Patients received CI, prolonged infusion (over 4 h), or intermittent infusion (over ⩽1 h) of C/T 2/1 g or renally adjusted equivalent based on simulations from plasma concentrations.⁷⁹ A total of 72 patients were enrolled in the clinical setting, with 79% being intensive care unit patients. For C/T MICs less than 4 mg/L, 100% ƒT_{>4_×MIC} was achieved with the three modalities for all patients. However, intermittent bolus and prolonged infusion did not achieve this target when the C/T MIC was 4 mg/L or greater. In patients receiving CI of C/T, 100% ƒT_{>4_×MIC} was achieved for strains with MICs up to 8 mg/L.⁷⁹

The first clinical report of C/T administered by CI in the outpatient setting was for a 71-year-old woman with MDR P. aeruginosa urinary tract infection without other treatment options that could avoid hospital admission.⁸⁰ A regimen of CI C/T 4.5 g in 240 mL NS via ambulatory infusion pump was exchanged every 24 h at an infusion center. The patient was treated for 2 weeks, which resulted in microbiological clearance and no adverse drug events.⁸⁰ Another report, 2 years later, described the use of CI C/T (6 g in 500 mL of NS over 24 h) for a 30-year-old patient with cystic fibrosis having positive respiratory cultures for P. aeruginosa and extended-spectrum β-lactamase-producing Escherichia coli.⁸¹ The CI regimen was initiated in the acute care setting with a 3 g C/T loading dose, then later continued as OPAT over a total of 10 days. Adequate drug exposure was confirmed using TDM of ceftolozane and tazobactam. The patient had clinical resolution without adverse drug events.⁸¹

Two case series from 2020, both including outpatients, describe the use of CI C/T.^82,83 One was a single-center retrospective analysis of CI C/T from December 2016 to June 2019 that included inpatients and outpatients.⁸³ Seven unique CI C/T regimens were used, primarily for deep-seated infections caused by MDR P. aeruginosa. Four regimens were used for outpatient transitions of care. The typical C/T dose was 6 g every 24 h, with a renal dose adjustment in two cases. Serum TDM demonstrated target attainment in four of four patients.⁸³ Jones et al.⁸² retrospectively reviewed the cases of seven adults receiving CI C/T entirely in the outpatient setting at an infusion center, from August 2016 through January 2018. Patients received either 4.5 or 9 g of C/T (1 g ceftolozane/0.5 g tazobactam per 1.5 g of mixture) in 240 mL NS IV every 24 h via a Continuous Ambulatory Delivery Device pump (ICU Medical, Inc), infused at 10 mL/h. The medication cassette was replaced at the infusion center daily. Six of seven patients had symptom resolution, three of three patients had microbiologic cure, and patient satisfaction scores were overall positive.⁸²

Furthermore, C/T has been investigated for CI via elastomeric devices (FOLfusor LV10; Baxter Healthcare and Easypump II; B. Braun Medical Ltd) in the UK.²² C/T, diluted in NS at 5 mg/mL or 20 mg/mL (combined active drugs), degraded during in-use storage at 32°C, with less than 95% of the drugs remaining at 24 h at both concentrations in both devices. Extended storage up to 8 days at 2°C–8°C plus 12 h at 32°C in use with both devices was supported. The authors concluded that C/T can be administered via CI for 12 h at 32°C and as 24-h CI in countries where a 10% loss of C/T is acceptable.²²

Ceftazidime/Avibactam

Ceftazidime/avibactam (C/A), a combination cephalosporin/β-lactamase inhibitor, may be a necessary treatment for complex infections with Klebsiella pneumoniae carbapenemase-producing, OXA-48 carbapenemase-producing Enterobacterales, or carbapenem-resistant P. aeruginosa. However, using C/A in OPAT may be challenging due to the frequency and duration of infusions, as well as drug stability. In an elastomeric device, C/A was stable only up to 12 h in NS at 37°C.²¹

In 2021, a case series including PK data detailed the use of C/A via CI for OPAT at a single center in Belgium.⁸⁴ It included 10 patients with infections mainly caused by MDR P. aeruginosa (55%) and K pneumoniae (36%) from December 2016 to October 2019. After a 2.5 g loading dose, patients received C/A as a CI of 5 g every 12 h diluted in 250 mL of NS, with renal dose adjustment (Table 3). Dosages were subsequently adjusted based on ceftazidime TDM to a goal of at least 4–5×MIC in plasma and/or at the site of infection. Clinical cure was achieved in 80% and microbiologic eradication was achieved in 90% of cases, and no adverse drug events were reported. Ceftazidime TDM of 4×MIC in plasma and/or at the site of infection was achieved in 100% of cases. Subsequently, two small case series of non-OPAT with PK analysis have further supported achievement of PK-PD targets with CI C/A.^85,86

Table 3.

Antimicrobial CI dosing.

Antimicrobial agent	Standard bolus dose	Standard renal dose adjustments^a	CI dose (normal kidney function)
Ampicillin	1–2 g IV every 4–6 h	Cl_Cr 10–29: 1–2 g IV every 8–12 hCl_Cr < 10 or anuric: 1–2 g IV every 12–24 h	1–2 g bolus followed by 8–12 g CI over 24 h
Ampicillin/sulbactam	1.5–3 g every 6 h	Cl_Cr 15–29: 1.5–3 g IV every 12 hCl_Cr 15 to <10 or anuric: 1.5–3 g IV every 24 h	(Limited data) 1.5–3 g bolus dose followed by 12 g CI over 24 h. (Higher doses up to 24–27 g/d have been used off-label for MDR Acinetobacter infections)
Cefazolin	1–2 g IV every 8 h	Cl_Cr 10–29: 1–2 g IV every 12 hCl_Cr < 10 or anuric: 1 g IV every 24 h	Give loading dose of 1 g over 10 min for daily doses ⩽4 g or 2 g for daily doses >4 g, then give 60–80 mg/kg per d administered over 12 h twice daily as a CI (max 12 g/d)
Cefepime	Most infections: 2 g IV every 12 h	Cl_Cr 30–59: 1–2 g IV every 24 hCl_Cr 10–29: 500 mg to 1 g IV every 24 hCl_Cr < 10 or anuric: 250–500 mg IV	Administered via ambulatory infusion pump at 100 mg/kg over 24 h (max dose 6 g/24 h)
	Pseudomonas infections and/or neutropenic fever: 2 g IV every 8 h	Cl_Cr 30–59: 2 g IV every 12 hCl_Cr 10–29: 2 g IV every 24 hCl_Cr < 10 or anuric: 1 g IV every 24 h
Ceftazidime/avibactam	2.5 g IV every 8 h	Cl_Cr 31–49: 1.25 g IV every 8 hCl_Cr 16–30: 0.94 g IV every 12 hCl_Cr 6–15: 0.94 g IV every 24 hCl_Cr ⩽ 5: 0.94 g IV every 48 h	(Limited evidence) In 250 mL NS via continuous ambulatory infusion pump:Cl_Cr ⩾ 60: 5 g every 12 hCl_Cr 30–59: 2.5 g every 12 hCl_Cr 15–29: 1.25 g every 12 h
Ceftolozane/tazobactam	UTI and intra-abdominal infections: 1.5 g IV every 8 h	Cl_Cr 30–49: 750 mg every 8 h or 1.5 g every 8 h for HAP/VAPCl_Cr 15–29: 375 mg every 8 h or 750 mg every 8 h for HAP/VAPCl_Cr < 10 or anuric: 750 mg load, then 150 mg every 8 h or 2.25 g load, then 450 mg every 8 h for HAP/VAP	4.5–9 g in 240 mL via continuous ambulatory infusion pump
	HAP/VAP: 3 g IV every 8 h
Meropenem	Mild to moderate infections: 1 g IV every 8 h	Cl_Cr 26–49: 1 g every 12 hCl_Cr 10–25: 500 mg every 12 hCl_Cr < 10 or anuric: 500 mg every 24 h	Loading dose of 1–2 g followed by 2 g every 8 h or 3 g every 12 h⁸⁷ via CI
	Alternative: 500 mg IV every 6 h	Cl_Cr 26–49: 500 mg every 8 hCl_Cr 10–25: 500 mg every 12 hCl_Cr < 10 or anuric: 500 mg every 24 h
	Severe infections or meningitis: 2 g IV every 8 h	Cl_Cr 26–49: 2 g every 12 hCl_Cr 10–25: 1 g every 12 hCl_Cr < 10 or anuric: 1 g every 24 h
Nafcillin	1–2 g IV every 4 or 6 h	No renal dose adjustments	8–12 g administered via CI over 24 h
Oxacillin	1–2 g IV every 4 or 6 h	No renal dose adjustments	8–12 g administered via CI over 24 h
Penicillin G IV	12–30 million U/d divided every 4 h IV or CI (3–5 million U load for serious infections)	Cl_Cr 10–49: 75% of total doseCl_Cr < 10: 25%−50% total dose	3–5 million U load over 3–5 min 1 h before CI of 12–30 million U over 24 h
Piperacillin/tazobactam	For most infections: 3.375 g IV every 6 h	Cl_Cr 20–39: 2.25 g IV every 6 hCl_Cr < 20: 2.25 g IV every 8 h	9–18 g delivered over 24 hGive loading dose 1 h before or start CI within 1 h of the last intermittent dose in an observed setting
	For severe infections: 4.5 g IV every 6 h	Cl_Cr 20–39: 3.375 g IV every 6 hCl_Cr < 20: 2.25 g IV every 6 h
Vancomycin	15–20 mg/kg IV every 8–24 h	Dose based on pharmacokinetic calculations and therapeutic drug monitoring	Load 15–20 mg/kg (max 2.5 g)Maintenance:Cl_Cr > 60: 30–40 (up to 60) mg/kg per dayCl_Cr 30–59: 15 mg/kg per dayTarget random vancomycin levels 17–25 mg/L = approximate AUC:MIC ratio of 400–600⁶¹

Source: Wilson et al.⁸⁸

Existing evidence is extremely limited for renal dose adjustments of CI antimicrobials. When no evidence exists for drugs with standard renal dose adjustment, a proportionate dose adjustment to the total daily dose when using CI dosing is generally recommended.

AUC, area under the curve; CI, continuous infusion; Cl_Cr, creatinine clearance (mL/min); HAP/VAP, hospital-acquired pneumonia/ventilator-associated pneumonia; IV, intravenous; max, maximum; MDR, multidrug-resistant; MIC, minimum inhibitory concentration; NS, normal saline (0.9% sodium chloride); NTM, nontuberculous mycobacteria; UTI, urinary tract infection.

Ceftaroline

Ceftaroline is a cephalosporin, administered as a prodrug (ceftaroline fosamil), that is US Food and Drug Administration approved for complicated skin and skin structure infections and community-acquired bacterial pneumonia at a dosage of 600 mg IV every 12 h infused over 5 min to 1 h for those with creatinine clearance greater than 50 mL/min.⁸⁹ Ceftaroline exhibits gram-negative antibacterial and broad gram-positive antibacterial activity, including against methicillin-resistant S. aureus.

With an every-12-h bolus dose regimen option, CI ceftaroline is less compelling from a practical standpoint for OPAT. One study has reported on the stability of ceftaroline in elastomeric infusion devices for CI.⁹⁰ Ceftaroline 6 mg/mL in NS or D5W was stable for 144 h at 4°C, 24 h at 25°C, and 12 h at 30°C. At 35°C, ceftaroline was stable for 12 h in NS and for 6 h in D5W. The results supported a 12- or 24-h elastomeric CI of a ceftaroline-NS admixture. However, no known clinical reports of CI ceftaroline use in OPAT exist to date.

Conclusion

New data continue to emerge supporting the use of CI antimicrobials as a safe and effective administration strategy for OPAT; however, its use should be individualized by patient preference, feasibility, cost, and medication stability and supported by clinical outcome data. Multidisciplinary teams including pharmacists, physicians, advanced practice providers, nurses, and others are needed to determine when CI is the preferred OPAT option. On the basis of this review and author experience, CI antimicrobials that are the best fit for the OPAT setting include penicillin, piperacillin/tazobactam, and vancomycin. Ampicillin and meropenem, in contrast, have important stability issues that create a barrier to their use for CI. Areas for future research include the in-use stability of medications in elastomeric devices under various storage conditions and clinical outcome data between CI and traditional intermittent infusions. As demonstrated by recent reports of CI methods with newer antimicrobial agents, CI in the OPAT setting remains an exciting and relevant field.

Footnotes

Acknowledgements

The Scientific Publications staff at Mayo Clinic provided editorial consultation, proofreading, and administrative and clerical support. The authors have authorized Scientific Publications to submit the article on their behalf, and the authors have approved all statements and declarations.

Correction (December 2025):

article updated to include footnote “d” in Table 2 and to correct the links in References 16 and 18.

Declarations

ORCID iDs

Amy L. Van Abel

Keenan L. Ryan

References

Shah

Norris

Allison

, et al. (eds) Handbook of outpatient parenteral antimicrobial therapy for infectious diseases. 3rd ed. Tarrytown, NY: CRG Publishing, 2016.

Hamad

Dodda

Frank

, et al. Perspectives of patients on outpatient parenteral antimicrobial therapy: experiences and adherence. Open Forum Infect Dis 2020; 7: ofaa205.

Loriaux

Desmond

. A primer on home infusion administration methods. Open Forum Infect Dis 2022; 9: ofac525.

Longuet

Lecapitaine

Cassard

, et al. Preparing and administering injectable antibiotics: how to avoid playing God. Med Mal Infect 2016; 46: 242–268.

Zahnd

Aebi

Rusterholz

, et al. A randomized crossover trial assessing patient preference for two different types of portable infusion-pump devices. Ann Oncol 1999; 10: 727–729.

Karimaghaei

Rao

Chijioke

, et al. Characteristics, safety and cost-effectiveness analysis of self-administered outpatient parenteral antibiotic therapy via a disposable elastomeric continuous infusion pump at two county hospitals in Houston, Texas, United States. J Clin Pharm Ther 2022; 47: 211–217.

García-Queiruga

Feal Cortizas

Lamelo Alfonsín

, et al. Continuous infusion of antibiotics using elastomeric pumps in the hospital at home setting. Rev Esp Quimioter 2021; 34: 200–206.

Dimitrova

Gilchrist

Seaton

. Outpatient parenteral antimicrobial therapy (OPAT) versus inpatient care in the UK: a health economic assessment for six key diagnoses. BMJ Open 2021; 11: e049733.

Hobbs

Ryan

Ritchie

, et al. Protocol for a randomised crossover trial to evaluate patient and nurse satisfaction with electronic and elastomeric portable infusion pumps for the continuous administration of antibiotic therapy in the home: the Comparing Home Infusion Devices (CHID) study. BMJ Open 2017; 7: e016763.

10.

Diamantis

Dawudi

Cassard

, et al. Home intravenous antibiotherapy and the proper use of elastomeric pumps: systematic review of the literature and proposals for improved use. J Infect Dis 2021; 51: 39–49.

11.

Voumard

Van Neyghem

Cochet

, et al. Antibiotic stability related to temperature variations in elastomeric pumps used for outpatient parenteral antimicrobial therapy (OPAT). J Antimicrob Chemother 2017; 72: 1462–1465.

12.

Jones

Selby

Mellor

, et al. Ceftazidime stability and pyridine toxicity during continuous i.v. Infusion. Am J Health Syst Pharm 2019; 76: 200–205.

13.

Viaene

Chanteux

Servais

, et al. Comparative stability studies of antipseudomonal beta-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother 2002; 46: 2327–2332.

14.

Bing

. Extended stability for Parenteral Drugs. 3rd ed. Bethesda: American Society of Health-System Pharmacists, 2005.

15.

Merative. Micromedex: IV compatibility, powered by Trissel’s 2 clinical pharmaceutics database, 2023.

16.

Epic Medical. SMARTeZ stability data for drugs using elastomeric infusion pumps, https://cdn.prod.website-files.com/65dc8baf0ab572e68bbfaa66/68bf8f41a21d4efb46ea5f5d_Drug%20Stability%20List%20SMARTeZ%20Table.pdf (2015, accessed 22 March 2023).

17.

Wolf Medical Supply. MEDI-FLO elastomeric pump drug stability guide. Sunrise, FL: Wolf Medical Supply, 2021.

18.

Braun

. Drug Stability List for Easypump II, https://www.scribd.com/document/879872015/Easypump-II-Drug-Stability-June-2020 (2020, accessed 20 March 2023).

19.

Esteban-Cartelle

Vicente-Oliveros

Pérez Menéndez-Conde

, et al. Antibiotic stability in portable elastomeric infusion devices: a systematic review. Am J Health Syst Pharm 2022; 79: 1355–1368.

20.

Fernández-Rubio

Del Valle-Moreno

Herrera-Hidalgo

, et al. Stability of antimicrobials in elastomeric pumps: a systematic review. Antibiotics 2021; 11: 45.

21.

Loeuille

D’Huart

Vigneron

, et al. Stability Studies of 16 antibiotics for continuous infusion in intensive care units and for performing outpatient parenteral antimicrobial therapy. Antibiotics 2022; 11: 458.

22.

Jamieson

Drummond

Hills

, et al. Assessment of ceftolozane/tazobactam stability in elastomeric devices and suitability for continuous infusion via outpatient parenteral antimicrobial therapy. JAC Antimicrob Resist 2021; 3: dlab141.

23.

Terracciano

Rhee

Walsh

. Chemical stability of ceftolozane/tazobactam in polyvinylchloride bags and elastomeric pumps. Curr Ther Res Clin Exp 2017; 84: 22–25.

24.

Briggs

Broom

Duffy

, et al. Outpatient continuous-infusion benzylpenicillin combined with either gentamicin or ceftriaxone for enterococcal endocarditis. J Antimicrob Chemother 2021; 76: 2168–2171.

25.

Ingram

Mathieson

, et al. A clinical and in vitro assessment of outpatient parenteral benzylpenicillin and ceftriaxone combination therapy for enterococcal endovascular infections. JAC Antimicrob Resist 2021; 3: dlab128.

26.

Tice

Strait

Ramey

, et al. Outpatient parenteral antimicrobial therapy for central nervous system infections. Clin Infect Dis 1999; 29: 1394–1399.

27.

Allen

Jr Stiles

Prince

, et al. Stability of 14 drugs in the latex reservoir of an elastomeric infusion device. Am J Health Syst Pharm 1996; 53: 2740–2743.

28.

Huskey

Lewis

Brown

. Stability of ampicillin in normal saline following refrigerated storage and 24-Hour pump recirculation. Hosp Pharm 2021; 56: 507–512.

29.

Arensdorff

Boillat-Blanco

Decosterd

, et al. Adequate plasma drug concentrations suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps. J Antimicrob Chemother 2017; 72: 2613–2615.

30.

Belliveau

Nightingale

Quintiliani

. Stability of aztreonam and ampicillin sodium-sulbactam sodium in 0.9% sodium chloride injection. Am J Hosp Pharm 1994; 51: 901–904.

31.

Tamma

Aitken

Bonomo

, et al. IDSA guidance on the treatment of antimicrobial-resistant gram-negative infections: Version 2.0, https://www.idsociety.org/practice-guideline/amr-guidance-2.0/ (2022, accessed 20 March 2023).

32.

Voumard

Gardiol

André

, et al. Efficacy and safety of continuous infusions with elastomeric pumps for outpatient parenteral antimicrobial therapy (OPAT): an observational study. J Antimicrob Chemother 2018; 73: 2540–2545.

33.

Ferreiro

JLL

Otero

JÁ

Rivo

, et al. Outpatient therapy with piperacillin/tazobactam using elastomeric pumps in patients with Pseudomonas aeruginosa infection. Sci Rep 2021; 11: 8610.

34.

Browning

Loewenthal

Freelander

, et al. Safety of prolonged outpatient courses of intravenous antibiotics: a prospective cohort study. Clin Microbiol Infect 2022; 28: 832–837.

35.

Bidell

Patel

O’Donnell

. Optimal treatment of MSSA bacteraemias: a meta-analysis of cefazolin versus antistaphylococcal penicillins. J Antimicrob Chemother 2018; 73: 2643–2651.

36.

Echevarria

Traugott

. β-lactam therapy for methicillin-susceptible Staphylococcus aureus bacteremia: a comparative review of cefazolin versus Antistaphylococcal penicillins. Pharmacotherapy 2017; 37: 346–360.

37.

Loubet

Burdet

Vindrios

, et al. Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review. Clin Microbiol Infect 2018; 24: 125–132.

38.

Rindone

Mellen

. Meta-analysis of trials comparing cefazolin to antistaphylococcal penicillins in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia. Br J Clin Pharmacol 2018; 84: 1258–1266.

39.

Shi

Xiao

Zhang

, et al. Efficacy and safety of cefazolin versus antistaphylococcal penicillins for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia: a systematic review and meta-analysis. BMC Infect Dis 2018; 18: 508.

40.

Lecomte

Bourreau

Deschanvres

, et al. Comparative outcomes of cefazolin versus antistaphylococcal penicillins in methicillin-susceptible Staphylococcus aureus infective endocarditis: a post hoc analysis of a prospective multicentre French cohort study. Clin Microbiol Infect 2021; 27: 1015–1021.

41.

Monogue

Ortwine

Wei

, et al. Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia. J Infect Public Health 2018; 11: 727–731.

42.

Youngster

Shenoy

Hooper

, et al. Comparative evaluation of the tolerability of cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. Clin Infect Dis 2014; 59: 369–375.

43.

Zeller

Durand

Kitzis

, et al. Continuous cefazolin infusion to treat bone and joint infections: clinical efficacy, feasibility, safety, and serum and bone concentrations. Antimicrob Agents Chemother 2009; 53: 883–887.

44.

David

Devlin

. Continuous infusion of ceftazidime in cystic fibrosis. Lancet 1989; 1: 1454–1455.

45.

Kuzemko

Crawford

. Continuous infusion of ceftazidime in cystic fibrosis. Lancet 1989; 2: 385.

46.

Vinks

Touw

Heijerman

, et al. Pharmacokinetics of ceftazidime in adult cystic fibrosis patients during continuous infusion and ambulatory treatment at home. Ther Drug Monit 1994; 16: 341–348.

47.

Pais

Chang

Barreto

, et al. Clinical pharmacokinetics and pharmacodynamics of cefepime. Clin Pharmacokinet 2022; 61: 929–953.

48.

Foong

Hsueh

Bailey

, et al. A cluster of cefepime-induced neutropenia during outpatient parenteral antimicrobial therapy. Clin Infect Dis 2019; 69: 534–537.

49.

Wong

. Neutropenia in patients receiving long-term cefepime therapy for osteomyelitis. Am J Health Syst Pharm 2003; 60: 2229–2232.

50.

Norris

Shrestha

Allison

, et al. 2018 Infectious Diseases Society of America Clinical Practice Guideline for the management of outpatient parenteral antimicrobial therapya. Clin Infect Dis 2019; 68: e1–e35.

51.

Viehman

Oleksiuk

Sheridan

, et al. Adverse events lead to drug discontinuation more commonly among patients who receive nafcillin than among those who receive oxacillin. Antimicrob Agents Chemother 2016; 60: 3090–3095.

52.

Timbrook

McKay

Sutton

, et al. Disproportionality analysis of safety with nafcillin and oxacillin with the FDA Adverse Event Reporting System (FAERS). Antimicrob Agents Chemother 2020; 64: e01818–19.

53.

Baddour

Wilson

Bayer

, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132: 1435–1486.

54.

Roberts

Abdul-Aziz

Lipman

, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14: 498–509.

55.

Gatti

Tedeschi

Trapani

, et al. A proof of concept of the usefulness of a TDM-Guided strategy for optimizing pharmacokinetic/pharmacodynamic target of continuous infusion ampicillin-based regimens in a case series of patients with enterococcal bloodstream infections and/or endocarditis. Antibiotics 2022; 11: 20220801.

56.

Thauvin

Eliopoulos

Willey

, et al. Continuous-infusion ampicillin therapy of enterococcal endocarditis in rats. Antimicrob Agents Chemother 1987; 31: 139–143.

57.

Gil-Navarro

Lopez-Cortes

Luque-Marquez

, et al. Outpatient parenteral antimicrobial therapy in Enterococcus faecalis infective endocarditis. J Clin Pharm Ther 2018; 43: 220–223.

58.

Lewis

Jones

Amodei

, et al. Continuous infusion ampicillin for the outpatient management of enterococcal endocarditis: a case report and literature review. J Pharm Pract 2020; 33: 392–394.

59.

Conil

Favarel

Laguerre

, et al. [Continuous administration of vancomycin in patients with severe burns]. Presse Med 1994; 23: 1554–1558.

60.

Longuet

Vallée

Michel

, et al. [Vancomycin in meningitis caused by penicillin G resistant Streptococcus pneumoniae]. Presse Med 1993; 22: 1818–1819.

61.

Rybak

Lodise

, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of health-system Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2020; 71: 1361–1364.

62.

Chu

Luo

Quan

, et al. Intermittent vs. Continuous vancomycin infusion for gram-positive infections: a systematic review and meta-analysis. J Infect Public Health 2020; 13: 591–597.

63.

Hanrahan

Whitehouse

Lipman

, et al. Vancomycin-associated nephrotoxicity: a meta-analysis of administration by continuous versus intermittent infusion. Int J Antimicrob Agents 2015; 46: 249–253.

64.

Hao

Chen

Zhou

. Continuous versus intermittent infusion of vancomycin in adult patients: a systematic review and meta-analysis. Int J Antimicrob Agents 2016; 47: 28–35.

65.

Schmelzer

Christmas

Norton

, et al. Vancomycin intermittent dosing versus continuous infusion for treatment of ventilator-associated pneumonia in trauma patients. Am Surg 2013; 79: 1185–1190.

66.

Wysocki

Delatour

Faurisson

, et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother 2001; 45: 2460–2467.

67.

Vuagnat

Stern

Lotthe

, et al. High dose vancomycin for osteomyelitis: continuous vs. Intermittent infusion. J Clin Pharm Ther 2004; 29: 351–357.

68.

Shakeraneh

Fazili

Wang

, et al. Nephrotoxicity risk and clinical effectiveness of continuous versus intermittent infusion vancomycin among patients in an outpatient parenteral antimicrobial therapy program. Pharmacotherapy 2020; 40: 357–362.

69.

Verrall

Llorin

Tam

, et al. Efficacy of continuous infusion of vancomycin for the outpatient treatment of methicillin-resistant Staphylococcus aureus infections. J Antimicrob Chemother 2012; 67: 2970–2973.

70.

Ingram

Lye

Fisher

, et al. Nephrotoxicity of continuous versus intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy. Int J Antimicrob Agents 2009; 34: 570–574.

71.

Sakoulas

Geriak

. Vancomycin or daptomycin for outpatient parenteral antibiotic therapy: does it make a difference in patient satisfaction? Open Forum Infect Dis 2021; 8: ofab418.

72.

Thijs

Quintens

Vander Elst

, et al. Clinical efficacy and safety of vancomycin continuous infusion in patients treated at home in an outpatient parenteral antimicrobial therapy program. Antibiotics 2022; 11: 702.

73.

Berthoin

Le Duff

Marchand-Brynaert

, et al. Stability of meropenem and doripenem solutions for administration by continuous infusion. J Antimicrob Chemother 2010; 65: 1073–1075.

74.

Jamieson

Allwood

Stonkute

, et al. Investigation of meropenem stability after reconstitution: the influence of buffering and challenges to meet the NHS yellow cover document compliance for continuous infusions in an outpatient setting. Eur J Hosp Pharm 2020; 27: e53–e57.

75.

Smith

Bauer

Nicolau

. Stability of meropenem in polyvinyl chloride bags and an elastomeric infusion device. Am J Health Syst Pharm 2004; 61: 1682–1685.

76.

Legg

Halford

McCarthy

. Plasma concentrations resulting from continuous infusion of meropenem in a community-based outpatient program: a case series. Am J Health Syst Pharm 2020; 77: 2074–2080.

77.

Liscio

Mahoney

Hirsch

. Ceftolozane/tazobactam and ceftazidime/avibactam: two novel β-lactam/β-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. Int J Antimicrob Agents 2015; 46: 266–271.

78.

ZERBAXA (ceftolozane/tazobactam). Prescribing information. Rahway, NJ: Merck Sharp Dohme Corp, 2022.

79.

Pilmis

Petitjean

Lesprit

, et al. Continuous infusion of ceftolozane/tazobactam is associated with a higher probability of target attainment in patients infected with Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 2019; 38: 1457–1461.

80.

Jones

Smith

Bland

. Use of continuous-infusion ceftolozane/tazobactam in a multidrug-resistant Pseudomonas aeruginosa urinary tract infection in the outpatient setting. Ann Pharmacother 2017; 51: 715–716.

81.

Elizabeth Davis

Ham

Hucks

, et al. Use of continuous infusion ceftolozane–tazobactam with therapeutic drug monitoring in a patient with cystic fibrosis. Am J Health Syst Pharm 2019; 76: 501–504.

82.

Jones

Huelfer

Bland

. Clinical and safety evaluation of continuously infused ceftolozane/tazobactam in the outpatient setting. Open Forum Infect Dis 2020; 7: ofaa014.

83.

Sheffield

Nelson

O’Neal

, et al. Use of continuous-infusion ceftolozane/tazobactam for resistant Gram-negative bacterial infections: a retrospective analysis and brief review of the literature. Int J Antimicrob Agents 2020; 56: 106158.

84.

Goncette

Layios

Descy

, et al. Continuous infusion, therapeutic drug monitoring and outpatient parenteral antimicrobial therapy with ceftazidime/avibactam: a retrospective cohort study. J Glob Antimicrob Resist 2021; 26: 15–19.

85.

Gatti

Giannella

Rinaldi

, et al. Pharmacokinetic/pharmacodynamic analysis of continuous-infusion fosfomycin in combination with extended-infusion cefiderocol or continuous-infusion ceftazidime-avibactam in a case series of Difficult-to-Treat resistant Pseudomonas aeruginosa bloodstream infections and/or hospital-acquired pneumonia. Antibiotics 2022; 11: 1739.

86.

Gatti

Pascale

Cojutti

, et al. A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam in a case series of critically ill renal patients treated for documented carbapenem-resistant Gram-negative bloodstream infections and/or ventilator-associated pneumonia. Int J Antimicrob Agents 2023; 61: 106699.

87.

Evans

Rhodes

Alhazzani

. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47: 1181–1247.

88.

Wilson

Estes

. Section I: antimicrobial dosing-adult. In: Mayo Clinic antimicrobial therapy: Quick guide, 3rd ed. New York: Oxford University Press, 2018.

89.

TEFLARO (ceftaroline fosamil). Prescribing information. Madison, NJ: Allergan USA, Inc, 2021.

90.

Al Madfai

Zaidi

STR

Ming

, et al. Physical and chemical stability of ceftaroline in an elastomeric infusion device. Eur J Hosp Pharm 2018; 25: e115–e119.