What data is available reviewing IV push ertapenem?

What data is available reviewing IV push ertapenem?

Comment by InpharmD Researcher

Although intravenous push (IVP) ertapenem is not an FDA-approved route of administration, a moderate body of literature has evaluated its pharmacokinetics, safety, and operational utility. Most studies describe ertapenem 1 g administered over approximately 5 minutes, with available literature supporting dilution of the 1-g dose in 10 mL of sterile water for injection (SWFI) or 0.9% sodium chloride for IVP administration. Pharmacokinetic studies demonstrate bioequivalent exposure and similar pharmacodynamic target attainment compared with the labeled 30-minute infusion. Clinical studies generally report comparable tolerability and administration-site safety between IVP and IV piggyback administration, while emergency department data suggest that IVP may reduce time to antibiotic administration without increasing adverse events. However, the evidence is derived primarily from small pharmacokinetic studies and retrospective observational data, and robust clinical evidence remains limited.

Background

Reviews describe the use of ertapenem via intravenous push (IVP) administration. Ertapenem has been described as being administered once daily over 5 minutes at a concentration of 100 mg/mL, although IVP administration is not FDA approved and syringe stability is poor unless frozen. A pharmacokinetic study in 12 healthy volunteers found that ertapenem 1 g diluted in normal saline to 10 mL and administered over 5 minutes at 2 mL/min through a peripheral IV catheter was bioequivalent to a 30-minute infusion for Cmax and AUC, with no serious adverse events such as vomiting or seizures; pharmacokinetic data also suggest similar T > MIC profiles between IVP and 30-minute infusions. Clinical experience includes a prospective outpatient parenteral antimicrobial therapy (OPAT) study in which ertapenem was administered over 5 minutes, with no rapid infusion-related adverse reactions among 184 patients receiving 4,326 combined doses of ertapenem and other antimicrobials, although ertapenem-specific outcomes were not reported. [1], [2]

Relevant Prescribing Information

DOSAGE AND ADMINISTRATION [3]
Instructions for Use in All Patients: For Intravenous or Intramuscular Use

Ertapenem for injection may be administered by intravenous infusion for up to 14 days or intramuscular injection for up to 7 days. When administered intravenously, ertapenem for injection should be infused over a period of 30 minutes. Intramuscular administration of ertapenem for injection may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate.

Literature Review

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

What data is available reviewing IV push ertapenem?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-5 for your response.

Safety of Intravenous Push Ertapenem Compared to Intravenous Piggyback at a Tertiary Academic Medical Center
Design	Single-center, retrospective study N= 174
Objective	To evaluate the infusion site safety of ertapenem given as peripheral intravenous push (IVP) compared to intravenous piggyback (IVPB) in adult patients
Study Groups	IVP group (n= 92, total 292 administrations) IVPB group (n= 82, total 319 administrations)
Inclusion Criteria	Patients ≥18 years of age who received at least 1 dose of 500 mg or 1000 mg of IVP or IVPB ertapenem via peripheral line
Exclusion Criteria	Ertapenem administered via central line or incomplete/duplicated medical records
Methods	Retrospective analysis using electronic health records to identify patients who received at least one dose of ertapenem 500 mg or 1,000 mg by IVP over at least 5 minutes or IVPB through a peripheral IV line. Infusion-site reactions, including phlebitis and infiltration, were assessed, and the Naranjo Nomogram was used to evaluate the causality of identified reactions.
Duration	April 1, 2017, to September 30, 2018
Outcome Measures	Infusion site reactions (including phlebitis and infiltration); causality of reactions assessed by Naranjo Nomogram
Baseline Characteristics		IVP (n= 92)	IVPB (n= 82)
	Mean age, years	62.0	59.5
	Male	43 (46.74%)	43 (52.44%)
	Mean weight, kg	82.3	82.4
	Hypertension	57 (61.96%)	35 (42.68%)
	Peripheral arterial disease or peripheral vascular disease	19 (20.65%)	5 (6.11%)
	Ertapenem dose 500 mg 1000 mg	27 (9.6%) 255 (90.4%)	57 (17.9%) 262 (82.1%)
Results		IVP (n= 282)	IVPB (n= 319)	p-value
	Total IV site reactions	13 (4.61%)	8 (2.51%)	0.16
	Phlebitis	4 (1.42%)	3 (0.94%)	0.58
	Infiltration	9 (3.19%)	5 (1.57%)	0.09
Adverse Events	Infusion site reactions were similar between groups. In the IVP group, 13 reactions were noted (4.61%), while in the IVPB group, 8 reactions were noted (2.51%). Phlebitis and infiltration were the main adverse events observed. There was no significant difference between IVP vs IVPB administration in possible (p= 0.15), probable (p= 0.43), or doubtful (p= 0.27) adverse drug reactions per Naranjo Nomogram.
Study Author Conclusions	The administration of IVP ertapenem showed comparable rates of infusion site reactions compared to IVPB. Implementation of IVP ertapenem appears to be associated with infusion site safety similar to IVPB and should be considered safe to administer.
Critique	The study's retrospective design may limit the accuracy of documentation in medical records. The presence of dedicated IV nurses and specific institutional policies may not reflect practices at other institutions, potentially affecting the generalizability of the findings. Additionally, the study did not assess catheter size or efficacy outcomes, focusing solely on safety.

Table 1 References:
[4] Corrado MJ, Riselli A, McLaughlin KC, Szumita PM, Anger KE. Safety of Intravenous Push Ertapenem Compared to Intravenous Piggyback at a Tertiary Academic Medical Center. J Pharm Pract. 2023;36(2):281-285. doi:10.1177/08971900211038355

Evaluation of First-Dose, Intravenous Push Penicillins and Carbapenems in the Emergency Department
Design	Single-center, retrospective, pre-post intervention comparison study N= 696 orders
Objective	To compare the time to first-dose intravenous push (IVP) ampicillin/sulbactam, piperacillin/tazobactam, and ertapenem in the emergency department (ED) to the traditional intravenous piggyback (IVPB) administration, and to evaluate safety and cost savings
Study Groups	IVPB (n= 351 orders) IVP (n= 345 orders)
Inclusion Criteria	Patients between 18 and 89 years of age at the time of ED visit, who received ampicillin/sulbactam, piperacillin/tazobactam, or ertapenem during pre-specified time points via IVPB or IVP
Exclusion Criteria	Incarcerated, pregnant, or received other antibiotics prior to administration of the index antibiotic
Methods	In the pre-intervention period, study antibiotics were administered by IVPB; following protocol implementation in October–November 2017, they were administered by IVP, with subsequent doses administered by IVPB over 30 minutes or extended infusion according to institutional protocol. The IVP protocol consisted of ampicillin/sulbactam 1.5–3 g in 10–20 mL sterile water over 10 minutes, piperacillin/tazobactam 3.375–4.5 g in 20 mL sterile water over 10 minutes, and ertapenem 1 g in 10 mL sterile water over 5 minutes.
Duration	October 24, 2015 to November 3, 2018 (An IVP protocol was implemented on October 25, 2017 for ampicillin/sulbactam and piperacillin/tazobactam, and on November 3, 2017 for ertapenem. Pre-intervention considered IVPB, and post-intervention considered IVP.)
Outcome Measures	Primary: Time from ED arrival to antibiotic administration Secondary: Safety events, cost savings
Baseline Characteristics		IVPB (n= 351)	IVP (n= 345)
	Median age, years	56 ± 17.4	53 ± 17.8
	Female	150 (42.6%)	153 (44.2%)
	High acuity admission	43 (12%)	54 (16%)
	Antibiotic received Ampicillin/sulbactam Piperacillin/tazobactam Ertapenem	136 (38.6%) 168 (47.7%) 48 (13.6%)	129 (37.3%) 170 (49.1%) 47 (13.6%)
Results		IVPB (n= 351)	IVP (n= 345)	p-value
	ED arrival to administration, minutes (IQR) Ertapenem	140 (87-221) 214 (123-281)	110 (68-181) 139 (92-222)	<0.01 <0.03
	Order to antibiotic administration, minutes (IQR) Ertapenem	42 (26-70) 61 (30-100)	30 (17-44) 24 (15-47)	<0.01 <0.01
	Abbreviations: IQR, interquartile range.
	Supplies for IVP and IVPB preparations totaled $1.22 and $8.68 per dose, respectively. Annualized supply costs for the 3 indexed antibiotics during the reference year totaled $863 for IVP and $6,144 for IVPB preparations, a difference of $5,281. On average, antibiotics for IVP administration took 3 minutes and 48 seconds to prepare, while preparations for IVPB administration took 9 minutes and 16 seconds.
Adverse Events	No difference in adverse drug reactions between IVP and IVPB cohorts (1.7% vs 2.6%, respectively).
Study Author Conclusions	IVP administration of ampicillin/sulbactam, piperacillin/tazobactam, and ertapenem improved times to initiation of empiric, first-dose antibiotics in the ED without an increase in adverse events, saving over $5,000 annually.
Critique	The study demonstrated improved time to administration and cost savings with IVP administration without increased adverse events. However, the retrospective, single-center design may limit generalizability. The study did not assess clinical outcomes beyond administration timing and safety events.

Table 2 References:
[5] Academia EC, Jenrette JE, Mueller SW, McLaughlin JM. Evaluation of First-Dose, Intravenous Push Penicillins and Carbapenems in the Emergency Department. J Pharm Pract. 2022;35(3):369-376. doi:10.1177/0897190020977758

Effect of IV Push Antibiotic Administration on Antibiotic Therapy Delays in Sepsis
Design	Single-center, retrospective analysis N= 274
Objective	To evaluate the difference in time from sepsis diagnosis to first-dose completion of β-lactam antibiotics between IV push and IV piggyback administration
Study Groups	IV push (n= 143) IV piggyback (n= 131)
Inclusion Criteria	Adult patients diagnosed with severe sepsis or septic shock per Sepsis-2 criteria from September to November 2016 and from September to November 2017; received β-lactam antibiotic
Exclusion Criteria	Patients who did not receive β-lactam agents or received them in a manner inconsistent with the study arms
Methods	Patients received β-lactams by either IV push (estimated administration duration, 3 minutes) or IV piggyback (estimated duration, 30 minutes) according to institutional administration policies. Antibiotics eligible for IV push included aztreonam, cefepime, ceftriaxone, ertapenem, meropenem, and piperacillin/tazobactam; antibiotics were ordered at physician discretion. Patients who did not receive a β-lactam or received it in a manner inconsistent with the study arms were excluded.
Duration	September to November 2016 and September to November 2017
Outcome Measures	Time from sepsis diagnosis to administration of β-lactam antibiotics; time to administration of complete broad-spectrum regimen; compliance with 1-hour and 3-hour antibiotic administration goals; adverse events
Baseline Characteristics		IV Piggyback (n= 143)	IV Push (n= 131)
	Age, years (IQR)	63.5 (50.7–74.7)	61 (52–75)
	Male	65 (45.5%)	51 (38.9%)
	Body mass index, kg/m2 (IQR)	25.7 (22.1–32.1)	25.8 (21.3–31.2)
	Initial serum creatinine (IQR)	1.6 (1.1–2.3)	1.3 (0.9–2.1)
	Acute kidney injury	69 (48%)	57 (44%)
	Initial lactic acid (IQR)	2.4 (1.6–3.7)	2.5 (1.5–4.1)
	Shock on presentation	85 (59.4%)	82 (62.5%)
	Vasopressor within 12 hr	18 (12.6%)	13 (9.9%)
	Dobutamine within 12 hr	4 (2.8%)	2 (1.5%)
	Patients admitted to an ICU	65 (45.4%)	47 (35.9%)
	Suspected source Pneumonia Genitourinary Skin and soft-tissue infection Bacteremia Gastrointestinal Other Unknown	27 (19%) 43 (30%) 24 (17%) 8 (6%) 16 (11%) 3 (2%) 22 (15%)	32 (24%) 30 (23%) 14 (11%) 17 (13%) 20 (15%) 5 (4%) 13 (10%)
	Time to sepsis, hours (IQR)	1.5 (0.6–2.6)	0.8 (0.5–1.6)
	Mortality in Emergency Department Sepsis score (IQR)	9 (6–13)	9 (6–13)
	Abbreviations: IQR, interquartile range.
Results		IV Piggyback (n= 143)	IV Push (n= 131)
	Time to first β-lactam dose, min (IQR)	72 (8–180)	48 (19–96)
	Time to broad-spectrum regimen, min (IQR)	114 (42–282)	108 (66–144)
	Patients who did not receive β-lactam within 1 hr	82 (57.3%)	58 (44.6%)
	Patients who did not receive β-lactam within 3 hr	35 (24.5%)	10 (7.6%)
	Patients who did not receive β-lactam before transfer from ED	12 (8.4%)	3 (2.3%)
	ED length of stay, hr (IQR)	8.0 (6.1–10.2)	7.5 (6–9.7)
	ICU length of stay, d (IQR)	4.5 (2–6)	2.3 (1.0–2.6)
	Hospital length of stay, d (IQR)	10.4 (4.3–11.8)	9.1 (3.9–10.1)
	Overall mortality	14 (9.7%)	16 (12.2%)
	Septic shock mortality	11 (12.9%)	13 (16%)
	Adverse events	0 (0%)	0 (0%)
	After adjustment, IV push was associated with approximately 32 minutes of time savings in β-lactam and broad-spectrum antibiotic administration, with no impact on mortality, intensive care unit (ICU) length of stay, or ICU admission.
Adverse Events	No adverse events, including infusion reactions, were found in either arm.
Study Author Conclusions	Use of an IV push strategy may safely facilitate more rapid administration of β-lactam antibiotics and may allow for better compliance with sepsis management guidelines.
Critique	The study demonstrated a significant reduction in time to antibiotic administration with IV push without increased adverse effects. However, the single-center design and retrospective nature may limit generalizability. Additionally, the variability in β-lactams administered and the lack of patients receiving piperacillin/tazobactam in the IVP arm could affect the results. Although ertapenem was eligible for IV push administration, ertapenem-specific utilization or outcomes were not reported in the provided results.

Table 3 References:
[6] Gregorowicz AJ, Costello PG, Gajdosik DA, et al. Effect of IV Push Antibiotic Administration on Antibiotic Therapy Delays in Sepsis. Crit Care Med. 2020;48(8):1175-1179. doi:10.1097/CCM.0000000000004430

Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients
Design	Prospective, single-center, open-label study N= 7
Objective	To evaluate the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis
Study Groups	All patients (N= 7)
Inclusion Criteria	Patients aged 18-88 years with end-stage renal disease (ESRD) on hemodialysis three times a week for at least 3 months, no documented allergy to beta-lactam antibiotics, no active infection, and agreement to blood collections
Exclusion Criteria	Evidence of hepatic disease, history of alcoholism or drug abuse within the past 2 years, pregnancy, history of seizures or epilepsy, use of valproic acid or probenecid, receiving antimicrobial agents, recent Clostridium difficile infection, inability to provide blood samples
Methods	Participants received a single 1-g dose of ertapenem reconstituted with 10 mL of normal saline and administered post-hemodialysis by IV bolus over 5 minutes. Blood samples were collected before administration and at 0.5, 1, 2, 6, 12, and approximately 48 hours after the dose to assess ertapenem pharmacokinetics. Safety and tolerability were assessed before administration, 24 hours after administration, and 5–7 days after the dose or through the last day of hospitalization.
Duration	January 2015 to April 2016
Outcome Measures	Primary: Pharmacokinetic parameters of ertapenem Secondary: Safety and tolerability
Baseline Characteristics		All patients (N= 7)
	Age, years	60 ± 11.4
	Weight, kg	77.7 ± 18.3
	Male	5 (71.43%)
	African American	5 (71.43%)
	Caucasian	2 (28.57%)
Results		All patients (N= 7)
	Elimination half-life, h	19.3 ± 6.6
	Plasma clearance, mL/h	135 ± 39
	Volume of distribution, mL	3,295 ± 1,187
	AUCinf, h•mg/mL	7,494 ± 1,424
	The investigators reported that ertapenem concentrations remained above the cited MIC thresholds for anaerobes, Enterobacteriaceae, and streptococci throughout the 48-hour period.
Adverse Events	Six patients (85.7%) experienced adverse events, but no serious adverse events or deaths occurred; most events were considered possibly unrelated to ertapenem, while muscle jerks in one patient were considered possibly related.
Study Author Conclusions	Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy.
Critique	The study was limited by a small sample size and lack of data on cumulative dosing effects. The absence of post-hemodialysis plasma levels limits understanding of drug clearance. The study's focus on pharmacokinetics rather than clinical outcomes may limit its applicability to patient care.

Table 4 References:
[7] Hsaiky LM, Salinitri FD, Wong J, et al. Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients. Nephrol Dial Transplant. 2019;34(10):1766-1772. doi:10.1093/ndt/gfy166

Comparative Pharmacokinetics, Pharmacodynamics, and Tolerability of Ertapenem 1 Gram/Day Administered as a Rapid 5-Minute Infusion versus the Standard 30-Minute Infusion in Healthy Adult Volunteers
Design	Prospective, randomized, crossover pharmacokinetic study N= 12
Objective	To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5-minute infusion to the standard 30-minute infusion
Study Groups	5-minute infusion (n= 12) 30-minute infusion (n= 12)
Inclusion Criteria	Healthy adults who were at least 18 years old
Exclusion Criteria	Known allergy to ertapenem or other b-lactam antibiotics, pregnant or breastfeeding, significant medical condition
Methods	Each regimen was administered for 3 days, followed by a 4-day washout period before subjects crossed over to the alternate regimen. For the 5-minute infusion, ertapenem 1 g was diluted with 0.9% sodium chloride to a total volume of 10 mL (100 mg/mL) and administered through a peripheral IV catheter by a nurse at 2 mL/min; the 30-minute infusion was diluted to 50 mL (20 mg/mL) and administered by infusion pump.
Duration	3 days for each infusion phase with a 4-day washout period
Outcome Measures	Primary: Maximum plasma drug concentration (Cmax) and area under the concentration-time curve for the dosing interval (AUC0-τ) Secondary: Population pharmacokinetics, pharmacodynamic target attainment, and tolerability
Baseline Characteristics		All subjects (N= 12)
	Age, years	32.4 ± 13.9
	Height, in	68.3 ± 3.7
	Weight, kg	76.2 ± 9.3
	Body mass index, kg/m2	25.4 ± 3.3
Results		5-minute infusion	30-minute infusion
	Cmax, mg/L	193.3 ± 43.3	165.7 ± 20.4
	AUC0-24, µg·hr/ml	561.2 ± 77.0	531.3 ± 56.9
	Probability of target attainment at MIC 0.25 mg/L	97.0%	97.9%
	Probability of target attainment at MIC 0.5 mg/L	1.7%	2.8%
	Among 11 subjects who completed both study phases, the 5-minute IV bolus and 30-minute infusion were bioequivalent for Cmax and AUC0–24, although Cmax was significantly higher with the 5-minute bolus. Steady-state half-life was similar between regimens (5.5 ± 0.7 vs 5.3 ± 0.5 hours; p= 0.267), and Monte Carlo simulations demonstrated similar probabilities of target attainment across the MIC range tested.
Adverse Events	Ertapenem was generally well tolerated with both administration methods, with no serious adverse events, vomiting, or seizures; the most common adverse events were mild and included diarrhea (5-minute: n= 6 vs 30-minute: n= 3), headache (n= 3 vs n= 3), and nausea (n= 3 vs n= 1).
Study Author Conclusions	Ertapenem administered as a 5-minute intravenous bolus is well tolerated and bioequivalent to the standard 30-minute infusion in healthy adult volunteers. The level of pharmacodynamic attainment was not compromised with the 5- minute intravenous bolus, as it produced similar PTA compared to the 30-minute infusion across the entire MIC range tested. Additional studies in infected patients are warranted to determine the safety and value of this dosing scheme.
Critique	The study's strengths include its prospective, randomized, crossover design, which minimizes variability and allows for direct comparison between the two infusion methods. However, the small sample size and the study being conducted in healthy volunteers may limit the generalizability of the findings to infected patients. Additionally, the study did not address the potential differences in pharmacokinetics and protein binding in infected patients compared to healthy volunteers.

Table 5 References:
[8] Wiskirchen DE, Housman ST, Quintiliani R, Nicolau DP, Kuti JL. Comparative pharmacokinetics, pharmacodynamics, and tolerability of ertapenem 1 gram/day administered as a rapid 5-minute infusion versus the standard 30-minute infusion in healthy adult volunteers. Pharmacotherapy. 2013;33(3):266-274. doi:10.1002/phar.1197