Maximum Single Dose for IV Push

Recommended Dilution Instructions

Rate of Administration for IV push

Stability

¹Comments/Monitoring

Meropenem

1 gram

(5 to 20 mL)

FDA Approved:

Vials of 500 mg or 1 gram: reconstitute with 10 mL and 20 mL sterile water for injection (SWFI), respectively, to a resulting concentration of 50 mg/mL

Adults and children ≥ 3 months: inject over 3 to 5 min

- Reconstituted vial: 3 h at 25°C and 13 h at 5°C
- Plastic Luer-Tip syringes with tubing attached and capped, 50 mg/mL in SWFI: 8 h at RT and 44 h under refrigeration

²Children < 3 months should receive IV infusion over 30 min; safety data is limited with 40 mg/kg doses up to a maximum of 2 grams

Cefepime

2 grams

Off-label:

³1- and 2-gram doses diluted in NS to a total volume of 10 mL
⁴1- and 2-gram doses diluted in 10 and 20 mL of SWFI, respectively

Off-label:

³Inject over 2 to 5 min
⁴Inject over 5 min

- Reconstituted compatible solutions: 24 h at 20 to 25°C and 7 d at 2 to 8°C
- Polypropylene syringes, 100 and 200 mg/ mL in D5W, NS, or SWFI: 14 d at 4°C, 1 d at RT, and up to 90 d at -20°C

^3,4Evaluated use of IV push for first dose only in ED

Aztreonam

2 grams

⁵FDA Approved:

Vials of 1 and 2 gram: reconstitute with 6 to 10 mL SWFI; no further dilution required

Inject over 3 to 5 min, directly into vein or through the tubing of a running compatible IV infusion

Reconstituted solutions > 20 mg/mL in SWFI: 48 h at RT and 7 d under refrigeration

IV route is preferred for doses > 1 gram or in patients with severe life-threatening infections

Piperacillin/tazobactam

4.5 gram

Off-label:

⁶Vials of 3.375 gram: reconstitute with 10 mL NS
⁶Vials of 4.5 gram: reconstitute with 20 mL NS

Off-label:

⁶Inject over 2 to 3 min

Reconstituted vial: use immediately; 24 h at RT (20°C to 25°C [68°F to 77°F]) or 48 h at refrigerated temperature (2°C to 8°C [36°F to 46°F]); vials should not be frozen after reconstitution

⁶Evaluated adverse drug reactions after administration of a single dose of IV push piperacillin/tazobactam through a peripheral line in an emergency department, including 300 patients

NOTE: other commonly used penicillin, including ampicillin/sulbactam (10 to 15 min), nafcillin (5 to 10 min), and oxacillin (10 min) are only FDA-approved for slow IV injection instead of IV push; phlebitis may occur if these agents are injected too rapidly.

*Dosing may not be suitable for special populations. See included citations for details of off-label experiences.

Generally, for concentration-dependent antibiotics, a change in the rate of infusion is less likely to impair the rate and extent of bactericidal effects (AUC > MIC); whereas for time-dependent agents, a change from an infusion to IV push may diminish the duration of time that the drug concentration remains above the MIC (T > MIC). Note: most data supporting IV push antibiotic administration is based on small sample size, retrospective studies limited to outpatient/ED settings, or PK studies. Substitution of IV push for extended or continuous infusion may lead to patient harms in critically ill or immunocompromised individuals or when the MICs are ≥ the clinical breakpoint for susceptibility.

AE= adverse events; AUC= area under the curve; ED= emergency department; FDA= Food and Drug Administration; IM= intramuscular; IV= intravenous; MIC= minimum inhibitory concentration; OPAT= outpatient parenteral antibiotic therapy; PK= pharmacokinetic; RT= room temperature; USP= United States Pharmacopeia

1⁄2 NS= half-normal saline (0.45% sodium chloride); BWFI= bacteriostatic water for injection; D5W= dextrose 5% in water; NS= normal saline (0.9% sodium chloride); SWFI= sterile water for injection

 T= time; min= minute(s); h= hour(s); d= day(s); wk= week(s); mo= month(s)

Outcomes of Intravenous Push versus Intermittent Infusion Administration of Cefepime in Critically Ill Patients

Design

Single center, retrospective, observational, pre/post-protocol change study

N= 285

Objective

To examine the effects of cefepime administration strategies on antibiotic treatment failure and safety

Study Groups

Intravenous piggyback (IVPB) (n= 87)

Intravenous push (IVP) (n= 198)

Inclusion Criteria

At least 18 years of age; admitted to the intensive care unit (ICU) who received cefepime either IVPB or IVP

Exclusion Criteria

Infected with a pathogen intermediate or resistant to cefepime (including susceptible-dose-dependent); pregnant patients; received cefepime for < 72 h; received cefepime both through IVP and IVPB

Methods

The standard empiric dose of cefepime was 2 g IV every 8 h for critically ill patients, and adjusted per manufacturer's recommendations when calculated creatinine clearance < 60 mL/min. IVPB doses were prepared in a total volume of 100 mL and administered by infusion pump over 30 min; IVP doses were reconstituted with 10 mL of sterile water for injection and administered by the patient's bedside nurse as a slow IVP over 5 min. Patients were identified by pharmacy dispensing logs of cefepime. The institution changed its standard practice for cefepime infusion after August 14, 2018, after which cefepime was administered by IVP. 

Duration

IVPB: 2015 to August 13, 2018

IVP: August 14, 2018 to 2021

Outcome Measures

Primary: treatment failure (composite of inpatient mortality and/or switching from cefepime to a broader Gram-negative antibiotic [i.e., carbapenem] due to clinical worsening, as documented by the electronic medical record)

Secondary: adverse drug events; days of cefepime therapy; total days of antibiotic therapy; ICU and hospital length of stay; ICU and hospital mortality 

Baseline Characteristics

IVPB (n= 87)

IVP (n= 198)

Age, years*

Male

White

African-American

82%

18%

72%

26%

CrCl, mL/min*

SOFA score*

Source of infection

Pneumonia

Intraabdominal

Urinary tract

Severe**

Skin and soft tissue

Multiple sources

55%

1%

8%

8%

5%

23%

51%

7%

5%

10%

8%

20%

Sepsis

Septic shock

83%

17%

69%

31%

0.044

0.044

Isolated pathogen(s)

Pseudomonas aeruginosa

Methicillin-resistant Staphylococcus spp.

Methicillin-sensitive Staphylococcus spp.

Streptococcus spp.

Klebsiella spp.

Escherichia coli

Proteus spp.

Enterobacter spp.

Serratia spp.

Bacteroides

Citrobacter spp.

Haemeophilus spp.

Other bacteria

Polymicrobial

16%

5%

3%

5%

3%

2%

3%

6%

5%

2%

2%

1%

6%

10%

17%

5%

5%

4%

5%

3%

3%

1%

1%

1%

1%

1%

6%

9%

*Data presented as median (interquartile range [IQR])

**Severe infections defined as bacteremia, central nervous system infection, osteomyelitis, or endocarditis 

CrCl: creatinine clearance; SOFA: sequential organ failure assessment

Results

Endpoint

IVPB (n= 87)

IVP (n= 198)

p-Value

Treatment failure

Escalation of therapy

All-cause mortality

18%

2%

18%

27%

9%

22%

0.109

0.093

0.339

Adverse drug event

Therapy change due to ADE

1%

1%

1%

1%

Average cefepime daily dose, g*

Duration of cefepime, days*

Duration of antibiotics, days*

3.33 (2-4)

6 (4-8)

9 (6-12)

3.785 (2.65-5)

6 (5-8)

10 (7-14)

< 0.001

0.314

0.194

ICU LOS, days*

Hospital LOS, days*

6 (2-10)

11 (8-22)

7 (4-14)

13 (9-22)

0.06

0.148

*data presented as median (interquartile range [IQR])

ADE: adverse drug event; LOS: length of stay 

Binary logistic regression: longer duration of antibiotics (odds ratio [OR] 1.057; 95% confidence interval [CI] 1.013 to 1.103; p= 0.011), higher SOFA score (OR 1.274; 95% CI 1.157 to 1.404; p< 0.001), and IVP administration fo cefepime (OR 2.4; 95% CI 1.149 to 5.017; p= 0.02)

Adverse Events

N/A

Study Author Conclusions

Critically ill patients had a similar rate of treatment failure with IVPB and IVP administration of cefepime. Treatment failure was more likely with IVP administration of cefepime in an adjusted analysis. Current practice of IVP administration of cefepime should be further evaluated in the critically ill population.

InpharmD Researcher Critique

Limitations of the study include the single-center and retrospective design, which may introduce the risk for selection bias and limit ability to control for confounding variables. As data was collected by chart review, adverse events may be underreported. The higher incidence of sepsis in the IVPB group and septic shock in the IVP group may have affected the outcome results. Additionally, there were substantially more patients in the IVP group than the IVPB group. As the study interventions took place during different time periods, antimicrobial resistance, antibiotic prescribing patterns, and standard of ICU care may have varied between time periods. 

Intravenous Push Versus Intravenous Piggyback Beta-Lactams for the Empiric Management of Gram-Negative Bacteremia

Design

Retrospective cohort

N= 213

Objective

To evaluate and compare clinical and microbiological outcomes between empiric cefepime (FEP) and meropenem (MEM) administered as intravenous push (IVP) compared to intravenous piggyback (IVPB) in Gram-negative bacteremia (GNB)

Study Groups

IVPB (n= 105)

IVP (n= 108)

Inclusion Criteria

Unique adult patients with first episode of GNB during study period that was susceptible to the study drug and received FEP or MEM IVPB or IVP empirically for at least two days of therapy

Exclusion Criteria

No repeat blood cultures drawn; concomitant Gram-positive bacteremia or fungemia; empiric combination Gram-negative coverage longer than 48 h; extended infusion used as empiric treatment; patients who died, were discharged, or were transitioned to hospice within 48 h of culture collection 

Methods

Due to a critical shortage of small-volume parenteral solutions (SVPS), a mandatory IVP action plan was implemented in October 2017; FEP 1 g and 2 g and MEM 500 mg and 1 g doses were reconstituted by nursing or pharmacy staff with 10-20 mL of normal saline or sterile water for injection and administered by nursing as IVP over a period of 5 min. Antimicrobials were dosed according to local guidelines. MEM was allowed to be administered as extended infusion over 3 h in critically ill patients with septic shock or in patients with minimum inhibitor concentrations of 4-16 mg/L.

A retrospective review of patients with GNB at two academic centers in the New York Metropolitan area was conducted. A list of patients with GNB who received FEP or MEM at any time point during their hospitalization was generated using microbiology laboratory reports and pharmacy database of medication administration. Empiric antibiotic selection and escalation of therapy were at the discretion of the primary team. 

Duration

July 1, 2016 to September 30, 2018

Outcome Measures

Primary: need for escalation of therapy (change in empiric antibiotic to a broader spectrum agent, the addition of a second Gram-negative agent, or a change to extended infusion over 3 hours at any time during the course of bacteremia treatment); 

Change to broader spectrum agent defined as: escalation from FEP to piperacillin/tazobactam (TZP), carbapenem, ceftazidime/avibactam (CZA), or ceftolozane/tazobactam (C/T); or from MEM to CZA or C/T

Secondary: microbiological clearance; recurrence of bacteremia during hospitalization; time to defervescence; time to white blood cell (WBC) normalization; time to vasopressor discontinuation; in-hospital and 90-day mortality; hospital and intensive care unit (ICU) length of stay; time to antibiotic administration; neurologic adverse events; any infection-related readmission within 90 days 

Baseline Characteristics

IVPB (n= 105)

IVP (n= 108)

Median age, years (IQR)

Male

Median BMI, kg/m² (IQR)

Median Charlson Comorbidity Index (IQR)

Past medical history

Diabetes mellitus

Immunocompromising condition

Heart failure

End-stage renal disease

Chronic obstructive pulmonary disease

Cirrhosis

32%

22%

13%

10%

9%

6%

34%

32%

16%

15%

8%

6%

Severity of illness

Sepsis at time of culture collection

Febrile at time of blood culture collection

CrCl, median, mL/min (IQR)

CRRT at time of culture collection

Pitt Bacteremia Score, median (IQR)

WBC at start of therapy, median, x 10⁹ cells/L (IQR)

ICU admission

ICU length of stay, median, days (IQR)

Mechanical ventilation

Vasopressor use

Length of hospital stay, median, days  (IQR)

87%

79%

37 (27-68)

0

2 (0-3)

14 (8-19)

40%

4 (3-7)

4%

19%

9 (5-17)

81%

73%

39 (25-64)

1%

2 (0-3)

14 (10-19)

40%

3 (2-5)

0

17%

7 (5-11)

Empiric treatment prior to FEP/MEM

Number of doses, median, IQR

Received empiric combination therapy

Susceptible to empiric combination therapy

Patients treated with FEP

Total daily dose, median, g (IQR)

Duration of therapy, median, days (IQR)

Patients treated with MEM

Total daily dose, median, g (IQR)

Duration of therapy, median, days (IQR)

FEP/MEM duration of therapy, median, days (IQR)

57%

2 (1-2)

25%

75%

50%

3 (3-6)

4 (3-4.25)

50%

2 (1.5-2)

4 (3-8)

4 (3-5)

45%

1 (1-2)

19%

84%

67%

3 (3-3)

3 (3-5)

33%

1.5 (1-2)

5 (3-7)

4 (3-5)

Source of bacteremia

Urine

Intra-abdominal

Pneumonia

Catheter

Skin and soft tissue infection

Osteomyelitis

Central nervous system

Joint

Endocarditis

Sternal wound

Surgical

Unknown

Removable source

Source control achieved

Time to source control, median, days (IQR)

49%

18%

11%

6%

4%

2%

3%

2%

1%

1%

1%

6%

32%

76%

2 (1-6)

53%

31%

5%

3%

3%

2%

0

0

0

0

0

8%

21%

83%

2 (1-5)

Isolated pathogen

Escherichia coli

Klebisella pneumoniae

Proteus mirabilis

Enterobacter cloacae

Pseudomonas aeruginosa

Serratia marcescens

Other

44%

29%

8%

4%

5%

5%

12%

60%

21%

5%

6%

3%

2%

6%

ESBL organism identified

Patients who received FEP empirically

Patients who received MEM empirically

30%

19%

40%

19%

7%

44%

IQR: interquartile range; CrCl: creatinine clearance; CRRT: continuous renal replacement therapy; ESBL: extended-spectrum beta-lactamase

Results

Endpoint

IVPB (n= 105)

IVP (n= 108)

p-Value

Escalation of therapy

Broader spectrum agent

Addition of aminoglycoside

Change to extended infusion MEM

Time to escalation from culture collection, median, days (IQR)

14%

87%

13%

7%

3 (3-5)

10%

100%

0

0

3 (2-4)

0.36

0.68

Microbiological clearance

Empiric FEP

Empiric MEM

Recurrence of bacteremia

Time to defervescence, median, days (IQR)

WBC normalization

Duration of vasopressor, median, h (IQR)

Neurologic adverse events

Transitioned to hospice during hospital admission

In-hospital mortality

Non-ICU patients

ICU patients

90-day mortality

90-day infection-related readmission

95%

97%

92%

1%

2 (1-2)

57/75 (76%)

25 (14-56)

1%

4%

9%

1/63 (2%)

8/42 (19%)

11%

20%

96%

98%

94%

1%

1 (1-2)

62/81 (77%)

24 (13-47)

0

5%

3%

3%

2%

7%

32%

1

1

0.68

1

0.24

0.94

0.63

0.49

1

0.07

1

0.02

0.21

0.08

Adverse Events

See results section

Study Author Conclusions

InpharmD Researcher Critique

Limitations of the study are the retrospective design and inclusion of two centers in the same geographic area, possibly limited generalizability of the results. Limited deep-seated infections (i.e., meningitis, osteomyelitis, endocarditis) were included in the study and limited number of patients had P. aeruginosa isolated; as these infections may be more difficult to eradicate, the results of the study may not be applicable to these infections/organism. Adverse events other than neurologic events were not evaluated, limiting the safety evaluation in this study. 

Intravenous Push Cephalosporin Antibiotics in the Emergency Department

Design

Practice improvement project, retrospective review

N= 2,256

Objective

To determine whether the implementation of an intravenous push (IVP) cephalosporin antibiotic protocol would improve time from provider order to administration for all emergency department (ED) patients who were ordered a cephalosporin antibiotic

Study Groups

Preintervention arm (intravenous piggyback [IVPB]) (n= 1,146)

Postintervention arm (IVP) (n= 1,110)

Inclusion Criteria

Received IV cephalosporins either by 30 min IV infusion or 2-5 min IVP

Exclusion Criteria

Received antibiotics prior to arrival to ED (i.e., transferred from another facility)

Methods

An interprofessional team designed an IVP cephalosporin antibiotic protocol which allowed providers to order the cephalosporin class of antibiotics (including cefazolin, cefepime, ceftriaxone, and ceftazidime) via the IVP route for the first dose. IVP medication kits that included the antibiotic plus the diluent were added to the automated medication dispensing system. The electronic medical record was searched to identify patients who presented to the ED and were given an IV cephalosporin antibiotic for any indication in the preintervention and postintervention period. All patients who received IV cephalosporins by infusion over 30 min were included in the preintervention group; the postintervention group included patients who received IVP antibiotic over 2-5 min. 

Duration

Preintervention: November 1, 2015 to January 31, 2016

Postintervention: March 1, 2016 to May 30, 2016

Outcome Measures

Primary: time from order to cephalosporin administration 

Secondary: crude in-hospital mortality (subgroup analysis of patients with sepsis); cost analysis for supplies associated with cephalosporin administration 

Baseline Characteristics

Preintervention (n= 1,146)

Postintervention (n= 1,110)

Sepsis, n

Results

Endpoint

Preintervention (n= 1,146)

Postintervention (n= 1,110)

p-Value

Median time from order to administration, min (IQR)

Ceftriaxone, min

Ceftazidime, min

Cefepime, min

Cefazolin, min

31 (18-49)

42 (26-63)

42 (29-65)

30 (17-49)

23 (12-42)

30 (15-52)

28 (17-46)

17 (7-35)

< 0.0001

0.0064

< 0.0001

0.0007

In-hospital mortality (subgroup)

IQR: interquartile range

Cost of infusion supplies: almost 11.5 times higher for IVPB ($9.53) vs. IVP ($0.83); approximately $10,000 in savings to the institution in a 3-month period and $40,000 annually

87% of nurses favored switching to IVP administration

Adverse Events

No reports of adverse effects regarding IVP antibiotics were filed during the study period 

Study Author Conclusions

Administering the first dose of cephalosporin antibiotic as an IVP instead of an IV infusion resulted in faster treatment times for patients. Adverse effects and crude mortality were not different between the two groups. In addition, cost savings were realized and nursing time was decreased. 

InpharmD Researcher Critique

The study is limited by its single-center, retrospective design. Baseline demographics were not reported in the study, limiting the evaluation of any differences between groups. The only efficacy outcome evaluated was in-hospital mortality. Only patients who received the first dose were included, and subsequent doses or antibiotic therapy after the first dose were not included or evaluated, limiting the association of the effect of IVP administration on mortality in the subgroup analysis. 

Cefepime Intravenous Push Versus Intravenous Piggyback on Time to Administration of First-Dose Vancomycin in the Emergency Department

Design

Retrospective, pre–post comparison study

N= 1071

Objective

Study Groups

IVPB group (n= 536)

IVP group (n= 535)

Inclusion Criteria

Exclusion Criteria

Patients who received antibiotics prior to ED presentation, received other antibiotics in addition to cefepime and vancomycin, were admitted to inpatient units prior to administration of both agents, or if cefepime and vancomycin were not ordered together

Methods

Cefepime IVPB was mixed in 100 mL normal saline and infused over 30 to 60 minutes. Cefepime IVP was diluted with normal saline to a total volume of 10-mL syringe and injected over 2 to 5 minutes. Vancomycin doses were supplied as premixed bags

Duration

Outcome Measures

Primary: Time to initiation of vancomycin administration

Secondary: Time from order placement to the start of cefepime administration, cost savings

Baseline Characteristics

IVPB group (n= 536)

IVP group (n= 535)

Age, years

Female

Race

White

Black

Hispanic

Other/unknown

66.4%

8.4%

20.9%

4.3%

70.5%

11.8%

14.4%

3.4%

Emergency department diagnosis

Sepsis

Pneumonia

Sepsis and pneumonia

Others

26.3%

29.3%

40.5.%

3.9%

30.3%

32.0%

32.5%

5.2%

Results

Endpoint

IVPB group (n= 536)

IVP group (n= 535)

p-Value

Time between administration of cefepime to vancomycin (interquartile range [IQR])

63.5 (37 to 95)

2.0 (2 to 4)

< 0.001

Time between cefepime to administration (IQR)

47.0 (30 to 74)

47.0 (31.5 to 73)

0.597

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique