Prolonged Infusions of Beta Lactams

UptoDate: Dosing for Prolonged Infusions of Beta Lactams

	Creatinine  clearance	Dose	Dosing interval	Infusion time
Piperacillin-tazobactam*	>20 mL/minute	3.375 or 4.5 g	Every 8 hours	4 hours
	≤20 mL/minute or intermittent HD or PD	3.375 or 4.5 g	Every 12 hours	4 hours
	CRRT¶	3.375 or 4.5 g	Every 8 hours	4 hours
CefepimeΔ	≥50 mL/minute	2 g	Every 8 hours	3 to 4 hours
	30 to 49 mL/minute	2 g	Every 12 hours	3 to 4 hours
	15 to 29 mL/minute	1 g	Every 12 hours	3 to 4 hours
	<15 mL/minute or intermittent HD	1 g	Every 24 hours	3 to 4 hours
	CRRT¶	2 g	Every 12 hours	3 to 4 hours
Imipenem◊	>70	500 mg or 1 g	Every 6 hours	3 hours
	41 to 70	500 mg or 750 mg	Every 8 hours	3 hours
	21 to 40	250 or 500 mg	Every 6 hours	3 hours
	6 to 20 or intermittent HD or PD	250 or 500 mg	Every 12 hours	3 hours
	CRRT¶	500 mg	Every 6 hours	3 hours
Meropenem§	≥50 mL/minute	1 or 2 g	Every 8 hours	3 hours
	25 to 49 mL/minute	1 or 2 g	Every 12 hours	3 hours
	10 to 24 mL/minute	500 mg or 1 g	Every 12 hours	3 hours
	<10 mL/minute or intermittent HD	500 mg or 1 g	Every 24 hours, given after HD	3 hours
	CRRT¶	1 or 2 g	Every 12 hours	3 hours

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HD: hemodialysis; PD: peritoneal dialysis; CRRT: continuous renal replacement therapy; CVVHDF: continuous venovenous hemodiafiltration; MIC: minimum inhibitory concentration.

* The higher dose of piperacillin-tazobactam (4.5 g) is used in certain situations, such as expected augmented drug clearance (as with critical illness or cystic fibrosis) or in cases of infections with pathogens that have high, but still susceptible, MICs to piperacillin-tazobactam when alternative agents are not appropriate. This higher dose can also be used for empiric treatment in communities or institutions where the P. aeruginosa MICs to piperacillin-tazobactam range higher than 32. Some studies have also used a dose of 4.5 g every six hours infused over three hours.

¶ The recommendations for CRRT dosing are based off of CVVHDF with a flow rate of 1 liter per hour and minimal residual renal function.

Δ Some studies have also used a 3-hour infusion time for cefepime.

◊ Imipenem is dosed by both weight and renal function. Dosing above is based on patient weight >70 kg.

§ The higher dose of meropenem is used in patients with infections of the central nervous system or other life-threatening infections such as necrotizing fasciitis.

Data from:

1.    Lodise TP, Lomaestro BM, Drusano GL, Society of Infectious Diseases Pharmacists. Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on beta-lactam antibiotics: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2006; 26:1320.

2.    Bauer KA, West JE, O'Brien JM, Goff DA. Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob Agents Chemother 2013; 57:2907.

3.    Hershberger E, Moukasassi MS, Steenbergen J, et al. CXA-101/Tazobactam (CXA/TAZ) probability of target attainment using population pharmacokinetic analysis. Presented at the 21st European Congress of Clinical Microbiology and Infectious Diseases, Milan Italy May 2011.

4.    Avycaz [Prescribing Information]. Cincinnati, OH: Forrest Pharmaceuticals, Inc.; 2015.

5.    Hughes DW, Frei CR, Maxwell PR, et al. Continuous versus intermittent infusion of oxacillin for treatment of infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother 2009; 53:2014.

6.    Cheatham SC, Shea KM, Healy DP, et al. Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients. Int J Antimicrob Agents 2011; 37:46.

7.    Patel N, Scheetz MH, Drusano GL, Lodise TP. Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients. Antimicrob Agents Chemother 2010; 54:460.

8.       Koomanachai P, Bulik CC, Kuti JL, Nicolau DP. Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States. Clin Ther 2010; 32:766.

Guide to Antimicrobial Therapy in the ICU 2017

The use of extended or continuous infusions of s-lactam antibiotics has been shown to improve the time the free drug remains above MIC which predicts the killing characteristic of the antibiotic. This is pertinent when dealing with multi-drug resistant organisms. A loading dose must be given prior to regular dosing of the antimicrobial followed by either:

• Extended infusion: Infusion lasting 3-4 hours, usually 50% of dosing interval.

• Continuous infusion: Infusion over 24 hours at a fixed rate.

The diluted antibiotic should be stable throughout the infusion duration at room temperature of less than 24°C and has no incompatibilities with other medication administered concurrently. The stability may differ with different manufacturers.

Antibiotic	Loading dose over 30 mins	Duration of infusion	Notes
Ampicillin / Sulbactam * For High dose sulbactam		Over 4 hrs	3g of Ampicillin/Sulbactam dilute in 70 mL NS / D5
Cefepime	2 g	Over 4 hrs Or Continuous infusion over interval prescribed	1-2 g in 50mL NS
Ceftazidime	2 g	Over 4 hrs Or Continuous infusion over interval prescribed	1-2 g in 50mL NS
Imipenem	1 g	Over 4 hrs	500mg or 1g : Dilute in 100-200 mL NS (5 mg/mL)
Meropenem	1-2 g	Over 4 hrs	500mg or 1g : Dilute in 50 mL NS 2g : Dilute in 100 mL NS
Piperacillin / Tazobactam	4.5 g	Over 4 hrs Or Continuous infusion over interval prescribed	2.25g or 4.5g : Dilute in 50 mL NS

Data from Product Leaflet:

Piptazo	AUROTAZ: Recon each vial with 10mL SWFI / NS, inject over at least 3-5 mins; or further dilute with at least 50 mL SWFI / NS / D5. Store in a refrigerator can use within 24 hrs.
Cefepime	CEFMEX: IV infusion of a volume between 50-100 mL should be administered over ~30 mins. Compatible at 1-40 mg/ml with SWFI, D5, NS ; stable for 48 hrs at 2-8°C
Imipenem	TIENAM: Recon each vial with 100 mL of NS / D5 / D10 / NSD5 / HSD5 / QSD5 / Maniitol 5% / Mannitol 10% (LACTATE INCOMPATIBLE). Stable at 25°C for 4 hrs or at 4°C for 24 hrs.
Meropenem	NURONEM: Recon each 500mg with 10mL SWFI, then may be further diluted with 50-200 mL diluents, producing concentration of 1-20 mg/mL. Diluent Solution (1-20 mg/mL) prepared with: Hours stable up to 25°C 4°C NS 8 48 D5 3 14 NSD5 QSD5 D5 + 0.15% KCl Mannitol 2.5 % or 10 % D10 2 8 D5 + 0.02 % NaHCO3 .