Based on the pharmacokinetic profile of cefepime, would a prolonged (3 hour) infusion or an IV push have a higher risk of nephrotoxicity?

Comment by InpharmD Researcher

Available pharmacokinetic studies do not directly establish whether cefepime administered as a prolonged 3-hour infusion or intravenous (IV) push has a higher risk of nephrotoxicity. Prolonged cefepime infusion has been shown to improve pharmacodynamic target attainment by increasing the percentage of time that free drug concentrations remain above the MIC (%fT>MIC), while an IV push study in critically ill patients demonstrated rapid peak concentrations, substantial interpatient pharmacokinetic variability, and systemic exposure comparable to traditional intermittent infusion. In the summarized literature, cefepime-associated toxicity was primarily discussed in relation to renal impairment, reduced cefepime clearance, elevated plasma/trough concentrations, and drug accumulation rather than infusion duration itself. Overall, available data support prolonged infusion for pharmacodynamic optimization, but do not demonstrate that prolonged infusion or IV push carries a higher nephrotoxicity risk.

A targeted literature search was conducted in PubMed and Google Scholar using combinations of the terms “cefepime,” “pharmacokinetics,” “prolonged infusion,” “extended infusion,” “intravenous push,” “IV push,” “nephrotoxicity,” and “toxicity.” The search identified 2 primary pharmacokinetic studies relevant to cefepime prolonged-infusion or IV-push administration, although neither directly compared 3-hour infusion versus IV push for nephrotoxicity risk.

Background

A 2022 review comprehensively evaluated the pharmacokinetics, pharmacodynamics, and toxicodynamics of cefepime across diverse patient populations, highlighting the cephalosporin's utility and safety profile while underscoring areas of complexity and therapeutic concern. The review synthesized data from numerous pharmacokinetic models evaluating cefepime disposition in healthy volunteers, critically ill patients, those with renal impairment, pediatric populations, and special categories including individuals undergoing extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. In subjects with normal renal function, cefepime demonstrated linear pharmacokinetics with an approximate volume of distribution of 0.2 L/kg and a half-life of 2 hours. Cefepime is primarily excreted unchanged in the urine (~85%), and the clearance correlates closely with creatinine clearance. Notably, a 2015 pharmacokinetic analysis in febrile neutropenic patients revealed significant interindividual variability in clearance (12.88 ± 0.04 L/h) and volume of distribution (26.43 ± 4.01 L), largely attributed to fluid shifts and augmented renal clearance. Similarly, a 2009 population pharmacokinetic study in ventilated ICU patients reported cefepime clearance averaging 7.6 L/h and recommended that adjustments be made based on renal function and body weight to optimize pharmacodynamic target attainment. Extended or continuous cefepime infusions may improve pharmacodynamic target attainment (%fT>MIC), particularly for elevated MICs or pharmacokinetically variable patients; however, this review does not directly establish that these infusion strategies reduce nephrotoxicity risk or universally avoid increases in overall exposure, and AUC would be expected to remain similar only when the same total daily dose and clearance are maintained. A 2015 pharmacodynamic analysis of cefepime in bloodstream infections found that maintaining 100% fT>MIC was associated with improved survival, and further analyses identified survival benefit thresholds above 68% and 74% fT>MIC. These findings were supported by the 2014 DALI study, a prospective pharmacokinetic evaluation in ICU patients, demonstrating that failing to achieve 50% fT>MIC with cefepime was linked to a 32% reduction in clinical cure. Beyond efficacy, the review examined cefepime’s toxicodynamic profile, emphasizing neurotoxicity as a dose-limiting adverse event. A 2017 systematic review of 135 cases revealed neurotoxicity occurred most frequently in patients with renal impairment, with trough concentrations exceeding 35–49 mg/L associated with increased risk. However, the relationship between serum concentration and neurologic toxicity remains variably defined due to inconsistent definitions, sampling methodologies, and timing. The authors concluded that therapeutic drug monitoring, particularly using validated LC-MS/MS methods, may be appropriate in critically ill patients, those with fluctuating renal function, or individuals with underlying neurologic comorbidities. Extended and continuous infusion strategies were endorsed to enhance pharmacodynamic targets, especially when confronting organisms with elevated MICs. [1]

Background References: [1] Pais GM, Chang J, Barreto EF, Stitt G, Downes KJ, Alshaer MH, Lesnicki E, Panchal V, Bruzzone M, Bumanglag AV, Burke SN, Scheetz MH. Clinical Pharmacokinetics and Pharmacodynamics of Cefepime. Clin Pharmacokinet. 2022 Jul;61(7):929-953. doi:10.1007/s40262-022-01137-y
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Based on the pharmacokinetic profile of cefepime, would a prolonged (3 hour) infusion or an IV push have a higher risk of nephrotoxicity?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Steady-state Pharmacokinetics and Pharmacodynamics of Cefepime Administered by Prolonged Infusion in Hospitalised Patients
Design

Prospective study

N= 9
Objective

To evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy.
Study Groups

All patients (n= 9)
Inclusion Criteria

Adult patients aged ≥18 years, hospitalised at St Francis Hospital or Methodist Hospital, requiring antimicrobial therapy for a suspected or documented bacterial infection.
Exclusion Criteria

History of allergy to any β-lactam antibiotic, history of drug or alcohol abuse, pregnancy, history of any seizure disorder, acute or chronic renal failure, dialysis of any type, or hepatic dysfunction defined as serum bilirubin and alanine aminotransferase concentrations ≥2 and ≥4 times the upper normal limit, respectively
Methods

Patients received cefepime 1 g every 8 hours, infused over 4 hours. Blood samples were collected at specified intervals to determine cefepime concentrations. Pharmacokinetic parameters were determined using non-compartmental and compartmental methods. Monte Carlo simulations were performed to estimate pharmacokinetic profiles for six prolonged-infusion dosing regimens. Cefepime concentrations in serum were measured byreversed phase high-performance liquid chromatography (RP-HPLC) with ultraviolet detection.
Duration

Not specified
Outcome Measures

Primary: Steady-state pharmacokinetic parameters of cefepime

Secondary: Probability of target attainment (PTA) at various MICs, cumulative fraction of response (CFR) for Gram-negative pathogens
Baseline Characteristics  

All patients (n= 9)
Mean age, years

51.4 ± 17.9 
Mean weight, kg

76.7 ± 17.3
Mean height, cm

167 ± 12
Mean estimated CLCr, mL/min

86 ± 31
Results

 

 1 g q8h (4 h infusion) 2 g q8h (4 h infusion) 1 g q6h (3 h infusion) 2 g q6h (3 h infusion)

PTA

MIC 8 µg/mL

MIC 4 µg/mL

MIC 2 µg/mL

 

>90%

>90%

>90%

 

>92.7%

>90%

>90%

 

>92.7%

>90%

>90%

 

>92.7%

>90%

>90%

PTA at MIC 2 µg/mL

 >90% >90% >90% >90%

CFR

Pseudomonas aeruginosa

Escherichia coli

Klebsiella pneumoniae

Enterobacter spp. 

Serratia marcescens

Citrobacter

 

88.6%

97.7%

90.9%

97.1%

99.1%

98.7%

 

>92.7%

98.9%

95.4%

98.9%

99.6%

99.5%

 

>92.7%

98.2%

92.6%

98.0%

99.3%

99.1%

 

>92.7%

98.4%

97.5%

99.4%

99.8%

99.7%
Adverse Events

No adverse events related to cefepime therapy were reported during the study
Study Author Conclusions

Cefepime 1 g q8h infused over 4 h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤8 µg/mL. Higher dose regimens may be considered for infections where Pseudomonas aeruginosa is a likely pathogen.
Critique

The study provides valuable insights into the pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion. However, the small sample size and the specific patient population may limit the generalizability of the findings. Additionally, the study did not include a comparison with traditional infusion methods, which could have provided a more comprehensive understanding of the benefits of prolonged infusion.
Table 1 References:
[2] Cheatham SC, Shea KM, Healy DP, Humphrey ML, Fleming MR, Wack MF, Smith DW, Sowinski KM, Kays MB. Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients. Int J Antimicrob Agents. 2011 Jan;37(1):46-50. doi:10.1016/j.ijantimicag.2010.08.016

Pharmacokinetic Analysis of Intravenous Push Cefepime in Critically Ill Patients With Sepsis
Design

Prospective, noninterventional PK study

N= 17
Objective

To characterize the pharmacokinetic (PK) profile and pharmacodynamic (PD) target attainment of intravenous push (IVP) cefepime in critically ill patients with sepsis
Study Groups

IVP cefepime every 8 hours (n= 9)

IVP cefepime every 12 hours (n= 8)
Inclusion Criteria

Hospitalized adult patients with a central/midline catheter, intensive care unit (ICU) length of stay ≥ 48 h, creatinine clearance > 30 mL/min without renal replacement therapy, and diagnosis of sepsis
Exclusion Criteria Patients undergoing renal replacement therapy, pregnant or breastfeeding women, and prisoners
Methods

Patients with active cefepime orders were screened daily. Cefepime was prescribed at the discretion of the ICU team and administered as 1–2 g every 8–12 hours, reconstituted in 5 mL sterile water, and given IV push over 5 minutes. Blood samples were obtained at steady state, defined as the fifth cefepime dose, immediately before dosing and at 5, 15, 30, 60, 120, and 240 minutes post-dose. Free cefepime plasma concentrations were quantified using validated liquid chromatography-ultraviolet methods. PK parameters were estimated using a one-compartment model with first-order elimination. Clinical outcomes and adverse drug reactions were collected retrospectively from the electronic health record.
Duration

Not specified
Outcome Measures

Primary: PK profile of cefepime following IVP administration

Secondary: Steady-state cefepime trough concentration, treatment failure, ICU and hospital length of stay
Baseline Characteristics   All patients (n= 17) Q8H dosing (n= 9) Q12H dosing (n= 8)

p-value

Age, years (IQR)

 69 (64–75) 67 (45–72) 71 (66–77) 0.200

Male

 11 (64.7%) 7 (77.8%) 4 (50%) 0.232

Race/Ethnicity

Caucasian

African–American

Unknown

 

15 (88.2%)

1 (5.9%)

1 (5.9%)

 

8 (88.9%)

1 (11.1%)

0

 

7 (87.5%)

0

1 (12.5%)

 

0.365

-

-

Height, cm (IQR)

 168 (164–182) 180 (168–182) 164 (159–182) 0.167

Weight, kg (IQR)

 93 (84–119) 96 (83–129) 92 (75–116) 0.673

BMI, kg/m2 (IQR)

 29.9 (27.1–40.9) 29.9 (26.0–45.7) 31.0 (27.0–40.0) 1.000

Serum creatinine, mg/dL (IQR)

 0.8 (0.6–1.7) 0.8 (0.6–1.2) 1.3 (0.7–1.9) 0.277

Creatinine clearance, mL/min (IQR)

 94 (72–148) 105 (84–175) 76 (53–101) 0.093

SOFA score (IQR)

 9 (6–11) 7 (5–11) 10 (8–11) 0.200

Sepsis

Septic shock

Sepsis without shock

 

15 (88.2%)

2 (11.8%)

 

7 (77.8%)

2 (22.2%)

 

8 (100%)

0

 

0.156

-

Type of venous access device

Central line

Arterial line

 

6 (35.3%)

6 (35.3%)

 

4 (44.4%)

3 (33.3%)

 

2 (25%)

3 (37.5%)

 

0.455

-

Type of venous access device

Peripherally inserted central catheter

Midline

 

4 (23.5%)

1 (5.9%)

 

1 (11.1%)

1 (11.1%)

 

3 (37.5%)

0

 

-

-

Abbreviations: IQR, interquartile range.
Results   All patients (N= 17) Q8H dosing (N= 9) Q12H dosing (N= 8)

p-value

Cmax, μg/mL

 158 ± 56.18 154 ± 64.74 162 ± 48.84 0.782

Tmax, min

 5 ± 0 5 ± 0 5 ± 0 1.000

AUC, μg × h/mL

 286.950 ± 101.98 265.948 ± 115.44 310.578 ± 85.64 0.385

t½, hours

 3.76 ± 3.77 3.56 ± 4.77 3.99 ± 2.55 0.821

Ke, h−1

 0.31 ± 0.18 0.34 ± 0.15 0.27 ± 0.22 0.429

CL, L/h

 7.86 ± 2.83 8.67 ± 3.23 6.94 ± 2.14 0.218

Vd, L

 43.91 ± 51.64 45.58 ± 63.56 42.03 ± 38.33 0.893

T > MIC

 86% ± 19.71% 90% ± 14.03% 82% ± 24.89% 0.395

Hospital length of stay, days (IQR)

 24 (20–31) 23 (20–24) 25 (17–41) 0.370

ICU length of stay, days (IQR)

 15 (12–22) 15 (12–22) 17 (10–28) 0.370

Treatment failure

 6 (35.3%) 3 (33.3%) 3 (37.5%) 0.858

The mean trough concentration across all patients was 28 mg/L. Five minutes following the administration of the drug, a substantial surge in plasma concentrations was observed for all patients.

Plasma concentrations remained elevated at the 15‐min time point, although concentrations appeared to have started to level off for certain patients. The average concentration at 15 min was 118 mg/L. 

Five minutes following the administration of the drug, a substantial surge in plasma concentrations was observed for all patients.

Plasma concentrations remained elevated at the 15‐min time point, although concentrations appeared to have started to level off for certain patients. The average concentration at 15 min was 118 mg/L. 
Adverse Events

One adverse drug reaction was identified, but the study was not designed to report a true rate of adverse drug reactions. 
Study Author Conclusions

Intravenous push cefepime in critically ill patients achieved systemic exposure comparable to traditional intermittent infusion but demonstrated substantial interpatient PK variability. These findings highlight the impact of critical illness on cefepime disposition and support further evaluation of personalized cefepime dosing for the ICU population. 
Critique

This prospective PK study provides direct steady-state concentration data for IV push cefepime in critically ill patients with sepsis, including detailed sampling through 240 minutes and reporting of exposure-related parameters relevant to cefepime toxicity risk. However, it does not directly compare IV push with 3-hour prolonged infusion and did not evaluate nephrotoxicity as an outcome; therefore, it can only support that IV push produced variable trough concentrations and systemic exposure comparable to historical intermittent infusion, not that IV push or prolonged infusion has a higher nephrotoxicity risk.
Table 2 References:
[3] Smith SE, Halbig Z, Fox NR, Bland CM, Branan TN. Outcomes of Intravenous Push versus Intermittent Infusion Administration of Cefepime in Critically Ill Patients. Antibiotics (Basel). 2023 Jun 1;12(6):996. doi:10.3390/antibiotics1206099