Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients

https://doi.org/10.1016/j.ijantimicag.2010.08.016Get rights and content

Abstract

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1 g every 8 h (q8h), infused over 4 h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 μg/mL to 32 μg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005–2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT > MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 μg/mL, 9.5 ± 5.2 μg/mL, 2.4 ± 0.7 h, 0.316 ± 0.116 h−1, 21.3 ± 6.5 L and 6.6 ± 3.6 L/h, respectively. At the susceptibility breakpoint of 8 μg/mL, the PTA was >90% for 1 g and 2 g q8h (4-h infusion) and 1 g and 2 g every 6 h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1 g q8h (4-h infusion) and ≥92.7% for 2 g q8h (4-h infusion) and 1 g and 2 g q6h (3-h infusion). Cefepime 1 g q8h infused over 4 h provides excellent target attainment for susceptible bacterial pathogens with MICs  8 μg/mL.

Introduction

Cefepime is a fourth-generation parenteral cephalosporin with in vitro activity against aerobic Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa [1], [2], [3]. Cefepime also retains in vitro activity against certain Gram-negative organisms that are resistant to the third-generation cephalosporin ceftazidime [4]. In a surveillance study of bacterial strains from North American hospitals, ca. 90% of ceftazidime-resistant Enterobacteriaceae and 30% of ceftazidime-resistant P. aeruginosa remained susceptible to cefepime [4]. Cefepime is approved by the US Food and Drug Administration (FDA) for the treatment of pneumonia, urinary tract infection, skin and skin-structure infection and febrile neutropenia, as well as for intra-abdominal infection when combined with metronidazole [5]. In patients with normal renal function, cefepime is typically dosed at 1 g every 12 h (q12h) for mild-to-moderate infections, 2 g q12h for severe infections and 2 g every 8 h (q8h) for febrile neutropenia, with doses administered by intravenous (i.v.) infusion over 30 min [5].

Like other β-lactam antibiotics, cefepime exhibits time-dependent bactericidal activity, and the pharmacodynamic parameter predicting clinical and bacteriological outcomes is the time for which the free drug concentration remains above the minimum inhibitory concentration (fT > MIC) of the infecting pathogen [6], [7]. For cephalosporins, in vitro and animal studies have shown that bacteriostatic activity is observed when the fT > MIC is ca. 35–40% of the dosing interval, and bactericidal activity is observed when the fT > MIC is 60–70% of the dosing interval or longer [7]. Similar findings were reported in a recent human study evaluating the clinical pharmacodynamics of cefepime in patients with non-urinary tract infections caused by P. aeruginosa [8]. Patients were significantly more likely to experience microbiological failure if the fT > MIC was ≤60%; thus, achievement of cefepime exposures of >60% fT > MIC was suggested to minimise the possibility of a poor microbiological response [8].

Several studies have shown that the typical cefepime dosing regimens of 1 g and 2 g q12h are less likely to provide adequate exposures for organisms with minimum inhibitory concentrations (MICs) at or near the susceptibility breakpoint of 8 μg/mL [9], [10], [11]. Since cefepime is recommended for empirical treatment of serious infections, including nosocomial and ventilator-associated pneumonia [12], the initial empirical dosing regimen should provide adequate exposure for susceptible bacterial pathogens and/or the most likely aetiological organisms for a given infection. Alternative dosing strategies for cefepime have been suggested in order to maximise the likelihood of achieving the desired pharmacodynamic target for less-susceptible pathogens. These strategies include more frequent drug administration (e.g. every 4–8 h), continuous infusion of the daily dose over 24 h, and prolonging the infusion time from 30 min to 3–4 h [9], [10], [13], [14], [15]. However, the pharmacokinetic profile of cefepime administered by prolonged infusion has not been well studied and pharmacodynamic evaluations of prolonged infusion regimens have utilised pharmacokinetic parameters derived from standard 30-min infusions [3], [16].

The objectives of this study were to determine the steady-state pharmacokinetics of cefepime administered by prolonged infusion in hospitalised patients and to evaluate the pharmacodynamics of several prolonged infusion regimens at specific MICs and against common Gram-negative bacterial pathogens using Monte Carlo simulations.

Section snippets

Patients

Adult patients who were hospitalised at St Francis Hospital (Beech Grove, IN) or Methodist Hospital, Clarian Health Partners, Inc. (Indianapolis, IN) were eligible for the study. All patients were aged  18 years and required antimicrobial therapy for a suspected or documented bacterial infection. Exclusion criteria included 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

Results

Nine patients (seven men and two women) completed the study. Patient demographics were as follows (mean ± S.D.): age, 51.4 ± 17.9 years; weight, 76.7 ± 17.3 kg; and height, 167 ± 12 cm. Mean ± S.D. estimated CLCr was 86 ± 31 mL/min (range 50–137 mL/min). Seven patients were hospitalised in an ICU and two patients were hospitalised on a general medical ward. The primary infection-related diagnosis was pneumonia in six patients, osteomyelitis in two patients and peritonitis/sepsis in one patient. No adverse

Discussion

With the declining development of new antimicrobial agents active against nosocomial Gram-negative pathogens, it is critical to dose available antimicrobials in a manner that maximises patient outcomes and optimises pharmacodynamic exposures whilst minimising the potential for the development and propagation of resistance in order to prolong the clinical utility of these agents. For β-lactam antibiotics, continuous and prolonged infusion regimens have been shown to improve pharmacodynamic

Conclusions

Cefepime 1 g q8h infused over 4 h provides optimum target attainment for bacterial pathogens with MICs  8 μg/mL. However, higher dose regimens may be considered to provide adequate coverage in infections where P. aeruginosa is a likely pathogen. After the results of susceptibility testing are known, dosage reductions may be considered without sacrificing adequate pharmacodynamic exposures if the MIC is ≤2 μg/mL.

Acknowledgments

The authors acknowledge the laboratory personnel at St Francis Hospital (Microbiology) (Beech Grove, IN) and at Methodist Hospital (Indianapolis, IN) for use of their laboratory equipment and for support in conducting this study.

Funding: No funding sources.

Competing interests: None declared.

Ethical approval: This study was approved by the institutional review boards at each study site; written informed consent was obtained from each patient or from a first-degree relative if the patient was

References (28)

  • W.A. Craig

    Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men

    Clin Infect Dis

    (1998)
  • T.P. Lodise et al.

    Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on β-lactam antibiotics

    Pharmacotherapy

    (2006)
  • J.L. Crandon et al.

    Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa

    Antimicrob Agents Chemother

    (2010)
  • J. Lipman et al.

    Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing

    Antimicrob Agents Chemother

    (1999)
  • Cited by (22)

    • The Pharmacodynamics of Prolonged Infusion β-Lactams for the Treatment of Pseudomonas aeruginosa Infections: A Systematic Review

      2019, Clinical Therapeutics
      Citation Excerpt :

      The PTA of PI cefepime has been evaluated in 2 studies. Cheatham et al30 found that a dosing regimen of 1 g and 2 g q8h infused over 4 h resulted in a PK/PD breakpoint of 8 mg/L and 16 mg/L, respectively. Eagye et al18 identified that a cefepime PI dosing regimen of 2 g q8h infused over 3 h resulted in near optimal PTA (87%) at an MIC of 8 mg/L.

    • Beta-lactam carryover in arterial and central venous catheters is negligible

      2018, Clinica Chimica Acta
      Citation Excerpt :

      The Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 state that best practice includes the use of dosing strategies for antibiotics based on pharmacokinetic/pharmacodynamic principles in patients with sepsis when such tests are available [3]. The focus of prior pharmacokinetic studies for these antibiotics has been in healthy populations and children rather than the critically ill population [4–6]. Antimicrobial pharmacokinetics in critical illness likely differ from those in patients without organ failure [7,8].

    • Cefepime extended infusion versus intermittent infusion: Clinical and cost evaluation

      2023, Antimicrobial Stewardship and Healthcare Epidemiology
    View all citing articles on Scopus

    Presented at the 2010 Annual Meeting, American College of Clinical Pharmacy, 17–20 October 2010, Austin, TX.

    View full text