Tissue penetration and exposure of cefepime in patients with diabetic foot infections

So, Wonhee; Kuti, Joseph L.; Shepard, Ashley; Nugent, James F.; Nicolau, David P.

doi:10.1016/j.ijantimicag.2016.01.002

Cited by 6 publications

(8 citation statements)

References 4 publications

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“…Tazobactam also demonstrated excellent penetration into the soft tissue of these healthy volunteers and patients with DFI with median penetration ratios of 0.85 (range, 0.63 to 2.05) and 1.18 (range, 0.54 to 1.44), respectively. While diabetic patients are known to suffer from peripheral vascular disease, the penetration of ceftolozane and tazobactam into the target site was not compromised, similar to findings for other ␤-lactam antibiotics, cefepime and cefazolin (19,20).…”

Section: Discussionsupporting

confidence: 66%

“…Microdialysis procedure. The microdialysis procedure was performed as previously described (19,20,(29)(30)(31). Following the local injection of a 0.5% lidocaine solution near the site of insertion, a microdialysis probe (63 microdialysis catheter; M Dialysis, Inc., North Chelmsford, MA) with a membrane length of 30 mm and a molecular mass cutoff of 20 kDa was inserted within 10 cm of the wound margin in the patients or in the thigh tissue in healthy volunteers.…”

Section: Study Protocolmentioning

confidence: 99%

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Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

Monogue

Stainton

Baummer-Carr

et al. 2017

Antimicrob Agents Chemother

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Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients ( = 10) with DFI were compared with those in healthy volunteers ( = 6) using microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUC; where AUC was the AUC for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (AUC) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows:, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); , 2.0 h (range, 0.7 to 2.4 h); and AUC, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUC (where AUC was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/AUC for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: , 91.5 μg/ml (range, 65.7 to 110.7 μg/ml);, 1.9 h (range, 1.6 to 2.1 h); and AUC, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUC/AUC was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: , 17.5 μg/ml (range, 15.4 to 27.3 μg/ml);, 0.7 h (range, 0.6 to 0.8 h); and AUC, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUC/AUC for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.).

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Section: Discussionsupporting

confidence: 66%

Section: Study Protocolmentioning

confidence: 99%

Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

Monogue

Stainton

Baummer-Carr

et al. 2017

Antimicrob Agents Chemother

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“…in the epithelial lining fluid (ELF) can be estimated using bronchoalveolar lavage, and microdialysis has emerged in recent years as an experimental method to directly measure free drug concentrations in various tissues. [28][29][30][31] Microdialysis has been used extensively to measure unbound drug concentrations in large interstitial spaces, such as in subcutaneous tissues or muscle, as well as in specialized infection sites, such as lung cavities in patients with tuberculosis and in diabetic foot infections, [32][33][34][35][36][37] and direct measurement of infected biological fluids, such as cereberospinal fluid, peritoneal fluid, and ELF in pneumonia. A special warning should be given to the frequently applied collection of biopsies to measure "tissue concentrations."…”

Section: Reviewmentioning

confidence: 99%

“…Drug concentrations in the epithelial lining fluid (ELF) can be estimated using bronchoalveolar lavage, and microdialysis has emerged in recent years as an experimental method to directly measure free drug concentrations in various tissues 28–31 . Microdialysis has been used extensively to measure unbound drug concentrations in large interstitial spaces, such as in subcutaneous tissues or muscle, as well as in specialized infection sites, such as lung cavities in patients with tuberculosis and in diabetic foot infections, 32–37 and direct measurement of infected biological fluids, such as cereberospinal fluid, peritoneal fluid, and ELF in pneumonia. A special warning should be given to the frequently applied collection of biopsies to measure “tissue concentrations.” The average concentrations usually do not reflect the actual free drug concentration at the infection site but represent an average number that should not be related to PD activity, and for xenobiotics that accumulate intracellularly homogenization destroys tissue architecture resulting in overestimation of unbound interstitial concentrations where many pathogens reside.…”

Section: General Considerations For Midd In Infectious Diseasesmentioning

confidence: 99%

Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

Rayner

Smith

Andes

et al. 2021

Clin Pharma and Therapeutics

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Model‐informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti‐infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug‐drug interactions. Examples are presented for state‐of‐the‐art, empiric, mechanistic, interdisciplinary, and real‐world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration‐based models, mechanism‐based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; “depth” and “breadth” of MIDD methods. “MIDD depth” refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired‐resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. “MIDD breadth” refers to greater adoption of model‐centered approaches to anti‐infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.

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“…In diabetic foot infection, a condition known to be associated with altered local perfusion, lipophilic molecules such as daptomycin, linezolid, and trimethoprim-sulfamethoxazole have shown good tissue penetration [95][96][97][98], while it was altered for hydrophilic molecules such as vancomycin [103]. While ceftazidime penetration was not affected by diabetes, it highly depended on tissue perfusion in another work [101], and employing high doses is suggested for cefepime [100]. Maximal concentration in soft tissue was both reduced and delayed when compared to healthy-volunteers for tedizolid and ceftolozane-tazobactam [114,115].…”

Section: Available Data On Antibiotic Diffusion In the Presence Of Altered Perfusionmentioning

confidence: 99%

Antibiotics in Necrotizing Soft Tissue Infections

et al. 2021

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Necrotizing soft tissue infections (NSTIs) are rare life-threatening bacterial infections characterized by an extensive necrosis of skin and subcutaneous tissues. Initial urgent management of NSTIs relies on broad-spectrum antibiotic therapy, rapid surgical debridement of all infected tissues and, when present, treatment of associated organ failures in the intensive care unit. Antibiotic therapy for NSTI patients faces several challenges and should (1) carry broad-spectrum activity against gram-positive and gram-negative pathogens because of frequent polymicrobial infections, considering extended coverage for multidrug resistance in selected cases. In practice, a broad-spectrum beta-lactam antibiotic (e.g., piperacillin-tazobactam) is the mainstay of empirical therapy; (2) decrease toxin production, typically using a clindamycin combination, mainly in proven or suspected group A streptococcus infections; and (3) achieve the best possible tissue diffusion with regards to impaired regional perfusion, tissue necrosis, and pharmacokinetic and pharmacodynamic alterations. The best duration of antibiotic treatment has not been well established and is generally comprised between 7 and 15 days. This article reviews the currently available knowledge regarding antibiotic use in NSTIs.

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Tissue penetration and exposure of cefepime in patients with diabetic foot infections

Cited by 6 publications

References 4 publications

Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

Antibiotics in Necrotizing Soft Tissue Infections

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