Comparison of 99m Tc‐DTPA and urea for measuring cefepime concentrations in epithelial lining fluid

WCK 5222 is a combination of cefepime and the novel β-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug () and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.

Section: Discussionsupporting

confidence: 81%

Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects

Rodvold

Gotfried

Chugh

et al. 2018

“…The use of BAL fluid to determine ELF drug concentrations is a commonly used approach; however, large differences in antibiotic ELF concentrations using this method have been observed (32,33). Using results from healthy subjects may also underestimate antibiotic concentrations at the site of infection, because penetration of antibiotics into the lung of pneumonia patients may be higher as a result of the increased permeability of inflamed lung tissue (32,34). The methodology used to evaluate antibiotic concentrations in the lung continues to develop and serves as a valuable tool in evaluating antibiotics for the treatment of pneumonia.…”

Section: Discussionmentioning

confidence: 99%

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

Riccobene¹,

Pushkin²,

Jandourek³

et al. 2016

c Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with bactericidal activity against Grampositive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to (i) evaluate ceftaroline concentrations in human plasma and epithelial lining fluid (ELF) and (ii) develop a population pharmacokinetic (PK) model for plasma and ELF to be used in PK/pharmacodynamic (PD) target attainment simulations. Ceftaroline concentrations in ELF and plasma at steady state (day 4) were measured in healthy adult subjects for two dosages: 600 mg every 12 h (q12h) and 600 mg every 8 h (q8h). Both were well tolerated with no serious adverse events. The penetration of free ceftaroline into ELF, assuming 20% protein binding in plasma and no protein binding in ELF, was Ϸ23%. The population PK model utilized a two-compartment model for both ceftaroline fosamil and ceftaroline. Goodness-of-fit criteria revealed the model was consistent with observed data and no systematic bias remained. At 600 mg q12h and a MIC of 1 mg/liter, 98.1% of simulated patients would be expected to achieve a target free drug concentration above the MIC (fT>MIC) in plasma of 42%, and in ELF 81.7% would be expected to achieve a target fT>MIC of 17%; at 600 mg q8h, 100% were predicted to achieve an fT>MIC in plasma of 42% and 94.7% to achieve an fT>MIC of 17% in ELF. The literature and data suggest the 600 mg q12h dose is adequate for MICs of <1 mg/liter. There is a need for clinical data in patients with MRSA pneumonia and data to correlate PK/PD relationships in ELF with clinical outcomes. C eftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin antibiotic with bactericidal activity against Gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) (1, 2). Ceftaroline is also active in vitro against Gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis and non-extended-spectrum ␤-lactamaseproducing Enterobacteriaceae (1, 2). Ceftaroline fosamil is approved in the United States for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), with approval in Europe for similar indications. At a dosage of 600 mg every 12 h (q12h), ceftaroline fosamil demonstrated noninferiority to ceftriaxone given at 1 g q24h in the treatment of patients with moderate to severe CABP in two phase 3 clinical studies (ClinicalTrials registration no. NCT00621504 and NCT00509106) (3-5). Ceftaroline fosamil (600 mg q12h) has also been demonstrated to be superior to ceftriaxone (2 g q24h) in the treatment of Asian patients with community-acquired pneumonia (ClinicalTrials registration no. NCT01371838) (6), and in a recent meta-analysis ceftaroline fosamil was shown to be superior to ceftriaxone as an empirical treatment for adult patients hospitalized with PORT risk class 3 to 4 community-acquired pneumonia (7). Ceftaro...

“…BALF was collected in order to assess TMC353121 concentrations in the lung epithelial lining fluid (ELF) after correction for the dilution with lavage fluid. A single lavage with a short dwelling time was applied as previously recommended for better accuracy of the determination of ELF dilution (2). BSA was added to the lavage fluid in order to prevent the adsorption of TMC353121 to syringes or other containers.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics-Pharmacodynamics of a Respiratory Syncytial Virus Fusion Inhibitor in the Cotton Rat Model

Rouan¹,

Gevers²,

Roymans³

et al. 2010

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple E max model with a maximal viral titer reduction (E max ) of 1.5 log 10 . The plasma drug level required to achieve 50% of the E max (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors.Since its first isolation from two hospitalized infants with severe lower respiratory tract infection, human respiratory syncytial virus (RSV) has emerged as an important human respiratory pathogen (5,6,12,24). In many cases, infection is restricted to the upper respiratory tract and not associated with long-term pathology, but progression to a more severe lower respiratory tract infection in infants and children Ͻ6 years of age is frequent. Today, RSV is considered to be the main causative agent of lower respiratory tract infections such as bronchiolitis and pneumonia in infants and young children (12,16,23,24). In healthy adults, infection usually causes symptoms similar to those of the common cold, but in hospitalized elderly or severely immunocompromised patients, RSV is a significant pathogen, often resulting in pneumonia and high mortality rates (11,25).In spite of extensive efforts, development of an anti-RSV vaccine has proven to be particularly challenging and has not been successful to date (22,26). Prophylactic options are limited to passive immunization with the humanized monoclonal antibody Synagis. However, administration of Synagis is restricted to at-risk infants Ͻ2 years old. For therapeutic intervention, the antiviral drug ribavirin is the only option, but its use is limited due to its problematic mode of administration as an aerosol, its limited efficacy, and its teratogenicity (15).Hence, effective therapeutic options are needed for treatment of the at-risk population, including adults and the elderly.Several animal models have been established to study RSV pathogenesis and treatment (4...