bCeftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fT MIC ) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC 0-) for free CPT in soft tissues and the AUC 0-for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fT MIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies. Ceftaroline fosamil (CPT-F; brand names, Zinforo in Europe and Teflaro in the United States) was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTIs) and community-acquired pneumonia (CAP) in adults. Ceftaroline (CPT) is a cephalosporin antibiotic and acts, like all beta-lactam agents, via inhibition of peptidoglycan synthesis. In contrast to other cephalosporins, CPT is active against some resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), and is therefore often referred to as a "fifth generation," or advanced-generation, cephalosporin. CPT-F, a water soluble N-phosphono prodrug, is converted to the active CPT in human plasma, and CPT is further converted into the inactive ring-opened metabolite CPT M-1.Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1-5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) cal...

Background In patients with atopic dermatitis (AD), Staphylococcus aureus frequently colonizes lesions and is hypothesized to be linked to disease severity and progression. Treatments that reduce S. aureus colonization without significantly affecting the skin commensal microbiota are needed. Methods and findings In this study, we tested ATx201 (niclosamide), a small molecule, on its efficacy to reduce S. aureus and propensity to evolve resistance in vitro. Various cutaneous formulations were then tested in a superficial skin infection model. Finally, a Phase 2 randomized, double‐blind and placebo‐controlled trial was performed to investigate the impact of ATx201 OINTMENT 2% on S. aureus colonization and skin microbiome composition in patients with mild‐to‐severe AD (EudraCT:2016‐003501‐33). ATx201 has a narrow minimal inhibitory concentration distribution (.125–.5 μg/ml) consistent with its mode of action – targeting the proton motive force effectively stopping cell growth. In murine models, ATx201 can effectively treat superficial skin infections of methicillin‐resistant S. aureus. In a Phase 2 trial in patients with mild‐to‐severe AD (N = 36), twice‐daily treatment with ATx201 OINTMENT 2% effectively reduces S. aureus colonization in quantitative colony forming unit (CFU) analysis (primary endpoint: 94.4% active vs. 38.9% vehicle success rate, p = .0016) and increases the Shannon diversity of the skin microbiome at day 7 significantly compared to vehicle. Conclusion These results suggest that ATx201 could become a new treatment modality as a decolonizing agent.

Cation-dependent inhibition of antimicrobial activity was reported for polymyxin antibiotics. Ca(2+) and Mg(2+) concentrations recommended by the Clinical and Laboratory Standards Institute (CLSI) for the supplementation of Müller-Hinton broth (MHB) are markedly lower than interstitial space fluid (ISF) concentrations in vivo. Hence, it was speculated that the antimicrobial activity of colistin might be overestimated if tested using conventional cation-adjusted MHB. The antimicrobial activity of colistin against n = 100 clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Escherichia coli (n = 25 each) was evaluated by broth microdilution and, for selected isolates, by time-kill curves, in MHB without cations (MHB(ONLY)), MHB supplemented with 25 mg/L Ca(2+) and 12.5 mg/L Mg(2+) according to CLSI recommendations (MHB(CLSI)), and in MHB adjusted to 50 mg/L Ca(2+) and 20 mg/L Mg(2+) simulating ISF concentrations (MHB(ISF)). The minimum inhibitory concentration (MIC) values of colistin against the vast majority of isolates of both P. aeruginosa and A. baumannii increased significantly with higher cation concentrations. The susceptibility of K. pneumoniae isolates to colistin did not show significant changes between cation-supplemented media, while the MICs of E. coli decreased with ascending cation concentrations. These findings were confirmed in time-kill studies, where colistin killing against P. aeruginosa 1514 and A. baumannii 1485 declined with increasing cation concentrations. Contrarily, the killing of selected concentrations of colistin against K. pneumoniae 15 and E. coli 16 was enhanced in the presence of increasing cation concentrations. The present data suggest that the clinical antimicrobial activity of colistin might be misestimated in vitro if tested in conventional growth media.

Objectives: Pharmacokineticepharmacodynamic (PK-PD) considerations are at the heart of defining susceptibility breakpoints for antibiotic therapy. However, current approaches follow a fragmented workflow. The aim of this study was to develop an integrative pharmacometric approach to define MICbased breakpoints for killing and suppression of resistance development for plasma and tissue sites, integrating clinical microdialysis data as well as in vitro timeekill curves and heteroresistance information, exemplified by moxifloxacin against Staphylococcus aureus and Escherichia coli. Methods: Plasma and target site samples were collected from ten patients receiving 400 mg moxifloxacin/day. In vitro timeekill studies with three S. aureus and two E. coli strains were performed and resistant subpopulations were quantified. Using these data, a hybrid physiologically based (PB) PK model and a PK-PD model were developed, and utilized to predict site-specific breakpoints. Results: For both bacterial species, the predicted MIC breakpoint for stasis at 400 mg/day was 0.25 mg/L. Less reliable killing was predicted for E. coli in subcutaneous tissues where the breakpoint was 0.125 mg/ L. The breakpoint for resistance suppression was 0.06 mg/L. Notably, amplification of resistant subpopulations was highest at the clinical breakpoint of 0.25 mg/L. High-dose moxifloxacin (800 mg/day) increased all breakpoints by one MIC tier. Conclusions: An efficient pharmacometric approach to define susceptibility breakpoints was developed; this has the potential to streamline the process of breakpoint determination. Thereby, the approach provided additional insight into target site PK-PD and resistance development for moxifloxacin. Application of the approach to further drugs is warranted.

There is evidence that Staphylococcus aureus colonisation is linked to severity of atopic dermatitis. As no gold standard for S. aureus sampling on atopic dermatitis skin lesions exists, this study compared three commonly used methods. In addition, effectiveness of standard skin disinfection to remove S. aureus colonisation from these inflamed skin lesions was investigated. In 30 atopic dermatitis patients, three different S. aureus sampling methods, i.e. detergent scrubbing, moist swabbing and tape stripping, were performed on naïve and disinfected skin lesions. Two different S. aureus selective media, mannitol salt agar and chromID agar, were used for bacterial growing. Quantifying the S. aureus load varied significantly between the different sampling methods on naïve skin lesions ranging from mean 51 to 1.5 × 104 CFU/cm2 (p < 0.001). The qualitative detection on naïve skin was highest with the two detergent-based techniques (86% each), while for tape stripping, this value was 67% (all on chromID agar). In comparison, mannitol salt agar was less sensitive (p < 0.001). The disinfection of the skin lesions led to a significant reduction of the S. aureus load (p < 0.05) but no complete eradication in the case of previously positive swab. The obtained data highlight the importance of the selected sampling method and consecutive S. aureus selection agar plates to implement further clinical studies for the effectiveness of topical anti-staphylococcal antibiotics. Other disinfection regimes should be considered in atopic dermatitis patients when complete de-colonisation of certain skin areas is required, e.g. for surgical procedures.