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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.

Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development.

Objectives of the present study were to investigate the physico-chemical properties of municipal solid waste (MSW)-enriched compost and its effect on nutrient mineralization and subsequent plant growth. The enrichment of MSW compost by inorganic salts enhanced the humification rate and reduced the carbon nitrogen (C/N) ratio in less time than control compost. The chemical properties of compost, C/N ratio, humic acid, fulvic acid, degree of polymerization and humification index revealed the significant correlation amid properties. A laboratory-scale experiment evaluated the conjunctive effect of MSW compost and inorganic fertilizer on tomato plants in a pot experiment. In the pot experiment five treatments, Inorganic fertilizer (T1), enriched compost (T2), enriched compost 80% + 20% inorganic fertilizer (T3), enriched compost 60% + 40% inorganic fertilizer (T4) were defined including control (Ts), applied at the rate of 110 kg-N/ha and results revealed that all treatments significantly enhanced horticultural production of tomato plant; however T4 was most effectual as compared with control, T1, T2 and T3. Augmentation in organic matter and available phosphorus (P) potassium (K) and nitrogen (N) were also observed in compost treatments. The leachability and phytoavailability of phosphorus (P), potassium (K) and nitrogen (N) from sandy soil, amended with enriched, control compost and inorganic fertilizer at rates of 200, 400 and 600 kg-N/ha were evaluated in a lysimeter study. Results illustrated that concentration of mineral nitrogen was elevated in the leachate of inorganic fertilizer than enriched and control composts; therefore compost fortifies soil with utmost nutrients for plants' growth.

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