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• An AUC 24 /MIC of 100 was required to achieve a bacterial51 eradication rate of 80% for sepsis patients treated with linezolid. • An 800 mg/12 h (safety probability 66.8%) dosing regimen was appropriate for sepsis patients with normal renal function or mild kidney damage. • There is a high thrombocytopenia probability with 600 mg/12 h for sepsis patients on CRRT, so dosing should be adjusted based on TDM. Significant alterations in the pharmacokinetic characteristics of linezolid are often seen in sepsis patients. The study aimed to identify a target pharmacokinetics/pharmacodynamics (PK/PD) index of the efficacy of linezolid treatment, and to estimate the optimum dosage regimen of linezolid in sepsis patients. The PK data were modeled using the one-compartment model, which determined the target PK/PD index for successful treatment by logistic regression. The probability of thrombocytopenia was identified by establishing a logistic model. Different dosing regimens were evaluated using Monte Carlo simulation. Reaching 80% bacterial eradication required an AUC 24 /MIC of 100, which defined the therapeutic target. The proposed regimen to attain a cumulative fraction of response ≥80% was 800 mg/12 h (safety probability 66.8%) for sepsis patients with normal renal function or mild kidney damage. By contrast, the target cumulative fraction of response was attained with a standard dosing regimen in sepsis patients on continuous renal replacement therapy [600 mg/12 h (safety probability 49.7%)]. This study identified different dosing strategies to achieve target linezolid PK/PD values according to whether sepsis patients were treated with continuous renal replacement therapy. Due to the high incidence of thrombocytopenia in sepsis patients on continuous renal replacement therapy, therapeutic drug monitoring should be encouraged for optimizing linezolid exposure in sepsis patients. [ABSTRACT FROM AUTHOR]

• Etest method is useful for in vitro testing of combination antifungal therapy. • A combination of caspofungin and triazoles was effective for Candida infections. • Caspofungin and triazole combination was effective for Candida. glabrata with FKS mutation. Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata , direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation. [ABSTRACT FROM AUTHOR]

• The methodological quality of guidelines for treatment on candidiasis is suboptimal. • Only the ESCMID guideline had a quality score >70% in all domains except applicability. • The CPGs noted an important role for fluconazole as an initial drug in prophylaxis. • Echinocandins are considered preferred in both empirical and targeted therapy. • The timing of initiating prophylaxis and empirical/pre-emptive therapy are unclear. Recommendations in clinical practice guidelines (CPG) may differ and cause confusion. Our objective was to appraise CPGs for antifungal treatment of invasive candidiasis (IC) in non-neutropenic critically ill adult patients. We systematically searched the literature for CPGs published between 2008 and 2018. We assessed the quality of each guideline using six domains of the AGREE II instrument. We extracted and compared recommendations for different treatment strategies and assessed content quality. Of 19 guidelines, the mean overall AGREE II score was 58%. The domain 'clarity of presentation' received the highest scores (88%) and 'applicability' the lowest (18%). CPGs provided detailed recommendations on antifungal prophylaxis (n = 10), with fluconazole recommended as initial prophylaxis in all seven CPGs citing a specific drug. Echinocandin was recommended as the initial drug in all 16 CPGs supporting empirical/pre-emptive treatment; and in 18 of 19 for targeted invasive candidiasis treatment. However, it remains unclear when to initiate prophylaxis, empirical or pre-emptive therapy or when to step down. The methodological quality of CPGs for antifungal treatment of IC in non-neutropenic critically ill patients is suboptimal. Some treatment recommendations were inconsistent across indications and require local guidance to help clinicians make better informed decisions. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to investigate the pharmacokinetic profile and safety of voriconazole treatment in patients with Child–Pugh class B and C cirrhosis. Methods Liver cirrhosis patients who had received the recommended voriconazole maintenance dose (group A) or halved maintenance dose (group B), orally or intravenously, were included. Voriconazole-related adverse events (AEs) were defined according to the Common Terminology Criteria for Adverse Events. Results A total of 110 trough plasma concentrations of voriconazole ( C min ) were measured in 78 patients. There was a significant difference in voriconazole C min between group A and group B ( C min , 6.95 ± 3.42 mg/l vs. 4.02 ± 2.00 mg/l; p < 0.001). No significant difference in voriconazole C min between Child–Pugh class B and C cirrhosis patients was observed in either of the two groups. The international normalized ratio and co-medication with a CYP2C19 inhibitor had a significant effect on voriconazole C min in group B. The incidence of AEs in group A was 26.5% and in group B was 15.9%, and 87.5% of AEs developed within 7 days after starting voriconazole treatment. Conclusions These results suggest that the recommended dose and halved maintenance dose may be inappropriate in patients with Child–Pugh class B and C cirrhosis due to the high C min , and that voriconazole C min should be monitored earlier to avoid AEs. [ABSTRACT FROM AUTHOR]

Summary: Objectives: This study evaluated the efficacy of the pharmacokinetic/pharmacodynamic (PK/PD) index for increasing the success rate of linezolid treatment based on Monte Carlo simulation, and compared differences between the calculated PK/PD breakpoints and those defined by committee for critically ill patients with linezolid treatment. Methods: A Monte Carlo simulation involving 10000 subjects was used to analyze the pharmacokinetic parameters and microbiological data of linezolid for an effectiveness evaluation at the corresponding AUC24/MIC values (area under the serum concentration–time curve over 24h/minimum inhibitory concentration). Results: As the PK/PD index of linezolid increased from 80 to 120, the corresponding probability of target attainment (PTA) decreased from 99.91% to 18.97%, with a MIC of 2mg/l. Furthermore, the cumulative fraction of response (CFR) reached <90% for several pathogens at an AUC24/MIC of 100–120, revealing a relatively lower efficacy with recommended linezolid dosing. Conclusions: These findings reveal that the target AUC24/MIC value of 80–120 requires further classification for more accurate assessment of the linezolid dose regimen. At a MIC of ≥2mg/l, the clinical outcome varies greatly for different AUC24/MIC values when applying the same dose of linezolid. In such cases, we suggest optimized adjustment of the linezolid dosage regimen. [Copyright &y& Elsevier]

Summary: Background: The number of reported cases of resistance to tigecycline is increasing. The aim of this study was to evaluate the current standard tigecycline dosage regimen from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. Methods: Pharmacokinetic parameters and microbiological data were analyzed by Monte Carlo simulation in an evaluation of effectiveness. Results: Tigecycline exhibits excellent in vitro antimicrobial activity, however the standard tigecycline dosing regimen fails to achieve the best outcome in vivo for the common drug-resistant strains, including Acinetobacter baumannii, Enterobacter spp, and Klebsiella pneumoniae. This may result in a lack of response to tigecycline therapy or to a further increase in the resistance rate. Conclusions: In the absence of new drugs on the horizon, rather than using a single fixed dosing regimen, tigecycline dosing needs to be optimized in order to achieve the desired successful clinical response and to prevent an escalation in drug resistance. [ABSTRACT FROM AUTHOR]