Stenotrophomonas maltophilia is an opportunistic, multidrug-resistant non-fermentative Gram-negative bacillus, posing a significant challenge in clinical treatment due to its numerous intrinsic and acquired resistance mechanisms. This study aimed to evaluate the adequacy of antibiotics used for the treatment of S. maltophilia infections in critically ill patients using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The antibiotics studied included cotrimoxazole, levofloxacin, minocycline, tigecycline, cefiderocol, and the new combination aztreonam/avibactam, which is not yet approved. By Monte Carlo simulations, the probability of target attainment (PTA), the PK/PD breakpoints, and the cumulative fraction of response (CFR) were estimated. PK parameters and MIC distributions were sourced from the literature, the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and the SENTRY Antimicrobial Surveillance Program collection. Cefiderocol 2 g q8h, minocycline 200 mg q12h, tigecycline 100 mg q12h, and aztreonam/avibactam 1500/500 mg q6h were the best options to treat empirically infections due to S. maltophilia. Cotrimoxazole provided a higher probability of treatment success for the U.S. isolates than for European isolates. For all antibiotics, discrepancies between the PK/PD breakpoints and the clinical breakpoints defined by EUCAST (or the ECOFF) and CLSI were detected.

After SARS-CoV-2 infection, the molecular phenoreversion of the immunological response and its associated metabolic dysregulation are required for a full recovery of the patient. This process is patient-dependent due to the manifold possibilities induced by virus severity, its phylogenic evolution and the vaccination status of the population. We have here investigated the natural history of COVID-19 disease at the molecular level, characterizing the metabolic and immunological phenoreversion over time in large cohorts of hospitalized severe patients (n = 886) and non-hospitalized recovered patients that self-reported having passed the disease (n = 513). Non-hospitalized recovered patients do not show any metabolic fingerprint associated with the disease or immune alterations. Acute patients are characterized by the metabolic and lipidomic dysregulation that accompanies the exacerbated immunological response, resulting in a slow recovery time with a maximum probability of around 62 days. As a manifestation of the heterogeneity in the metabolic phenoreversion, age and severity become factors that modulate their normalization time which, in turn, correlates with changes in the atherogenesis-associated chemokine MCP-1. Our results are consistent with a model where the slow metabolic normalization in acute patients results in enhanced atherosclerotic risk, in line with the recent observation of an elevated number of cardiovascular episodes found in post-COVID-19 cohorts.

Background/Objectives: Oritavancin therapy for complex infections remains challenging due to the lack of well-established dosing regimens. The objective of this work was to apply PK/PD modeling and Monte Carlo simulation considering different PK/PD targets to identify multiple-dosing regimens that may ensure effective concentrations of oritavancin for the treatment of long-term infections. Methods: Plasma concentration–time profiles were simulated for different regimens (single dose of 1200 mg, 1200 mg followed by 800 mg every 7 days (q7d), 1200 mg followed by 800 mg q10d, 1200 mg q7d, 1200 mg q10d, 1200 mg q14d, 1200 mg q21d, and 1200 mg followed by 1200 mg on day 8, then 1200 mg q14d), and the probability of target attainment (PTA), indicative of treatment success, was estimated. Results: All dosing regimens provided probabilities of target attainment of 100% up to MICs of 0.5 mg/L when AUC_0–24/MIC and C_max/MIC were applied. Considering AUC_0–72/MIC, the regimens would be adequate up to an MIC of 0.125 mg/L. For fC_min > MIC, all except 1200 mg q21d were adequate for an MIC of 0.125 mg/L, and 1200 mg day 1 + 800 mg q7d and 1200 mg q10d may be useful to treat infections due to bacteria with an MIC of 0.25 mg/L. Conclusions: More studies involving patients with complex infections are needed to better stablish the relationships among plasma concentrations, MIC values, and clinical outcomes. fC_min > MIC should be investigated as a potential PK/PD target for the treatment of these infections with oritavancin.

Background/Objectives: Oritavancin therapy for complex infections remains challenging due to the lack of well-established dosing regimens. The objective of this work was to apply PK/PD modeling and Monte Carlo simulation considering different PK/PD targets to identify multiple dosing regimens that may ensure effective concentrations of oritavancin for the treatment of long-term infections. Methods: Plasma concentration–time profiles were simulated for different regimens (single dose of 1200 mg, 1200 mg followed by 800 mg every 7 days, 1200 mg followed by 800 mg every 10 days, 1200 mg q7d, 1200 mg q10d, 1200 mg every 14 days, 1200 mg every 21 days, and 1200 mg followed by 1200 mg on day 8, then 1200 mg q14d), and the probability of target attainment (PTA), indicative of treatment success, was estimated. Results: All dosing regimens provided probabilities of target attainment of 100% up to MICs of 0.5 mg/L when AUC_0-24/MIC and C_max/MIC were applied. Considering AUC_0-72/MIC, the regimens would be adequate up to MIC of 0.125 mg/L. For fC_min > MIC, all except 1200 mg q21d resulted adequate for MIC of 0.125 mg/L, and 1200 mg day 1 + 800 mg q7d, and 1200 mg q10d may be useful to treat infections due to bacteria with MIC of 0.25 mg/L. Conclusions: More studies involving patients with complex infections are needed to better stablish the relationships among plasma concentrations, MIC values, and clinical outcomes. fC_min > MIC should be investigated as a potential PK/PD target for the treatment of these infections with oritavancin.

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