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Oral and intravenous (IV) omadacycline formulations are approved in the United States for treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in adults. Oral omadacycline bioavailability is 34.5%; similar exposures are obtained following 300 mg oral and 100 mg IV doses. Oral administration should be in a fasted state, with dairy products, antacids, or multivitamins avoided for ≥4 hours after dosing. Low protein binding (21%), large volume of distribution (190 L), low systemic clearance (10 L/hour), and long elimination half-life (16–17 hours) support once-daily dosing. Omadacycline is excreted unchanged in feces (81.1%) and urine (14.4%), with low potential for drug–drug interactions. Dose adjustments are unnecessary for age, sex, and renal or hepatic impairment. Pharmacokinetic–pharmacodynamic studies identify fAUC0–24/MIC ratio as the parameter that correlates with in vivo efficacy. Systemic exposure of omadacycline in epithelial lining fluid is greater than/equal to plasma concentrations in healthy adults.

The genome of Mycobacterium tuberculosis , the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca 2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism. IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease. Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.

Antibiotic renal dose adjustments are determined in patients with stable chronic kidney disease and may not translate to patients in late-phase trials and practice. Ceftolozane/tazobactam, ceftazidime/avibactam, and telavancin all carry precautionary statements for reduced clinical response in patients with baseline creatinine clearance of 30–50 mL/min, potentially due to unnecessary dose reduction in the setting of acute kidney injury (AKI). In this review, we discuss the regulatory landscape for antibiotics eliminated by the kidney and highlight the importance of the first 48 hours of therapy. Using a clinical database, we identified AKI on admission in a substantial proportion of patients with pneumonia (27.1%), intraabdominal (19.5%), urinary tract (20.0%), or skin and skin structure infections (9.7%) that resolved by 48 hours in 57.2% of cases. We suggest that deferred renal dose reduction of wide therapeutic index antibiotics could improve outcomes in patients with infectious diseases.

Background Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h. Objectives The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. Patients and Methods Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤ 25% of probability of a linezolid trough of > 8.06 mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. Results A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCL CKD-EPI )] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCL CKD-EPI < 130 mL/min/1.73 m 2 . Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCL CKD-EPI ≥ 60 mL/min/1.73 m 2 . Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCL CKD-EPI ≥ 130 mL/min/1.73 m 2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. Conclusions Dosage adjustments of linezolid in this population should be based on CrCL CKD-EPI estimates, rather than on body size descriptors.

Accurate kidney function estimation hinges on essential markers of age and body size. The relative benefit of both markers has been debated with the emerging biological age and novel body size descriptors. We used radiomic biomarkers of age-related changes in body composition to construct new biological age indices as covariates of kidney function. A retrospective cohort of hospitalized patients with plasma concentrations of aminoglycosides and computed tomography images were evaluated. Aminoglycoside clearance served as a kidney function surrogate. A population pharmacokinetic model was constructed to determine whether biological age indices improved aminoglycoside clearance estimation compared to chronological age. The final dataset included 156 patients (51.92% female) with a median (minimum-maximum) age and body weight of 58 [21, 93] years and 81 [43.8, 139.3] Kg. A 1-compartment clearance model with linear elimination, incorporating biological index, serum creatinine, and drug type best fits the concentration-time data. The best radiomic biological age model included dorsal muscle group area, bone mineral density, visceral fat area, and subcutaneous fat density. The radiomic biological age model offered a modest improvement over the chronological age model. This work offers a proof-of-concept, highlighting the potential for more precise methods for aging-related kidney function estimation to aid personalized pharmacotherapy.

While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW. Sixty-three adult patients (71.4% female) with a median age of 53.4 years and mean BMI of 36.84 having both DEXA and CT scans were retrospectively analyzed to assess the relationship between CT-based skeletal muscle variables and DEXA-derived LBW. Linear regression results revealed significant correlations. CT-derived skeletal muscle area (SMA) strongly predicted DEXA-derived LBW (p value < 0.05 and R between 0.67 and 0.80) at four different vertebra levels. DEXA-derived LBW showed a strong correlation with a height, weight, and sex-based estimate of LBW using an equation developed in 2005 (LBW ). A final model incorporating SMA with the LBW equation improved the coefficient of determination at all four vertebra levels (R 0.82-0.86). This study demonstrates opportunistic CT scan data may improve an existing equation for LBW that has been predictive of select drug pharmacokinetic parameters. Improving LBW estimation may enable improved personalized drug dosing strategies in patients with obesity and other populations that benefit from using LBW over total body weight.

Mycobacterium tuberculosis (M.tb), the pathogen causing tuberculosis, is a major threat to human health worldwide. Nearly 10% of M.tb genome encodes for a unique family of PE/PPE/PGRS proteins present exclusively in the genus Mycobacterium. The functions of most of these proteins are yet unexplored. The PGRS domains of these proteins have been hypothesized to consist of Ca2+ binding motifs that help these intrinsically disordered proteins to modulate the host cellular responses. Ca2+ is an important secondary messenger that is involved in the pathogenesis of tuberculosis in diverse ways. This study presents the calcium-dependent function of the PGRS domain of Rv0297 (PE_PGRS5) in M.tb virulence and pathogenesis. Tandem repeat search revealed the presence of repetitive Ca2+ binding motifs in the PGRS domain of the Rv0297 protein (Rv0297PGRS). Molecular Dynamics simulations and fluorescence spectroscopy revealed Ca2+ dependent stabilization of the Rv0297PGRS protein. Calcium stabilized Rv0297PGRS enhances the interaction of Rv0297PGRS with surface localized Toll like receptor 4 (TLR4) of macrophages. The Ca2+ stabilized binding of Rv0297PGRS with the surface receptor of macrophages enhances its downstream consequences in terms of Nitric Oxide (NO) production and cytokine release. Thus, this study points to hitherto unidentified roles of calcium-modulated PE_PGRS proteins in the virulence of M.tb. Understanding the pathogenic potential of Ca2+ dependent PE_PGRS proteins can aid in targeting these proteins for therapeutic interventions.

Omadacycline is a novel aminomethylcycline antibiotic (antibacterial). Omadacycline has had chemical structure modifications at the C9 and C7 positions of the core tetracycline rings that allow stability in the efflux pump and ribosomal protection protein mechanisms of tetracycline resistance. The systemic exposure (i.e., maximum plasma concentrations [ C max ] and area under the plasma concentration–time curve [AUC]) after intravenous (IV) administration were linear and predictable over the dose range of 25 and 600 mg in healthy subjects. The oral bioavailability of omadacycline was 34.5% under fasted conditions (no food intake 6 h before and 4 h after dosing). Both AUC and C max values significantly decreased (41–61%) when a high-fat meal, with and without dairy, were administered 2 h before oral dosing of omadacycline. Similar to other tetracyclines, it is advisable to avoid concurrent administration of divalent- or trivalent cation-containing products (e.g., antacids and iron-containing preparations) for at least 4 h after oral administration of omadacycline. Omadacycline has a large volume of distribution (190 L) and low plasma protein binding (21.3%) that was concentration independent. Systemic exposure of omadacycline in epithelial lining fluid (ELF) and alveolar macrophages was greater than in plasma in healthy adult subjects. Omadacycline is excreted unchanged in the feces (81.1%) and urine (14.4%), and has a low potential for drug–drug interactions since it was not a substrate, inhibitor, or inducer of major cytochrome-metabolizing enzymes or organic anion transporters (OATs). No clinically significant differences in the pharmacokinetics of omadacycline have been observed for age, sex, and renal or hepatic impairment. Pharmacokinetic–pharmacodynamic studies have confirmed that the AUC from time zero to 24 h (AUC 24 )/minimum inhibitory concentration (MIC) ratio was the best index for correlating unbound plasma and total-drug ELF concentrations with the efficacy of omadacycline. A population pharmacokinetic model was developed with data from healthy subjects and infected patients and used to establish interpretive criteria for in vitro susceptibility testing and dosing regimens of omadacycline for treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.

Background. Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)–related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients. Methods. We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6–8 mg/kg/day for primarily Staphylococcus species–related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens. Results. Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients. Conclusions. A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients.