Importance:Dalbavancin is an alternative to prolonged intravenous therapy for complicated Staphylococcus aureus bacteremia, yet its pharmacokinetics (PK) in patients with this condition are uncertain. Objective:To characterize dalbavancin PK and evaluate associations of total and unbound exposures of dalbavancin with clinical success in patients with complicated S aureus bacteremia. Design, Setting, and Participants:This study was an exploratory prespecified secondary analysis of PK and exposure response within Dalbavancin as an Option for Treatment of S aureus Bacteremia (DOTS), a multicenter, randomized, open-label, assessor-blinded clinical trial conducted from April 2021 to December 2023. Data analysis was conducted from January 2024 to December 2025. Adults with complicated S aureus bacteremia who achieved bloodstream clearance were randomized to dalbavancin or standard therapy; PK analyses included dalbavancin recipients with at least 1 postdose concentration measurement. Intervention:Dalbavancin 1500 mg intravenously on days 1 and 8 (1125 mg for patients with severe kidney impairment not receiving dialysis). Main Outcomes and Measures:Individual exposure metrics, including day 22 concentration and area under the concentration-time curve (AUC) from days 0 to 22, were derived using nonlinear mixed-effects population PK modeling. Exposure metrics were then assessed for association with clinical success at day 70 (exposure-response analysis). Results:A total of 97 patients (mean [SD] age, 54.5 [15.8] years; 69 male [71.1%]) contributing 640 PK samples were included. Clearance was estimated at 0.066 L/h (95% CI, 0.062 to 0.069 L/h), and the central volume of distribution was estimated at 5.67 L (95% CI, 5.37 to 5.99 L). Interindividual variability was 22.6% (95% CI, 18.9% to 25.6%) for clearance and 19.7% (95% CI, 13.8% to 25.0%) for the central volume of distribution. Clearance increased with creatinine clearance according to a power function (exponent, 0.21; 95% CI, 0.16 to 0.30). Distribution volumes increased with body weight following power relationships, including the central volume (exponent, 0.57; 95% CI, 0.37 to 0.86), second peripheral volume (0.82; 95% CI, 0.37 to 1.46), and third peripheral volume (0.56; 95% CI, 0.30 to 0.82). Albumin was inversely associated with the second peripheral volume (exponent, -0.81; 95% CI, -1.79 to -0.32) and unbound-fraction scaling factor (exponent, -0.78; 95% CI, -0.98 to -0.54), and age was positively associated with the third peripheral volume via a power relationship (exponent, 0.63; 95% CI, 0.44 to 0.83). Among 93 evaluable patients, 72 individuals (77.4%) achieved clinical success at day 70. Patients with a day 22 concentration greater than 32 μg/mL (30 patients [32.3% of evaluable patients receiving dalbavancin]) had higher clinical success compared with 63 patients with a day 22 concentration of 32 μg/mL or less (29 patients [96.7%] vs 43 patients [68.3%]; adjusted difference, 25.3 percentage points; 95% CI, 3.5-47.0 percentage points) and experienced similar rates of serious adverse events (8 patients [26.7%] vs 27 patients [42.9%]; unadjusted difference, -16.2 percentage points, 95% CI -36.2 to 3.8 percentage points). Conclusions and Relevance:In this study, dalbavancin pharmacokinetics were predictably influenced by kidney function, body weight, albumin levels, and age, and higher total day 22 concentrations were associated with greater clinical success without increased serious adverse events. These findings are exploratory and support further evaluation of exposure-guided dosing strategies. Trial Registration:Clinical Trials.gov Identifier: NCT04775953.

This prespecified secondary analysis of a randomized clinical trial investigates the pharmacokinetics of a 2-dose dalbavancin regimen and its association with clinical success among patients with complicated Staphylococcus aureus bacteremia. QuestionWhat are the pharmacokinetics of a 2-dose dalbavancin regimen used for consolidation therapy in complicated Staphylococcus aureus bacteremia, and is dalbavancin exposure associated with clinical success?FindingsIn this prespecified secondary analysis that included 97 adults with complicated S. aureus bacteremia from a randomized clinical trial, kidney function, weight, albumin level, and age influenced dalbavancin pharmacokinetics. Total day 22 concentrations greater than 32 mu g/mL were associated with increased rates of day 70 clinical success, without corresponding increases in serious adverse events.MeaningAlthough 2 doses of dalbavancin were noninferior to standard therapy in complicated S. aureus bacteremia in the parent trial, these findings suggest that future studies should assess whether patients with day 22 concentrations of 32 mu g/mL or less may benefit from an additional dose. ImportanceDalbavancin is an alternative to prolonged intravenous therapy for complicated Staphylococcus aureus bacteremia, yet its pharmacokinetics (PK) in patients with this condition are uncertain.ObjectiveTo characterize dalbavancin PK and evaluate associations of total and unbound exposures of dalbavancin with clinical success in patients with complicated S aureus bacteremia.Design, Setting, and ParticipantsThis study was an exploratory prespecified secondary analysis of PK and exposure response within Dalbavancin as an Option for Treatment of S aureus Bacteremia (DOTS), a multicenter, randomized, open-label, assessor-blinded clinical trial conducted from April 2021 to December 2023. Data analysis was conducted from January 2024 to December 2025. Adults with complicated S aureus bacteremia who achieved bloodstream clearance were randomized to dalbavancin or standard therapy; PK analyses included dalbavancin recipients with at least 1 postdose concentration measurement.InterventionDalbavancin 1500 mg intravenously on days 1 and 8 (1125 mg for patients with severe kidney impairment not receiving dialysis).Main Outcomes and MeasuresIndividual exposure metrics, including day 22 concentration and area under the concentration-time curve (AUC) from days 0 to 22, were derived using nonlinear mixed-effects population PK modeling. Exposure metrics were then assessed for association with clinical success at day 70 (exposure-response analysis).ResultsA total of 97 patients (mean [SD] age, 54.5 [15.8] years; 69 male [71.1%]) contributing 640 PK samples were included. Clearance was estimated at 0.066 L/h (95% CI, 0.062 to 0.069 L/h), and the central volume of distribution was estimated at 5.67 L (95% CI, 5.37 to 5.99 L). Interindividual variability was 22.6% (95% CI, 18.9% to 25.6%) for clearance and 19.7% (95% CI, 13.8% to 25.0%) for the central volume of distribution. Clearance increased with creatinine clearance according to a power function (exponent, 0.21; 95% CI, 0.16 to 0.30). Distribution volumes increased with body weight following power relationships, including the central volume (exponent, 0.57; 95% CI, 0.37 to 0.86), second peripheral volume (0.82; 95% CI, 0.37 to 1.46), and third peripheral volume (0.56; 95% CI, 0.30 to 0.82). Albumin was inversely associated with the second peripheral volume (exponent, -0.81; 95% CI, -1.79 to -0.32) and unbound-fraction scaling factor (exponent, -0.78; 95% CI, -0.98 to -0.54), and age was positively associated with the third peripheral volume via a power relationship (exponent, 0.63; 95% CI, 0.44 to 0.83). Among 93 evaluable patients, 72 individuals (77.4%) achieved clinical success at day 70. Patients with a day 22 concentration greater than 32 mu g/mL (30 patients [32.3% of evaluable patients receiving dalbavancin]) had higher clinical success compared with 63 patients with a day 22 concentration of 32 mu g/mL or less (29 patients [96.7%] vs 43 patients [68.3%]; adjusted difference, 25.3 percentage points; 95% CI, 3.5-47.0 percentage points) and experienced similar rates of serious adverse events (8 patients [26.7%] vs 27 patients [42.9%]; unadjusted difference, -16.2 percentage points, 95% CI -36.2 to 3.8 percentage points).Conclusions and RelevanceIn this study, dalbavancin pharmacokinetics were predictably influenced by kidney function, body weight, albumin levels, and age, and higher total day 22 concentrations were associated with greater clinical success without increased serious adverse events. These findings are exploratory and support further evaluation of exposure-guided dosing strategies.Trial RegistrationClinical Trials.gov Identifier: NCT04775953

Importance:Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access. Objective:To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia. Design, Setting, and Participants:Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n = 22) and Canada (n = 1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus bacteremia who achieved blood culture clearance following at least 72 hours but no more than 10 days of initial antibacterial therapy were included. Participants were excluded if they had central nervous system infection, retained infected prosthetic material, left-sided endocarditis, or severe immune compromise. Interventions:Participants were randomly assigned to receive either 2 doses of intravenous dalbavancin (n = 100; 1500 mg on days 1 and 8) or 4 to 8 total weeks of standard intravenous therapy (n = 100; cefazolin or antistaphylococcal penicillin if methicillin susceptible; vancomycin or daptomycin if methicillin resistant). Main Outcomes and Measures:The primary outcome was the desirability of outcome ranking (DOOR) at day 70, which involved 5 components (clinical success, infectious complications, safety complications, mortality, and health-related quality of life) and was assessed for superiority (achieved if the 95% CI for the probability of dalbavancin having a superior DOOR was >50%). Secondary outcomes included clinical efficacy at day 70 (prespecified noninferiority margin of 20%) and safety. Results:Of 200 participants randomized (mean [SD] age, 56 [16.2] years; 62 females [31%]), 167 (84%) survived to day 70 and had an efficacy assessment. Participants without a day 70 efficacy assessment were treated as clinical failures in the analyses. The probability of a more desirable day 70 outcome with dalbavancin vs standard therapy was 47.7% (95% CI, 39.8% to 55.7%). Regarding secondary outcomes, clinical efficacy was documented in 73 of 100 for dalbavancin and 72 of 100 for standard therapy (difference, 1.0% [95% CI, -11.5% to 13.5%]), meeting the noninferiority criterion. Serious adverse events were reported in 40 of 100 participants who received dalbavancin and 34 of 100 participants who received standard therapy; treatment-related adverse events were uncommon in both groups. Conclusions and Relevance:Among adult participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy by desirability of outcome ranking. When considered with other efficacy and safety outcomes these findings may help inform use of dalbavancin in clinical practice. Trial Registration:ClinicalTrials.gov Identifier: NCT04775953.

ABSTRACT This Phase 1 trial described the intrapulmonary pharmacokinetics and safety profile of IV fosfomycin in healthy participants . Fosfomycin, a broad-spectrum antibiotic mainly used to treat urinary tract infections, is being considered for treatment of more complex conditions, including lung infections, due to the emergence of multidrug-resistant (MDR) organisms. Despite its potential, the pharmacokinetics and safety profile of intravenous (IV) fosfomycin, particularly its penetration into the lower respiratory tract, are unknown. To address this gap, we conducted a Phase 1, open-label trial to assess the safety and pulmonary pharmacokinetics of IV fosfomycin in healthy participants. Thirty-seven healthy volunteers aged 18–45 years received three doses of 6 g IV fosfomycin every 8 hours. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at randomly assigned time points after the third dose. BAL fluid, BAL cell pellets, and blood plasma samples for fosfomycin were analyzed using validated assays of liquid chromatography with tandem mass spectrometry (LC-MS/MS). Adverse events (AEs) were assessed. Fosfomycin exhibited penetration into alveolar macrophages (AM) at a rate of 16.8% and into the extracellular lining fluid (ELF) at 30.8%. Mean AM fosfomycin concentration ranged from 14.8 to 32 μg/mL, while the mean ELF concentration ranged from 15.7 to 82.5 μg/mL. All participants experienced at least one treatment-emergent adverse event (TEAE), mostly mild/grade 1, with no serious adverse events (SAEs) reported. Intravenous fosfomycin effectively penetrates both the extracellular (ELF) and intracellular (AM) compartments of the lower respiratory tract in healthy participants. The overall tolerability of IV fosfomycin was favorable, suggesting its potential as an effective antibacterial treatment for lower respiratory tract infections. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT03910673 .

Abstract Background The combination of CZA-ATM is frequently used to treat patients with metallo-β-lactamase (MBL)-producing Enterobacterales (EB) infections, but its safety has not been established in controlled trials. This phase 1 study evaluated the safety of the optimal CZA-ATM regimens identified in the hollow fiber infection model of MBL-producing EB (PMID: 32464664). Methods The phase I, open-label, single center study enrolled healthy adults aged 18-45 years (NCT03978091). Subjects were sequentially assigned to 1 of 6 Cohorts and administered investigational product(s) (IP) for 7 days (Table 1). Study safety was monitored by assessments of adverse events (AEs), vital signs, and clinical laboratory safety tests. Results Of 48 subjects enrolled, 50% were female and 60% were Black. The mean (SD) age was 33.5 (6.2) years and mean (SD) weight was 75.7 (12.1) kg. The number of subjects who had ≥ 1 AE and experienced ≥ 1 IP related AE was 46 (96%) and 41 (85%), respectively. Frequency of IP related AEs by MedDRA system organ class, severity, and Cohort are shown in Figure 1. The occurrence of IP related investigation AEs were more frequent in the combination vs single IP Cohorts (Table 2). The most common IP related investigation AEs were ALT/AST elevations (35%) with 94% occurring in subjects who received ATM alone or in combination. The incidence of ALT/AST elevation AEs in the combination Cohorts were comparable to the ATM alone Cohorts. In the ATM single IP Cohorts, 3 subjects experienced severe ALT/AST elevation AEs, which halted the study. All subjects who experienced ALT/AST elevations were asymptomatic, had no other clinical findings suggestive of liver injury, and all resolved without intervention. Most other IP related AEs were of mild severity and similar across Cohorts except prolonged prothrombin time (PT) AEs, which was more frequent in combination Cohorts. Conclusion Clinicians should only consider using CZA-ATM when the benefits outweigh the risks. If CZA-ATM is prescribed, clinicians are advised to monitor for hepatic injury. Close monitoring of coagulation parameters may also be prudent with CZA-ATM. Future comparator-controlled randomized clinical trials are required to better define the safety and efficacy of the CZA-ATM regimens. Disclosures Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant J Nicholas O'Donnell, Pharm.D., Merck & Co, Inc: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Stephen Balevic, MD, Purdue Pharma: Grant/Research Support|UCB: Advisor/Consultant Jeffrey Guptill, MD, argenx: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds henry chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations.

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.