Enteritidis, the most prevalent serovar-causing human gastroenteritis, has been traditionally linked to poultry sources. Although antimicrobial resistance (AMR) is not common in this serovar, increasing levels of resistance to fluoroquinolones and ampicillin have been reported in the last few years. Here, 298 isolates retrieved from different sources (human, livestock, wildlife, food, and environment) and years (2002-2021) in Spain were analyzed to evaluate their diversity, the distribution of AMR-conferring genes (ARGs), and mutations and reconstruct the epidemiology of infection due to this serovar. Isolates were clustered in two major clades (I and II), with strains in clade I (including 61.5% of all human isolates) displaying a pan-susceptible phenotype and not carrying AMR determinants. In contrast, clade II included 80.7% of isolates from animal/food/environmental sources, with the majority (69.8%) harboring mutations in the quinolone resistance determinant regions (QRDR). ARGs, although rare, were mostly found in clade II strains that also carried plasmid replicons, among which IncX1 was the most common. Although higher levels of phenotypic resistance were found in animal isolates, extended-spectrum beta-lactamase, plasmid-mediated AmpC, and carbapenemase-encoding genes were only found among human isolates. In summary, the majority of human and animal isolates from Spanish sources in our collection were classified in different phylogenetic branches, suggesting that additional sources are contributing to the occurrence of foodborne infections in Spain. Furthermore, the different distributions of virulence factors and ARGs in isolates from different sources and their association with specific plasmids suggest the presence of different dynamics contributing to the selection of resistant strains.

Polymyxin B, a last resort for carbapenem-resistant gram-negative bacteria (CRGNB) infections, has infection site-specific pharmacokinetic/pharmacodynamic (PK/PD) properties. However, there is little clinical evidence to support optimal exposures of polymyxin B for different site infections. We performed a prospective, observational, multicenter study to evaluate the clinical outcomes and PK/PD of intravenous polymyxin B treatment for various site CRGNB infections. The main clinical outcomes were 14-day all-cause mortality and nephrotoxicity, and the secondary outcomes were 28-day mortality and clinical response. The area under curves (AUCs) of polymyxin B were determined, and their associations with clinical outcomes were analyzed by stratification based on the infection site. A total of 312 patients were ultimately enrolled from 10 research centers. The overall 14-day mortality was 29.5%, and those of patients with lower respiratory tract infection (LRTI), intra-abdominal infection (IAI), and bloodstream infection (BSI) were 32.3%, 19.7%, and 30.3%, respectively. The 28-day mortality rate was 38.1%, while LRTI patients had the highest mortality (41.4%) and IAI patients lowest (34.8%). The clinical response rate was 46.2%, which was similar among the subgroups. The overall AKI rate was 60.9%. An AUC greater than 50 mg∙h/L was related to lower mortality in IAI patients but not in LRTI patients, which led to a lower but not significant difference in the overall analysis. The AUC of polymyxin B was an independent risk factor for 14-day mortality in IAI patients, and the cutoff value was 76 mg∙h/L. The results would be helpful for personalized dosing and monitoring of polymyxin B.CLINICAL TRIALSThis study is registered with the Chinese Clinical Trial Registry as ChiCTR2200056667.

Non-tuberculosis mycobacteria (NTM) are extensively drug-resistant organisms that require long-term therapy. The study purpose was to quantify the incidence of and risk factors for antimycobacterial-associated adverse drug events (ADEs) in persons with NTM infections receiving outpatient therapy. A multicenter, retrospective cohort was performed of persons with NTM infections who received antimycobacterial treatment from 2013 to 2024. Inclusion criteria were age ≥18 years, ≥1 month of outpatient treatment, and ≥1 follow-up outpatient visit within 3 months of index encounter. complex and complex were excluded. The primary outcome was development of pre-specified treatment-related ADE or acute kidney injury (AKI), thrombocytopenia, and/or infection (CDI) through 12 months of therapy. Secondary outcomes included therapy discontinuation due to any treatment-related ADEs. Two hundred patients were included: 14% developed a pre-specified ADE. (29%) was the most common pathogen; most initial regimens included a macrolide (54%), systemic aminoglycoside (24%), β-lactam (24%), or tetracycline derivative (22%). The most common pre-specified ADEs were thrombocytopenia (9%), AKI (8%), and CDI (<1%). The median (IQR) time-to-ADE was 25 (18-38) days from initial outpatient regimen; patients who received aminoglycoside- or oxazolidinone-based therapies were more likely to develop a pre-specified ADE (adjOR, 3.9; 95% CI, 1.7-9.2). Therapy discontinuation due to any ADE occurred in 35% of patients; the median (IQR) time-to-any ADE was 32 (21-58) days. ADEs in persons with NTM infections are common and occur near the first month of outpatient treatment. Intensified monitoring and/or use of more tolerable antimycobacterial regimens early in treatment may be an appropriate approach to avoid harms.Treatment of non-tuberculosis mycobacteria is complicated by adverse drug events (ADEs). This work quantified the incidence and time course of pre-determined, clinically relevant ADEs (acute kidney injury, thrombocytopenia, and infection), which occurred in 14% of patients within 30 days of outpatient treatment.

Amoxicillin plus gentamicin is the recommended first-line empiric therapy for neonates with infection. Guidelines vary widely in dose (mg/kg), dose frequency, and adjustments according to post-menstrual age (PMA) and post-natal age (PNA). We aimed to develop a population pharmacokinetic (PK) model for amoxicillin in neonates with clinical evidence of sepsis and design optimal dosing regimens. One hundred seventy-seven neonates receiving intravenous amoxicillin for infection were enrolled in a prospective, observational PK study in Papua New Guinea (PNG). The probability of PK-pharmacodynamic target attainment (PK-PD PTA) was determined based on minimum inhibitory concentrations (MIC) and the proportion of time concentrations that remained above these values (%T > MIC). Neonates with concentrations > 140 mg/L were considered to be at increased risk of amoxicillin neurotoxicity. A population PK model was developed. Simulations tested existing guidelines and proposed simplified regimens. The median PMA and PNA were 38 (37-40) weeks and 0 (0-2) days, respectively. From simulations, existing regimens with 50 or 100 mg/kg doses were associated with higher potential neurotoxic concentrations (24.9% and 84.5%, respectively). With the existing 30 mg/kg PNG regimen, neonates receiving twice-daily dosing between 3 and 7 days were systematically underdosed. A proposed 30 mg/kg regimen, with twice-daily dosing for the first 2 days PNA and three times daily from day 3, provides an optimal balance between the probability of PK-PD target attainment while minimizing toxicity. For fixed volume dosing, using 52 mg (0.25 mL of 250 mg in 1.2 mL) for those <3 kg and 104 mg (0.5 mL) for those ≥3 kg is proposed.

Fidaxomicin may exhibit cross-reactivity in patients with known macrolide allergies. In this analysis, compared to patients without macrolide allergies, the odds of fidaxomicin allergy were 2.31, 8.37, and 1.58 times higher in patients with azithromycin, clarithromycin, and erythromycin allergies, respectively; the absolute risk of fidaxomicin allergy was 0.033, 0.01, and 0.039 in patients with azithromycin, clarithromycin, and erythromycin allergies, respectively. The highest risk of anaphylaxis and angioedema was observed within 1 year of a non-fidaxomicin macrolide allergy.

In the ATTACK Phase 3 trial examining the efficacy of sulbactam (SUL)/durlobactam (DUR) to treat primarily complex (ABC) infections, imipenem (IPM)/cilastatin was added as a common therapy to both the SUL/DUR and the comparator colistin arms. This raised the question of whether the use of IPM in the SUL/DUR arm of the study influenced the efficacy of SUL/DUR. To investigate this issue on a microbiological and molecular level, we performed static concentration time-kill studies and molecular modeling of binding of SUL to PBP1a and PBP3, IPM to PBP1a, PBP2, and PBP3, and DUR to OXA-23 and OXA-51. The time-kill studies performed using carbapenemase- and non-carbapenemase-producing isolates demonstrated synergy between SUL and IPM in the presence of DUR, supporting the notion that the efficacy of the SUL/DUR arm against spp. in the ATTACK trial was enhanced by the addition of IPM. We also hypothesize that the protection of SUL and IPM from OXA carbapenemases by DUR enabled IPM and SUL to synergistically deactivate multiple PBPs ("target redundancy"). Docking simulations supported the favorable binding of SUL to PBP1a and PBP3, resulting in the formation of acyl-enzyme complexes. Molecular docking analysis of OXA carbapenemase enzymes with DUR also revealed favorable interactions. Although clinical trials are warranted, these analyses provide mechanistic support for the addition of IPM to SUL/DUR.

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. People living with HIV are at risk of liver disease. ISL is metabolized by adenosine deaminase (ADA), which is expressed in the liver; thus, ISL pharmacokinetics (PK) may be affected by hepatic impairment. This study evaluated the effect of moderate hepatic impairment on ISL PK. This nonrandomized, open-label, phase 1 study (MK-8591-030) evaluated the effects of a single oral dose of ISL 60 mg in HIV-seronegative adults with moderate hepatic insufficiency ( = 6) and matched healthy adult participants ( = 6). Blood samples for plasma ISL and 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) and peripheral blood mononuclear cell (PBMC) ISL-triphosphate (ISL-TP) were collected at multiple time points through 672 h, and safety was monitored throughout. Modest decreases in maximum measured concentration () and area under the concentration-time curve (AUC) of plasma ISL and AUC of PBMC ISL-TP were observed in participants with moderate hepatic impairment versus matched healthy participants, while ISL-TP was relatively unchanged. In contrast, plasma M4 was modestly increased in the moderate hepatic impairment group, suggesting that hepatic impairment may result in increased metabolism of ISL to M4 via ADA. The clinical relevance of the overall modest changes in M4, ISL, and ISL-TP levels with moderate hepatic impairment will be contextualized once exposure response data from ongoing clinical studies are available to elucidate the thresholds for clinical efficiency. A single oral dose of ISL 60 mg was generally well tolerated in both groups.CLINICAL TRIALSThis study is registered with Clinicaltrials.gov as NCT04515641.

We evaluated the antimicrobial susceptibility of 1,400 clinical isolates of consecutively collected from United States medical centers in 2019-2023. Aztreonam-avibactam (MIC, 2/4 µg/mL; 99.6% inhibited at ≤8 µg/mL) was the most active compound, followed by trimethoprim-sulfamethoxazole (MIC, ≤0.12/0.5 µg/mL; 96.9% susceptible), minocycline (MIC, 0.5/2 µg/mL; 89.2% susceptible), and levofloxacin (MIC, 1/8 µg/mL; 78.9% susceptible). Aztreonam-avibactam retained potent activity against isolates not susceptible to trimethoprim-sulfamethoxazole, minocycline, and/or levofloxacin (99.3%-100.0% inhibited at ≤8 µg/mL).

Primaquine is the only widely available drug to prevent relapses of malaria. Primaquine is underused because of concerns over oxidant hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency. A pharmacometric trial showed that ascending-dose radical cure primaquine regimens causing 'slow burn' hemolysis were safe in G6PD-deficient Thai and Burmese male volunteers. We developed and calibrated a within-host model of primaquine hemolysis in G6PD deficiency, using detailed serial hemoglobin and reticulocyte count data from 23 hemizygote deficient volunteers given ascending-dose primaquine (1,523 individual measurements over 656 unique time points). We estimate that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian variants. We predict that 5 mg/kg primaquine total dose can be administered safely to G6PD-deficient individuals over 14 days with expected hemoglobin drops of 18 to 43% (2.7 to 6.5 g/dL drop from a baseline of 15 g/dL).CLINICAL TRIALSThis study is registered with the Thai Clinical Trials Registry (TCTR) as TCTR20170830002 and TCTR20220317004.

acquires fosfomycin resistance through chromosomal mutations that reduce drug uptake and by drug-inactivating enzymes. However, the complete resistance mechanisms remain to be elucidated. The aim of this study was to elucidate the genetic mechanisms regulating fosfomycin susceptibility in uropathogenic (UPEC). We constructed a highly saturated transposon mutant library containing >340,000 unique Tn5 insertions in a clinical UPEC strain. We conducted transposon-directed insertion site sequencing (TraDIS) to screen for chromosomal genes whose mutations are beneficial for bacterial growth and survival in the presence of fosfomycin at 4 and 32 µg/mL. TraDIS analysis identified 67 genes including known resistance determinants ( = 13) as well as a set of novel genes modulating fosfomycin susceptibility ( = 54). These genes are involved in pyruvate metabolism, pentose phosphate pathway, nucleotide biosynthesis, DNA repair, protein translation, cellular iron homeostasis, and biotin biosynthesis. Deletion of 16 selected genes in the wild-type strain resulted in growth advantages and decreased susceptibility when exposed to fosfomycin. Notably, deletion of DNA repair genes (i.e. and ) and purine synthesis genes (i.e., and its upstream gene ) led to the most significant advantages in competitive and non-competitive growth in the presence of fosfomycin, as well as the highest increase of fosfomycin MIC (8- to 16-fold). These findings provide a genome-wide overview of genes required for maintaining fosfomycin susceptibility in , highlighting new mutations and functional pathways that may be used by UPEC to develop clinical resistance.

Ibezapolstat (IBZ) is a competitive inhibitor of the bacterial Pol IIIC enzyme in clinical development for the treatment of infection (CDI). Previous studies demonstrated that IBZ carries a favorable microbiome diversity profile compared to vancomycin (VAN). However, head-to-head comparisons with other CDI antibiotics have not been done. The purpose of this study was to compare microbiome changes associated with IBZ to other clinically used CDI antibiotics. Groups of germ-free (GF) mice received a fecal microbiota transplant from one of two healthy human donors and were subsequently exposed to either IBZ, VAN, fidaxomicin (FDX), metronidazole (MET), or no antibiotic (control). 16S rRNA encoding gene sequencing of temporally collected stool samples was used to compare the gut microbiome perturbations between treatment and no-drug control groups. Among the tested antibiotics, the most significant change in microbiome diversity was observed in MET-treated mice. Each antibiotic had a unique effect, but changes in alpha and beta diversities following FDX- and IBZ-treated groups were less pronounced than those observed in VAN- or MET-treated groups. By the end of therapy, both IBZ and FDZ increased the relative abundance of (phylum), with IBZ additionally increasing the relative abundance of (phylum). In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity than VAN and MET. Notable differences were observed between the microbiome of IBZ- and FDX-treated groups, which may allow for differentiation of these two antibiotics in future studies.

The increase in multidrug-resistant (MDR) complex (ECC) infections, particularly those resistant to carbapenems, underscores the urgent need for alternative therapies. Phage therapy, with its specific bactericidal action, offers a promising solution. However, there remains a shortage of well-characterized ECC-targeting phages, and dosing and timing optimization for ECC-specific phage cocktails is largely unexplored. In this study, we isolated and characterized three novel lytic phages with diverse genome sizes and host ranges. Notably, ФEBU8 demonstrated broad-spectrum activity, lysing both species and . ФECL22 displayed stability across a wide temperature range (4-50°C), pH tolerance (6-10), and a burst size of 19 PFU/cell, with OmpA identified as its receptor. Our formulated phage cocktail, comprising ФEBU8, ФECL22, and ФECL30, effectively rescued mice with bacteremia in a dose-dependent manner, with a mid-dose regimen showing particularly strong efficacy. Immediate phage administration achieved full survival, whereas a combined prophylactic and therapeutic regimen ("-24 + 6") also resulted in 100% survival. These findings highlight the critical roles of dosing and timing in optimizing phage therapy for carbapenem-resistant infections, with prophylactic use providing a valuable window for delayed treatment and a promising strategy for combating severe bacterial infections.

Ibezapolstat (IBZ), a first-in-class antibiotic targeting the PolC-type DNA polymerase III alpha-subunit (PolC) in low G + C bacteria, is in clinical development for the treatment of infection (CDI). In the phase 2 trials, IBZ had potent activity against while sparing or causing regrowth of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales, common commensal low G + C bacteria. The purpose of this study was to utilize approaches to better interpret the narrower than expected IBZ spectrum of activity. IBZ susceptibility to human commensal microbiota was predicted using genomic analysis and PolC phylogenetic tree construction in relation to and commensal low G + C bacteria. Protein structure prediction was performed using AlphaFold2 and binding pocket homology modeling was performed using Schrodinger Maestro and UCSF ChimeraX. An amino acid phylogenetic tree identified certain residues that were phylogenetically variant in Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales and conserved in . Chemical modeling showed that these residues ablated key PolC•IBZ predicted interactions including two lysine "" (Lys1148 and Lys1327) that "" onto the compound; an "" interaction (Thr1331) to the central moiety; and a stabilized set of sensitizer residues (Thr1291 and Lys1292) that resulted in the prolonged inhibition of a catalytic residue (Asp1090). The observed IBZ sparing of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichaceae/Coprobacillaceae was predicted using techniques. Further studies that confirm a PolC structural basis for the IBZ narrower than expected activity are needed to confirm these phylogenetic and chemical modeling data.

Flaviviruses are the causative agents of viral hemorrhagic fever (VHF) globally and have demonstrated the capacity to result in fatal outcomes if not managed effectively. Among different types of flaviviruses, dengue (DENV) and Japanese encephalitis (JEV) viruses are the most common in tropical and subtropical countries. While vaccines have been developed and licensed for both DENV and JEV, effective treatment options remain sparse. Hence, there is a pressing need to develop small molecules that can target machineries crucial for virus replication and remain conserved across different flaviviruses, thereby could serve as a promising therapeutic option. This study outlines the synthesis of novel thiazole compounds as flavivirus NS2B-NS3 protease inhibitor and characterization of their antiviral activity against DENV and JEV. We synthesized a heterocyclic template derived from a substrate-based retrotripeptide dengue protease inhibitor, leading to 48 thiazole derivatives. Two compounds, 3aq and 3au demonstrated significant inhibition of dengue virus protease activity . Comprehensive characterization of these two compounds was conducted through biochemical assay, which revealed an uncompetitive mode of inhibition. Subsequent cell-based assays using Dengue and Japanese encephalitis viruses as representative flaviviruses revealed the potential of these compounds to block viral RNA synthesis, and viral replication exhibiting 50% inhibitory concentrations (IC50s) in the low-micromolar range. Time-course experiments unveiled that the two compounds impeded the accumulation of viral genomic RNA primarily at later stages of infection, aligning with their capacity to hinder NS2B-NS3 protease activity, polyprotein processing and viral genomic RNA replication. Finally, time of addition experiment showed the compounds remain effective even when added 9 hpi, thereby confirming their potential as promising antivirals. Together, our work presents the development and validation of flavivirus protease inhibitors with therapeutic potential against Dengue (DENV2) and Japanese encephalitis viruses.

ZSP1273 is a novel small-molecule anti-influenza drug that targets the RNA polymerase PB2 subunit, while oseltamivir is the first-line medication that inhibits neuraminidase. ZSP1273 showed high efficacy against human influenza viruses both and , including oseltamivir-resistant strains . In future clinical applications, the combination of these two antiviral drugs with different mechanisms can reduce the potential for antiviral resistance that may arise from monotherapy. To evaluate the drug-drug interaction between ZSP1273 and oseltamivir by the pharmacokinetics and safety of co-administration in healthy subjects, a phase I, single-center, randomized, open-label, three-period crossover study was conducted. Thirty-six subjects enrolled were randomized in a 1:1:1 ratio into three crossover treatment sequences with oral administration detailed as follows: treatment A: ZSP1273 tablets 600 mg once daily (QD) for 5 days; treatment B: oseltamivir capsules 75 mg twice daily (BID) for 5 days; treatment C: ZSP1273 tablets 600 mg once daily (QD) + oseltamivir capsules 75 mg twice daily (BID) for 5 days. Plasma samples were collected from all subjects at scheduled time points after drug administration to measure the plasma concentrations of ZSP1273, oseltamivir, and its active metabolite oseltamivir carboxylate, for pharmacokinetic analysis. Compared with monotherapy, the geometric mean ratios (90% confidence intervals) of C, AUC, AUC, and AUC for ZSP1273 after co-administration were all within the ineffective boundary range of 80% to 125%, supporting that no drug-drug interaction occurs with ZSP1273. After co-administration, the AUC, AUC, and AUC of oseltamivir were all within 80% to 125%, while C decreased by 39.9%. The pharmacokinetic parameters above of oseltamivir carboxylate remained within 80%-125%, except only the lower bound of the 90% CI for C slightly below 80% (77.0%). Considering the rapid metabolism of oseltamivir into the active metabolite oseltamivir carboxylate and the minor impact of co-administration on the pharmacokinetic parameters of oseltamivir carboxylate, it is believed that no clinically significant drug-drug interaction was observed with the combination of these two drugs. During the trial, the safety and tolerability of both combination therapy and monotherapy were good, with no increased safety risks observed from the combination therapy.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05108051.

Malaria parasites acquire drug resistance through genetic changes, the mechanisms of which remain incompletely understood. Understanding the mechanisms of drug resistance is crucial for the development of effective treatments against malaria, and for this purpose, new genetic tools are needed. In a previous study, as a forward genetic tool, we developed the rodent malaria parasite mutator (PbMut) line, which has a greatly increased rate of mutation accumulation and from which we isolated a mutant with reduced susceptibility to piperaquine (PPQ). We identified a mutation in the (PbCRT N331I) as responsible for this phenotype. In the current study, we generated a marker-free PbMut to enable further genetic manipulation of the isolated mutants. Here, we screened again for PPQ-resistant mutants in marker-free PbMut and obtained a parasite population with reduced susceptibility to PPQ. Of five isolated clones, none had the mutation PbCRT N331I; rather, they possessed a nonsense mutation at amino acid 119 (PbCRT Y119*), which would truncate the protein before eight of its ten predicted transmembrane domains. The PbCRT orthologue in the human malaria parasite , PfCRT, is an essential membrane transporter. To address the essentiality of PbCRT, we successfully deleted the full gene [(-)] from wild-type parasites. (-) parasites exhibited reduced susceptibility to PPQ, along with compromised fitness in mice and following transmission to mosquitoes. Taken together, our findings provide the first evidence that can acquire reduced PPQ susceptibility through complete loss of PbCRT function.

Methicillin-resistant (MRSA), a principal causative agent of infections worldwide, urgently requires innovative interventions to counter its increasing risk. The present study revealed the profound impact of farrerol (FA), a robust bioactive agent, on the virulence and resistance mechanisms of MRSA. Our in-depth investigation revealed that FA significantly mitigated the β-lactam resistance of MRSA USA300, an achievement attributed to its precise interference with the BlaZ and Pbp2a protein. Additionally, FA indirectly diminishes the oligomerization of PBP2a by disrupting pigment synthesis, further contributing to its efficacy. In addition, FA extends its functional footprint beyond resistance modulation, exhibiting substantial antivirulence efficacy through selective inhibition of the accessory gene regulator (Agr) system, thereby significantly curbing MRSA pathogenicity in A549 cell and murine models. This study comprehensively explored the multiple impacts of FA on MRSA, shedding light on its versatile role as a BlaZ suppressor, pigment synthesis regulator, and AgrA activity modulator. These intricate findings firmly position FA as a compelling therapeutic candidate for addressing MRSA infections in the clinic.

A hub and spoke model for optimizing long-term treatment of chronic staphylococcal infections with dalbavancin based on therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) was implemented. This multicentric retrospective cohort study included patients receiving dalbavancin monotherapy lasting >6 weeks at different spoke hospitals having treatment optimized by means of a TDM-guided ECPA program at a hub hospital. Optimal pharmacokinetic/pharmacodynamic target against staphylococci with an MIC up to 0.125 mg/L was defined as dalbavancin concentrations >8.04 mg/L. Patients received dalbavancin therapy for curative (curative group) or suppressive (suppressive group) purposes. Clinical outcome was assessed by means of repeated ambulatory visits. A total of 12 spoke hospitals applied for 414 TDM-based ECPA for 101 patients, of whom 64.4% (65/101) were treated for curative and 35.6% (36/101) were for suppressive purposes. In the curative and suppressive groups, TDM-based ECPA optimized treatment for up to 14 and 28 months, respectively, and ensured median optimal exposure of 95.7% and 100%, respectively. In the curative group, having <70% of treatment time with concentrations above the optimal target increased failure risk [odds ratio (OR), 6.71; confidence interval (CI), 0.97-43.3; = 0.05]. In the suppressive group, infective endocarditis was associated with an increased risk of ineffective treatment (OR, 8.65; CI, 1.29-57.62; = 0.046). Mild adverse events were reported in 4.5% (5/101) of cases. A hub and spoke TDM-guided ECPA program of dalbavancin may be cost-effective for optimizing long-term treatment of chronic staphylococcal infections and for patients admitted to hospitals lacking in-house MD clinical pharmacologists.

Despite the various strategies that microorganisms have evolved to resist antibiotics, survival to drug treatments can be driven by subpopulations of susceptible bacteria in a transient state of dormancy. This phenotype, known as bacterial persistence, arises due to a natural and ubiquitous heterogeneity of growth states in bacterial populations. Nonetheless, the unifying mechanism of persistence remains unknown, with several pathways being able to trigger the phenotype. Here, we show that asymmetric damage partitioning, a form of cellular aging, produces the underlying phenotypic heterogeneity upon which persistence is triggered. Using single-cell microscopy and microfluidic devices, we demonstrate that deterministic asymmetry in exponential phase populations leads to a state of growth stability, which prevents the spontaneous formation of persisters. However, as populations approach stationary phase, aging bacteria-those inheriting more damage upon division-exhibit a sharper growth rate decline, increased probability of growth arrest, and higher persistence rates. These results indicate that persistence triggers are biased by bacterial asymmetry, thus acting upon the deterministic heterogeneity produced by cellular aging. This work suggests unifying mechanisms for persistence and offers new perspectives on the treatment of recalcitrant infections.