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Staphylococcus aureus (SA) is a leading cause of bloodstream infection. The liver represents the sentinel immune organ for clearance of bloodstream pathogens and eradication of intracellular SA from liver-resident macrophages (Kupffer cells, KCs) eliminates the likely pathogenic reservoir that contributes to persistent bacteraemia., Objectives: We assessed antimicrobial activity at phagolysosome-mimicking pH, intracellular penetration, and SA eradication within KCs in vitro for clinically prescribed antistaphylococcal agents alone or in combination: vancomycin, daptomycin, ceftaroline, ceftobiprole, oritavancin, oxacillin, cefazolin; rifampin and fosfomycin., Methods: pH-adjusted broth microdilution assays, intracellular bioaccumulation assays, and intracellular killing assays against clinical bloodstream isolates were performed using a murine KC line with study agents., Results: Rifampin and β-lactams exhibited enhanced activity [2- to 16-fold minimum inhibitory concentrations (MIC) decrease] at phagolysosomal pH while vancomycin, oritavancin, daptomycin and fosfomycin demonstrated reduced activity (2- to 32-fold MIC increase in order of least to greatest potency reduction). All agents evaluated had poor to modest intracellular to extracellular concentration ratios (0.024-7.8), with exceptions of rifampin and oritavancin (intracellular to extracellular ratios of 17.4 and 78.2, respectively). Finally, we showed that the first-line treatment for SA bacteraemia (SAB), vancomycin, performed worse than all other tested antibiotics in eradicating intracellular SA at human Cmax concentration (0.20 log cfu decrease), while oritavancin performed better than all other agents alone (2.05 versus 1.06-1.36 log cfu decrease)., Conclusions: Our findings raise concerns about the efficacy of commonly prescribed antibiotics against intracellular SA reservoirs and emphasize the need to consider targeting pathogen eradication from the liver to achieve early control of SAB., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Up to 32% of ESBL-producing Enterobacterales strains display a carbapenem-heteroresistant (cHR) phenotype but its clinical relevance is unknown., Objectives: To determine risk factors and clinical outcome associated with infection due to cHR ESBL-producing Escherichia coli (ESBL-EC)., Methods: A retrospective, case-control study was conducted on patients from whom a pair of clonally related E. coli strains were isolated during separate healthcare encounters with (case) or without (control) development of cHR phenotype in the latter strain. Study groups were compared for host and microbial characteristics and carbapenem exposure. Outcome measures included ICU admission, length of hospitalization, and mortality., Results: Study patients (15 cases, 10 controls) were elderly (median age: 74 years) with half admitted from home (52%), most (80%) having ≥3 comorbid conditions and severe functional impairment. Case patients were more likely to have 'index' ESBL-EC isolating from blood (27% versus 0%; P =  0.125) and have greater cumulative amount and duration of carbapenem exposure than controls. All control 'subsequent' isolates were from urine whereas five cHR case isolates were from blood or respiratory sources. More hospitalized case patients required ICU admission (23% versus 0%; P =  0.257) and prolonged hospital stay (>7 days) than controls (62% versus 38%%; P =  0.387)., Conclusions: Our findings deserve confirmation with a larger study population and call attention to the potential for increased morbidity with cHR ESBL-EC infections, which underscores the need to screen for cHR phenotype in patients with repeated growth of ESBL-EC, particularly from systemic sites and patients that have had extensive carbapenem exposure., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: Socioeconomic status (SES) is a complex variable that is derived primarily from an individual's education, income, and occupation and has been found to be inversely related to outcomes of health conditions. Sepsis is the sixth most common admitting diagnosis and one of the most costly conditions for in-hospital spending in the United States. The objective of this review is to report on the relationship between SES and sepsis incidence and associated outcomes., Content: Sepsis epidemiology varies when explored by race, education, geographic location, income, and insurance status. Sepsis incidence was significantly increased in individuals of Black race compared with non-Hispanic white race; in persons who have less formal education, who lack insurance, and who have low income; and in certain US regions. People with low SES are likely to have onset of sepsis significantly earlier in life and to have poorly controlled comorbidities compared with those with higher SES. Sepsis mortality and hospital readmission is increased in individuals who lack insurance, who reside in low-income or medically underserved areas, who live far from healthcare, and who lack higher level education; however, a person's race was not consistently found to increase mortality., Summary: Interventions to minimize healthcare disparity for individuals with low SES should target sepsis prevention with increasing measures for preventive care for chronic conditions. Significant barriers described for access to care by people with low SES include cost, transportation, poor health literacy, and lack of a social network. Future studies should include polysocial risk scores that are consistently defined to allow for meaningful comparison across studies., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please contact: journals.permissions@oup.com.)

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Carbapenem-heteroresistant (cHR) Enterobacteriaceae strains have been reported worldwide; however, the prevalence among clinical ESBL-producing Enterobacteriaceae isolates obtained from patients with repeated hospital admissions remains largely unknown., Methods: Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem and ceftolozane/tazobactam. MIC testing was performed by broth microdilution against carbapenems and a panel of agents with potential activity against ESBL-producing strains., Results: One hundred and seventy-three ESBL-producing meropenem-susceptible Escherichia coli and Klebsiella pneumoniae isolates were selected for testing. A total of 519 bacteria/carbapenem combinations were screened by disc diffusion; 84 combinations were identified as cHR. Modified PAP confirmed 70 bacteria/carbapenem combinations as heteroresistant; most (63%, 44/70) confirmed cHR colonies grew within the ertapenem zone of inhibition, followed by imipenem (30%, 21/70), then meropenem (7%, 5/70). In total, one-third of the unique patient isolates (32%, 55/173) were identified as being heteroresistant to at least one carbapenem; of those patients, 16% (9/55) had a carbapenem-non-susceptible isolate on subsequent visits. Only two cHR isolates screened positive for ceftolozane/tazobactam heteroresistance (1%, 2/173), of which one was confirmed heteroresistant by modified PAP. cHR isolates were more likely to be collected from a non-urinary source (e.g. respiratory) compared with non-cHR isolates (31% versus 19%, P = 0.02). MIC distributions of all tested antibiotic agents did not differ between non-cHR and cHR isolates., Conclusions: Our findings raise concerns for the continued use of carbapenems as first-line therapy for ESBL infections and for the potential selection for strains with full carbapenem resistance., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Persistent Staphylococcus aureus bacteremia (SAB) is defined based on varying duration in literature. The primary objective was to determine the risk of poor outcomes in relation to bacteremia duration., Methods: Multicenter, prospective, observational study of adult hospitalized patients with SAB. Medical records were reviewed for pertinent data. Patients were grouped by bacteremia duration: short (1-2 days), intermediate (3-6 days), and prolonged (≥7 days) and compared for risk factors and outcomes., Results: Of 884 patients, 63% had short, 28% intermediate, and 9% prolonged bacteremia. Overall mean age was 57 years, and 70% were male. The prolonged group had the highest proportion of methicillin-resistant SAB (P < .0001). Choice of antibiotic therapy did not significantly affect bacteremia duration; however, time to source-control procedure was delayed in the prolonged and intermediate groups compared with the short group (3.5 vs 3 vs 1 day, P < .0001). Metastatic complications, length of stay, and 30-day mortality were progressively worse as bacteremia duration increased (P < .0001). Every continued day of bacteremia was associated with a relative risk of death of 1.16 (95% confidence interval, 1.10-1.22; P < .0001), with a significant increase in risk starting at 3 days as determined by receiver operating characteristic analysis., Conclusions: Optimal management of SAB should target bacterial clearance as soon as possible to minimize incremental risk of mortality with each day of positive blood culture. Delay in source control but not type of antistaphylococcal therapy was significantly associated with prolonged bacteremia and worse outcomes., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Chronic endobronchial infections with Pseudomonas aeruginosa contribute to bronchiectasis and progressive loss of lung function in patients with cystic fibrosis. This study aimed to evaluate the therapeutic potential of a novel macrocyclic peptide, rhesus θ-defensin-1 (RTD-1), by characterizing its in vitro antipseudomonal activity and in vivo efficacy in a murine model of chronic Pseudomonas lung infection., Methods: Antibacterial testing of RTD-1 was performed on 41 clinical isolates of P. aeruginosa obtained from cystic fibrosis patients. MIC, MBC, time-kill and post-antibiotic effects were evaluated following CLSI-recommended methodology, but using anion-depleted Mueller-Hinton broth. RTD-1 was nebulized daily for 7 days to cystic fibrosis transmembrane conductance regulator (CFTR) F508del-homozygous mice infected using the agar bead model of chronic P. aeruginosa lung infection. In vivo activity was evaluated by change in lung bacterial burden, airway leucocytes and body weight., Results: RTD-1 exhibited potent in vitro bactericidal activity against mucoid and non-mucoid strains of P. aeruginosa (MIC90 = 8 mg/L). Cross-resistance was not observed when tested against MDR and colistin-resistant isolates. Time-kill studies indicated very rapid, concentration-dependent bactericidal activity of RTD-1 with ≥3 log10 cfu/mL reductions at concentrations ≥4× MIC. No post-antibiotic effect was observed. In vivo, nebulized treatment with RTD-1 significantly decreased lung P. aeruginosa burden (mean difference of -1.30 log10 cfu; P = 0.0061), airway leucocytes (mean difference of -0.37 log10; P = 0.0012) and weight loss (mean difference of -12.62% at day 7; P < 0.05) when compared with controls., Conclusions: This study suggests that RTD-1 is a promising potential therapeutic agent for cystic fibrosis airway disease., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Candida non-albicans species cause an increasing proportion of invasive candidiasis (IC). Prompt initiation of effective antifungal therapy has been shown to positively impact the outcomes of IC. Caspofungin is often reserved as a second-line agent after suboptimal response to initial therapy. We determined the impact of the timing of caspofungin administration on outcomes of IC., Methods: Medical records were reviewed on all hospitalized adults who received >or=72 h of caspofungin for IC (isolation of Candida species from blood, intra-abdominal or other sterile sites). Clinical data were extracted from medical charts and recorded. Patients were classified based on delayed initiation (DI; >3 days) versus early initiation (EI;

Background: We previously reported ciprofloxacin resistance (CR) and empirical use of fluoroquinolones as predictors of mortality in patients infected with Pseudomonas aeruginosa in a case-control study. Here, we assessed the clinical impact of reducing empirical fluoroquinolone use for P. aeruginosa infections in hospitalized patients by performing a follow-up study in 2005-06 [period 2 (P2)] and comparing this with prior data from 2001-02 [period 1 (P1)]., Methods: Medical charts of infected patients who received at least 72 h of antibiotic therapy were reviewed. Patients were subgrouped based on the susceptibility of infected strains into the CR or ciprofloxacin-susceptible group. Antibiograms, patient and treatment variables and outcome measures were compared between groups and between study periods., Results: Study patients were elderly (median age, 76 years), had a median of three co-morbidities and a median APACHE II score of 13. Most (75%) had pneumonia or urosepsis. Empirical use of fluoroquinolones was reduced by 30% in P2 versus P1, with a corresponding 39% increase in piperacillin/tazobactam use. The resultant positive impact observed in the CR group during P2 includes shortened delay to receipt of effective therapy (1 versus 3.5 days, P < 0.0001), reduced length of stay (13 versus 16 days, P = 0.03) and 2-fold lower mortality (9% versus 22%, P = 0.05). Susceptibility of P. aeruginosa improved by 10% to all antipseudomonal agents tested., Conclusions: In settings where high rates of fluoroquinolone resistance exist, use of non-fluoroquinolone-based empirical regimens for P. aeruginosa infections improves patient outcomes and organism susceptibility over time.

Objectives: Resistance among Pseudomonas aeruginosa has risen dramatically and parallels the increase in fluoroquinolone (FQ) prescribing in recent years. Risk factors for FQ resistance in P. aeruginosa and its impact on outcomes need to be well characterized., Methods: A case-control study was carried out on hospitalized adult patients from whom FQ-resistant (case) and FQ-susceptible (control) P. aeruginosa were isolated., Results: A total of 177 patients with positive cultures (91 cases and 86 controls) and 119 with documented infections (65 cases, 54 controls) were included in risk factor and outcomes analysis, respectively. Independent risk factors for FQ resistance were: FQ exposure (OR 12.6, CI 4.95-32), nosocomial acquisition (OR 8.6, CI 3.5-20.7), and diabetes mellitus (OR 6.4, CI 2.1-19.3). An FQ agent was prescribed in 59% of patients receiving an 'antipseudomonal' empirical regimen. Compared with controls, FQ-resistant cases had a median delay to receiving effective therapy of 3.5 days versus 1 day and poorer outcomes: (i) lower complete response rate (45% versus 63%, P=0.04); (ii) longer time to achieve clinical stability (8 days versus 3 days, P=0.005); and (iii) higher infection-related mortality (21% versus 7%; OR = 2.9, 0.9-9.4). Empirical FQ use (OR 4.6, CI 1.5-14.3), FQ resistance (OR 3.6, CI 1.0-13.1), and high APACHE II score (OR 1.1, CI 1.0-1.2) were independent risk factors for increased mortality., Conclusions: FQ exposure from widespread prescribing is a modifiable risk factor for FQ resistance in P. aeruginosa. FQ empirical therapy for Pseudomonas infections may be associated with significant delays in administering effective therapy resulting in adverse outcomes.

Data are limited on outcomes of treatment with extended-spectrum cephalosporins (ESCs) for infections caused by Enterobacteriaceae that produce extended-spectrum beta-lactamases (ESBLs). This study describes the largest treatment experience of a nonoutbreak series of bloodstream infections caused by strains of Escherichia coli (23 episodes) and Klebsiella pneumoniae (13 episodes) with a ceftazidime minimal inhibitory concentration of > or =2 microg/mL. E. coli isolates produced a greater variety of beta-lactamase types than did K. pneumoniae isolates, among which ESBL production was predominant. Five ESBL types were identified: TEM-12, TEM-71, TEM-6, SHV-12, and SHV-5. Most patients were treated empirically with an ESC-based regimen. A favorable response to treatment with a nonceftazidime ESC was observed when the causative pathogen produced either TEM-6 or TEM-12; ceftazidime treatment was associated with failure of therapy in all patients. Despite the limited clinical success, ESCs are currently not recommended for the treatment of serious infections caused by ESBL-producing strains.