Longitudinal Analysis of Inflammatory Response to SARS-CoV-2 in the Upper Respiratory Tract Reveals an Association with Viral Load, Independent of Symptoms.

BACKGROUND: SARS-CoV-2 infection leads to high viral loads in the upper respiratory tract that may be determinant in virus dissemination. The extent of intranasal antiviral response in relation to symptoms is unknown. Understanding how local innate responses control virus is key in the development of therapeutic approaches. METHODS: SARS-CoV-2-infected patients were enrolled in an observational study conducted at the Geneva University Hospitals, Switzerland, investigating virological and immunological characteristics. Nasal wash and serum specimens from a subset of patients were collected to measure viral load, IgA specific for the S1 domain of the spike protein, and a cytokine panel at different time points after infection; cytokine levels were analyzed in relation to symptoms. RESULTS: Samples from 13 SARS-CoV-2-infected patients and six controls were analyzed. We found an increase in CXCL10 and IL-6, whose levels remained elevated for up to 3 weeks after symptom onset. SARS-CoV-2 infection also induced CCL2 and GM-CSF, suggesting local recruitment and activation of myeloid cells. Local cytokine levels correlated with viral load but not with serum cytokine levels, nor with specific symptoms, including anosmia. Some patients had S1-specific IgA in the nasal cavity while almost none had IgG. CONCLUSION: The nasal epithelium is an active site of cytokine response against SARS-CoV-2 that can last more than 2 weeks; in this mild COVID-19 cohort, anosmia was not associated with increases in any locally produced cytokines.

Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial.

Importance: Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. Objective: To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Design, Setting, and Participants: Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Intervention: Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). Main Outcomes and Measures: The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Results: Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Conclusions and Relevance: Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. Trial Registration: ClinicalTrials.gov Identifier: NCT03101072.

The pharmacokinetics of nitrofurantoin in healthy female volunteers: a randomized crossover study.

BACKGROUND: Use of nitrofurantoin has increased significantly since its recent repositioning as a first-line agent for uncomplicated cystitis by multiple guidelines. However, current dosing regimens were developed in an era before robust pharmacokinetic testing and may not be optimal. Furthermore, formulations have been modified over the years. OBJECTIVES: To reassess the plasma and urinary pharmacokinetic profile of macrocrystalline nitrofurantoin in two commonly used dosing regimens. METHODS: In this open-label, randomized crossover pharmacokinetic trial, 12 healthy adult female volunteers were randomized to receive oral nitrofurantoin 100 mg q8h on days 1 and 2 and, after a washout period, 50 mg q6h on days 30 and 31, or the same dosing schemes in reversed order. Urine and blood were collected at steady state and analysed by UPLC. Pharmacokinetic analysis was performed by WinNonlin. RESULTS: Plasma peak concentrations were low (mean 0.33 mg/L, SD 0.08, and 0.69 mg/L, SD 0.35, after 50 and 100 mg, respectively) and dose dependent. The AUC0-24 was higher (6.49 versus 4.43 mg·h/L, P = 0.021) for the 100 mg q8h dosing regimen, but the dose-normalized AUC was similar for the two regimens. In contrast, urinary concentrations were dose independent: increasing the nitrofurantoin dose delayed the time to peak urinary concentration, while steady-state AUC0-24 values remained unchanged (943.49 and 855.95 mg·h/L at 50 mg q6h and 100 mg q8h, respectively). CONCLUSIONS: Plasma concentrations were relatively low and dose dependent. The dose-independent urinary concentrations suggest that excretion of nitrofurantoin into the urine is saturable. Pharmacodynamic studies are urgently required to determine the impact of these findings.

Remission in diabetic foot infections: Duration of antibiotic therapy and other possible associated factors.

AIM: To determine the most appropriate duration of antibiotic therapy for diabetic foot infections (DFIs). METHODS: Using a clinical pathway for adult patients with DFIs (retrospective cohort analysis), we created a cluster-controlled Cox regression model to assess factors related to remission of infection, emphasizing antibiotic-related variables. We excluded total amputations as a result of DFI and DFI episodes with a follow-up time of <2 months. RESULTS: Among 1018 DFI episodes in 482 patients, we identified 392 episodes of osteomyelitis, 626 soft tissue infections, 246 large abscesses, 322 episodes of cellulitis and 335 episodes of necrosis; 313 cases involved revascularization. Patients underwent surgical debridement for 824 episodes (81%), of which 596 (59%) required amputation. The median total duration of antibiotic therapy was 20 days. After a median follow-up of 3 years, 251 of the episodes (24.7%) were followed by ≥1 additional episode(s). Comparing patients with and without additional episodes, risk of recurrence was lower in those who underwent amputation, had type 1 diabetes, or underwent revascularization. On multivariate analysis including the entire study population, risk of remission was inversely associated with type 1 diabetes (hazard ratio [HR] 0.3, 95% confidence interval [CI] 0.2-0.6). Neither duration of antibiotic therapy nor parenteral treatment affected risk of recurrence (HR 1.0, 95% CI 0.99-1.01 for both). Similarly, neither >3 weeks versus <3 weeks of therapy, nor >1 week versus <1 week of intravenous treatment affected recurrence. In stratified analyses for both soft tissue DFIs or osteomyelitis separately, we did not observe associations of antibiotic duration with microbiological or clinical recurrences of DFI. The HRs were 1.0 (95% CI 0.6-1.8) for an antibiotic duration >3 weeks overall and 0.6 (95% CI 0.2-1.3) for osteomyelitis cases only. Plotting of duration of antibiotic therapy failed to identify any optimal threshold for preventing recurrences. CONCLUSIONS: Our analysis found no threshold for the optimal duration or route of administration of antibiotic therapy to prevent recurrences of DFI. These limited data might support possibly shorter treatment duration for patients with DFI.

Oral amoxicillin-clavulanate for treating diabetic foot infections.

AIM: To assess amoxicillin-clavulanate (AMC) for the oral therapy of diabetic foot infections (DFIs), especially for diabetic foot osteomyelitis (DFO). METHODS: We performed a retrospective cohort analysis among 794 DFI episodes, including 339 DFO cases. RESULTS: The median duration of antibiotic therapy after surgical debridement (including partial amputation) was 30 days (DFO, 30 days). Oral AMC was prescribed for a median of 20 days (interquartile range, 12-30 days). The median ratio of oral AMC among the entire antibiotic treatment was 0.9 (interquartile range, 0.7-1.0). After a median follow-up of 3.3 years, 178 DFIs (22%) overall recurred (DFO, 75; 22%). Overall, oral AMC led to 74% remission compared with 79% with other regimens (χ2 -test; P = 0.15). In multivariate analyses and stratified subgroup analyses, oral AMC resulted in similar clinical outcomes to other antimicrobial regimens, when used orally from the start, after an initial parenteral therapy, or when prescribed for DFO. CONCLUSIONS: Oral AMC is a reasonable option when treating patients with DFIs and DFOs.

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial.

Importance: The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI). Objective: To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis. Design, Setting, and Participants: Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel. Interventions: Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection. Main Outcomes and Measures: The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events. Results: Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively). Conclusions and Relevance: Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion. Trial Registration: ClinicalTrials.gov Identifier: NCT01966653.

Ubiquitin-mediated mRNP dynamics and surveillance prior to budding yeast mRNA export.

The evolutionarily conserved mRNA export receptor Mex67/NXF1 associates with mRNAs through its adaptor, Yra1/REF, allowing mRNA ribonucleoprotein (mRNP) exit through nuclear pores. However, alternate adaptors should exist, since Yra1 is dispensable for mRNA export in Drosophila and Caenorhabditis elegans. Here we report that Mex67 interacts directly with Nab2, an essential shuttling mRNA-binding protein required for export. We further show that Yra1 enhances the interaction between Nab2 and Mex67, and becomes dispensable in cells overexpressing Nab2 or Mex67. These observations appoint Nab2 as a potential adaptor for Mex67, and define Yra1/REF as a cofactor stabilizing the adaptor-receptor interaction. Importantly, Yra1 ubiquitination by the E3 ligase Tom1 promotes its dissociation from mRNP before export. Finally, loss of perinuclear Mlp proteins suppresses the growth defects of Tom1 and Yra1 ubiquitination mutants, suggesting that Tom1-mediated dissociation of Yra1 from Nab2-bound mRNAs is part of a surveillance mechanism at the pore, ensuring export of mature mRNPs only.

Comparative Genomics of Community-Associated Methicillin-Resistant Staphylococcus aureus Shows the Emergence of Clone ST8-USA300 in Geneva, Switzerland.

BACKGROUND: Previous investigations of community-associated methicillin-resistant Staphylococcus aureus(CA-MRSA) isolates have revealed a wide diversity of genetic backgrounds, with only sporadic occurrence of ST8-USA300, in Geneva, Switzerland. We conducted a molecular epidemiologic analysis to identify the origin of a sudden increase of ST8 PVL-positive isolates in Geneva during 2013. METHODS: On the basis of prospective CA-MRSA surveillance, we collected colonizing and infecting ST8-USA300 isolates and compared them to non-ST8 CA-MRSA isolates. Whole-genome sequencing (WGS) was performed for each isolate of this collection, and discriminating molecular features were linked to patient data. RESULTS: In 2013, 22 isolates with the ST8-USA300 profile were identified among 46 cases of CA-MRSA. WGS revealed 2 groups of strains that differed by the type of the SCCmec IV element encoded and whether they harbored an arginine catabolism mobile element (ACME) locus. ACME-negative strains were mainly isolated from patients traveling in or originating from South America. Single-nucleotide polymorphism positions in isolate groups were used to infer their common ancestor, determine their geographical origin, and trace their relatedness. CONCLUSIONS: WGS allowed the identification of transmission events and revealed that the increased prevalence of USA300 CA-MRSA isolates resulted from multiple importation events from the Americas but not from local clonal expansion of a successful clone.

Duration of antibiotic treatment for Gram-negative bacteremia - Systematic review and individual participant data (IPD) meta-analysis.

Background: We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups. Methods: Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence.Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment. Findings: Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73-1.58; 30-day mortality: 1.08, 0.62-1.91). Relapse (1.00, 0.50-1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80-1.22); and infection complications (local: 1.62 0.76-3.47; distant: 2.00, 0.18-22.08), were without significant difference, and so were adverse events or resistance emergence.No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection. Interpretation: For patients hemodynamically stable and afebrile at 48 h prior to discontinuation, seven days of antibiotic therapy for enterobacterales bacteremia result in similar outcomes as 14 days, in terms of mortality, relapse, length of hospital stay, complications of infection, resistance emergence, and adverse events. These results apply for any adult age group, gender, source of infection, immune status, and hemodynamic status on presentation. Funding: There was no funding source for this study.

Pseudomonal Diabetic Foot Infections: Vive la Différence?

Objective: To assess the outcomes of diabetic foot infections (DFIs) due to Pseudomonas aeruginosa. Patients and Methods: From April 24, 2013 to July 31, 2016, we analyzed data from patients prospectively enrolled in our clinical pathway of DFIs, comparing those with infection due to Pseudomonas with those without infection due to Pseudomonas. Results: Overall, we assessed 1018 cases of DFIs: 392 with osteomyelitis and 626 with only soft tissue infections. The prevalence of P aeruginosa in deep wound cultures was 10% (104/1018); of the 1018 cultures, 22 were monomicrobial, 82 were polymicrobial, and 46 were with osteomyelitis. Overall, the patients were treated with a median of 1 surgical debridement and a total of 20 days of antibiotic therapy. In a comparison of crude groups, the proportion of clinical failures was significantly higher with Pseudomonas than with other pathogens (36/104 [35%] vs 218/914 [24%], respectively; P=.02). A multivariate analysis showed that pseudomonal DFIs did not recur more often than nonpseudomonal DFIs (hazard ratio, 1.0; 95% confidence interval, 0.6-1.7). Among the 104 cases of pseudomonal DFIs, there was no association between failure of treatment and the total duration of antibiotic therapy, duration of intravenous therapy, duration of combined antibiotic therapy with more than 1 agent, or duration of oral (fluoroquinolone) therapy. Among 15 cases of pseudomonal recurrence, 2 (13%) developed resistance to the antibiotic agent used for the index episode. Conclusion: For DFIs caused by P aeruginosa, other than choosing an antibiotic agent that is active against the organism, it does not appear necessary to treat with a different therapeutic regimen compared with the treatment of nonpseudomonal DFIs. There is no difference!

Therapeutic drug monitoring and clinical outcomes in severely ill patients receiving amoxicillin: a single-centre prospective cohort study.

Therapeutic drug monitoring (TDM) of ß-lactam antibiotics is increasingly used to overcome rising antimicrobial resistance and improve antibiotic exposure. However, there is little guidance on target amoxicillin plasma concentrations. We aimed to define these by evaluating associations between amoxicillin concentrations and clinical outcomes. This single-centre prospective cohort study enrolled severely ill and/or immunosuppressed adult patients receiving amoxicillin for suspected or confirmed bacterial infection. TDM with ≥1 intermediate and ≥1 trough level was performed 24 h after therapy initiation. Primary and secondary outcomes were incidence of adverse events (AEs) and clinical failure through Day 30, respectively. A total of 156 patients were included. Important variations were observed both for intermediate (mean 13 mg/L, S.D. 13) and trough (mean 7 mg/L, S.D. 9) amoxicillin levels. Of 111 patients, 33 (30%) had trough levels below the non-species-related breakpoint (2 mg/L). AEs occurred in 27/156 patients (17%); no intermediate- or trough-level threshold predicting toxicity could be established. Patients with the highest-quartile trough levels (9.07-51.5 mg/L) did not experience significantly increased AEs [6/28 (21%) vs. 13/83 (16%); P = 0.6]. Nearly one-third (48/156; 31%) experienced clinical failure; low trough levels did not correlate with failure. There were few amoxicillin AEs yet a relatively high incidence of clinical failure. While no toxicity threshold could be established, the absence of increased AEs among patients with the highest trough concentrations suggests that trough levels up to 40 mg/L may be safe, at least for limited durations. Larger trials must further define optimal amoxicillin concentrations. [ClinicalTrials.gov ID: NCT03790631].

Steering Away from Current Amoxicillin Dose Reductions in Hospitalized Patients with Impaired Kidney Function to Avoid Subtherapeutic Drug Exposure.

Current dose reductions recommended for amoxicillin in patients with impaired kidney function could lead to suboptimal treatments. In a prospective, observational study in hospitalized adults with varying kidney function treated with an IV or oral dose of amoxicillin, amoxicillin concentrations were measured in 1−2 samples on the second day of treatment. Pharmacometric modelling and simulations were performed to evaluate the probability of target attainment (PTA) for 40% of the time above MIC following standard (1000 mg q6h), reduced or increased IV dosing strategies. A total of 210 amoxicillin samples was collected from 155 patients with kidney function based on a CKD-EPI of between 12 and 165 mL/min/1.73 m2. Amoxicillin clearance could be well predicted with body weight and CKD-EPI. Recommended dose adjustments resulted in a clinically relevant reduction in the PTA for the nonspecies-related PK/PD breakpoint MIC of 8 mg/L (92%, 62% and 38% with a CKD-EPI of 10, 20 and 30 mL/min/1.73 m2, respectively, versus 100% for the standard dose). For MICs ≤ 2 mg/L, PTA > 90% was reached in these patients following both reduced and standard dose regimens. Our study showed that for amoxicillin, recommended dose reductions with impaired kidney function could lead to subtherapeutic amoxicillin concentrations in hospitalized patients, especially when targeting less susceptible pathogens.

Impact of restricting procalcitonin measurements in a Swiss tertiary-care hospital on antibiotic use, clinical outcomes, and costs: An interrupted time-series analysis.

We evaluated the impact of a restriction of procalcitonin measurements on antibiotic use, length of stay, mortality, and cost in a Swiss tertiary-care hospital using interrupted time-series analysis. There was no significant change in level or slope for rates of antibiotic consumption, and costs decreased considerably, by ~54,488 CHF (US$55,714) per month.

Effects of antibiotic duration on the intestinal microbiota and resistome: The PIRATE RESISTANCE project, a cohort study nested within a randomized trial.

BACKGROUND: Shortening antibiotic-treatment durations is a key recommendation of antibiotic-stewardship programmes, yet it is based on weak evidence. We investigated whether halving antibiotic courses would reduce antibiotic-resistance genes (ARG) in the intestinal microbiomes of patients treated for gram-negative bacteraemia. METHODS: This nested prospective cohort study included adult patients hospitalized at Geneva University Hospitals (Switzerland) participating in the PIRATE randomized trial assessing non-inferiority of shorter antibiotic courses (7 versus 14 days) for gram-negative bacteraemia ('cases') and, simultaneously, hospitalized patients with similar demography and comorbidity yet no antibiotic therapy ('controls'). Stool was collected from case and control patients on days 7, 14, 30 and 90 after antibiotic initiation (day 1) and days 7 and 14 after admission, respectively, and analysed by whole-metagenome shotgun sequencing. The primary outcome was ARG abundance at day 30; secondary outcomes included microbiota-species composition and clustering over time. FINDINGS: Forty-five patients and 11 controls were included and evaluable; ARG analyses were conducted on the 29 per-protocol patients receiving 7 (±2) days or 14 (±3) days of antibiotic therapy. At day 30, ARGs were not detected at similar abundance in patients receiving 7 and 14 days (median counts/million [mCPM]: 96 versus [vs] 71; p=.38). By day 30, total ARG content between both groups was not significantly different from that of controls at D7 (362 and 370 mCPM vs 314 mCPM, p=.24 and 0.19). There were no significant differences amongst antibiotic-treated patients at any timepoint in bacterial diversity or clustering, but Shannon species diversity was significantly reduced compared to controls through day 14 (median 3.12 and 3.24 in the 7-day and 14-day groups vs 3.61 [controls]; p=.04 and 0.012). Patients treated for 14 days had reduced faecal phage content during and after therapy compared to other patient groups. INTERPRETATION: Reducing antibiotic durations by half did not result in decreased abundance of ARGs in patients treated for gram-negative bacteraemia, nor did it improve microbiota species diversity. FUNDING: The study was funded by the University of Geneva's Louis-Jeantet Foundation (grant no. S04_12) and the Swiss National Science Foundation (NRP Smarter Healthcare, grant no. 407,440_167359).

Risk factors for treatment failure in women with uncomplicated lower urinary tract infection.

Given rising antibiotic resistance and increasing use of delayed prescription for uncomplicated lower urinary tract infections (UTI), patients at risk for treatment failure should be identified early. We assessed risk factors for clinical and microbiological failure in women with lower UTI. This case-control study nested within a randomized clinical trial included all women in the per-protocol population (PPP), those in the PPP with microbiologically confirmed UTI, and those in the PPP with UTI due to Escherichia coli. Cases were women who experienced clinical and/or microbiologic failure; controls were those who did not. Risk factors for failure were assessed using multivariate logistic regression. In the PPP, there were 152 clinical cases for 307 controls. Among 340 women with microbiologically confirmed UTI, 126 and 102 cases with clinical and microbiological failure were considered with, respectively, 214 and 220 controls. Age ≥52 years was independently associated with clinical (adjusted OR 3.01; 95%CI 1.84-4.98) and microbiologic failure (aOR 2.55; 95%CI 1.54-4.25); treatment with fosfomycin was associated with clinical failure (aOR 2.35; 95%CI 1.47-3.80). The association with age persisted among all women, and women with E. coli-related UTI. Diabetes was not an independent risk factor, nor were other comorbidities. Postmenopausal age emerged as an independent risk factor for both clinical and microbiological treatment failure in women with lower UTI and should be considered to define women at-risk for non-spontaneous remission, and thus for delayed antibiotic therapy; diabetes mellitus was not associated with failure.

Population Pharmacokinetics of Imipenem in Critically Ill Patients: A Parametric and Nonparametric Model Converge on CKD-EPI Estimated Glomerular Filtration Rate as an Impactful Covariate.

BACKGROUND: Population pharmacokinetic (popPK) models for antibiotics are used to improve dosing strategies and individualize dosing by therapeutic drug monitoring. Little is known about the differences in results of parametric versus nonparametric popPK models and their potential consequences in clinical practice. We developed both parametric and nonparametric models of imipenem using data from critically ill patients and compared their results. METHODS: Twenty-six critically ill patients treated with intravenous imipenem/cilastatin were included in this study. Median estimated glomerular filtration rate (eGFR) measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 116 mL/min/1.73 m2 (interquartile range 104-124) at inclusion. The usual dosing regimen was 500 mg/500 mg four times daily. On average, five imipenem levels per patient (138 levels in total) were drawn as peak, intermediate, and trough levels. Imipenem concentration-time profiles were analyzed using parametric (NONMEM 7.2) and nonparametric (Pmetrics 1.5.2) popPK software. RESULTS: For both methods, data were best described by a model with two distribution compartments and the CKD-EPI eGFR equation unadjusted for body surface area as a covariate on the elimination rate constant (Ke). The parametric population parameter estimates were Ke 0.637 h-1 (between-subject variability [BSV]: 19.0% coefficient of variation [CV]) and central distribution volume (Vc) 29.6 L (without BSV). The nonparametric values were Ke 0.681 h-1 (34.0% CV) and Vc 31.1 L (42.6% CV). CONCLUSIONS: Both models described imipenem popPK well; the parameter estimates were comparable and the included covariate was identical. However, estimated BSV was higher in the nonparametric model. This may have consequences for estimated exposure during dosing simulations and should be further investigated in simulation studies.

One- vs 2-Stage Bursectomy for Septic Olecranon and Prepatellar Bursitis: A Prospective Randomized Trial.

OBJECTIVE: To assess the optimal surgical approach and costs for patients hospitalized with septic bursitis. PATIENTS AND METHODS: From May 1, 2011, through December 24, 2014, hospitalized patients with septic bursitis at University of Geneva Hospitals were randomized (1:1) to receive 1- vs 2-stage bursectomy. All the patients received postsurgical oral antibiotic drug therapy for 7 days. RESULTS: Of 164 enrolled patients, 130 had bursitis of the elbow and 34 of the patella. The surgical approach used was 1-stage in 79 patients and 2-stage in 85. Overall, there were 22 treatment failures: 8 of 79 patients (10%) in the 1-stage arm and 14 of 85 (16%) in the 2-stage arm (Pearson χ2 test; P=.23). Recurrent infection was caused by the same pathogen in 7 patients (4%) and by a different pathogen in 5 (3%). Outcomes were better in the 1- vs 2-stage arm for wound dehiscence for elbow bursitis (1 of 66 vs 9 of 64; Fisher exact test P=.03), median length of hospital stay (4.5 vs 6.0 days), nurses' workload (605 vs 1055 points), and total costs (Sw₣6881 vs Sw₣11,178; all P<.01). CONCLUSION: For adults with moderate to severe septic bursitis requiring hospital admission, bursectomy with primary closure, together with antibiotic drug therapy for 7 days, was safe, effective, and resource saving. Using a 2-stage approach may be associated with a higher rate of wound dehiscence for olecranon bursitis than the 1-stage approach. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01406652.

Augmented renal clearance, low ß-lactam concentrations and clinical outcomes in the critically ill: an observational prospective cohort study.

Whilst augmented renal clearance (ARC) is associated with reduced ß-lactam plasma concentrations, its impact on clinical outcomes is unclear. This single-centre prospective, observational, cohort study included non-pregnant, critically ill patients aged 18-60 years with presumed severe infection treated with imipenem, meropenem, piperacillin/tazobactam or cefepime and with creatinine clearance (CL(Cr)) ≥60 mL/min. Peak, intermediate and trough levels of ß-lactams were drawn on Days 1-3 and 5. Concentrations were deemed 'subthreshold' if they did not meet EUCAST-defined non-species-related breakpoints. Primary and secondary endpoints were clinical response 28 days after inclusion, and ARC prevalence (CL(Cr)≥130 mL/min) and subthreshold and undetectable concentrations, respectively. Logistic regression was used to evaluate associations between ARC, antibiotic concentrations and clinical failure. From 2010 to 2013, 100 patients were enrolled (mean age, 45 years; median CL(Cr) at inclusion, 144.1 mL/min). ARC was present in 64 (64%) of the patients. Most patients received imipenem/cilastatin (54%). Moreover, 86% and 27% of patients had at least one subthreshold or undetectable trough level, respectively. Among imipenem and piperacillin trough levels, 77% and 61% were subthreshold, respectively, but intermediate levels of both antibiotics were largely above threshold. ARC strongly predicted undetectable trough concentrations (OR=3.3, 95% CI 1.11-9.94). A link between ARC and clinical failure (18/98; 18%) was not observed. ARC and subthreshold ß-lactam antibiotic concentrations were widespread but were not associated with clinical failure. Larger studies are necessary to determine whether standard dosing regimens in the presence of ARC impact negatively on clinical outcome and antibiotic resistance.