Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

BACKGROUND: Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For ß-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES: To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS: Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS: Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS: The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial.

BACKGROUND: Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). METHODS: Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. RESULTS: Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. CONCLUSIONS: RZF was safe and efficacious in the treatment of candidemia and/or IC. CLINICAL TRIALS REGISTRATION: NCT02734862.

Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections.

In recent years, the worldwide spread of the so-called high-risk clones of multidrug-resistant or extensively drug-resistant (MDR/XDR) Pseudomonas aeruginosa has become a public health threat. This article reviews their mechanisms of resistance, epidemiology, and clinical impact and current and upcoming therapeutic options. In vitro and in vivo treatment studies and pharmacokinetic and pharmacodynamic (PK/PD) models are discussed. Polymyxins are reviewed as an important therapeutic option, outlining dosage, pharmacokinetics and pharmacodynamics, and their clinical efficacy against MDR/XDR P. aeruginosa infections. Their narrow therapeutic window and potential for combination therapy are also discussed. Other "old" antimicrobials, such as certain ß-lactams, aminoglycosides, and fosfomycin, are reviewed here. New antipseudomonals, as well as those in the pipeline, are also reviewed. Ceftolozane-tazobactam has clinical activity against a significant percentage of MDR/XDR P. aeruginosa strains, and its microbiological and clinical data, as well as recommendations for improving its use against these bacteria, are described, as are those for ceftazidime-avibactam, which has better activity against MDR/XDR P. aeruginosa, especially strains with certain specific mechanisms of resistance. A section is devoted to reviewing upcoming active drugs such as imipenem-relebactam, cefepime-zidebactam, cefiderocol, and murepavadin. Finally, other therapeutic strategies, such as use of vaccines, antibodies, bacteriocins, anti-quorum sensing, and bacteriophages, are described as future options.

COVID-19 in elderly kidney transplant recipients.

The SARS-Cov-2 infection disease (COVID-19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed COVID-19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti-retroviral and tocilizumab. Short-term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D-dimer, C-reactive protein, and IL-6 at their first tests. COVID-19 is frequent among the elderly KT population and associates a very early and high mortality rate.

Efficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in an In Vitro Pharmacodynamic Model.

Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Colistin has been the only treatment available for these infections for many years, but its results are suboptimal. Ceftolozane-tazobactam (C/T) is a newly available therapeutic option that has shown good antipseudomonal activity, even against a number of XDR P. aeruginosa strains. However, data about combinations containing C/T are scarce. The aim of this study was to analyze the activity of C/T and colistin alone and in combination against a collection of XDR P. aeruginosa strains containing 24 representative clinical isolates from a multicentre Spanish study. Twenty-four time-kill experiments performed over 24 h were conducted in duplicate to determine the effects of colistin and C/T alone and combined. An in vitro pharmacodynamic chemostat model then was used to validate this combination against three selected XDR P. aeruginosa ST175 isolates with different susceptibility levels to C/T. Static time-kill assays demonstrated superior synergistic or additive effect for C/T plus colistin against 21 of the 24 isolates studied. In the in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, the C/T regimen of 2/1 g every 8 h with a steady-state concentration of 2 mg/liter colistin effectively suppressed the bacterial growth at 24 h. Additive or synergistic interactions were observed for C/T plus colistin against XDR P. aeruginosa strains and particularly against C/T-resistant strains. C/T plus colistin may be a useful treatment for XDR P. aeruginosa infections, including those caused by high risk-clones resistant to C/T.

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial.

BACKGROUND: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia.

OBJECTIVES: To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. RESULTS: Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12-0.23) and 0.17 (0.11-0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11-0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) and 0.23 (0.11-0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed. CONCLUSIONS: In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m² for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45⁻95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2⁻2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

Evaluation of Ceftolozane-Tazobactam in Combination with Meropenem against Pseudomonas aeruginosa Sequence Type 175 in a Hollow-Fiber Infection Model.

The aim of this study was to investigate the efficacy of ceftolozane-tazobactam in combination with meropenem against an extensively drug-resistant (XDR) Pseudomonas aeruginosa high-risk clone, sequence type 175, isolated in a Spanish university hospital. A 14-day hollow-fiber infection model was used to simulate clinical exposure of the two drug regimens alone and in combination, and serial samples were collected to determine drug concentrations and CFU counts. The untreated control failed, as did each study regimen when administered alone. However, when ceftolozane-tazobactam was administered in combination with meropenem, there was a >4-log10 CFU/ml bacterial density reduction and suppression of resistance for the duration of the study. These data suggest that ceftolozane-tazobactam plus meropenem may be a useful combination for treating XDR P. aeruginosa.

Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial.

Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. Objective: To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. Design, Setting, and Participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (≥18 years) with complicated UTI, stratified by infection type and geographic region. Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. Main Outcomes and Measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated. Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam. Conclusions and Relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage. Trial Registration: clinicaltrials.gov Identifier: NCT02166476.

Discriminant biomarkers of acute respiratory distress syndrome associated to H1N1 influenza identified by metabolomics HPLC-QTOF-MS/MS platform.

Acute respiratory distress syndrome (ARDS) is a serious complication of influenza A (H1N1) virus infection. Its pathogenesis is unknown and biomarkers are lacking. Untargeted metabolomics allows the analysis of the whole metabolome in a biological compartment, identifying patterns associated with specific conditions. We hypothesized that LC-MS could help identify discriminant metabolites able to define the metabolic alterations occurring in patients with influenza A (H1N1) virus infection that developed ARDS. Serum samples from patients diagnosed with 2009 influenza A (H1N1) virus infection with (n = 25) or without (n = 32) ARDS were obtained on the day of hospital admission and analyzed by LC-MS/MS. Metabolite identification was determined by MS/MS analysis and analysis of standards. The specificity of the patterns identified was confirmed in patients without 2009 influenza A(H1N1) virus pneumonia (15 without and 17 with ARDS). Twenty-three candidate biomarkers were found to be significantly different between the two groups, including lysophospholipids and sphingolipids related to inflammation; bile acids, tryptophan metabolites, and thyroxine, related to the metabolism of the gut microflora. Confirmation results demonstrated the specificity of major alterations occurring in ARDS patients with influenza A (H1N1) virus infection.

C-reactive protein may misdiagnose prosthetic joint infections, particularly chronic and low-grade infections.

BACKGROUND: Periprosthetic tissue cultures, sonication and synovial fluid cultures remain the gold standard for prosthetic joint infection (PJI) diagnosis. However, some 15-20% culture-negative PJI are still reported. Therefore, there is the need for other diagnostic criteria. One point of concern relative to the different definitions of PJI is as to the inclusion of the c-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) as diagnostic criteria for PJI despite them being non-specific inflammatory blood tests. PURPOSE: The purpose of the present study was to determine the relevance of CRP and the ESR in the diagnosis of PJI. METHODS: All PJI with positive cultures over a two-year period in two hospitals were reviewed. The main variables of the present study were the type of prosthesis and the CRP level. More information was recorded in those patients with normal CRP: radiographs, physical examination records and the ESR. RESULTS: Seventy-three patients were included in study. Pre-operative CRP levels were normal (lower than 0.8 mg/dl) in 23 patients, representing 32% of all PJI with positive cultures. Low virulence micro-organisms, 12 coagulase-negative staphylococci and four P. acnes, grew in most of them. They represented 70% of all PJI with normal CRP levels. In addition, 17 patients (23% of all PJI with positive cultures) had a normal ESR, a normal physical examination (they only presented with pain) and no clear loosening was observed in the radiographs. CONCLUSIONS: Per the American Association of Orthopaedic Surgeons (AAOS) guidelines or the Musculoskeletal Infection Society (MSIS), 23% of the patients in the present study with PJI would never have been identified. Blood inflammatory markers such as the CRP level and ESR may not be accurate as diagnostic tools in PJI, particularly to identify low-grade and chronic PJI.

Improved diagnosis of orthopedic implant-associated infection by inoculation of sonication fluid into blood culture bottles.

Sonication improved the diagnosis of orthopedic implant-associated infections (OIAI). We investigated the diagnostic performance of sonication fluid inoculated into blood culture bottles in comparison with that of intraoperative tissue and sonication fluid cultures. Consecutive patients with removed orthopedic hardware were prospectively included and classified as having OIAI or aseptic failure (AF) according to standardized criteria. The diagnostic procedure included the collection of five intraoperative tissue cultures and sonication of the removed device, followed by conventional culture of the sonication fluid. Cultures were incubated for 7 days (aerobic) or 14 days (anaerobic). In addition, 10 ml of sonication fluid was inoculated into each aerobic and anaerobic BacT/Alert FAN blood culture bottle and incubated in the automated blood culture system for 5 days. Of 75 included patients, 39 had OIAI and 36 AF. The sensitivity of sonication fluid inoculated into blood culture bottles (100%) was higher than that of conventional sonication fluid (87%; P = 0.05) or intraoperative tissue cultures (59%; P < 0.01). Previous antibiotic therapy reduced the culture sensitivity of conventional sonication fluid to 77% and that of intraoperative tissue to 55%, while it remained 100% for blood culture-inoculated sonication fluid. The time to positivity was shorter in blood culture-inoculated sonication fluid, with detection of 72% of microorganisms after 1 day of incubation, than for intraoperative tissue and conventional sonication fluid cultures, with detection of 18% and 28% of microorganisms, respectively. In conclusion, compared to conventional sonication fluid and intraoperative tissue cultures, sonication fluid inoculated into blood culture bottles improved the diagnosis of OIAI and considerably reduced the time to culture positivity.

Ceftazidime-Avibactam in the Treatment of Patients with Bacteremia or Nosocomial Pneumonia: A Systematic Review and Meta-analysis.

INTRODUCTION: Ceftazidime-avibactam (CAZ-AVI) is a combination of the third-generation cephalosporin ceftazidime and the novel, non-ß-lactam ß-lactamase inhibitor avibactam that is approved for the treatment of pediatric (≥ 3 months) and adult patients with complicated infections including hospital-acquired and ventilator-associated pneumonia (HAP/VAP), and bacteremia. This systematic literature review and meta-analysis (PROSPERO registration: CRD42022362856) aimed to provide a quantitative and qualitative synthesis to evaluate the effectiveness of CAZ-AVI in treating adult patients with bacteremia or nosocomial pneumonia caused by carbapenem-resistant Enterobacterales (non metallo-ß-lactamase-producing strains) and multi-drug resistant (MDR) Pseudomonas aeruginosa infections. METHODS: The databases included in the search, until November 7, 2022, were Embase and PubMed. A total of 24 studies (retrospective: 22, prospective: 2) with separate outcomes for patients with bacteremia or pneumonia were included. RESULTS: The outcomes assessed were all-cause mortality, clinical cure, and microbiological cure. Qualitative (24 studies) and quantitative (8/24 studies) syntheses were performed. The quality of the studies was assessed using the MINORS checklist and the overall risk of bias was moderate to high. CONCLUSIONS: In studies included in the meta-analysis, lower all-cause mortality for patients with bacteremia (OR = 0.30, 95% CI 0.19-0.46) and improved rates of clinical cure for patients with bacteremia (OR = 4.90, 95% CI 2.60-9.23) and nosocomial pneumonia (OR = 3.20, 95% CI 1.55-6.60) was observed in the CAZ-AVI group compared with the comparator group. Data provided here may be considered while using CAZ-AVI for the treatment of patients with difficult-to-treat infections. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022362856.

Pseudomonas stutzeri bloodstream infection is a prevailing community-onset disease with important mortality rates: results from a retrospective observational study in Australia.

BACKGROUND: The recognition of Pseudomonas stutzeri as a cause of infections in humans has been increasing. However, only case reports and small series of P. stutzeri bloodstream infections have been published. Epidemiological data on these infections are extremely scarce. Our objective was to describe the incidence, epidemiology, antimicrobial resistance rates, and outcomes of P. stutzeri bloodstream infections in a large population-based cohort in Australia. METHODS: Retrospective, laboratory-based surveillance study conducted in Queensland, Australia (population ≈ 5 million) during 2000-2019. Clinical information was obtained from public hospital admissions and vital statistics databases. RESULTS: In total, 228 episodes of P. stutzeri bloodstream infections were identified. Increased incidence was observed in the later years, especially in older men, and was higher during the rainy months of the year and in the warmest and more humid regions of the state. The majority of bloodstream infections were community-onset with 120 (52.6%) community-associated and 59 (25.9%) ambulatory healthcare-associated episodes. Only 49 cases (21.5%) were nosocomial. The most common foci of infection were skin and soft tissue, lower respiratory tract, and intra-abdominal. No isolate showed antimicrobial resistance. Thirty-one patients (13.6%) died. The mortality rate in patients with a respiratory infectious source was higher (21%). CONCLUSIONS: P. stutzeri bloodstream infection was predominantly a community-onset condition including ambulatory healthcare related cases, with increasing incidence, especially in older males. No antimicrobial resistance was observed. Mortality was high in patients with respiratory infectious source. This new observational data have implications when considering the epidemiology of these infections and for patient management.

Impact of an antimicrobial stewardship program indicator on the appropriateness of the empiric antibiotic treatment of urinary source Escherichia coli bacteraemia.

A prospective multicentre study was carried out between 2017 and 2021 to assess (1) the appropriateness of the empirical treatment to the local guidelines of urinary source Escherichia coli bacteraemia, (2) the appropriateness of empirical treatment to antibiotic sensitivity results and (3) the degree of error in the local guidelines regarding the antibiotic sensitivity reported in acute care hospitals enrolled in the vigilància de les infeccions relacionades amb l'atenció sanitària de Catalunya program. During the study period, 79.0% of the empirical treatments analysed complied with the guidelines and 88.1% were appropriate in view of the in vitro activity of the isolated strain. The rate of appropriateness rose from 73.8% in 2017 to 81.0% in 2021 (P < 0.001). The degree of error in the recommendations regarding the in vitro activity of the isolated strains was 5.9% and remained stable during the study period. Antibiotic families correctly prescribed according to the guidelines were third-generation cephalosporins (54.9%), carbapenems (16.8%) and combinations of penicillins and beta-lactamase inhibitors (16.4%). Of the 8009 E. coli strains, 19.0% were extended-spectrum beta-lactamases producers, 36.8% were resistant to quinolones and 0.5% were resistant to carbapenems. The broad implementation of an antimicrobial stewardship program with quality indicators of antibiotic use improved compliance to local guidelines in the empiric treatment of urinary tract E. coli bacteraemia. The degree of error in local guidelines was low but higher in more complex hospitals and in healthcare-associated infections. Guidelines need to be constantly updated with the use of epidemiological data, rapid diagnostic tests and the analysis of patient risk factors specific to each geographical area.

Safety and efficacy of favipiravir in COVID-19 patients with pneumonia. A randomized, double-blind, placebo-controlled study (FAVID).

PURPOSE: To design a randomized clinical trial to assess the efficacy and safety of favipiravir in patients with COVID-19 disease with pneumonia. METHODS: A randomized, double blind, placebo-controlled clinical trial of favipiravir in patients with COVID-19 pneumonia was conducted in three Spanish sites. Randomization 1:1 to favipiravir or placebo (in both groups added to the Standard of Care) was performed to treat the patients with COVID-19 pneumonia. The primary endpoint was "time to clinical improvement," measured as an improvement for ≥ two categories on a 7-point WHO ordinal scale in an up to 28 days' time frame. RESULTS: Forty-four patients were randomized (23 in the favipiravir group and 21 in the placebo group). The median time to clinical improvement was not different between the favipiravir and the placebo arms (10 days for both groups) and none of the secondary endpoints showed significant differences between arms. The proportion of adverse events (both serious and non-serious) was statistically different between the favipiravir group (68.29%) and the placebo group (31.7%) (p = 0.019), but there was insufficient statistical evidence to correlate the degree of severity of the events with the treatment group. CONCLUSIONS: Favipiravir administered for ten days to patients with COVID-19 and pneumonia did not improve outcomes compared with placebo. Although this is an underpowered negative study, efficacy results align with other randomized trials. However, in the present study, the non-serious adverse events were more frequent in the favipiravir group.