Treatment of positive catheter tip culture without bloodstream infections in critically ill patients. A case-cohort study from the OUTCOMEREA network.

PURPOSE: This study aimed to evaluate the impact on subsequent infections and mortality of an adequate antimicrobial therapy within 48 h after catheter removal in intensive care unit (ICU) patients with positive catheter tip culture. METHODS: We performed a retrospective analysis of prospectively collected data from 29 centers of the OUTCOMEREA network. We developed a propensity score (PS) for adequate antimicrobial treatment, based on expert opinion of 45 attending physicians. We conducted a 1:1 case-cohort study matched on the PS score of being adequately treated. A PS-matched subdistribution hazard model was used for detecting subsequent infections and a PS-matched Cox model was used to evaluate the impact of antibiotic therapy on mortality. RESULTS: We included 427 patients with a catheter tip culture positive with potentially pathogenic microorganisms. We matched 150 patients with an adequate antimicrobial therapy with 150 controls. In the matched population, 30 (10%) subsequent infections were observed and 62 patients died within 30 days. Using subdistribution hazard models, the daily risk to develop subsequent infection up to Day-30 was similar between treated and non-treated groups (subdistribution hazard ratio [sHR] 1.08, 95% confidence interval [CI] 0.62-1.89, p = 0.78). Using Cox proportional hazard models, the 30-day mortality risk was similar between treated and non-treated groups (HR 0.89, 95% CI 0.45-1.74, p = 0.73). CONCLUSIONS: Antimicrobial therapy was not associated with decreased risk of subsequent infection or death in short-term catheter tip colonization in critically ill patients. Antibiotics may be unnecessary for positive catheter tip cultures.

Risk factors for Pseudomonas aeruginosa VIM colonization/infection in the ICU: Case control study.

BACKGROUND: Carbapenem-resistant strains of Pseudomonas aeruginosa (CRPA) have become a major healthcare concern in many countries, against which anti-infective strategies are limited and which require adequate infection control interventions. Knowing the different modes of transmission of CRPA in intensive care units (ICUs) would be helpful to adapt the means of prevention. METHODS: The aim of this retrospective case-control study was conducted between 01/01/2017 and 02/28/2022 to identify the risk factors for the acquisition of CRPA in ICUs. RESULTS: During the study period, 147 patients were included (49 cases and 98 controls). Among the 49 patients, 31 (63%) acquired CRPA in clusters and 18 (37%) sporadically. An univariate analysis showed that five variables were associated with CRPA acquisition including (i) prior antibiotic prescriptions, (ii) admission to rooms 203 and 207, (iii) severity of illness at admission, and (iv) use of mechanical ventilation. Multivariate analysis identified three factors of CRPA acquisition including admission to room 203 (OR = 29.5 [3.52-247.09]), previous antibiotic therapy (OR = 3.44 [1.02 - 11.76]) and severity of condition at admission (OR = 1.02 [1 - 1.04]). CONCLUSION: Our study suggests the role of a contaminated environment in the acquisition of CRPA in the ICU, along with antibiotic use.

Routes of SARS-Cov2 transmission in the intensive care unit: A multicentric prospective study.

BACKGROUND: The risk of SARS-CoV-2 transmission to health care workers in intensive care units (ICU) and the contribution of airborne and fomites to SARS-CoV-2 transmission remain unclear. To assess the rate of air and surface contamination and identify risk factors associated with this contamination in patients admitted to the ICU for acute respiratory failure due to SARS-CoV-2 pneumonia. METHODS: Prospective multicentric non-interventional study conducted from June 2020 to November 2020 in 3 French ICUs. For each enrolled patient, 3 predefined surfaces were swabbed, 2 air samples at 1 m and 3 m from the patient's mouth and face masks of 3 health care workers (HCW) were collected within the first 48 h of SARS-CoV-2 positive PCR in a respiratory sample. Droplet digital PCR and quantitative PCR were performed on different samples, respectively. RESULTS: Among 150 included patients, 5 (3.6%, 95%CI: 1.2% to 8.2%) had positive ddPCR on air samples at 1 m or 3 m. Seventy-one patients (53.3%, CI95%: 44.5% to 62.0%) had at least one surface positive. Face masks worn by HCW were positive in 6 patients (4.4%, CI: 1.6% to 9.4%). The threshold of RT-qPCR of the respiratory sample performed at inclusion (odds ratio, OR= 0.88, 95%CI: 0.83 to 0.93, p < 0.0001) and the presence of diarrhea (OR= 3.28, 95%CI: 1.09 to 9.88, p = 0.037) were significantly associated with the number of contaminated surfaces. CONCLUSION: In this study, including patients admitted to the ICU for acute respiratory failure " contact route " of transmission, i.e. through fomites, seems dominant. While presence of SARS-CoV-2 in the air is rare in this specific population, the presence of diarrhea is associated to surface contamination around Covid patients.

Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study.

KEY MESSAGES: In this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy. BACKGROUND: The benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria. METHODS: We included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock. RESULTS: Among the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73-1.77; P = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53-1.20; P = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71-1.63; P = 0.73). Multivariable regression models and subgroup analyses provided similar results. CONCLUSIONS: Initial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

Bloodstream Infections: Comparison of Diagnostic Methods and Therapeutic Consequences between a Hospital in a Resource-Limited Setting and Two French Hospitals.

In recent years, the diagnosis of bloodstream infections has been complemented by rapid microbiological methods, unattainable to most clinical laboratories in resource-limited settings. We evaluated the impact of their shortage on antibiotic therapy adequacy. We conducted a prospective multicenter cohort study including 150 adult Gram-negative bacilli bacteremia episodes, evenly distributed across three university hospitals: one in Lebanon, a resource-limited setting, and two in France, a resource-rich setting. Previous colonization by multidrug-resistant organisms (MDRO) was significantly more prevalent among the Lebanese than the French group of patients (16/50 vs. 5/100; p < 0.01). Bloodstream infections by carbapenemase-producing Enterobacterales and other MDRO were higher among the Lebanese than the French group of patients (25/50 vs. 12/100; p < 0.01). For the French group, rapid identification of species and mechanisms of resistance significantly shortened turnaround time for definitive laboratory diagnosis and increased antibiotic therapy adequacy. No statistically significant differences were noted in targeted antibiotic therapy between the two groups. This study suggests that, in settings where bacterial resistance is prevalent, rapid microbiological methods have not provided any additional value. The clinical and economic impact of rapid microbiological methods will likely depend on local CPE, VRE, and other MDRO epidemiology and are areas for future research.

Prevalence and risk factors of toxigenic Clostridioides difficile asymptomatic carriage in 11 French hospitals.

Clostridioides difficile infection (CDI) incidence has increased over the last 20 years. Studies suggest that asymptomatic carriers may be an important reservoir of C. difficile in healthcare settings. We conducted a point prevalence study to estimate the toxigenic C. difficile asymptomatic carriage rate and the associated risk factors in patients >3 years old. Between September 16, 2019 and January 15, 2020, all patients hospitalized in 11 healthcare facilities in the Paris urban area were included in the study. They were screened on the day of the survey for toxigenic C. difficile carriage by rectal swab and interviewed. Isolates were characterized by PCR ribotyping and multiplex PCR targeting toxin genes. A logistic regression model was used to determine the risk factors associated with toxigenic C. difficile asymptomatic carriage using uni- and multivariate analysis in the subpopulation of patients >3 years old. During the study period, 2,389 patients were included and screened. The median age was 62 years (interquartile range 35-78 years) and 1,153 were male (48.3%). Nineteen patients had a previous CDI (0.9%). Overall, 185/2389 patients were positive for C. difficile (7.7%), including 93 toxigenic strains (3.9%): 77 (82.8%) were asymptomatic (prevalence 3.2%) whereas 12 (12.9%) were diarrheic. Prevalences of toxigenic C. difficile were 3.5% in patients >3 years old and 7.0% in ≤3 years old subjects, respectively. Toxigenic strains mainly belonged to PCR ribotypes 106 (n = 14, 15.0%), 014 (n = 12, 12.9%), and 020 (n = 10, 10.8%). Among toxigenic strains, 6 (6.4%) produced the binary toxin. In multivariate analysis, two factors were positively associated with toxigenic C. difficile asymptomatic carriage in patients >3 years old: multidrug-resistant organisms co-carriage [adjusted Odd Ratio (aOR) 2.3, CI 95% 1.2-4.7, p = 0.02] and previous CDI (aOR 5.8, CI 95% 1.2-28.6, p = 0.03). Conversely, consumption of raw milk products were associated with reduced risk of toxigenic C. difficile colonization (aOR 0.5, CI 95% 0.2-0.9, p = 0.01). We showed that there was a low prevalence of asymptomatic toxigenic C. difficile carriage in hospitalized patients. Consumption of raw milk prevents toxigenic C. difficile colonization, probably due to the barrier effect of milk-associated bacteria.

Rationale and evidence for the use of new beta-lactam/beta-lactamase inhibitor combinations and cefiderocol in critically ill patients.

BACKGROUND: Healthcare-associated infections involving Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) phenotype are associated with impaired patient-centered outcomes and poses daily therapeutic challenges in most of intensive care units worldwide. Over the recent years, four innovative ß-lactam/ß-lactamase inhibitor (BL/BLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam) and a new siderophore cephalosporin (cefiderocol) have been approved for the treatment of certain DTR-GNB infections. The literature addressing their microbiological spectrum, pharmacokinetics, clinical efficacy and safety was exhaustively audited by our group to support the recent guidelines of the French Intensive Care Society on their utilization in critically ill patients. This narrative review summarizes the available evidence and unanswered questions on these issues. METHODS: A systematic search for English-language publications in PUBMED and the Cochrane Library database from inception to November 15, 2022. RESULTS: These drugs have demonstrated relevant clinical success rates and a reduced renal risk in most of severe infections for whom polymyxin- and/or aminoglycoside-based regimen were historically used as last-resort strategies-namely, ceftazidime-avibactam for infections due to Klebsiella pneumoniae carbapenemase (KPC)- or OXA-48-like-producing Enterobacterales, meropenem-vaborbactam for KPC-producing Enterobacterales, ceftazidime-avibactam/aztreonam combination or cefiderocol for metallo-ß-lactamase (MBL)-producing Enterobacterales, and ceftolozane-tazobactam, ceftazidime-avibactam and imipenem-relebactam for non-MBL-producing DTR Pseudomonas aeruginosa. However, limited clinical evidence exists in critically ill patients. Extended-infusion scheme (except for imipenem-relebactam) may be indicated for DTR-GNB with high minimal inhibitory concentrations and/or in case of augmented renal clearance. The potential benefit of combining these agents with other antimicrobials remains under-investigated, notably for the most severe presentations. Other important knowledge gaps include pharmacokinetic information in particular situations (e.g., pneumonia, other deep-seated infections, and renal replacement therapy), the hazard of treatment-emergent resistance and possible preventive measures, the safety of high-dose regimen, the potential usefulness of rapid molecular diagnostic tools to rationalize their empirical utilization, and optimal treatment durations. Comparative clinical, ecological, and medico-economic data are needed for infections in whom two or more of these agents exhibit in vitro activity against the causative pathogen. CONCLUSIONS: New BL/BLI combinations and cefiderocol represent long-awaited options for improving the management of DTR-GNB infections. Several research axes must be explored to better define the positioning and appropriate administration scheme of these drugs in critically ill patients.

Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas.

BACKGROUND: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. OBJECTIVES: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. SOURCES: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. CONTENT: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton's tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. IMPLICATIONS: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations.

What to Do with the New Antibiotics?

Multidrug-resistant Gram-negative bacteria-related infections have become a real public health problem and have exposed the risk of a therapeutic impasse. In recent years, many new antibiotics have been introduced to enrich the therapeutic armamentarium. Among these new molecules, some are mainly of interest for the treatment of the multidrug-resistant infections associated with Pseudomonas aeruginosa (ceftolozane/tazobactam and imipenem/relebactam); others are for carbapenem-resistant infections associated with Enterobacterales (ceftazidime/avibactam, meropenem/vaborbactam); and finally, there are others that are effective on the majority of multidrug-resistant Gram-negative bacilli (cefiderocol). Most international guidelines recommend these new antibiotics in the treatment of microbiologically documented infections. However, given the significant morbidity and mortality of these infections, particularly in the case of inadequate therapy, it is important to consider the place of these antibiotics in probabilistic treatment. Knowledge of the risk factors for multidrug-resistant Gram-negative bacilli (local ecology, prior colonization, failure of prior antibiotic therapy, and source of infection) seems necessary in order to optimize antibiotic prescriptions. In this review, we will assess these different antibiotics according to the epidemiological data.

Antimicrobial Stewardship for Ventilator Associated Pneumonia in Intensive Care (the ASPIC trial): study protocol for a randomised controlled trial.

INTRODUCTION: Ventilator-associated pneumonia (VAP) remains the leading cause of infections treated in the intensive care units (ICU). In a personalised care approach, we hypothesise that the duration of treatment of VAP can be reduced in function of the response to treatment. METHODS AND ANALYSIS: The Antimicrobial Stewardship for Ventilator-Associated Pneumonia in Intensive Care (ASPIC) trial is a pragmatic national multicentre, phase III, non-inferiority, comparative randomised (1:1) single-blinded clinical trial. Five hundred and ninety adult patients hospitalised in 24 French ICU with a microbiologically confirmed first episode of VAP that received appropriate empirical antibiotic therapy will be included. They will be randomly allocated to standard management with duration of appropriate antibiotic fixed for 7 days according to international guidelines or antimicrobial stewardship based on daily clinical assessment of clinical cure. The assessment of clinical cure will be repeated daily until at least three criteria of clinical cure are met, allowing the discontinuation of antibiotic therapy in experimental group. The primary endpoint is a composite endpoint combining of all-cause mortality measured at day 28, treatment failure or new episode of microbiologically confirmed VAP until day 28.The aim of the study is to demonstrate that a strategy to reduce the duration of antibiotic therapy for VAP based on clinical assessment is safe could lead to changes in practice as part of a personalised therapeutic approach, by reducing exposure to antibiotics and their side effects. ETHICS AND DISSEMINATION: The ASPIC trial has been approved by the French regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM; EUDRACT number 2021-002197-78, 19 August 2021) and an independent ethics committee the Comité de Protection des Personnes Ile-de-France III (CNRIPH : 21.03.25.60729, 10 October 2021) for the study protocol (version ASPIC-1.3; 03 September 2021) for all study centres. Participant recruitment is scheduled to begin in 2022. Results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT05124977.

Limiting the Spread of Multidrug-Resistant Bacteria in Low-to-Middle-Income Countries: One Size Does Not Fit All.

The spread of multidrug-resistant organisms (MDRO) is associated with additional costs as well as higher morbidity and mortality rates. Risk factors related to the spread of MDRO can be classified into four categories: bacterial, host-related, organizational, and epidemiological. Faced with the severity of the MDRO predicament and its individual and collective consequences, many scientific societies have developed recommendations to help healthcare teams control the spread of MDROs. These international recommendations include a series of control measures based on surveillance cultures and the application of barrier measures, ranging from patients' being isolated in single rooms, to the reinforcement of hand hygiene and implementation of additional contact precautions, to the cohorting of colonized patients in a dedicated unit with or without a dedicated staff. In addition, most policies include the application of an antimicrobial stewardship program. Applying international policies to control the spread of MDROs presents several challenges, particularly in low-to-middle-income countries (LMICs). Through a review of the literature, this work evaluates the real risks of dissemination linked to MDROs and proposes an alternative policy that caters to the means of LMICs. Indeed, sufficient evidence exists to support the theory that high compliance with hand hygiene and antimicrobial stewardship reduces the risk of MDRO transmission. LMICs would therefore be better off adopting such low-cost policies without necessarily having to implement costly isolation protocols or impose additional contact precautions.

Evaluation of ceftolozane-tazobactam susceptibility on a French nationwide collection of Enterobacterales.

OBJECTIVES: Ceftolozane-tazobactam (C/T) proved its efficacy for the treatment of infections caused by non-carbapenemase producing Pseudomonas aeruginosa and Enterobacterales. Here, we aimed to provide susceptibility data on a large series of Enterobacterales since the revision of EUCAST categorization breakpoints in 2020. METHODS: First, C/T susceptibility was determined on characterized Enterobacterales resistant to third generation cephalosporins (3GCs) (extended spectrum ß-lactamase [ESBL] production or different levels of AmpC overexpression) (n = 213) and carbapenem-resistant Enterobacterales (CRE) (n = 259), including 170 carbapenemase producers (CPE). Then, 1632 consecutive clinical Enterobacterales responsible for infection were prospectively collected in 23 French hospitals. C/T susceptibility was determined by E-test® (biomérieux) and broth microdilution (BMD) (Sensititre™, Thermo Scientific) to perform method comparison. RESULTS: Within the collection isolates, 88% of 3GC resistant strains were susceptible to C/T, with important variation depending on the resistance mechanism: 93% vs. 13% susceptibility for CTX-M and SHV-ESBL producers, respectively. Only 20% of the CRE were susceptible to C/T. Among CPE, 80% of OXA-48-like producers were susceptible to C/T, whereas all metallo-ß-lactamase producers were resistant. The prospective study revealed that 95.6% of clinical isolates were susceptible to C/T. Method comparison performed on these 1632 clinical isolates demonstrated 99% of categorization agreement between MIC to C/T determined by E-test® in comparison with the BMD (reference) and only 74% of essential agreement. CONCLUSION: Overall, C/T showed good activity against wild-type Enterobacterales, AmpC producers, and ESBL-producing Escherichia coli but is less active against ESBL-producing Klebsiella pneumoniae, and CRE. E-test® led to an underestimation of the MICs in comparison to the BMD reference.

Multidrug-resistant Enterobacterales infections in abdominal solid organ transplantation.

BACKGROUND: Transplant recipients are highly susceptible to multidrug-resistant (MDR) related infections. The lack of early appropriate antimicrobial treatment may contribute to the high mortality due to MDR-related infections in transplant recipients especially in case of metallo-ß-lactamases. OBJECTIVES: In this review, we present the current state of knowledge concerning multidrug-resistant Gram negative bacilli's risk management in the care of solid-organ transplant recipients and suggest control strategies. SOURCES: We searched for studies treating MDR g-negative bacilli related infections in the renal and hepatic transplant patient population. We included randomized and observational studies. CONTENT: Solid-organ transplant is the best therapeutic option for patients diagnosed with end-stage organ disease. While the incidence of opportunistic infections is decreasing due to better prevention, the burden of "classical" infections related to MDR bacteria especially related to Gram-negative bacteria is constantly increasing. Over the last two decades, various MDR pathogens have emerged as a relevant cause of infection in this specific population associated with significant mortality. Several factors related to the management of transplant donor candidates and recipients increase the risk of MDR infections in transplant recipients. The awareness of this high susceptibility of transplant recipients to MDR-related infections challenges the choice of empirical therapy, while its appropriateness can only be validated a posteriori. Indeed, the lack of early appropriate antimicrobial treatment may contribute to the high mortality due to MDR-related infections in transplant recipients especially in case of metallo-ß-lactamases. IMPLICATIONS: Multidrug-resistant Gram-negative bacteria are associated with high morbidity and mortality in solid organ transplant recipients. It seems important to identify patients at risk of colonization/MDR bacteria to evaluate strategies to limit the risk of secondary infections and to minimize the inappropriate use of broad-spectrum antibiotics.

Risk factors for colonization and infection with multidrug-resistant Pseudomonas aeruginosa in intensive care unit: protocol for a systematic review and meta-analysis.

BACKGROUND: Infection with resistant Pseudomonas aeruginosa (RPA) in the intensive care unit (ICU) is known to be either endogenous or exogenous or both, but the roles of each of these contamination routes are yet to be clarified. Data regarding prevalence, risk factors, and environmental factors associated with RPA in ICU are very scanty and even when they exist, they seem to be contradictory. So, there is a strong interest in understanding both individual and environmental factors associated with RPA infection. This systematic review aims to investigate individual and environmental factors associated with the colonization and infection with RPA in ICU. METHODOLOGY: MEDLINE (Pubmed), EMBASE (OVID), the Cochrane Library (Wiley), Web of Science, CINAHL (EBSCOHost), and LILACS (BIREME) will be searched from inception onwards. Grey literature will be identified through Google Scholar and Open Grey. Two reviewers will independently screen all citations, abstracts, and full-text articles. Potential conflicts will be resolved through discussion. Methodological quality including bias will be appraised using appropriate approaches. A narrative synthesis will describe the quality and content of the epidemiological evidence. Prevalence, odds ratio, relative risk, and hazard radio with their respective 95% confidence intervals will be calculated. A meta-analysis of data extracted from eligible studies with similar populations and RPA testing will be performed. The analysis will evaluate factors influencing the estimates. A random effect model will be used to summarize effect sizes. DISCUSSION: Two contrasting hypotheses on risk factors of acquisition, colonization, and infection of RPA are being debated, especially in a context where available data are scanty or exhibit high discrepancy. Indeed, most of the reviews have been focalized on hospitalized patients, and not in ICU, and few of them address the issue of environmental factors. To fill that gap, this review will combine both analyses of individual and environmental risk factors using prevalence studies in ICU and evaluation of different methodologies. These two hypotheses will be tested and challenged and could serve as a basis for a more in-depth study to fill the methodological gaps that will be identified as part of this current review. SYSTEMATIC REVIEW REGISTRATION: This protocol has been submitted to the Prospective Register of Systematic Reviews (PROSPERO) and the registration number attributed was CRD42021233832 of 07 March 2021.

When and How to Use MIC in Clinical Practice?

Bacterial resistance to antibiotics continues to be a global public health problem. The choice of the most effective antibiotic and the use of an adapted dose in the initial phase of the infection are essential to limit the emergence of resistance. This will depend on (i) the isolated bacteria and its resistance profile, (ii) the pharmacodynamic (PD) profile of the antibiotic used and its level of toxicity, (iii) the site of infection, and (iv) the pharmacokinetic (PK) profile of the patient. In order to take account of both parameters to optimize the administered treatment, a minimal inhibitory concentration (MIC) determination associated with therapeutic drug monitoring (TDM) and their combined interpretation are required. The objective of this narrative review is thus to suggest microbiological, pharmacological, and/or clinical situations for which this approach could be useful. Regarding the microbiological aspect, such as the detection of antibiotic resistance and its level, the preservation of broad-spectrum ß-lactams is particularly discussed. PK-PD profiles are relevant for difficult-to-reach infections and specific populations such as intensive care patients, cystic fibrosis patients, obese, or elderly patients. Finally, MIC and TDM are tools available to clinicians, who should not hesitate to use them to manage their patients.

Empirical Antibiotic Therapy for Gram-Negative Bacilli Ventilator-Associated Pneumonia: Observational Study and Pharmacodynamic Assessment.

Background: Strong evidence suggests a correlation between pharmacodynamics (PD) index and antibiotic efficacy while dose adjustment should be considered in critically ill patients due to modified pharmacokinetic (PK) parameters and/or higher minimum inhibitory concentrations (MICs). This study aimed to assess pharmacodynamic (PD) target attainment considering both antibiotics serum concentrations and measured MICs in these patients. Method: A multicentric prospective open-label trial conducted in 11 French ICUs involved patients with Gram-negative bacilli (GNB) ventilator-associated pneumonia (VAP) confirmed by quantitative cultures. Results: We included 117 patients. Causative GNBs were P. aeruginosa (40%), Enterobacter spp. (23%), E. coli (20%), and Klebsiella spp. (16%). Hence, 117 (100%) patients received ß-lactams, 65 (58%) aminoglycosides, and two (1.5%) fluoroquinolones. For ß-lactams, 83% of the patients achieved a Cmin/MIC > 1 and 70% had a Cmin/MIC > 4. In the case of high creatinine clearance (CrCL > 100 mL/min/1.73 m2), 70.4% of the patients achieved a Cmin/MIC ratio > 1 versus 91% otherwise (p = 0.041), and 52% achieved a Cmin/MIC ratio > 4 versus 81% (p = 0.018). For aminoglycosides, 94% of the patients had a Cmax/MIC ratio > 8. Neither ß-lactams nor aminoglycosides PK/PD parameters were associated clinical outcomes, but our data suggest a correlation between ß-lactams Cmin/MIC and microbiological success. Conclusion: In our ICU patients treated for GNB VAP, using recommended antibiotic dosage led in most cases to PK/PD targets attainment for aminoglycosides and ß-lactams. High creatinine clearance should encourage clinicians to focus on PK/PD issues.

Automated HPLC-MS/MS assay for the simultaneous determination of ten plasma antibiotic concentrations.

Therapeutic drug monitoring (TDM) of antibiotics (ATB) in patients with serious bacterial infections allows optimization of the efficacy of the treatment while reducing the risk of toxicity. Notably, early measurement of plasma beta-lactam concentration has been shown to be associated with reduced mortality in intensive care patients. In this context, a rapid, robust, and accurate assay method is essential for daily TDM. A fully automated procedure for quantification of the plasma concentrations of ten ATB was developed. The ATB were divided into two calibration pools, with Pool 1: aztreonam, ceftobiprole, cefoxitin, avibactam, tazobactam and Pool 2: metronidazole, ceftriaxone, daptomycin, ceftolozane, moxifloxacin. Sample preparation consisting of acetonitrile plasma protein precipitation and H20 dilution was applied to all analytes. This procedure was carried out by an automated sample preparation system directly coupled to a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Since the instrument extracts sample n while sample n-1 is in the LC-MS/MS system, the delay between obtaining the results for two samples corresponds to the analytical run time, which is less than 7 min. The method was validated according to the Food and Drug Administration guidelines. The method was sensitive (lower limit of quantification 0.1-1 mg/L, depending on the ATB), accurate (intra/inter-assay bias -14.8 to 14.2 %) and precise (intra/inter-assay CVs 1.27 to 16.3 %). Application of the TDM assay was illustrated by the report of an intensive care patient treated with the ceftazidime/aztreonam/avibactam combination. Four assays were performed in 8 days with results returned within 24 h to quickly manage the dose regimen in this patient. An automated, simple, rapid, robust LC-MS/MS analysis was developed and validated for the simultaneous quantification of plasma concentrations of 10 ATB and was applied with success to perform TDM. This method provides a shorter turnaround time than classic sample batch-based analytical methods.

Risk stratification for selecting empiric antibiotherapy during and after COVID-19.

PURPOSE OF REVIEW: SARS-CoV-2 deeply modified the risk of bacterial infection, bacterial resistance, and antibiotic strategies. This review summarized what we have learned. RECENT FINDINGS: During the COVID-19 pandemic, we observed an increase in healthcare-acquired infection and multidrug-resistant organism-related infection, triggered by several factors: structural factors, such as increased workload and ongoing outbreaks, underlying illnesses, invasive procedures, and treatment-induced immunosuppression. The two most frequently healthcare-acquired infections described in patients hospitalized with COVID-19 were bloodstream infection, related or not to catheters, health-acquired pneumonia (in ventilated or nonventilated patients). The most frequent species involved in bacteremia were Gram-positive cocci and Gram-negative bacilli in health-acquired pneumonia. The rate of Gram-negative bacilli is particularly high in late-onset ventilator-associated pneumonia, and the specific risk of Pseudomonas aeruginosa- related pneumonia increased when the duration of ventilation was longer than 7 days. A specificity that remains unexplained so far is the increase in enterococci bacteremia. SUMMARY: The choice of empiric antibiotimicrobials depends on several factors such as the site of the infection, time of onset and previous length of stay, previous antibiotic therapy, and known multidrug-resistant organism colonization. Pharmacokinetics of antimicrobials could be markedly altered during SARS-CoV-2 acute respiratory failure, which should encourage to perform therapeutic drug monitoring.