BACKGROUND: Ceftazidime-avibactam (CAZ-AVI) is a combination of the third-generation cephalosporin ceftazidime and the novel, non-β-lactam β-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-β-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.
BACKGROUND: PROSPERO CRD42022362856.

BACKGROUND: Multiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP.
METHODS: We conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events.
RESULTS: Sixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17-0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19-3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00-2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03-2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02-2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin.
CONCLUSIONS: This network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria. Registration PROSPERO CRD42021226603.

Nosocomial pneumonia is a healthcare-associated infection with significant consequences for the patient and the healthcare system. The efficacy of treatment significantly depends on the timeliness and adequacy of the antibiotic therapy regimen. The growth of resistance of gram-negative pathogens of nosocomial pneumonia to antimicrobial agents increases the risk of prescribing inadequate empirical therapy, which worsens the results of patient treatment. Identification of risk factors for infection with multidrug-resistant microorganisms, careful local microbiological monitoring with detection of resistance mechanisms, implementation of antimicrobial therapy control strategy and use of rational combinations of antibacterial drugs are of great importance. In addition, the importance of using new drugs with activity against carbapenem-resistant strains, including ceftazidime/aviabactam, must be understood. This review outlines the current data on the etiology, features of diagnosis and antibacterial therapy of nosocomial pneumonia.
Нозокомиальная пневмония (НП) представляет собой инфекцию, связанную с оказанием медицинской помощи, которая характеризуется значительными последствиями для пациента и системы здравоохранения. Эффективность лечения в значительной степени зависит от своевременности и адекватности режима антибактериальной терапии. Рост устойчивости грамотрицательных возбудителей НП к антибиотикам повышает риск назначения неадекватной эмпирической терапии, что ухудшает результаты лечения пациентов. Выявление факторов риска инфицирования микроорганизмами с множественной лекарственной устойчивостью, тщательный локальный микробиологический мониторинг с детекцией механизмов устойчивости, реализация стратегии контроля антимикробной терапии и применение рациональных комбинаций антибактериальных препаратов имеют огромное значение. Кроме того, необходимо понимать важность использования новых препаратов с активностью в отношении карбапенемрезистентных штаммов, в том числе цефтазидима/авибактама. В обзоре изложены современные данные об этиологии НП, особенности диагностики и принципы антибактериальной терапии НП.

Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed.

UNASSIGNED: Carbapenems and β-lactam and β-lactamase inhibitors (BLBLIs) have been used empirically in nosocomial pneumonia, but their efficacy and safety are controversial.
UNASSIGNED: We carried out a systematic review with meta-analysis to evaluate the efficacy and safety of carbapenems versus BLBLIs against nosocomial pneumonia.
UNASSIGNED: PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI, Wangfang, VIP and Sinomed were searched systematically through April 29, 2023 for clinical trials comparing carbapenems with BLBLIs for treatment of nosocomial pneumonia. Random-effects models were used to evaluate the impact of treatment on the risk ratio (RR) of all-cause mortality, clinical response, microbiologic response, resistance by Pseudomonas aeruginosa, adverse effects (AEs), and serious adverse effects. The quality of the evidence was assessed with the Cochrane risk of bias tool. The review was registerted in the INPLASY (INPLASY202340113).
UNASSIGNED: Seven randomized controlled trials containing 3306 patients met our inclusion criteria Our meta-analysis showed no significant difference in all-cause mortality (RR = 0.88, 95% confidence interval [CI] = 0.75-1.03, I2 = 0%) or clinical cure (1.02, 0.96-1.09, 30%) or clinical failure (1.19, 0.97-1.47, 0%) or microbiologic clinical cure (0.98, 0.89-1.06, 40%) or Pseudomonas aeruginosa resistance (RR 2.43, CI 0.86-6.81, 49%, P = 0.09) or adverse events (0.98, 0.93-1.02, 0%) between carbapenems groups versus BLBLIs groups, but a significant difference was found for severe adverse events (RR 0.83, CI 0.73-0.94, 0%).
UNASSIGNED: Differences in the prevalence of mortality, clinical cure, or clinical failure were not observed between carbapenems groups versus BLBLIs groups in terms of nosocomial pneumonia. The use of carbapenems was linked to a tendency towards the emergence of P. aeruginosa resistance, however, no statistically significant difference was observed.

Carbapenem-resistant Gram-negative bacteria are frequent causes of sepsis and septic shock in intensive care unit (ICU) and thus considered a public health threat. Until now, the best available therapies consist of combinations of preexisting or new antibiotics with β-lactamase inhibitors (either new or preexisting). Several mechanisms of resistance, especially those mediated by metallo-β-lactamases (MBL), are responsible for the inefficacy of these treatments, leaving an unmet medical need. Intravenous cefiderocol has been recently approved by the American Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of complicated urinary tract infections and nosocomial pneumonia due to Gram-negative, when limited therapeutical options are available. In addition, its ability to hijack bacterial iron uptake mechanisms makes cefiderocol stable against the whole Ambler β-lactamase inhibitors and increases the in vitro efficacy against Gram-negative pathogens (e.g., Enterobacterales spp., Pseudomonas aeruginosa, and Acinetobacter baumannii). Trials have already demonstrated their non-inferiority to comparators. In 2021, ESCMID guidelines released a conditional recommendation supporting the use of cefiderocol against metallo-β-lactamase-producing Enterobacterales and against Acinetobacter baumannii. This review provides the opinion of experts about the general management of empiric treatment of patients with sepsis and septic shock in the intensive care unit and detects the proper place in therapy of cefiderocol considering recent evidence sought through a systematic search.

Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug-drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS-NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE-CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.

Nosocomial pneumonia ranks among the top 5 diseases that lead to additional financial costs due to hospitalization. This study aimed to evaluate the cost of oral care and its clinical effectiveness in preventing pneumonia in a systematic review.
The search was conducted in the following databases: PubMed, Cochrane Library, Web of Sciences, Scopus, CINAHL, LILACS, complemented by gray literature and manual search, between January/2021 and August/2022. Two independent reviewers extracted data from the selected articles, individually analyzing each study\'s quality using the BMJ Drummond checklist. The data were tabulated by clinical or economic type.
A total of 3,130 articles were identified; the eligibility criteria were verified, and 12 articles were selected for qualitative analysis. Only 2 achieved satisfactory quality assessment for economic analysis studies. There was heterogeneity between clinical and economic data. Eleven of the 12 studies reported a decrease in the incidence of nosocomial pneumonia following the application of oral care practices. Most authors reported a reduction in the estimate of individual costs, followed by a decrease in the need for antibiotic therapy. The costs of oral care were very low compared to other costs.
Despite the low level of evidence in the literature, heterogeneity and poor quality of the selected studies, most studies concluded that oral care seemed to lead to reduced costs in hospital expenses for treating pneumonia.

Infection is a common problem and a major cause of morbidity and mortality for patients in intensive care units (ICUs). According to published meta-analyses, oral care has been found to reduce the risk of nosocomial pneumonia, and has been recommended to improve the oral environment for patients in ICUs. However, relatively little information is available about the effects of oral care in patients without ventilatory support in ICUs. Therefore, this review proposes to evaluate the effectiveness of oral care in preventing pneumonia in non-ventilated ICU patients.
Eight databases will be searched for relevant literature, including four Chinese and four English online databases, from their inception to the protocol publication date. Records obtained will be managed and screened via Endnote X7. All literature will be selected following pre-established inclusion criteria by two independent review authors to obtain quality trials. The quality of the included records will be evaluated according to the \"risk of bias table\", recommended by the Cochrane Handbook for Systematic Reviews of Interventions. All the data will be extracted by one author and checked by another. If there is any disagreement, a final agreement will be reached with a third reviewer via consultation. If there are missing data, the original authors will be emailed to ask for it. If enough data were collected, the data synthesis will be performed using Review Manager (RevMan5.3). Both a random effect model and a fixed effect model will be undertaken. A Bayesian meta-analysis will also be performed to estimate the magnitude of the heterogeneity variance and comparing it with the distribution using the WinBUGS software. Otherwise, the results will be reported narratively. The sources of heterogeneity will be determined using meta-regression and subgroup analysis if there is significant heterogeneity. A funnel plot will be used to assess publication bias if there are enough records included. The Cochrane Handbook for Systematic Reviews of Interventions will be followed throughout the system evaluation process.
This review will provide evidence of oral care for intensive care unit patients without mechanical ventilation to prevent nosocomial pneumonia.
PROSPERO Research registration identifying number: CRD42020146932.

The aim of this study was to investigate the clinical efficacy and safety of cefiderocol in the treatment of acute bacterial infections.
The PubMed, Embase and Cochrane Library databases as well as the clinical trials registries of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched up to 8 November 2020. Only randomised controlled trials (RCTs) that compared the treatment efficacy of cefiderocol with that of other antibiotics for adult patients with acute bacterial infections were included in this meta-analysis. The primary outcome was clinical response at test of cure (TOC).
Three RCTs, including one phase 2 and two phase 3 trials, were included. No significant difference in clinical response rate was observed between cefiderocol and comparators [odds ratio (OR)=1.04]. In a subgroup analysis, no significant difference was observed in the clinical response at TOC between cefiderocol and comparators in patients with nosocomial pneumonia (OR=0.92) or complicated urinary tract infection (OR=1.28). In addition, all-cause mortality at Days 14 and 28 did not differ between the cefiderocol and control groups (14-day mortality, OR=1.25; 28-day mortality, OR=1.12). Furthermore, cefiderocol was associated with similar microbiological response to comparators at the TOC assessment (OR=1.44). Finally, cefiderocol was associated with a similar risk of adverse events as comparators.
Cefiderocol can achieve similar clinical and microbiological responses as comparators for patients with serious bacterial infections. In addition, cefiderocol shares a safety profile similar to that of comparators.