Equitable Access

The COVID-19 epidemic has once again highlighted the challenges to achieve equitable access to critical antimicrobials and vaccines. The problem is particularly acute for antimicrobials. Despite recent investments improving the pipeline for new treatments, most new treatments are not available to populations most in need, especially in low- and middle-income countries. Once a drug is approved a range of factors may hinder access, from lack incentives to register and commercialize products due to unattractive market potential to unfunded national action plans that can help improve the uptake and appropriate use of new tools to combat antibiotic resistance. Previous studies have shown that the majority of the 18 new antibacterials approved and launched between 2010-2020 were accessible in only 3 out of 14 high-income countries (Sweden, UK, and US). In low- and middle-income countries, the problem is even worse, with only 10 of the 25 new antibiotics that entered the market between 1999 and 2014 registered in more than ten countries. While lack of equitable access to life-saving medicines, diagnostics, and vaccines is not a new problem for infectious diseases, emerging opportunities and innovative approaches can help improve access globally. This talk will review promising recent developments in governance and collaborations, policies, economic models and initiatives that may help correct deadly inequities. For example, the objectives of the Access to COVID-19 Tools Accelerator may serve as model that convenes diverse actors to mount a coordinated access response which may be applied to access to other antimicrobials and vaccines. In addition, novel licensing agreements for access and stewardship to cefiderocol, an antimicrobial that is on the WHO Essential Medicines List can help serve as a pathfinder to accelerate equitable access to novel antimicrobials. The talk will also surface critiques of ongoing initiatives and raise questions for further study and discussion.Copyright © 2023

Antibiotic resistance of Klebsiella pneumoniae against the background of the COVID-19 pandemic: experience of the multidisciplinary hospital

Frequency of bacterial co-infections among patients with COVID-19 is not high, and over-prescribing of antibiotics may contribute the selection of resistant strains of enterobacteria and gram-negative non-fermenting bacteria. The aim of the study was to assess the local features of antibiotic resistance of K. pneumoniae and its genetic mechanisms against background of the COVID-19 infection pandemic. Material and methods. There was selected 37 carbapenem-resistant K. pneumoniae strains isolated in 2016, 2017 and 2020 from hospitalized patients, including 15 strains, isolated from patients with COVID-19 infection. Minimal inhibitory concentrations (MICs) of meropenem and colistin were determined by broth microdilution method. Determination of MICs of eravacycline, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam was performed using Sensititre diagnostic system on EUMDROXF plates. Susceptibility to 11 combinations of 2 antibiotics was detected by modified method of multiply combination bactericidal testing. For 4 K. pneumoniae strains high-throughput sequencing was performed, followed with the subsequent search for determinants of antibiotic resistance and virulence, assessment of plasmid profiles. Results. All strains were resistant to meropenem (MIC50 32 mg/l, MIC90 128 mg/l) and produced KPC and OXA-48 carbapenemases. Strains isolated in 2016-2017 were susceptible to colistin (MIC <=2 mg/l), in 2020 only 26.7% of the strains retained their susceptibility (MIC50 64 mg/l, MIC90 256 mg/l). Susceptibility to combinations of two antibiotics with colistin included reduced from 84.6-100% in 2016-2017 till 26.6-66.7% in 2020. The strains isolated in 2020 retained their susceptibility to ceftazidime/avibactam (MIC <=1 mg/l). 5 strains resistant to cefiderocol with a MIC 8 mg/l were identified. Strains 2564 and 3125 isolated in 2020 from sputum of patients with COVID-19 infection belonged to different sequence-types (ST12 and ST23) and contained the blaOXA-48 carbapenemase gene, additionally strain 2564 contained the blaKPC-27carbapenemase gene. Resistance to colistin was caused by inactivation of the mgrB genes due to insertion of IS1 and IS5-like transposons. Conclusion. The performed genetic studies demonstrate a diversity of mechanisms of antibiotic resistance in K. pneumoniae leading to the formation of resistance including to antibiotics that haven't been used in Belarus till now.Copyright © 2021 Geotar Media Publishing Group. All Rights Reserved.

Evaluation of risk factors associated with mortality in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa with difficult-to-treat resistance

Introduction: Evaluation of prognostic factors in patients with ventilator- associated pneumonia (VAP) due to P. aeruginosa. The effectiveness of novel antipseudomonal antibiotics was reviewed. Method(s): Retrospective, single-center cohort analysis between April 2018 and June 2022. Data were obtained from the ENVIN-HELICS and electronic medical records. Demographic variables, underlying diseases and diagnosis to admission were registered. We considered each treatment appropriate according to Tamma PD et al. [1] criteria. We registered ventilator-associated tracheobronchitis (VAT) and pneumonia (VAP) episodes together with the recurrency of the infection. Result(s): From 61 patients included, 77% were admitted for ARDS due to COVID-19. The mean APACHE-II was 14.3 +/- 6.6. 7 patients required ECMO and 4 required RRT. The median length of stay in the ICU was 52 (ICR 36-84) days. 91 respiratory infections were recorded: 60 VAP and 31 VAT. On the first episode, carbapenem-resistance to meropenem was 40%;rising up to 58% on the second one. 6 patients developed a third episode (VAT) with a 100% of carbapenem- resistance. 13 (14%) respiratory infections showed resistance to the novel beta-lactamase inhibitor cephalosporins (8 to ceftalozanetazobactam and 5 to ceftazidime-avibactam). No resistance to cefiderocol was detected. During ICU stay, 21 patients (34%) developed secondary bacteremia from other foci and 7 (11%) invasive mycoses. Overall mortality was 49.2%. On the univariate analysis we found statistical significant relationships between mortality and COVID-19 admission, SOFA >= 7 points on the first VAP or the development of secondary bacteremia (Table 1). Conclusion(s): COVID-19 admission, SOFA >= 7 points on the first VAP or other secondary bacteremia were associated with mortality. The 14.3% of respiratory infections were resistant to the new beta-lactamase inhibitor cephalosporins. No resistance to cefiderocol was detected.

Antibiotics in Paediatrics: A Boon or a Bane?

Antibiotics play an essential role in antimicrobial therapy. Among all the medications in children, the most commonly prescribed therapy is antibiotics and is currently the indispensable means to cure transmissible diseases. Several categories of antibiotics have been introduced into clinical practice to treat microbial infections. Reducing the unnecessary use of antibiotics is a global need and priority. This article aims to provide better knowledge and understanding of the impact of the early use of antibiotics. This article highlights the proper use of antibiotics in chil-dren, detailing how early and inappropriate use of antibiotics affect the gut microbiome during normal body development and consequently affect the metabolism due to diabetes mellitus, obe-sity, and recurrence of infections, such as UTI. Several new antibiotics in their development stage, newly marketed antibiotics, and some recalled and withdrawn from the market are also briefly discussed in this article. This study will help future researchers in exploring the latest information about antibiotics used in paediatrics.Copyright © 2023 Bentham Science Publishers.

Pharmacokinetics of cefiderocol during extracorporeal membrane oxygenation: A case report.

Patients with extracorporeal membrane oxygenation (ECMO) support do frequently receive broad-spectrum antibiotics, due to the high frequency of infection by multidrug resistant microorganisms. The extracorporeal circuit can alter the pharmacokinetics (PK) of administered drugs, and in the case of antibiotics this may lead to treatment failure. Cefiderocol is a new cephalosporin that exhibits excellent in vitro activity against many multidrug-resistant (MDR) microorganisms, but there is no published data about the modifications of its PK in patients with ECMO support. Herein we report the results of a pharmacokinetic investigation of cefiderocol in a critically ill patient receiving extracorporeal respiratory support.

Ventilator-associated pneumonia (VAP) and pleural empyema caused by multidrug-resistant Acinetobacter baumannii in HIV and COVID 19 infected patient: A case report

We analyzed the case of a 49-year-old woman with HIV infection off-therapy with poor viro-immunological compensation, not vaccinated for SARS-COV-2, hospitalized for lobar pneumonia and severe COVID19-related respiratory failure in intensive care unit (ICU). The hospitalization was complicated by bacteraemic ventilator-associated pneumonia (VAP) caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) isolated on pleural fluid culture, treated with colistin and cefiderocol for about 3 weeks. The molecular research of MDR-AB on transtracheal aspirate was negative following this therapy. The aim is to show the safety, efficacy and tolerability of colistin-based combination therapy with cefiderocol for Acinetobacter baumannii infection in HIV-infected patient. © 2023 The Authors

Activity of Cefiderocol and Other New Antibiotics Against Extensively Drug-Resistant Klebsiella pneumoniae Strains.

Background. The spread of extensive drug-resistance among gram-negative bacteria calls for the search for antimicrobics with new mechanisms of actions. The aim was to assess susceptibility of extensively drug-resistant K.pneumoniae strains to cefiderocol and other new inhibitor-protected beta-lactams, and to determine genetic mechanisms of antibiotic resistance. Methods. This study included 30 extensively drug-resistant K.pneumoniae strains collected in 2016-2021 from 4 regions of Belarus. Carbapenemase genes were detected by real-time PCR. Minimum inhibitory concentrations (MICs) for cefiderocol and other new antibiotics were assessed by microdilution method using the Sensititre system. Whole genome sequencing was performed for 2 resistant and 3 cefiderocol-susceptible strains. Genome assemblies and annotation were performed using UGENE v. 37.0 software. Nucleotide sequences were translated using CLC Sequence Viewer v. 8.0 (QIAGEN) package. The PROVEAN software was used to assess amino asides substitutions and their influence on the functional activity of proteins. Results. KPC carbapenemase-producers were 4 strains, OXA-48 - 17, KPC+OXA-48 - 1, NDM - 7, OXA-48 + NDM - 1. All KPC-producers were susceptible to imipenem/relebactam and meropenem/vaborbactam. Resistance to ceftazidime-avibactam was noted in all NDM producers and OXA-48+NDM co-producer. The study has identified 9 cefiderocol-resistant strains. These were NDM and OXA-48-producers isolated from hospitalized patients with COVID-19 infection from 3 regions of Belarus. Resistant strains had functionally significant nonsynonymous substitutions in the genes of TonB-dependent receptors for catecholate siderophores FepA (F472V, P64S) and Fiu (T92S). Conclusion. The study has shown high efficacy of new inhibitor-protected carbapenems and cephalosporins against certain types of carbapenemase-producers. Strains with mutational resistance to cefiderocol, an antibiotic not previously used in Belarus, have been identified.Copyright © Team of Authors, 2022.

Cefiderocol-Based versus Colistin-Based Regimens for Severe Carbapenem-Resistant Acinetobacter baumannii Infections: A Propensity Score-Weighted, Retrospective Cohort Study during the First Two Years of the COVID-19 Pandemic.

BACKGROUND: A large increase in multi-drug-resistant Acinetobacter baumannii, especially carbapenem-resistant strains, occurred during the first two years of the COVID-19 pandemic, posing important challenges in its treatment. Cefiderocol appeared to be a good option for the treatment of Carbapenem-resistant Acinetobacter baumannii (CR-Ab), but to date, the guidelines and evidence available are conflicting. METHODS: We retrospectively included a group of patients with CR-Ab infections (treated with colistin- or cefiderocol-based regimens) at Padua University Hospital (August 2020-July 2022) and assessed predictors of 30-day mortality, and differences in microbiological and clinical treatment. To evaluate the difference in outcomes, accounting for the imbalance in antibiotic treatment allocation, a propensity score weighting (PSW) approach was adopted. RESULTS: We included 111 patients, 68% males, with a median age of 69 years (IQR: 59-78). The median duration of antibiotic treatment was 13 days (IQR:11-16). In total, 60 (54.1%) and 51 (45.9%) patients received cefiderocol- and colistin-based therapy, respectively. Notably, 53 (47.7%) patients had bloodstream infections, while 58 (52.3%) had pneumonia. Colistin was combined in 96.1%, 80.4%, and 5.8% of cases with tigecycline, meropenem, and fosfomycin, respectively. Cefiderocol was combined in 13.3%, 30%, and 18.3% of cases with fosfomycin, tigecycline, and meropenem, respectively. At the baseline, the two treatment groups significantly differed in age (patients treated with colistin were significantly older), the prevalence of diabetes and obesity (more frequent in the group treated with colistin), length of stay (longer in the group receiving cefiderocol), and type of infection (BSI were more frequent in the group receiving cefiderocol). The proportion of patients who developed acute kidney injury was significantly higher in the colistin group. By using PSW, no statistically significant differences emerged for mortality or clinical and microbiological cure between the two groups. No independent predictors were detected for hospital mortality or clinical cure, while for the length of stay, the only selected predictor was age, with a non-linear effect (p-value 0.025 for non-linearity) on the prolongation of hospital stay of 0.25 days (95% CI 0.10-0.39) at increasing ages (calculated over the IQR). CONCLUSIONS: Cefiderocol treatment did not differ in terms of main outcomes and safety profile from colistin-based regimens. More prospective studies with a larger number of patients are required to confirm our results.

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches.

In light of rising antimicrobial resistance and a decreasing number of antibiotics with novel modes of action, it is of utmost importance to accelerate development of novel treatment options. One aspect of acceleration is to understand pharmacokinetics (PK) and pharmacodynamics (PD) of drugs and to assess the probability of target attainment (PTA). Several in vitro and in vivo methods are deployed to determine these parameters, such as time-kill-curves, hollow-fiber infection models or animal models. However, to date the use of in silico methods to predict PK/PD and PTA is increasing. Since there is not just one way to perform the in silico analysis, we embarked on reviewing for which indications and how PK and PK/PD models as well as PTA analysis has been used to contribute to the understanding of the PK and PD of a drug. Therefore, we examined four recent examples in more detail, namely ceftazidime-avibactam, omadacycline, gepotidacin and zoliflodacin as well as cefiderocol. Whereas the first two compound classes mainly relied on the 'classical' development path and PK/PD was only deployed after approval, cefiderocol highly profited from in silico techniques that led to its approval. Finally, this review shall highlight current developments and possibilities to accelerate drug development, especially for anti-infectives.

Efficacy of cefiderocol- vs colistin-containing regimen for treatment of bacteraemic ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii in patients with COVID-19.

INTRODUCTION: Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) in patients hospitalized in intensive care units (ICUs) is an important and challenging complication, including in patients with coronavirus disease 2019 (COVID-19). Considering the poor lung penetration of most antibiotics, including intravenous colistin due to the poor pharmacokinetics/pharmacodynamics at the infection site, the choice of the best antibiotic regimen is still being debated. METHODS: This single-centre, observational study was conducted from March 2020 to August 2022, and included all patients hospitalized consecutively with VAP and concomitant bloodstream infection due to CRAB in the COVID-ICU. The main goal of the study was to evaluate risk factors associated with survival or death at 30 days from VAP onset. A propensity score for receiving therapy was added to the model. RESULTS: During the study period, 73 patients who developed VAP and concomitant positive blood cultures caused by CRAB were enrolled in the COVID-ICU. Of these patients, 67 (91.7%) developed septic shock, 42 (57.5%) had died at 14 days and 59 (80.8%) had died at 30 days. Overall, 54 (74%) patients were treated with a colistin-containing regimen and 19 (26%) were treated with a cefiderocol-containing regimen. Cox regression analysis showed that chronic obstructive pulmonary disease and age were independently associated with 30-day mortality. Conversely, cefiderocol-containing regimens and cefiderocol + fosfomycin in combination were independently associated with 30-day survival, as confirmed by propensity score analysis. CONCLUSIONS: This real-life study in patients with bacteraemic VAP caused by CRAB provides useful suggestions for clinicians, showing a possible benefit of cefiderocol and its association with fosfomycin.

Activity of Cefiderocol and Other New Antibiotics Against Extensively Drug-Resistant Klebsiella pneumoniae Strains

Background. The spread of extensive drug-resistance among gram-negative bacteria calls for the search for antimicrobics with new mechanisms of actions. The aim was to assess susceptibility of extensively drug-resistant K.pneumoniae strains to cefiderocol and other new inhibitor-protected β-lactams, and to determine genetic mechanisms of antibiotic resistance. Methods. This study included 30 extensively drug-resistant K.pneumoniae strains collected in 2016–2021 from 4 regions of Belarus. Carbapenemase genes were detected by real-time PCR. Minimum inhibitory concentrations (MICs) for cefiderocol and other new antibiotics were assessed by microdilution method using the Sensititre system. Whole genome sequencing was performed for 2 resistant and 3 cefiderocol-susceptible strains. Genome assemblies and annotation were performed using UGENE v. 37.0 software. Nucleotide sequences were translated using CLC Sequence Viewer v. 8.0 (QIAGEN) package. The PROVEAN software was used to assess amino asides substitutions and their influence on the functional activity of proteins. Results. KPC carbapenemase-producers were 4 strains, OXA-48 — 17, KPC+OXA-48 — 1, NDM — 7, OXA-48 + NDM — 1. All KPC-producers were susceptible to imipenem/relebactam and meropenem/vaborbactam. Resistance to ceftazidime-avibactam was noted in all NDM producers and OXA-48+NDM co-producer. The study has identified 9 cefiderocol-resistant strains. These were NDM and OXA-48-producers isolated from hospitalized patients with COVID-19 infection from 3 regions of Belarus. Resistant strains had functionally significant nonsynonymous substitutions in the genes of TonB-dependent receptors for catecholate siderophores FepA (F472V, P64S) and Fiu (T92S). Conclusion. The study has shown high efficacy of new inhibitor-protected carbapenems and cephalosporins against certain types of carbapenemase-producers. Strains with mutational resistance to cefiderocol, an antibiotic not previously used in Belarus, have been identified. © Team of Authors, 2022.

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study.

Introduction: Novel last resort beta-lactam antibiotics are now available for management of infections due to New-Delhi Metallo-Beta-Lactamase (NDM) producing Enterobacterales and non-fermenters with Difficult-to-Treat Resistance. However, data regarding the use of imipenem-cilastatin-relebactam (IMI-REL), cefiderocol (CFD) and ceftazidime-avibactam plus aztreonam (CAZ-AVI-ATM) are scarce in real-life settings. This study aimed to describe the use of last resort beta-lactam antibiotics, the microbiology and the outcome, in patients hospitalized in a tertiary hospital. Methods: We conducted a monocentric observational cohort study from 2020/01/01, to 2022/08/31. We screened all patients admitted to Nimes University Hospital who have received ≥ 1 dose of last resort beta-lactam antibiotics during the study period, using the Pharmacy database. We included patients treated with IMI-REL, CFD and CAZ-AVI-ATM. The primary endpoint was the infection-free survival rate. We also calculated rates of microbiological and clinical cure, recurrent infection, death and adverse events. Results: Twenty-seven patients were included in the study and 30 treatment courses were analyzed: CFD (N=24; 80%), CAZ-AVI-ATM (N=3; 10%) and IMI-REL (N=3; 10%). Antibiotics were used in 21 males (70%) and 9 females (30%) with a median age at 65-year-old [50-73.5] and a median Charlson index at 1 [0-2]. Almost all the patients had ≥ 1 risk factor for carbapenem resistant bacteria, a half of them was hospitalized for severe COVID-19, and most of antibiotic courses (N=26; 87%) were associated with ICU admission. In the study population, the probability of infection-free survival at day-90 after last resort beta-lactam therapy initiation was 48.4% CI95% [33.2-70.5]. Clinical failure rate was at 30%, microbiological failure rate at 33% and mortality rate at 23%. Adverse events were documented in 5 antibiotic courses (17%). In details, P. aeruginosa were mainly treated with CFD and IMI-REL, S. maltophilia with CFD and CAZ-AVI-ATM, A. baumannii with CFD, and NDM producing-K. pneumoniae with CAZ-AVI-ATM and CFD. After a treatment course with CFD, CAZ-AVI-ATM and IMI-REL, the probability of infection-free survival was 48% CI95% [10.4-73.5], 33.3% CI95% [6.7-100], 66.7% CI95% [30-100], respectively. Discussion/conclusion: Use of last resort beta-lactam antimicrobials in real-life settings was a safe and efficient therapeutic option for severe infections related to Gram-negative bacteria with Difficult-to-Treat Resistance.

CEFIDEROCOL FOR TREATMENT OF PATIENTS WITH GRAM-NEGATIVE RESPIRATORY INFECTIONS: US HOSPITAL EXPERIENCE FROM JANUARY 2020 TO JUNE 2021

SESSION TITLE: Late Breaking Chest Infections Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: Cefiderocol is a siderophore cephalosporin that has broad activity against Gram-negative (GN) pathogens including carbapenem resistant isolates through its unique mode of cell entry. This study describes the usage of cefiderocol in US hospitals, in patients with microbiology confirmed respiratory infections, during its first 1.5 years following commercial availability. METHODS: This was a retrospective study of patients with microbiology confirmed GN respiratory infections in US hospitals, treated with cefiderocol consecutively for ≥3 days between January 2020 to June 2021, as captured by the Premier Healthcare database. This study describes the clinical characteristics, microbiology profile, and 14-day and 28-day in-hospital all-cause mortality (IH-ACM) amongst patients treated with cefiderocol. Index culture was defined as the last culture sample(s) obtained before cefiderocol initiation, or the first culture obtained after cefiderocol initiation if no microbiology evaluation was performed prior to cefiderocol use. Index pathogen(s) were the pathogen(s) identified from the index culture(s). RESULTS: Among 113 hospitalized patients who received ≥3 days cefiderocol and had ≥1 positive respiratory culture for GN pathogens, median age was 61 years with interquartile range (IQR) of 48-72 years, 57% were male, and 93% were admitted via emergency room or urgent care. The most common comorbidities were renal disease (37%), diabetes (36%), congestive heart failure (35%), and chronic pulmonary disease (33%). Seventy-seven percent of patients received mechanical ventilation and 89% were treated in an intensive care unit. The most frequent index pathogens were Pseudomonas aeruginosa (56%), Stenotrophomonas maltophilia (24%), Klebsiella pneumoniae (13%), and Acinetobacter baumannii (11%). Also 28% of patients had more than one pathogen from index cultures and over 10% also had positive GN index cultures from other sites such as blood, urine or wound. Among 96 pathogens tested for carbapenems, 87% were resistant. Median time from hospital admission to cefiderocol initiation was 14 days (IQR: 5-25). Median cefiderocol duration was 8 days (IQR: 6-14). Before initiating cefiderocol, 88% of patients received other GN antibiotics. Median length of hospital stay was 28 days (IQR: 16-45). Crude 14-day and 28-day IH-ACM were 21.2% (95%CI: 13.7%-28.8%) and 27.4% (95%CI: 19.2-35.7%), respectively. IH-ACM was higher in COVID patients than non-COVID patient (53.1% vs. 8.6% for 14-day ACM and 65.6% vs. 12.3% for 28-day ACM, respectively). CONCLUSIONS: During the initial phase of availability, the most frequent use of cefiderocol was to treat critically ill patients with non-fermenter pathogen infections.IH-ACM appears to be affected by infection characteristics, especially COVID-19 status. CLINICAL IMPLICATIONS: Real-world data supports that Cefiderocol is effective in treating GN respiratory infections as shown in IH-ACM DISCLOSURES: Employee relationship with Shionogi Inc Please note: 2015 - present Added 06/02/2022 by Bin Cai, value=Salary No relevant relationships by Andrew Cooper Employee relationship with Shionogi, Inc Please note: 3 years Added 06/03/2022 by Stephen Marcella, value=Salary No relevant relationships by Yun Zhou

Cefiderocol for Carbapenem-Resistant Bacteria: Handle with Care! A Review of the Real-World Evidence.

(1) Background: healthcare-associated infections are one of the most frequent adverse events in healthcare delivery worldwide. Several antibiotic resistance mechanisms have been developed, including those to carbapenemase. Cefiderocol (CFD) is a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria. (2) Methods: we performed a systematic review of all cases reported in the literature to outline the existing evidence. We evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant (CR) bacteria. (3) Results: a total of 19 publications treating cases of infection by CR bacteria were included. The three most frequent CR pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. A regimen of 2 g every 8 h was most frequently adopted for CFD with a mean treatment duration of 25.6 days. CFD was generally well tolerated, with fewer side effects. The success rate of CFD therapy was satisfactory and almost 70% of patients showed clinical recovery; of these, nearly half showed negative blood cultures and infection-free status. (4) Conclusions: This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems to have a safe profile.

A case of toxic epidermal necrolysis in a COVID-19 patient

Background: We report a severe hypersensitivity reaction due to warfarin in a COVID19 patient with sepsis. Case Report: An 86-year-old man was admitted for COVID19 pneumonia. He was vaccinated with 2 ComirNaty doses. He was affected by hypertension and CKD in emodialysis. At the admission he presented fever and tachypnea, the laboratory tests showed a septic state. We started administration of empiric therapy with piperacillina/tazobactam, it was replaced with meropenem and linezolid on the 29th day. After 10 days linezolid was stopped for thrombocitopenia. On the 14th day we prescribed warfarin for tromboembolic risk prevention when paroxysmal atrial fibrillation occurred . At the fifth week there was a clinic and laboratory worsening so we started target antibiotic therapy with cefiderocol and colistin due to positive blood cultures for A. Baumanii XDR. On the 24th day an inguinal erytema with blister-like lesion occurred and involved progressively face, neck, limbs, trunk and abdomen with extensive skin sloughing and crusted lesions appeared in the perioral and perinasal mucosa. Nikolsky sign was negative. Skin biopsy showed signs of inflammatory reaction. Warfarin was stopped and 1mg/kg methylprednisone was started with slow and progressive benefit. Conclusions: The patient has developed a warfarin linked hypersensitivity reaction with clinical features similar to toxic epidermal necrolysis. We assume that it was a borderline condition of hypersensitivity to warfarin in a patient with hyperactivation of immune system due to COVID19 and sepsis.

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review.

P. aeruginosa is still one of the most threatening pathogens responsible for serious hospital-acquired infections. It is intrinsically resistant to many antimicrobial agents and additional acquired resistance further complicates the management of such infections. High rates of combined antimicrobial resistance persist in many countries, especially in the eastern and south-eastern parts of Europe. The aim of this narrative review is to provide a comprehensive assessment of the epidemiology, latest data, and clinical evidence on the current and new available drugs active against P. aeruginosa isolates with limited treatment options. The latest evidence and recommendations supporting the use of ceftolozane-tazobactam and ceftazidime-avibactam, characterized by targeted clinical activity against a significant proportion of P. aeruginosa strains with limited treatment options, are described based on a review of the latest microbiological and clinical studies. Cefiderocol, with excellent in vitro activity against P. aeruginosa isolates, good stability to all ß-lactamases and against porin and efflux pumps mutations, is also examined. New carbapenem combinations are explored, reviewing the latest experimental and initial clinical evidence. One section is devoted to a review of new anti-pseudomonal antibiotics in the pipeline, such as cefepime-taniborbactam and cefepime-zidebactam. Finally, other "old" antimicrobials, mainly fosfomycin, that can be used as combination strategies, are described.

Occurrence of multi-carbapenemases producers among carbapenemase-producing Enterobacterales and in vitro activity of combinations including cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam in the COVID-19 era.

PURPOSE: To evaluate the prevalence of multi-carbapenemase-producing Enterobacterales (EB) and the activity of cefiderocol (CFDC), meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), and combinations of CZA plus aztreonam (ATM), MEV plus ATM and CFDC plus CZA against them. METHODS: A collection of carbapenemase-producing EB clinical isolates (n = 1242) was investigated by lateral flow immunoassay NG-Test CARBA-5 and molecular testing. Cefiderocol MICs were determined using broth microdilution SensititreTM panel. MICs of CZA and MEV were determined by the gradient diffusion method. Antimicrobial synergy testing was performed using gradient diffusion strip crossing. RESULTS: KPC were the most frequent carbapenemases (83.2%), followed by VIM (9.2 %), OXA-48-like (4.3 %) and NDM enzymes (4.1%). Multi-carbapenemase producers were found in 10 (0.8%) isolates. Three combinations of two different carbapenemases were observed: KPC+VIM (n = 4), NDM+OXA-48-like (n = 4), and VIM+OXA-48-like (n = 2). CFDC showed potent activity against eight out of ten dual-carbapenemases producers, while resistance or reduced susceptibility was shown towards CZA and MEV. CFDC in combination with CZA showed no synergistic effects and only two additive effects on seven (87.5%) of the CFDC-susceptible strains. Conversely, CZA plus ATM and MEV plus ATM combinations were synergistic against all ATM-resistant strains regardless of dual-carbapenemases phenotype. CONCLUSIONS: The occurrence of multi-carbapenemase producers is not uncommon in Northern Italy area. MEV in combination with ATM might be considered as a potential therapeutic option, alternative to CZA plus ATM. CFDC susceptibility testing and synergy evaluation of ATM-based combinations should be performed in the lab routine to evaluate the most in vitro active antimicrobial regimen.

Cefiderocol for Severe Carbapenem-Resistant A. baumannii Pneumonia: Towards the Comprehension of Its Place in Therapy.

Cefiderocol use in A. baumannii pneumonia still represents an important matter of debate. The aim of this study is to describe 13 cases of carbapenem-resistant A. baumannii (CRAB) pneumonia treated with cefiderocol in real-life practice. We retrospectively included patients with CRAB pneumonia hospitalized at Fondazione Policlinico Universitario Agostino Gemelli Hospital treated with cefiderocol either in the general ward or the intensive care unit. A total of 11 patients out of 13 had ventilator-associated pneumonia caused by CRAB, and 12/13 patients had polymicrobial infection. We found a 30-day success rate of 54%. Cefiderocol may have a role when facing severe XDR A. baumannii pneumonia. Future studies are warranted to better define its place in therapy in CRAB infections.

Pan-drug resistant Providencia rettgeri contributing to a fatal case of COVID-19.

Following prolonged hospitalization that included broad-spectrum antibiotic exposure, a strain of Providencia rettgeri was cultured from the blood of a patient undergoing extracorporeal membrane oxygenation treatment for hypoxic respiratory failure due to COVID-19. The strain was resistant to all antimicrobials tested including the novel siderophore cephalosporin, cefiderocol. Whole genome sequencing detected ten antimicrobial resistance genes, including the metallo-ß-lactamase bla NDM-1, the extended-spectrum ß-lactamase bla PER-1, and the rare 16S methyltransferase rmtB2.