Epidemiology and clinical significance of carbapenemases in Australia: a narrative review.

Carbapenemase-producing gram-negative bacteria (CP-GNB) infections threaten public health with high mortality, morbidity and treatment costs. Although frequencies remain low in Australia (total number of CP-GNB infections reported was 907 in 2022), blaIMP-4 has established low levels of endemicity in many states. Imipenemase metallo-ß-lactamase types alone accounted for more than half of all carbapenemases in carbapenemase-producing Enterobacterales isolates in Australia, particularly in Enterobacter cloacae complex. New Delhi metallo-ß-lactamase constitutes almost 25% of all carbapenemases in Australia and was identified predominantly in Escherichia coli. The OXA-48-like carbapenemases include almost 10% of all carbapenemases and are mainly seen in Klebsiella pneumoniae and E. coli. Although K. pneumoniae carbapenemase-type carbapenemases are rare in Australia, some local outbreaks have occurred. Most carbapenem-resistant (CR) Pseudomonas aeruginosa strains in Australia do not produce carbapenemases. Finally, OXA-23-like carbapenemases are overwhelmingly positive in CR-Acinetobacter baumannii strains in Australia. Treatment of CR-GNB infections challenges physicians. Of 10 new antibiotics active against at least some CR-GNB infections that are approved by the US Food and Drug Administration, just three are approved for use in Australia. In this context, there is still an unmet need for novel antibacterials that can be used for the treatment of CR-GNB infections in Australia, as well as a pressing requirement for new mechanisms to 'de-link' antibiotic sales from their availability. In this narrative review, we aim to overview the epidemiology and clinical significance of carbapenem resistance in Australia as it pertains to Enterobacterales, P. aeruginosa and A. baumannii.

Epidemiology and risk factors of 28-day mortality of hospital-acquired bloodstream infection in Turkish intensive care units: a prospective observational cohort study.

OBJECTIVES: To uncover clinical epidemiology, microbiological characteristics and outcome determinants of hospital-acquired bloodstream infections (HA-BSIs) in Turkish ICU patients. METHODS: The EUROBACT II was a prospective observational multicontinental cohort study. We performed a subanalysis of patients from 24 Turkish ICUs included in this study. Risk factors for mortality were identified using multivariable Cox frailty models. RESULTS: Of 547 patients, 58.7% were male with a median [IQR] age of 68 [55-78]. Most frequent sources of HA-BSIs were intravascular catheter [182, (33.3%)] and lower respiratory tract [175, (32.0%)]. Among isolated pathogens (n = 599), 67.1% were Gram-negative, 21.5% Gram-positive and 11.2% due to fungi. Carbapenem resistance was present in 90.4% of Acinetobacter spp., 53.1% of Klebsiella spp. and 48.8% of Pseudomonas spp. In monobacterial Gram-negative HA-BSIs (n = 329), SOFA score (aHR 1.20, 95% CI 1.14-1.27), carbapenem resistance (aHR 2.46, 95% CI 1.58-3.84), previous myocardial infarction (aHR 1.86, 95% CI 1.12-3.08), COVID-19 admission diagnosis (aHR 2.95, 95% CI 1.25-6.95) and not achieving source control (aHR 2.02, 95% CI 1.15-3.54) were associated with mortality. However, availability of clinical pharmacists (aHR 0.23, 95% CI 0.06-0.90) and source control (aHR 0.46, 95% CI 0.28-0.77) were associated with survival. In monobacterial Gram-positive HA-BSIs (n = 93), SOFA score (aHR 1.29, 95% CI 1.17-1.43) and age (aHR 1.05, 95% CI 1.03-1.08) were associated with mortality, whereas source control (aHR 0.41, 95% CI 0.20-0.87) was associated with survival. CONCLUSIONS: Considering high antimicrobial resistance rate, importance of source control and availability of clinical pharmacists, a multifaceted management programme should be adopted in Turkish ICUs.

Characteristics and outcomes of carbapenemase harbouring carbapenem-resistant Klebsiella spp. bloodstream infections: a multicentre prospective cohort study in an OXA-48 endemic setting.

A prospective, multicentre observational cohort study of carbapenem-resistant Klebsiella spp. (CRK) bloodstream infections was conducted in Turkey from June 2018 to June 2019. One hundred eighty-seven patients were recruited. Single OXA-48-like carbapenemases predominated (75%), followed by OXA-48-like/NDM coproducers (16%). OXA-232 constituted 31% of all OXA-48-like carbapenemases and was mainly carried on ST2096. Thirty-day mortality was 44% overall and 51% for ST2096. In the multivariate cox regression analysis, SOFA score and immunosuppression were significant predictors of 30-day mortality and ST2096 had a non-significant effect. All OXA-48-like producers remained susceptible to ceftazidime-avibactam.

Different epidemiology of bloodstream infections in COVID-19 compared to non-COVID-19 critically ill patients: a descriptive analysis of the Eurobact II study.

BACKGROUND: The study aimed to describe the epidemiology and outcomes of hospital-acquired bloodstream infections (HABSIs) between COVID-19 and non-COVID-19 critically ill patients. METHODS: We used data from the Eurobact II study, a prospective observational multicontinental cohort study on HABSI treated in ICU. For the current analysis, we selected centers that included both COVID-19 and non-COVID-19 critically ill patients. We performed descriptive statistics between COVID-19 and non-COVID-19 in terms of patients' characteristics, source of infection and microorganism distribution. We studied the association between COVID-19 status and mortality using multivariable fragility Cox models. RESULTS: A total of 53 centers from 19 countries over the 5 continents were eligible. Overall, 829 patients (median age 65 years [IQR 55; 74]; male, n = 538 [64.9%]) were treated for a HABSI. Included patients comprised 252 (30.4%) COVID-19 and 577 (69.6%) non-COVID-19 patients. The time interval between hospital admission and HABSI was similar between both groups. Respiratory sources (40.1 vs. 26.0%, p < 0.0001) and primary HABSI (25.4% vs. 17.2%, p = 0.006) were more frequent in COVID-19 patients. COVID-19 patients had more often enterococcal (20.5% vs. 9%) and Acinetobacter spp. (18.8% vs. 13.6%) HABSIs. Bacteremic COVID-19 patients had an increased mortality hazard ratio (HR) versus non-COVID-19 patients (HR 1.91, 95% CI 1.49-2.45). CONCLUSIONS: We showed that the epidemiology of HABSI differed between COVID-19 and non-COVID-19 patients. Enterococcal HABSI predominated in COVID-19 patients. COVID-19 patients with HABSI had elevated risk of mortality. Trial registration ClinicalTrials.org number NCT03937245 . Registered 3 May 2019.

Comparison of teicoplanin versus vancomycin in combination with piperacillin-tazobactam or meropenem for the risk of acute kidney injury.

We compared the rates of acute kidney injury (AKI), 7-day and 30-day mortalities, and resolution of AKI at discharge in combination therapies involving either teicoplanin (TEI) or vancomycin (VAN) with piperacillin-tazobactam (TZP) or meropenem (MER). In a single-center, retrospective cohort study, adult patients (>18 years) who had a baseline serum creatinine level within 24 h of admission and who received study antibiotics for at least 48 h were included. The primary outcome was AKI incidence after therapy per RIFLE criteria. Multivariate logistic regression and propensity score match analyses were employed for statistical comparisons. Data from 379 patients were evaluated. In multivariate analysis (MVA) of the whole cohort, TZP-VAN combination was associated with significantly higher rate of AKI as compared with TZP-TEI (aOR: 3.21, 95% CI, 1.36-7.57; p = 0.008) or with MER-VAN (aOR: 2.28, 95% CI, 1.008-5.18; p = 0.048). In MVA of the matched cohorts, TZP-VAN as compared with TZP-TEI and MER-VAN was associated with 3.96 times (95% CI, 1.48-10.63, p = 0.006) and 3.11 times (95% CI, 1.12-8.62; p = 0.028) increased risk of AKI, respectively. No differences between MER-TEI and MER-VAN combinations were detected. Seven-day and 30-day mortalities and resolution rates of AKI were similar in all comparisons. Teicoplanin can be preferred instead of VAN when combination with TZP is used particularly for patients with high AKI risk.

Lack of awareness of Hepatitis B screening and vaccination in high-risk groups

Background/aim: Hepatitis B virus (HBV) vaccination rates are insufficient in high-risk patients worldwide. This study aimed to investigate the screening, immunization, and vaccination rates in three high-risk groups for HBV infection: allogeneic hematopoietic stem cell transplantation (AHSCT), renal transplantation (RT), and chronic hepatitis C (CHC) groups. Materials and methods: The serological data of consecutive patients between 2014 and 2019 were reviewed using the hospital database. Results: The HBV screening rates were 100.0%, 90.4%, and 82.4% in the AHSCT, CHC, and RT groups, respectively (p = 0.003). The immunization rates against HBV through either previous exposure or vaccination were 79.5%, 71.7%, and 46.5% in the AHSCT, RT, and CHC groups, respectively (p < 0.001). The HBV vaccination rate was significantly low in the CHC group (71.5%, 69.0%, 34.6% in the AHSCT, RT, and CHC groups, respectively, p < 0.001). If patients lost their immunity due to immunosuppressive therapy were accounted, the vaccination rates increased to 95.2% in the AHSCT group and 72.9% in the RT group. The rate of annual screening for HBV status was 97.9% in the AHSCT group, but it was only 23.9% in the RT group. Conclusion: HBV screening and vaccination rates were significantly lower in the RT and CHC groups than in the AHSCT group.

Scoping review of risk-scoring tools for early prediction of bloodstream infections caused by carbapenem-resistant Enterobacterales: do we really have a reliable risk-scoring tool?

Background: Bloodstream infections (BSIs) caused by carbapenem-resistant Enterobacterales (CRE) are a global health concern. Rapid identification of CRE may improve patient outcomes and reduce inappropriate antibiotic prescription. The use of risk-scoring tools (RSTs) can be valuable for optimizing the decision-making process for empirical antibiotic therapy of suspected CRE bacteraemia. These tools can also be used to triage use of expensive rapid diagnostic methods. Methods: We systematically reviewed the relevant literature in PubMed/MEDLINE, CINAHL, Cochrane, Web of Science, Embase and Scopus up to 1 November 2022 to identify RSTs that predict CRE BSIs. The literature review and analysis of the articles were performed by two researchers; any inconsistencies were resolved through discussion. Results: We identified 9 RSTs developed for early prediction of CRE BSIs and only logistic regression was used for most studies. These RSTs were quite different from each other in terms of their performance and the variables they included. They also had notable limitations and very few of them were externally validated. Conclusions: RSTs for early prediction of CRE BSIs have limitations and lack of external validity outside the local setting in which they were developed. Future studies to identify optimal RSTs in high and low CRE-endemic settings are warranted. Approaches based on rapid diagnostics and RSTs should be compared with a treatment approach using both methods in a randomized controlled trial.

The global epidemiology of ventilator-associated pneumonia caused by multi-drug resistant Pseudomonas aeruginosa: A systematic review and meta-analysis.

OBJECTIVES: The objective of this systematic review and meta-analysis was to estimate the global prevalence of multi-drug resistant (MDR) Pseudomonas aeruginosa causing ventilator-associated pneumonia (VAP). METHODS: The systematic search was conducted in four databases. Original studies describing MDR P. aeruginosa VAP prevalence in adults from 2012- 2022 were included. A meta-analysis, using the random effects model, was conducted for overall, subgroups (country, published year, study duration, and study design), and European data, respectively. Univariate meta-regression based on pooled estimates was also conducted. Systematic review registered in International Prospective Register of Systematic Review (CRD42022384035). RESULTS: In total of 31 studies, containing a total of 7951 cases from 16 countries, were included. The overall pooled prevalence of MDR among P. aeruginosa causing VAP was 33% (95% confidence interval [CI] 27.7-38.3%). The highest prevalence was for Iran at 87.5% (95% CI 69-95.7%), and the lowest was for the USA at 19.7% (95% CI 18.6-20.7%). The European prevalence was 29.9% (95% CI 23.2-36.7%). CONCLUSIONS: This review indicates that the prevalence of MDR P. aeruginosa in patients with VAP is generally high and varies significantly between countries; however, data are insufficient for many countries. The data in this study can provide a reference for VAP management and drug customisation strategies.

The role of centre and country factors on process and outcome indicators in critically ill patients with hospital-acquired bloodstream infections.

PURPOSE: The primary objective of this study was to evaluate the associations between centre/country-based factors and two important process and outcome indicators in patients with hospital-acquired bloodstream infections (HABSI). METHODS: We used data on HABSI from the prospective EUROBACT-2 study to evaluate the associations between centre/country factors on a process or an outcome indicator: adequacy of antimicrobial therapy within the first 24 h or 28-day mortality, respectively. Mixed logistical models with clustering by centre identified factors associated with both indicators. RESULTS: Two thousand two hundred nine patients from two hundred one intensive care units (ICUs) were included in forty-seven countries. Overall, 51% (n = 1128) of patients received an adequate antimicrobial therapy and the 28-day mortality was 38% (n = 839). The availability of therapeutic drug monitoring (TDM) for aminoglycosides everyday [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.03-2.14] or within a few hours (OR 1.79, 95% CI 1.34-2.38), surveillance cultures for multidrug-resistant organism carriage performed weekly (OR 1.45, 95% CI 1.09-1.93), and increasing Human Development Index (HDI) values were associated with adequate antimicrobial therapy. The presence of intermediate care beds (OR 0.63, 95% CI 0.47-0.84), TDM for aminoglycoside available everyday (OR 0.66, 95% CI 0.44-1.00) or within a few hours (OR 0.51, 95% CI 0.37-0.70), 24/7 consultation of clinical pharmacists (OR 0.67, 95% CI 0.47-0.95), percentage of vancomycin-resistant enterococci (VRE) between 10% and 25% in the ICU (OR 1.67, 95% CI 1.00-2.80), and decreasing HDI values were associated with 28-day mortality. CONCLUSION: Centre/country factors should be targeted for future interventions to improve management strategies and outcome of HABSI in ICU patients.

In vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam monotherapy with ceftazidime-avibactam-containing combination regimens against carbapenem-resistant Enterobacterales and multidrug-resistant Pseudomonas aeruginosa isolates or infections: a scoping review.

Introduction: Carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections are associated with a high risk of morbidity, mortality, and treatment costs. We aimed to evaluate in vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam (CZA) combination regimens with CZA alone against CRE and/or MDR-PA isolates or infections. Methods: We systematically reviewed the relevant literature in CINAHL/MEDLINE, Pubmed, Cochrane, Web of Science, Embase, and Scopus until December 1, 2022. Review articles, grey literature, abstracts, comments, editorials, non-peer reviewed articles, non-English articles, and in vitro synergy studies conducted on single isolates were excluded. Results: 22 in vitro, 7 in vivo and 20 clinical studies were evaluated. In vitro studies showed reliable synergy between CZA and aztreonam against metallo-ß-lactamase (MBL)-producing isolates. Some studies indicated good in vitro synergy between CZA and amikacin, meropenem, fosfomycin and polymyxins against CRE isolates. For MDR-PA isolates, there are comparatively fewer in vitro or in vivo studies. In observational clinical studies, mortality, clinical cure, adverse events, and development of CZA resistance after exposure were generally similar in monotherapy and combination therapy groups. However, antibiotic-related nephrotoxicity and infection relapses were higher in patients receiving CZA combination therapies. Discussion: The benefit, if any, of CZA combination regimens in MDR-PA infections is elusive, as very few clinical studies have included these infections. There is no currently documented clinical benefit for the use of CZA combination regimens rather than CZA monotherapy. CZA combined with aztreonam for serious infections due to MBL producers should be evaluated by randomized controlled trials. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278552, CRD42021278552.

Duration of antibiotic treatment and timing of oral switching for bloodstream infections: a survey on the practices of infectious diseases and intensive care physicians.

AIM: To understand current practice in terms of duration of antibiotic treatment and timing of intravenous (IV) to oral switching for common bacteraemic conditions amongst infectious diseases (ID) and intensive care unit (ICU) physicians. METHODS: An online survey consisting of 18 questions comprising five common clinical bacteraemia scenarios [adapted from the original survey designed by the University of Toronto (Toronto, Ontario, Canada)] was conducted amongst Turkish ID and ICU physicians between November 2020 and November 2021. RESULTS: In total, 236 physicians (76.5% ID and 17.5% ICU) responded. The most commonly recommended duration of antibiotic treatment for bacteraemia was 14 days (42%), followed by 10 (27%) and 7 (18%) days. The median recommended treatment durations were 10 [interquartile range (IQR) 10-14] days for central-venous-catheter-associated bloodstream infection, 10 (IQR 7-14) days for bacteraemic pneumonia, 14 (IQR 10-14) days for bacteraemic urinary tract and intra-abdominal infections, and 14 (IQR 7-14) days for bacteraemic skin and soft tissue infection. Carbapenem resistance influenced the recommendations, but pathogen type did not. No significant difference in responses for most scenarios was found between ID and ICU physicians. Switching to oral antibiotics after a median duration of 7 (IQR 5-7) days of IV treatment was considered by 80% of respondents. CONCLUSION: Prolonged treatment was recommended for most clinical scenarios. Extended IV durations were recommended before oral switching. A presumption that resistant bacterial infections require longer therapy may be responsible for prolonged treatment durations.

Epidemiology and outcomes of hospital-acquired bloodstream infections in intensive care unit patients: the EUROBACT-2 international cohort study.

PURPOSE: In the critically ill, hospital-acquired bloodstream infections (HA-BSI) are associated with significant mortality. Granular data are required for optimizing management, and developing guidelines and clinical trials. METHODS: We carried out a prospective international cohort study of adult patients (≥ 18 years of age) with HA-BSI treated in intensive care units (ICUs) between June 2019 and February 2021. RESULTS: 2600 patients from 333 ICUs in 52 countries were included. 78% HA-BSI were ICU-acquired. Median Sequential Organ Failure Assessment (SOFA) score was 8 [IQR 5; 11] at HA-BSI diagnosis. Most frequent sources of infection included pneumonia (26.7%) and intravascular catheters (26.4%). Most frequent pathogens were Gram-negative bacteria (59.0%), predominantly Klebsiella spp. (27.9%), Acinetobacter spp. (20.3%), Escherichia coli (15.8%), and Pseudomonas spp. (14.3%). Carbapenem resistance was present in 37.8%, 84.6%, 7.4%, and 33.2%, respectively. Difficult-to-treat resistance (DTR) was present in 23.5% and pan-drug resistance in 1.5%. Antimicrobial therapy was deemed adequate within 24 h for 51.5%. Antimicrobial resistance was associated with longer delays to adequate antimicrobial therapy. Source control was needed in 52.5% but not achieved in 18.2%. Mortality was 37.1%, and only 16.1% had been discharged alive from hospital by day-28. CONCLUSIONS: HA-BSI was frequently caused by Gram-negative, carbapenem-resistant and DTR pathogens. Antimicrobial resistance led to delays in adequate antimicrobial therapy. Mortality was high, and at day-28 only a minority of the patients were discharged alive from the hospital. Prevention of antimicrobial resistance and focusing on adequate antimicrobial therapy and source control are important to optimize patient management and outcomes.

Higher rates of cefiderocol resistance among NDM producing Klebsiella bloodstream isolates applying EUCAST over CLSI breakpoints.

BACKGROUND: Cefiderocol is generally active against carbapenem-resistant Klebsiella spp. (CRK) with higher MICs against metallo-beta-lactamase producers. There is a variation in cefiderocol interpretive criteria determined by EUCAST and CLSI. Our objective was to test CRK isolates against cefiderocol and compare cefiderocol susceptibilities using EUCAST and CLSI interpretive criteria. METHODS: A unique collection (n = 254) of mainly OXA-48-like- or NDM-producing CRK bloodstream isolates were tested against cefiderocol with disc diffusion (Mast Diagnostics, UK). Beta-lactam resistance genes and multilocus sequence types were identified using bioinformatics analyses on complete bacterial genomes. RESULTS: Median cefiderocol inhibition zone diameter was 24 mm (interquartile range [IQR] 24-26 mm) for all isolates and 18 mm (IQR 15-21 mm) for NDM producers. We observed significant variability between cefiderocol susceptibilities using EUCAST and CLSI breakpoints, such that 26% and 2% of all isolates, and 81% and 12% of the NDM producers were resistant to cefiderocol using EUCAST and CLSI interpretive criteria, respectively. CONCLUSIONS: Cefiderocol resistance rates among NDM producers are high using EUCAST criteria. Breakpoint variability may have significant implications on patient outcomes. Until more clinical outcome data are available, we suggest using EUCAST interpretive criteria for cefiderocol susceptibility testing.

Risk factors for Gram-negative bacterial infection of cardiovascular implantable electronic devices: multicentre observational study (CarDINe Study).

BACKGROUND: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. METHODS: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. RESULTS: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). CONCLUSIONS: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

The Role of Colistin in the Era of New ß-Lactam/ß-Lactamase Inhibitor Combinations.

With the current crisis related to the emergence of carbapenem-resistant Gram-negative bacteria (CR-GNB), classical treatment approaches with so-called "old-fashion antibiotics" are generally unsatisfactory. Newly approved ß-lactam/ß-lactamase inhibitors (BLBLIs) should be considered as the first-line treatment options for carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections. However, colistin can be prescribed for uncomplicated lower urinary tract infections caused by CR-GNB by relying on its pharmacokinetic and pharmacodynamic properties. Similarly, colistin can still be regarded as an alternative therapy for infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) until new and effective agents are approved. Using colistin in combination regimens (i.e., including at least two in vitro active agents) can be considered in CRAB infections, and CRE infections with high risk of mortality. In conclusion, new BLBLIs have largely replaced colistin for the treatment of CR-GNB infections. Nevertheless, colistin may be needed for the treatment of CRAB infections and in the setting where the new BLBLIs are currently unavailable. In addition, with the advent of rapid diagnostic methods and novel antimicrobials, the application of personalized medicine has gained significant importance in the treatment of CRE infections.

Piperacillin-Tazobactam Plus Vancomycin-Associated Acute Kidney Injury in Adults: Can Teicoplanin or Other Antipseudomonal Beta-Lactams Be Remedies?

Numerous observational studies and meta-analyses have suggested that combination therapy consisting of piperacillin-tazobactam (TZP) and vancomycin (VAN) augments acute kidney injury (AKI) risk when compared to viable alternatives, such as cefepime-vancomycin (FEP-VAN) and meropenem-VAN. However, the exact pathophysiological mechanisms of this phenomenon are still unclear. One major limitation of the existing studies is the utilization of serum creatinine to quantify AKI since serum creatinine is not a sufficiently sensitive and specific biomarker to truly define the causal relationship between TZP-VAN exposure and nephrotoxicity. Even so, some preventive measures can be taken to reduce the risk of AKI when TZP-VAN is preferred. These measures include limiting the administration of TZP-VAN to 72 h, choosing FEP-VAN in place of TZP-VAN in appropriate cases, monitoring the VAN area under the curve level rather than the VAN trough level, avoiding exposure to other nephrotoxic agents, and minimizing the prescription of TZP-VAN for patients with a high risk of AKI. More data are needed to comment on the beneficial impact of the extended-infusion regimen of TZP on nephrotoxicity. Additionally, TZP and teicoplanin can be reasonable alternatives to TZP-VAN for the purpose of lowering AKI risk. However, the data are scarce to advocate this practice convincingly.

Next-Generation Polymyxin Class of Antibiotics: A Ray of Hope Illuminating a Dark Road.

Although new-generation antimicrobials, in particular ß-lactam/ß-lactamase inhibitors, have largely replaced polymyxins in carbapenem-resistant Gram-negative bacterial infections, polymyxins are still needed for carbapanem-resistant Acinetobacter baumannii infections and in settings where novel agents are not readily available. Despite their potent in vitro activity, the clinical utility of polymyxins is significantly limited by their pharmacokinetic properties and nephrotoxicity risk. There is significant interest, therefore, in developing next-generation polymyxins with activity against colistin-resistant strains and lower toxicity than existing polymyxins. In this review, we aim to present the antibacterial activity mechanisms, in vitro and in vivo efficacy data, and toxicity profiles of new-generation polymyxins, including SPR206, MRX-8, and QPX9003, as well as the general characteristics of old polymyxins. Considering the emergence of colistin-resistant strains particularly in endemic regions, the restoration of the antimicrobial activity of polymyxins via PBT2 is also described in this review.

Barriers Against Hepatitis B Vaccination in High-Risk Adults: A Cross-Sectional Study.

BACKGROUND: The hepatitis B vaccination has been strongly recommended by regulatory bodies. However, there are great discrepan- cies between routine practices and the recommendations of regulatory agencies in many countries. We aimed to identify the barriers against Hepatitis B Vaccination (HBV) for high-risk patients by comparing the awareness, attitude, and knowledge among vaccinated and unvaccinated patients. METHODS: A 34-item questionnaire was applied to 156 patients, consisting of renal transplant recipients, allogeneic hematopoietic stem cell transplant recipients, and patients with chronic hepatitis C. Multiple logistic regression analysis was employed to identify indepen- dent predictors for patients receiving the hepatitis B virus vaccination. RESULTS: The multiple logistic regression analysis revealed that the independent risk factors against the HBV vaccination were a require- ment of a separate appointment for hepatitis B virus vaccination (aOR: 3.35, 95% CI, 1.18-9.47), and fear of severe side effects that can be related with hepatitis B virus vaccination (aOR: 3.67, 95% CI, 1.18-9.47). However, taking a recommendation for hepatitis B virus vaccination at least once from a health care provider (aOR: 0.04, 95% CI, 0.01-0.11), and having a health insurance (aOR: 0.09, 95% CI, 0.01-0.55) were independent protective factors for being vaccinated. In further analysis among patients with at least a single dose of vaccine, the lack of recommendation from a health care provider for hepatitis B virus vaccination and the absence of a healthcare pro- vider who is responsible for monitoring the completion of the 3-dose vaccination were identified as independent risk factors for failure to complete the 3-dose hepatitis B virus vaccination. CONCLUSION: In high-risk adults, the barriers against hepatitis B virus vaccination should be handled by a comprehensive action plan to achieve the WHO 2030 hepatitis elimination target.

Treatment strategies for OXA-48-like and NDM producing Klebsiella pneumoniae infections.

INTRODUCTION: OXA-48 and NDM are amongst the most prevalent carbapenemase types associated with Klebsiella pneumoniae worldwide, with an increase in their prevalence in recent years. Knowledge on the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) comes from KPC-producing CRKP with limited data available for OXA-48-like and NDM producers. Our aim is to review the literature on the treatment of OXA-48-like and NDM-producing CRKP with the goal of providing an update on the available antibiotic treatment strategies, particularly in light of changing carbapenemase epidemiology and increasing antimicrobial resistance. AREAS COVERED: We reviewed studies looking at the antibiotic treatment and outcome of OXA-48-like and/or NDM-producing CRKP. EXPERT OPINION: The best available treatment option for OXA-48 producers is ceftazidime-avibactam, where available and when the price permits its use. Colistin remains as the second-line option if in vitro susceptibility is demonstrated with an appropriate method. There is not enough evidence to support the use of meropenem-containing combination therapies for meropenem-resistant OXA-48 producers. Treatment of NDM producers is an unmet need. Ceftazidime-avibactam and aztreonam combination or cefiderocol can be used for NDM producers, where available. Higher cefiderocol MICs against NDM producers is concerning. Aztreonam-avibactam provides hope for the treatment of NDM producers.

Hepatitis E Virus Prevalence and Associated Risk Factors in High-Risk Groups: A Cross-Sectional Study.

BACKGROUND: Seroepidemiology, risk factors to hepatitis E virus exposure, and prevalence of hepatitis E virus viremia have not yet been investigated among patients under immunosuppression or with liver disease that are high risk for infection in Turkey. METHODS: In this cross-sectional study, 292 consecutive serum samples from renal transplant recipients, allogeneic hematopoietic stem cell transplant recipients, patients with acute hepatitis, and patients with chronic hepatitis C were prospectively collected in a ter- tiary university hospital. Sera were tested for hepatitis E virus immunoglobulin G/immunoglobulin M and hepatitis E virus ribonucleic acid using commercial enzyme-linked immunosorbent assay and in-house nested polymerase chain reaction with Sanger sequencing, respectively. Sociodemographic, clinical, laboratory data, and risk factors were collected using a questionnaire and hospital database. Multiple logistic regression analysis was employed to identify independent predictors for anti-hepatitis E virus seropositivity. RESULTS: Among all patients, only 2 patients (1 renal transplant recipient and 1 patient with acute hepatitis) were identified as having hepatitis E virus genotype 3 viremia. Hepatitis E virus viremia rate was 0.6% in whole group. These patients showed no signs of chronic hepatitis E virus infection for 6 months and were spontaneously seroconverted 6 months after enrollment. Anti-hepatitis E virus IgG was positive in 29 patients yielding a hepatitis E virus seroprevalence of 9.9%. Older age (adjusted odds ratio: 1.03, 95% CI, 1.00-1.06; P = .022) and eating undercooked meat (adjusted odds ratio: 3.11, 95% CI, 1.08-8.92; P = .034) were independent risk factors to anti- hepatitis E virus seropositivity in all patients. Similarly, multiple logistic regression analysis demonstrated that age (adjusted odds ratio: 1.03, 95% CI, 0.99-1.07, P = .058) and eating undercooked meat (adjusted odds ratio: 5.77, 95% CI, 1.49-22.25, P = .011) were indepen- dent risk factors for anti-hepatitis E virus IgG positivity in the liver disease subgroup consisting of acute hepatitis and chronic hepatitis C patients. CONCLUSION: The hepatitis E virus seroprevalence rate was high (9.9%), despite low viremia rate (0.6%) in high-risk patients. The emer- gence of hepatitis E virus genotype 3 might indicate a serious problem for these patients. Future investigations are needed to elucidate foodborne transmission routes of hepatitis E virus in Turkey.