Medical cannabis and its effect on oncological outcomes in patients with ovarian cancer treated with PARP inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. METHODS: The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. RESULTS: Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). CONCLUSION: Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance.

OBJECTIVES: To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries. METHODS: Isolates were collected during the 2013-17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed. RESULTS: In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily blaOXA-23. The chromosomal oxaAb (blaOXA-51-like) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1α. CONCLUSIONS: The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade's/ST's success.

Current state of antimicrobial stewardship in solid organ transplantation in Israel.

BACKGROUND: We aimed to review the current state, challenges, and needs of antimicrobial stewardship programs (ASPs) in adult solid organ transplantation (SOT) centers in Israel. METHODS: We conducted a survey using electronic questionnaires sent during February 2022 to infectious disease (ID) consultants of SOT centers, encompassing general and organ-specific ASP issues. RESULTS: All six centers performing adult SOTs in Israel participated. The institutional ASPs in all centers included SOT recipients, and five centers had specific stewardship activities targeting SOT recipients. ASP activities were performed by ID consultants in all centers, with clinical pharmacists in most. ASP protocols and activity scope were highly variable. Formulary restriction with pre-authorization was used in all centers. Antibiotic allergy was addressed in ASP guidelines in half of the centers. Peri-transplantation antibiotic, antifungal, and antiviral prophylactic regimens varied based on center, transplanted organ, and patient risk group. Approaches to surveillance cultures, diagnosis and treatment of various graft infections were also variable. ASP outcome measurement was not performed in all centers. The main challenges and barriers to successful ASP implementation were difficulty in defining appropriate durations of therapy for certain infections, high rates of antimicrobial resistance (AMR), and lack of dedicated ASP teams. CONCLUSION: Antimicrobial stewardship in SOT centers in Israel is performed by ID consultants and practices vary. Challenges are related to high AMR rates, insufficient evidence to support practices, lack of dedicated ASP teams, and lack of outcome measurement. There is an urgent need to establish a national collaborative program including all SOT centers.

New evidence for managing Gram-negative bloodstream infections.

PURPOSE OF REVIEW: Gram-negative bloodstream infections (GNBSI) are common and carry considerable mortality. Treatment is complicated by increasing antimicrobial resistance, posing a challenge for timely appropriate antibiotics and limiting the choices of effective definitive therapy. The present review aims to summarize recent studies addressing the management of GNBSI. RECENT FINDINGS: New rapid diagnostic tests (RDT) for pathogen identification and antibiotic susceptibility are associated with improved antimicrobial stewardship and reduced length of stay. No mortality benefit or patient-related outcomes are reported. Data regarding the use of new beta-lactam beta-lactamase inhibitors (BLBLIs) for treating multidrug resistance Gram-negative bacteria is supportive, though questions regarding combinations, optimal dosing, mode of administration, and resistance emergence remain to be clarified. Current data regarding cefiderocol necessitates further studies in order to support its use in GNBSI. Shortened (≤7 days) duration of therapy and early oral step down for GNBSI are supported by the literature. The role of repeated blood cultures should be further defined. SUMMARY: RDTs should be implemented to improve antibiotic stewardship. Clinical implications on patient-related outcomes should be evaluated. New BLBLIs show promise in the treatment of GNBSI. Additional data are needed regarding the use of cefiderocol. Antibiotic therapy should be shortened and early oral step down should be considered.

Surgical antibiotic prophylaxis in patients colonized with multidrug-resistant Gram-negative bacteria: practical and conceptual aspects.

Antibiotic resistance threatens the effectiveness of surgical antibiotic prophylaxis (SAP) regimens aimed at preventing surgical site infection (SSI). With a focus on procedures in which Gram-negative bacteria (GNB) are the main pathogens causing SSI, this review summarizes the evidence and describes how SAP must evolve in response to carriage of MDR GNB among surgical patients. Randomized controlled trials of SAP for carriers of resistant GNB require prohibitively large sample sizes. No professional guidelines address the topic of adapting SAP for known carriers of resistant GNB. For patients whose carrier status is unknown, the effects of different SAP strategies have been studied for transrectal ultrasound-guided prostate biopsy and colorectal surgery. The four possible strategies for SAP in the era of antibiotic resistance are: no SAP; universal standard SAP; pre-surgical screening for carriage of antibiotic-resistant pathogens before surgery and targeted SAP (i.e. broad-spectrum antibiotics only for those who screen positive); and universal broad-spectrum SAP. The prevalence of carriage determines the efficiency of each strategy. Decolonization is a potential adjunct to SAP.

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.

BACKGROUND: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. METHODS: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. RESULTS: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. CONCLUSION: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.

Personalized Ertapenem Prophylaxis for Carriers of Extended-spectrum ß-Lactamase-producing Enterobacteriaceae Undergoing Colorectal Surgery.

BACKGROUND: Carriers of extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) who receive cephalosporin-based prophylaxis have twice the risk of surgical site infection (SSI) following colorectal surgery as noncarriers. We tested whether ESBL-PE screening and personalized prophylaxis with ertapenem reduces SSI risk among carriers. METHODS: We conducted a prospective nonrandomized, nonblinded, interventional study in 3 hospitals in Israel, Switzerland, and Serbia. Patients were screened for ESBL-PE carriage before elective colorectal surgery. During the baseline phase, departmental guidelines advised prophylaxis with a cephalosporin plus metronidazole. In the intervention phase, guidelines were changed for ESBL-PE carriers to receive ertapenem. The primary outcome was any type of SSI within 30 days. We calculated adjusted risk differences (ARDs) following logistic regression. RESULTS: The intention-to-treat analysis compared 209 ESBL-PE carriers in the baseline phase to 269 in the intervention phase. SSI rates were 21.5% and 17.5%, respectively (ARD, -4.7% [95% confidence interval {CI}, -11.8% to 2.4%]). Unplanned crossover was high (15%), so to assess efficacy we performed an as-treated analysis comparing 247 patients who received cephalosporin-based prophylaxis with 221 who received ertapenem. SSI rates were 22.7% and 15.8%, respectively (ARD, -7.7% [95% CI, -14.6% to -.8%]), and rates of SSI caused by ESBL-PE were 6.5% and 0.9%, respectively (ARD, -5.6% [95% CI, -8.9% to -2.3%]). There was no significant difference in the rate of deep SSI. The number needed to treat to prevent 1 SSI in ESBL-PE carriers was 13. CONCLUSIONS: Screening for ESBL-PE carriage before colorectal surgery and personalizing prophylaxis for carriers is efficacious in reducing SSI.

Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms.

BACKGROUND: We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms. METHODS: This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E). RESULTS: Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475-10.184; P = .006). CONCLUSIONS: Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention.

Cost-effectiveness of diabetic retinopathy screening programs using telemedicine: a systematic review.

BACKGROUND: Diabetic retinopathy (DR) is a significant global public health and economic burden. DR accounts for approximately 15-17% of all cases of total blindness in the USA and Europe. Telemedicine is a new intervention for DR screening, however, there is not enough evidence to support its cost-effectiveness. The aim of this study is to review the most recent published literature on economic evaluations of telemedicine in DR screening and summarize the evidence on the cost-effectiveness of this technology. METHODS: A systematic search of PubMed, Embase and Google Scholar for relevant articles published between January 2010 and January 2020. Studies were included if they met the following criteria: (1) recruited subjects with either type 1, type 2 diabetes (2) evaluated telemedicine technology (3) patients underwent primary screening for DR (4) compared a telemedicine-based intervention with standard care (5) performed an economic evaluation or provided sufficient data for evaluating the cost-effectiveness of the technology used. RESULTS: Of 2238 articles screened, seven studies were included. Four of the studies were conducted in developed countries: The United States, Singapore and two studies in Canada. Three studies were conducted in developing countries: India, Brazil and South Africa. The patient populations in all studies were diabetic patients over the age of 18, previously not screened for DR. All seven studies used a telemedicine program which included capturing a retinal image and subsequently transmitting it to an ocular imaging center to assess the severity of DR. All studies compared telemedicine to a standard screening method for DR, including the option of no screening as standard of care. Although telemedicine requires initial and maintenance costs, it has the potential to provide significant cost savings by increasing patients' working ability, increasing independent living ability, increasing quality of life and reducing travel costs. CONCLUSIONS: Diabetic retinopathy telemedicine technology has the potential to provide significant cost savings, especially in low-income populations and rural patients with high transportation costs.

Carriage of Extended-spectrum Beta-lactamase-producing Enterobacteriaceae and the Risk of Surgical Site Infection After Colorectal Surgery: A Prospective Cohort Study.

BACKGROUND: Antibiotic prophylaxis that covers enteric pathogens is essential in preventing surgical site infections (SSIs) after colorectal surgery. Current prophylaxis regimens do not cover extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). We aimed to determine whether the risk of SSI following colorectal surgery is higher in ESBL-PE carriers than in noncarriers. METHODS: We conducted a prospective cohort study of patients who underwent elective colorectal surgery in 3 hospitals in Israel, Switzerland, and Serbia between 2012 and 2017. We included patients who were aged ≥18 years, were screened for ESBL-PE carriage before surgery, received routine prophylaxis with a cephalosporin plus metronidazole, and did not have an infection at the time of surgery. The exposed group was composed of ESBL-PE-positive patients. The unexposed group was a random sample of ESBL-PE-negative patients. We collected data on patient and surgery characteristics and SSI outcomes. We fit logistic mixed effects models with study site as a random effect. RESULTS: A total of 3600 patients were screened for ESBL-PE; 13.8% were carriers SSIs occurred in 55/220 carriers (24.8%) and 49/440 noncarriers (11.1%, P < .001). In multivariable analysis, ESBL-PE carriage more than doubled the risk of SSI (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.50-3.71). Carriers had higher risk of deep SSI (OR, 2.25; 95% CI, 1.27-3.99). SSI caused by ESBL-PE occurred in 7.2% of carriers and 1.6% of noncarriers (OR, 4.23; 95% CI, 1.70-10.56). CONCLUSIONS: ESBL-PE carriers who receive cephalosporin-based prophylaxis are at increased risk of SSI following colorectal surgery.

Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial.

BACKGROUND: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. METHODS: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. RESULTS: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). CONCLUSIONS: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. CLINICAL TRIALS REGISTRATION: NCT01732250.

The Association Between Empirical Antibiotic Treatment and Mortality in Severe Infections Caused by Carbapenem-resistant Gram-negative Bacteria: A Prospective Study.

Background: Empirical colistin should be avoided. We aimed to evaluate the association between covering empirical antibiotics (EAT) and mortality for infections caused by carbapenem-resistant gram-negative bacteria (CRGNB). Methods: This was a secondary analysis of a randomized controlled trial, including adults with bloodstream infections, pneumonia, or urosepsis caused by CRGNB. All patients received EAT followed by covering targeted therapy. The exposure variable was covering EAT in the first 48 hours. The outcome was 28-day mortality. We adjusted the analyses by multivariable regression analysis and propensity score matching. Results: The study included 406 inpatients with severe CRGNB infections, mostly Acinetobacter baumannii (312/406 [77%]). Covering EAT was given to 209 (51.5%) patients, mostly colistin (n = 200). Patients receiving noncovering EAT were older, more frequently unconscious and dependent, carrying catheters, and mechanically ventilated with pneumonia. Mortality was 84 of 197 (42.6%) with noncovering vs 96 of 209 (45.9%) with covering EAT (P = .504). Covering EAT was not associated with survival in the adjusted analysis; rather, there was a weak association with mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.02-1.84). Results were similar for colistin monotherapy and colistin-carbapenem combination EAT. In the propensity score-matched cohort (n = 338) covering antibiotics were not significantly associated with mortality (OR, 1.42; 95% CI, .91-2.22). Similar results were obtained in an analysis of 14-day mortality. Conclusions: Empirical use of colistin before pathogen identification, with or without a carbapenem, was not associated with survival following severe infections caused by CRGNBs, mainly A. baumannii.

Integration of individual preclinical and clinical anti-infective PKPD data to predict clinical study outcomes.

The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic-pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥2-log10 (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti-infective PKPD data can be integrated through pharmacodynamic modeling and identify patient- and pathogen-specific factors related to clinical outcomes - an approach that may improve understanding of study outcomes.

Hospital-acquired bacterial infections in coronavirus disease 2019 (COVID-19) patients in Israel.

BACKGROUND: We sought to determine incidence of common hospital-acquired bacteria among coronavirus disease 2019 (COVID-19) patients in Israeli general hospitals during the first year of the pandemic. METHODS: We analyzed routinely collected incidence data to determine hospital acquisition of the following sentinel bacteria: Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa, Acinetobacter baumannii, and Clostridioides difficile. We examined 3 acquisition measures: (1) sentinel bacteria, (2) sentinel bacteremia, and (3) antimicrobial-resistant sentinel bacteremia. The study period was March 1, 2020, through January 31, 2021. RESULTS: Analysis of pooled data from the 26 hospitals surveyed revealed that rates were higher for all 3 acquisition measures among COVID-19 patients than they were among patients on general medical wards in 2019, but lower than those among patients in intensive care units in 2019. The incidence rate was highest during the first COVID-19 wave, despite a lower proportion of severe COVID-19 cases among total hospitalized during this wave. Wide variation in incidence was evident between hospitals. CONCLUSIONS: Hospitalized COVID-19 patients experienced nosocomial bacterial infection at rates higher than those of patients on pre-pandemic general medical wards, adding to the complexity of their care. Lower rates of nosocomial infection after the first wave, despite higher proportions of severely ill patients, suggest that healthcare worker practices, rather than patient-related factors, were responsible for most of these infections.

Active surveillance for carbapenem-resistant Acinetobacter baumannii (CRAB) carriage.

IMPORTANCE: Our study's results provide promising evidence for the incorporation of a high-sensitivity carbapenem-resistant Acinetobacter baumannii (CRAB) screening method in healthcare settings. Such an approach could prove beneficial in enhancing infection prevention and control measures, leading to improved patient outcomes and potentially alleviating the burden of CRAB in healthcare systems.

Acinetobacter baumannii Bloodstream Infections: A Nationwide Study in Israel.

Acinetobacter baumannii (Ab) bloodstream infections (BSIs) are a major public health concern and associated with high mortality. We describe the nationwide incidence, antimicrobial resistance, and mortality of Ab-BSI in Israel using laboratory-based BSI surveillance data from January 2018 to December 2019. During the study period, there were 971 Ab-BSI events (508 in 2018 and 463 in 2019), with an average annual incidence of 8.08/100,000 population. The median age of patients was 72 (IQR 62-83), and 56.4% were males. Two-thirds of Ab-BSI events were hospital-onset (HO), with median day of onset 16 (IQR 9-30). HO-BSI incidence was 0.62/10,000 patient-days (rate per 10,000 patient-days: 2.78, 1.17, and 0.2 for intensive care, medical, and surgical wards, respectively). Carbapenem susceptibility was 23.4%; 41.4% and 14.9% in community and HO events, respectively. The 14-day, 30-day, and 1-year mortality were 51.2%, 59.3%, and 81.4%, respectively. Carbapenem-resistant Ab-BSI were associated with a significantly higher 14-day, 30-day, and 1-year mortality (p < 0.001 for all). In the multivariable model, age (aHR 1.02) and carbapenem resistance (aHR 3.21) were independent predictors of 30-day mortality. In conclusion, Ab-BSIs pose a significant burden with high mortality, especially associated with antimicrobial resistance. Attention should be focused on prevention and improving treatment.

Utilizing Ceftazidime/Avibactam Therapeutic Drug Monitoring in the Treatment of Neurosurgical Meningitis Caused by Difficult-to-Treat Resistant Pseudomonas aeruginosa and KPC-Producing Enterobacterales.

Background: Central nervous system (CNS) infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales and difficult-to-treat resistant (DTR) Pseudomonas aeruginosa represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections. Methods: Therapeutic drug monitoring (TDM) was performed in 3 patients with health care-associated ventriculitis and meningitis (HAVM) using CAZ-AVI 2.5 g infused intravenously every 8 hours as standard and extended infusion. Simultaneous CSF and plasma samples were obtained throughout the dosing interval in each patient. Concentrations of CAZ and AVI were determined by liquid chromatography/mass spectrometry. Results: Bacterial identification revealed KPC-producing Klebsiella pneumoniae (KPC-Kp), DTR Pseudomonas aeruginosa, and KPC-producing Enterobacter cloacae (KPC-Ent.c). All isolates were resistant to carbapenems. The minimum inhibitory concentrations (MICs) of CAZ-AVI were 0.25/4, 4/4, and 0.25/4 µg/mL, respectively. CAZ and AVI concentrations were determined in CSF samples ranging from 29.0 to 15.0 µg/mL (CAZ component) and 4.20 to 0.92 µg/mL (AVI component), respectively. AVI achieved concentrations ≥1 µg/mL in 11 out of 12 CSF samples collected throughout the dosing interval. Clinical and microbiologic cure were attained in all patients. Conclusions: Postinfusion concentrations of CAZ-AVI were measured in plasma and CSF samples obtained from 3 patients with complicated CNS infections caused by antimicrobial-resistant isolates. The measured concentrations revealed that standard CAZ and AVI exposures sufficiently attained values correlating to 50% fT > MIC, which are associated with efficient bacterial killing.

Prevalence and Clinical Consequences of Colistin Heteroresistance and Evolution into Full Resistance in Carbapenem-Resistant Acinetobacter baumannii.

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings.

Hospital-Onset Bloodstream Infections Caused by Eight Sentinel Bacteria: A Nationwide Study in Israel, 2018-2019.

Nationwide studies on hospital-onset bloodstream infections (HO-BSIs) are scarce. To describe incidence, mortality and antimicrobial resistance (AMR) of HO-BSI caused by eight sentinel bacteria in Israel, we used laboratory-based BSI surveillance data from 1 January 2018 to 31 December 2019. All hospitals reported positive blood cultures growing Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. We calculated HO-BSI incidence and 14-day, 30-day and 1-year mortality in adults. We performed multivariable logistic regression to identify predictors of 30-day mortality. The study included 6752 HO-BSI events: K. pneumoniae (1659, 22.1%), E. coli (1491, 19.8%), S. aureus (1315, 17.5%), P. aeruginosa (1175, 15.6%), E. faecalis (778, 10.4%), A. baumannii (654, 8.7%), E. faecium (405, 5.4%) and S. pneumoniae (43, 0.6%). Overall incidence was 2.84/1000 admissions (95% CI: 2.77-2.91) and 6.88/10,000 patient-days (95% CI: 6.72-7.05). AMR isolates accounted for 44.2% of events. Fourteen-day, thirty-day and one-year mortality were 30.6% (95% CI: 28.5%-32.8%), 40.2% (95% CI: 38.2%-42.1%) and 66.5% (95% CI: 64.7%-68.3%), respectively. Organisms with highest risk for 30-day mortality (compared with E. coli) were A. baumannii (OR 2.85; 95% CI: 2.3-3.55), E. faecium (OR 2.16; 95% CI: 1.66-2.79) and S. pneumoniae (OR 2.36; 95% CI: 1.21-4.59). Mortality was higher in AMR isolates (OR 1.57; 95% CI: 1.4-1.77). This study highlights the incidence, associated high mortality and important role of antibiotic resistance in HO-BSI.