Outcomes and Predictors of Mortality in Patients With KPC-Kp Infections Treated With Meropenem Vaborbactam: An Observational Multicenter Study.

Background: Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam. Methods: We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least ≥24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality. Results: The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index ≥ 3, dialysis, concomitant COVID-19, and INCREMENT score ≥ 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy. Conclusions: Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy.

Embracing tensions throughout crises: The case of an Italian university hospital during the COVID-19 pandemic.

BACKGROUND: Previous research has identified some tensions that public organizations may encounter during crises. However, there remains a scarcity of research examining how public health care organizations effectively navigate these tensions to reconcile the diverse interests, needs, and demands from various stakeholders. PURPOSES: The study seeks to shed light on the dynamics underlying the tensions experienced by public hospitals during the COVID-19 pandemic. It illustrates how different hospitals' actors have navigated these tensions, identifying solutions and approaches that fostered collaborative endeavors among internal and external stakeholders. METHODOLOGY: The study draws on qualitative analyses of 49 semistructured interviews and the notes from two focus groups involving key informants at one of the largest university hospitals in Italy. We also rely on the verbatim transcripts from meetings involving the members of the temporary emergency team constituting the taskforce. FINDINGS: The results highlight the tensions that emerged throughout the different waves of the COVID-19 pandemic and how various actors have managed them in a way to reconcile opposing forces while unleashing adaptability and creativity. PRACTICE IMPLICATIONS: Hospital managers would benefit from developing a paradoxical mindset for crisis preparedness, allowing them to embrace existing tensions and devise creative solutions to favor resilience and change.

Efficacy of a Novel Prophylactic Scheme of Fosfomycin Trometamol in Patients Undergoing Endoscopic Surgery for Benign Prostatic Hyperplasia: Findings from a Prospective Monocentric Single-Arm Study.

This study aimed to assess the efficacy of a novel prophylactic scheme of fosfomycin trometamol in patients undergoing elective HoLEP (holmium laser enucleation of the prostate) or TURP (transurethral resection of the prostate) procedures for treating benign prostatic hyperplasia. Patients affected by benign prostatic hyperplasia and undergoing elective HoLEP or TURP procedures during the period February 2022-June 2023 were prospectively enrolled. Two 3 g oral fosfomycin trometamol doses 12 h apart were administered at 8.00 p.m. on day -1 (i.e., the day before HoLEP or TURP procedure) and at 8.00 a.m. on day 0 (i.e., the day of the surgical procedure). The following outcomes were assessed: prevalence of fever occurring in the first 48 h after surgical procedure; prevalence of urological complications occurring after the surgical procedure; prevalence of proven urinary tract infections (UTIs) and/or bloodstream infections (BSIs) at 14 days post-procedure; and prevalence of emergency department admission for UTI-related sepsis at 14 days post-procedure. Univariate analysis comparing patients with and without proven UTI, BSI, or emergency department admission at 14 days post-procedure was carried out. Overall, 96 patients (median age 70 years) undergoing HoLEP (82.3%) or TURP (17.7%) were prospectively included. Median (IQR) time of surgical procedure after the morning fosfomycin dose was 226.5 min (range 88.5-393.75 min). Fever in the post-surgical 48 h occurred in 3/96 patients (3.1%). Prevalence of proven UTI at 14 days was as low as 1.0% (1/96), whereas no patient had proven BSI or UTI-related sepsis requiring emergency department admission at 14 days. Our findings support the contention that a prophylactic scheme based on two doses of fosfomycin trometamol 12 h apart before surgical intervention may represent a valuable strategy for preventing infectious complications in urologic patients undergoing HoLEP or TURP. Larger definitive confirmatory studies are warranted.

Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23.

BACKGROUND: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. METHODS: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. RESULTS: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. CONCLUSIONS: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Improvement in insulin sensitivity after switching from an integrase inhibitor-based regimen to doravirine/tenofovir disoproxil fumarate/lamivudine in people with significant weight gain.

OBJECTIVES: We performed an observational, retrospective, cohort study to assess changes in insulin sensitivity after a switch from dolutegravir/lamivudine (DOL/3TC) or bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) to doravirine/tenofovir disoproxil fumarate/3TC (DOR/TDF/3TC) in virologically suppressed people living with HIV with recent significant weight gain. METHODS: All non-diabetic patients with HIV treated with DOL/3TC or BIC/F/TAF for ≥12 months, with HIV RNA <20 copies/mL, and with a weight increase ≥3 kg in the last year, who underwent a switch to DOR/TDF/3TC were enrolled into the study. Serum levels of glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were evaluated every 6 months during a 12-month follow-up. RESULTS: Overall, 81 patients were enrolled: 41 were treated with DOL/3TC and 40 with BIC/F/TAF. At baseline, median HOMA-IR index was 3.18 and insulin resistance (HOMA-IR index >2.5) was present in 49 subjects (60%). At 12 months after the switch to DOR/TDF/3TC, change in mean serum glucose concentration was not significant, but the reduction in median concentration of insulin was significant (-3.54 mcrUI/L [interquartile range -4.22 to -2.87]; p = 0.012), associated with a significant reduction in mean HOMA-IR index (-0.54 [interquartile range -0.91 to -0.18]; p = 0.021). A significant reduction in total and low-density lipoprotein cholesterol was also reported, whereas decreases in mean body weight and mean body mass index were not significant. CONCLUSIONS: In our retrospective study in virologically suppressed people living with HIV treated with DOL/3TC or BIC/F/TAF and with recent weight gain, the switch to DOR/TDF/3TC led to a significant improvement in insulin sensitivity and plasma lipids, with a trend to decreased body weight.

Comparative Impact of an Optimized PK/PD Target Attainment of Piperacillin-Tazobactam vs. Meropenem on the Trend over Time of SOFA Score and Inflammatory Biomarkers in Critically Ill Patients Receiving Continuous Infusion Monotherapy for Treating Documented Gram-Negative BSIs and/or VAP.

(1) Background: The advantage of using carbapenems over beta-lactam/beta-lactamase inhibitor combinations in critically ill septic patients still remains a debated issue. We aimed to assess the comparative impact of an optimized pharmacokinetic/pharmacodynamic (PK/PD) target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of both Sequential Organ Failure Assessment (SOFA) score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) monotherapy with piperacillin-tazobactam or meropenem for treating documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). (2) Methods: We performed a retrospective observational study comparing critically ill patients receiving targeted treatment with CI meropenem monotherapy for documented Gram-negative BSIs or VAP with a historical cohort of critical patients receiving CI piperacillin-tazobactam monotherapy. Patients included in the two groups were admitted to the general and post-transplant intensive care unit in the period July 2021-September 2023 and fulfilled the same inclusion criteria. The delta values of the SOFA score between the baseline of meropenem or piperacillin-tazobactam treatment and those at 48-h (delta 48-h SOFA score) or at 7-days (delta 7-days SOFA) were selected as primary outcomes. Delta 48-h and 7-days C-reactive protein (CRP) and procalcitonin (PCT), microbiological eradication, resistance occurrence, clinical cure, multi-drug resistant colonization at 90-day, ICU, and 30-day mortality rate were selected as secondary outcomes. Univariate analysis comparing primary and secondary outcomes between critically ill patients receiving CI monotherapy with piperacillin-tazobactam vs. meropenem was carried out. (3) Results: Overall, 32 critically ill patients receiving CI meropenem monotherapy were compared with a historical cohort of 43 cases receiving CI piperacillin-tazobactam monotherapy. No significant differences in terms of demographics and clinical features emerged at baseline between the two groups. Optimal PK/PD target was attained in 83.7% and 100.0% of patients receiving piperacillin-tazobactam and meropenem, respectively. No significant differences were observed between groups in terms of median values of delta 48-h SOFA (0 points vs. 1 point; p = 0.89) and median delta 7-days SOFA (2 points vs. 1 point; p = 0.43). Similarly, no significant differences were found between patients receiving piperacillin-tazobactam vs. meropenem for any of the secondary outcomes. (4) Conclusion: Our findings may support the contention that in critically ill patients with documented Gram-negative BSIs and/or VAP, the decreases in the SOFA score and in the inflammatory biomarkers serum levels achievable with CI piperacillin-tazobactam monotherapy at 48-h and at 7-days may be of similar extent and as effective as to those achievable with CI meropenem monotherapy provided that optimization on real-time by means of a TDM-based expert clinical pharmacological advice program is granted.

Impact of a multidisciplinary management team on clinical outcome in ICU patients affected by Gram-negative bloodstream infections: a pre-post quasi-experimental study.

BACKGROUND: Bloodstream infections (BSIs) by Gram-negative pathogens play a major role in intensive care patients, both in terms of prevalence and severity, especially if multi-drug resistant pathogens are involved. Early appropriate antibiotic therapy is therefore a cornerstone in the management of these patients, and growing evidence shows that implementation of a multidisciplinary team may improve patients' outcomes. Our aim was to evaluate the clinical and microbiological impact of the application of a multidisciplinary team on critically ill patients. METHODS: Pre-post study enrolling critically ill patients with Gram negative bloodstream infection in intensive care unit. In the pre-intervention phase (from January until December 2018) patients were managed with infectious disease consultation on demand, in the post-intervention phase (from January until December 2022) patients were managed with a daily evaluation by a multidisciplinary team composed of intensivist, infectious disease physician, clinical pharmacologist and microbiologist. RESULTS: Overall, 135 patients were enrolled during the study period, of them 67 (49.6%) in the pre-intervention phase and 68 (50.4%) in the post-intervention phase. Median age was 67 (58-75) years, sex male was 31.9%. Septic shock, the need for continuous renal replacement therapy and mechanical ventilation at BSI onset were similar in both groups, no difference of multidrug-resistant organisms (MDRO) prevalence was observed. In the post-phase, empirical administration of carbapenems decreased significantly (40.3% vs. 62.7%, p = 0.02) with an increase of appropriate empirical therapy (86.9% vs. 55.2%, p < 0.001) and a decrease of overall antibiotic treatment (12 vs. 16 days, p < 0.001). Despite no differences in delta SOFA and all-cause 30-day mortality, a significant decrease in microbiological failure (10.3% vs. 29.9%, p = 0.005) and a new-onset 30-day MDRO colonization (8.3% vs. 36.6%, p < 0.001) in the post-phase was reported. At multivariable analysis adjusted for main covariates, the institution of a multidisciplinary management team (MMT) was found to be protective both for new MDRO colonization [OR 0.17, 95%CI(0.05-0.67)] and microbiological failure [OR 0.37, 95%CI (0.14-0.98)]. CONCLUSIONS: The institution of a MMT allowed for an optimization of antimicrobial treatments, reflecting to a significant decrease in new MDRO colonization and microbiological failure among critically ill patients.

Gut microbiome dynamics and Enterobacterales infection in liver transplant recipients: A prospective observational study.

Background & Aims: The aim of this study was to investigate gut microbiome (GM) dynamics in relation to carbapenem-resistant Enterobacterales (CRE) colonization, CRE infection, and non-CRE infection development within 2 months after liver transplant (LT). Methods: A single-center, prospective study was performed in patients undergoing LT from November 2018 to January 2020. The GM was profiled through 16S rRNA amplicon sequencing of a rectal swab taken on the day of transplantation, and fecal samples were collected weekly until 1 month after LT. A subset of samples was subjected to shotgun metagenomics, including resistome dynamics. The primary endpoint was to explore changes in the GM in the following groups: (1) CRE carriers developing CRE infection (CRE_I); (2) CRE carriers not developing infection (CRE_UI); (3) non-CRE carriers developing microbial infection (INF); and (4) non-CRE carriers not developing infection (NEG). Results: Overall, 97 patients were enrolled, and 91 provided fecal samples. Of these, five, nine, 22, and 55 patients were classified as CRE_I, CRE_UI, INF, and NEG, respectively. CRE_I patients showed an immediate and sustained post-LT decrease in alpha diversity, with depletion of the GM structure and gradual over-representation of Klebsiella and Enterococcus. The proportions of Klebsiella were significantly higher in CRE_I patients than in NEG patients even before LT, serving as an early marker of subsequent CRE infection. CRE_UI patients had a more stable and diverse GM, whose compositional dynamics tended to overlap with those of NEG patients. Conclusions: GM profiling before LT could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis. Impact and implications: Little is known about the temporal dynamics of gut microbiome (GM) in liver transplant recipients associated with carbapenem-resistant Enterobacterales (CRE) colonization and infection. The GM structure and functionality of patients colonized with CRE and developing infection appeared to be distinct compared with CRE carriers without infection or patients with other microbial infection or no infection and CRE colonization. Higher proportions of antimicrobial-resistant pathogens and poor representation of bacteria and metabolic pathways capable of promoting overall host health were observed in CRE carriers who developed infection, even before liver transplant. Therefore, pretransplant GM profiling could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

Survey on the approach to antibiotic prophylaxis in liver and kidney transplant recipients colonized with "difficult to treat" Gram-negative bacteria.

BACKGROUND: Performance of active screening for multidrug-resistant Gram-negative bacteria (MDR-GNB) and administration of targeted antibiotic prophylaxis (TAP) in colonized patients undergoing liver (LT) and/or kidney transplantation (KT) are controversial issues. METHODS: Self-administered electronic cross-sectional survey disseminated from January to February 2022. Questionnaire consisted of four parts: hospital/transplant program characteristics, standard screening and antibiotic prophylaxis, clinical vignettes asking for TAP in patients undergoing LT and KT with prior infection/colonization with four different MDR-GNB (extended-spectrum cephalosporin-resistant Enterobacterales [ESCR-E], carbapenem-resistant Enterobacterales [CRE], multidrug-resistant Pseudomonas aeruginosa [MDR-Pa], and carbapenem-resistant Acinetobacter baumannii [CRAb]). RESULTS: Fifty-five respondents participated from 14 countries, mostly infectious disease specialists (69%) with active transplant programs (>100 procedures/year for 34.5% KT and 23.6% LT), and heterogeneous local MDR-GNB prevalence from <15% (30.9%), 15%-30% (43.6%) to >30% (16.4%). The frequency of screening for ESCR-E, CRE, MDR-Pa, and CRAb was 22%, 54%, 17%, and 24% for LT, respectively, and 18%, 36%, 16%, and 11% for KT. Screening time-points were mainly at transplantation 100%, only one-third following transplantation. Screening was always based on rectal swab cultures (100%); multi-site sampling was reported in 40% of KT and 35% of LT. In LT clinical cases, 84%, 58%, 84%, and 40% of respondents reported TAP for prior infection/colonization with ESCR-E, CRE, MDR-Pa, and CRAb, respectively. In KT clinical cases, 55%, 39%, 87%, and 42% of respondents reported TAP use for prior infection/colonization with ESCR-E, CRE, MDR-Pa, and CRAb, respectively. CONCLUSION: There is a large heterogeneity in screening and management of MDR-GNB carriage in LT and KT.

Real-Time TDM-Guided Optimal Joint PK/PD Target Attainment of Continuous Infusion Piperacillin-Tazobactam Monotherapy Is an Effective Carbapenem-Sparing Strategy for Treating Non-Severe ESBL-Producing Enterobacterales Secondary Bloodstream Infections: Findings from a Prospective Pilot Study.

(1) Objectives: To assess the impact of optimal joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam monotherapy on the microbiological outcome of documented ESBL-producing Enterobacterlaes secondary bloodstream infections (BSIs). (2) Methods: Patients hospitalized in the period January 2022-October 2023, having a documented secondary BSI caused by ESBL-producing Enterobacterales, and being eligible for definitive targeted CI piperacillin-tazobactam monotherapy according to specific pre-defined inclusion criteria (i.e., absence of septic shock at onset; favorable clinical evolution in the first 48 h after starting treatment; low-intermediate risk primary infection source) were prospectively enrolled. A real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program was adopted for optimizing (PK/PD) target attainment of CI piperacillin-tazobactam monotherapy. Steady-state plasma concentrations (Css) of both piperacillin and tazobactam were measured, and the free fractions (f) were calculated based on theoretical protein binding. The joint PK/PD target attainment was considered optimal whenever the piperacillin fCss/MIC ratio was >4 and the tazobactam fCss/target concentration (CT) ratio was >1 (quasi-optimal or suboptimal if only one or neither of the two thresholds were achieved, respectively). Univariate analysis was carried out for assessing variables potentially associated with failure in achieving the optimal joint PK/PD target of piperacillin-tazobactam and microbiological eradication. (3) Results: Overall, 35 patients (median age 79 years; male 51.4%) were prospectively included. Secondary BSIs resulted from urinary tract infections as a primary source in 77.2% of cases. The joint PK/PD target attainment was optimal in as many as 97.1% of patients (34/35). Microbiological eradication occurred in 91.4% of cases (32/35). Attaining the quasi-optimal/suboptimal joint PK/PD target of CI piperacillin-tazobactam showed a trend toward a higher risk of microbiological failure (33.3% vs. 0.0%; p = 0.08) (4) Conclusions: Real-time TDM-guided optimal joint PK/PD target attainment of CI piperacillin-tazobactam monotherapy may represent a valuable and effective carbapenem-sparing strategy when dealing with non-severe ESBL-producing Enterobacterales secondary BSIs.

Attributable mortality of infections caused by carbapenem-resistant Enterobacterales: results from a prospective, multinational case-control-control matched cohorts study (EURECA).

OBJECTIVES: To assess the mortality attributable to infections caused by carbapenem-resistant Enterobacterales (CRE) and to investigate the effect of clinical management on differences in observed outcomes in a multinational matched cohort study. METHODS: A prospective matched-cohorts study (NCT02709408) was performed in 50 European hospitals from March 2016 to November 2018. The main outcome was 30-day mortality with an active post-discharge follow-up when applied. The CRE cohort included patients with complicated urinary tract infections, complicated intra-abdominal infections, pneumonia, or bacteraemia from other sources because of CRE. Two control cohorts were selected: patients with infection caused by carbapenem-susceptible Enterobacterales (CSE) and patients without infection. Matching criteria included type of infection for the CSE group, hospital ward of CRE detection, and duration of hospital admission up to CRE detection. Multivariable and stratified Cox regression was applied. RESULTS: The cohorts included 235 patients with CRE infection, 235 patients with CSE infection, and 705 non-infected patients. The 30-day mortality (95% CI) was 23.8% (18.8-29.6), 10.6% (7.2-15.2), and 8.4% (6.5-10.6), respectively. The difference in 30-day mortality rates between patients with CRE infection when compared with patients with CSE infection was 13.2% (95% CI, 6.3-20.0), (HR, 2.57; 95% CI, 1.55-4.26; p < 0.001), and 15.4% (95% CI, 10.5-20.2) when compared with non-infected patients (HR, 3.85; 95% CI, 2.57-5.77; p < 0.001). The population attributable fraction for 30-day mortality for CRE vs. CSE was 19.28%, and for CRE vs. non-infected patients was 9.61%. After adjustment for baseline variables, the HRs for mortality were 1.87 (95% CI, 0.99-3.50; p 0.06) and 3.65 (95% CI, 2.29-5.82; p < 0.001), respectively. However, when treatment-related time-dependent variables were added, the HR of CRE vs. CSE reduced to 1.44 (95% CI, 0.78-2.67; p 0.24). DISCUSSION: CRE infections are associated with significant attributable mortality and increased adjusted hazard of mortality when compared with CSE infections or patients without infection. Underlying patient characteristics and a delay in appropriate treatment play an important role in the CRE mortality.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine in Virologically Suppressed People Living with HIV-1 Aged Over 65 Years.

Clinical trials of dual regimen dolutegravir/lamivudine (DOL/3TC) demonstrated potent efficacy and favorable safety in both antiretroviral therapy-naïve and -experienced patients, but data on older people are lacking. We aimed to evaluate virological efficacy and safety of DOL/3TC in suppressed older patients over a 12-month period. We performed a retrospective cohort study evaluating people living with HIV (PLWHIV) aged ≥65 years at our HIV Clinic who were switched to DOL/3TC. Eligible patients had baseline HIV-1 RNA <20 copies/mL, and no previous virological failures or known resistance mutations for lamivudine or dolutegravir. Inclusion criteria were met by 72 patients: 59 were men, median age was 69.2 years, and one or more comorbidities were present in 89% of patients. The most common reason for switch was simplification, followed by drug-drug interactions (DDIs) and toxicities. After 12 months, 64 (88.9%, by the intention-to-treat analysis) patients maintained HIV-1 RNA <20 copies/mL, and reasons for treatment failure were virological failure in three cases, adverse events in three, and missing data in two. Genotype resistance testing showed no resistance mutations for lamivudine or dolutegravir in subjects with virological failure. The number of potential DDIs decreased from 92 to 12 after switching to DOL/3TC, and a significant reduction in median total and low-density lipoprotein cholesterol was reported, while median change in body weight was not significant. In this real-life cohort, switching to DOL/3TC was associated with maintenance of virological control and good tolerability among persons aged >65 years, supporting use of this dual regimen in older PLWHIV.

Clinical efficacy of cefiderocol-based regimens in patients with carbapenem-resistant Acinetobacter baumannii infections: A systematic review with meta-analysis.

OBJECTIVES: To perform a systematic review with meta-analysis to assess the clinical efficacy of cefiderocol-based regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections. METHODS: Two authors independently searched PubMed-MEDLINE, Scopus, and Cochrane databases, from inception to 02 July 2023, for randomised controlled trials (RCTs) or observational studies comparing clinical efficacy of cefiderocol-based vs. non-cefiderocol-based regimens in patients with CRAB infections. Data were extracted by the two authors independently, and the quality of included studies was independently assessed using ROB 2.0 or ROBINS-I tools. Primary outcome was mortality rate. Meta-analysis was performed by pooling odds ratios (ORs) retrieved from studies providing adjustment for confounders using a random-effects model with the inverse variance method. Multiple subgroups and sensitivity analyses were conducted to investigate the source of heterogeneity. RESULTS: A total of 530 articles were screened, and 6 studies (1 RCT and 5 observational; N=561; 247 cefiderocol-based vs. 314 non-cefiderocol-based regimens) were included. Cefiderocol did not significantly reduce in-hospital mortality compared to alternative therapies (predominantly colistin-based), but the confidence intervals around the effect estimate included clinically important benefit (N=5; OR 0.64; 95%CI 0.40-1.04; I2=57.5%). When only observational studies providing adjustment for confounders were considered, a lower risk of mortality was found in patients treated with cefiderocol-based regimens (N=4; OR 0.53; 95%CI 0.39-0.71; I2=0.0%). CONCLUSIONS: Cefiderocol-based regimens were associated with a significantly lower risk of mortality in patients with CRAB infections in observational studies providing proper adjustment for confounders.