Visceral Leishmaniasis in a Twin Pregnancy: A Case Report and Review of the Literature.

Visceral leishmaniasis (VL), often referred to as kala-azar, is quite rare in developed countries during pregnancy. Only few studies have evaluated its impact on perinatal outcome. It is caused primarily by Leishmania donovani or Leishmania infantum and presents with a wide spectrum of clinical manifestations from cutaneous ulcers to multisystem disease. Differential diagnosis is challenging as symptoms and signs are insidious, mimicking other diseases. Misdiagnosis can result in severe adverse perinatal outcomes, even maternal/neonatal death. Early treatment with liposomal amphotericin-B (LAmB) is currently the first choice with adequate effectiveness. We report a rare case of VL in a twin pregnancy with onset at the second trimester, presenting with periodic fever with rigors, right flank pain, and gradual dysregulation of all three cell lines. The positive rK39 enzyme-linked immunosorbent assay test confirmed the diagnosis. Treatment with LAmB resulted in clinical improvement within 48 h and in the delivery of two late-preterm healthy neonates with no symptoms or signs of vertical transmission. The one-year follow-up, of the mother and the neonates, was negative for recurrence. To our knowledge, this is the first reported case of VL in a twin pregnancy, and consequently treatment and perinatal outcome are of great importance.

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.

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

BACKGROUND: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. METHODS: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure. RESULTS: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively. CONCLUSIONS: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

Three Klebsiella pneumoniae lineages causing bloodstream infections variably dominated within a Greek hospital over a 15 year period.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a major clinical and public health threat. The rapid dissemination of this pathogen is driven by several successful clones worldwide. We aimed to investigate the CRKP clonal lineages, their antibiotic resistance determinants and their potential transmissions in a tertiary care hospital located in Athens, Greece. Between 2003 and 2018, 392 CRKP isolates from bloodstream infections were recovered from hospitalized patients. Whole genome sequencing (WGS) was performed on the Illumina platform to characterize 209 of these isolates. In total, 74 % (n=155) of 209 isolates belonged to three major clonal lineages: ST258 (n=108), ST147 (n=29) and ST11 (n=18). Acquired carbapenemase genes were the mechanisms of resistance in 205 isolates (bla KPC, n=123; bla VIM, n=56; bla NDM, n=20; bla OXA-48, n=6). Strong associations (P=0.0004) were observed between carbapenemase genes and clonal lineages. We first isolated bla VIM-1-carrying ST147 strains during the early sampling period in 2003, followed by the emergence of bla KPC-2-carrying ST258 in 2006 and bla NDM-1-carrying ST11 in 2013. Analysis of genetic distances between the isolates revealed six potential transmission events. When contextualizing the current collection with published data, ST147 reflected the global diversity, ST258 clustered with isolates representing the first introduction into Europe and ST11 formed a distinct geographically restricted lineage indicative of local spread. This study demonstrates the changing profile of bloodstream CRKP in a tertiary care hospital over a 15 year period and underlines the need for continued genomic surveys to develop strategies to contain further dissemination. This article contains data hosted by Microreact.

Clinical and Economic Value of Reducing Antimicrobial Resistance in the Management of Hospital-Acquired Infections with Limited Treatment Options in Greece.

INTRODUCTION: Antimicrobial resistance (AMR) is a major public health threat worldwide. Greece has the highest burden of infections due to antibiotic-resistant bacteria among European Union/European Economic Area (EU/EEA) countries. One of the most serious AMR threats in Greece is hospital-acquired infections (HAIs) with limited treatment options (LTO) caused by resistant gram-negative pathogens. Thus, this study sought to estimate the current AMR burden in Greece and the value of reducing AMR to gram-negative pathogens for the Greek healthcare system. METHODS: The current model was adapted from a previously published and validated model of AMR to investigate the overall and AMR-specific burden of treating the most common HAIs with LTO in Greece and scenarios to demonstrate the benefits associated with reducing AMR levels from a third-party payer perspective. Clinical and economic outcomes were estimated over a 10-year time horizon; life years (LYs) and quality-adjusted life years (QALYs) were calculated over a lifetime (based on the annual number of infections over 10 years) at a willingness-to-pay of €30,000 per QALY gained and a 3.5% discount rate. RESULTS: In Greece, the current AMR levels in HAIs with LTO caused by four gram-negative pathogens account for > 316,000 hospital bed days, €73 million in hospitalisation costs, and > 580,000 LYs and 450,000 QALYs lost over 10 years. The monetary burden is estimated at €13.9 billion. A reduction in current AMR levels by 10-50% results in clinical and economic benefit; 29,264-151,699 bed days may be saved, leading to decreased hospitalisation costs (€6.8 million-€35.3 million) and a gain in LYs (85,328-366,162) and QALYs (67,421-289,331), associated with a monetary benefit of between €2.0 billion and €8.7 billion. CONCLUSION: This study shows the substantial clinical and economic burden AMR represents to the Greek healthcare system and the value that can be achieved by effectively reducing AMR levels.

HIV RNA/DNA Levels at Diagnosis Can Predict Immune Reconstitution: A Longitudinal Analysis.

BACKGROUND: HIV DNA mirrors the number of infected cells and the size of the HIV viral reservoir. The aim of this study was to evaluate the effect of pre-cART HIV DNA levels as a predictive marker of immune reconstitution and on the post-cART CD4 counts trends. METHODS: HIV DNA was isolated from PBMCs and quantified by real-time PCR. Immune reconstitution was assessed up to four years. Piecewise-linear mixed models were used to describe CD4 count changes. RESULTS: 148 people living with HIV (PLWH) were included. The highest rate of immune reconstitution was observed during the first trimester. There was a trend showing that high HIV RNA level resulted in greater increase in CD4 count, especially during the first trimester of cART (difference above vs. below median 15.1 cells/µL/month; 95% CI -1.4-31.5; p = 0.073). Likewise, higher HIV DNA level would predict greater CD4 increases, especially after the first trimester (difference above vs. below median 1.2 cells/µL/month; 95% CI -0.1-2.6; p = 0.071). Higher DNA and RNA levels combined were significantly associated with greater CD4 increase past the first trimester (difference high/high vs. low/low 2.1 cells/µL/month; 95% CI 0.3-4.0; p = 0.024). In multivariable analysis, lower baseline CD4 counts predicted a greater CD4 rise. CONCLUSIONS: In successfully treated PLWH, pre-cART HIV DNA and HIV RNA levels are predictors of immune reconstitution.

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.

Risk factors for infections caused by carbapenem-resistant Enterobacterales: an international matched case-control-control study (EURECA).

Background: Data on risk factors for carbapenem-resistant Enterobacterales (CRE) with wider applicability are needed to inform preventive measures and efficient design of randomised trials. Methods: An international matched case-control-control study was performed in 50 hospitals with high CRE incidence from March 2016 to November 2018 to investigate different aspects of infections caused by CRE (NCT02709408). Cases were patients with complicated urinary tract infection (cUTI), complicated intraabdominal (cIAI), pneumonia or bacteraemia from other sources (BSI-OS) due to CRE; control groups were patients with infection caused by carbapenem-susceptible Enterobacterales (CSE), and by non-infected patients, respectively. Matching criteria included type of infection for CSE group, ward and duration of hospital admission. Conditional logistic regression was used to identify risk factors. Findings: Overall, 235 CRE case patients, 235 CSE controls and 705 non-infected controls were included. The CRE infections were cUTI (133, 56.7%), pneumonia (44, 18.7%), cIAI and BSI-OS (29, 12.3% each). Carbapenemase genes were found in 228 isolates: OXA-48/like, 112 (47.6%), KPC, 84 (35.7%), and metallo-ß-lactamases, 44 (18.7%); 13 produced two. The risk factors for CRE infection in both type of controls were (adjusted OR for CSE controls; 95% CI; p value) previous colonisation/infection by CRE (6.94; 2.74-15.53; <0.001), urinary catheter (1.78; 1.03-3.07; 0.038) and exposure to broad spectrum antibiotics, as categorical (2.20; 1.25-3.88; 0.006) and time-dependent (1.04 per day; 1.00-1.07; 0.014); chronic renal failure (2.81; 1.40-5.64; 0.004) and admission from home (0.44; 0.23-0.85; 0.014) were significant only for CSE controls. Subgroup analyses provided similar results. Interpretation: The main risk factors for CRE infections in hospitals with high incidence included previous colonization, urinary catheter and exposure to broad spectrum antibiotics. Funding: The study was funded by the Innovative Medicines Initiative Joint Undertaking (https://www.imi.europa.eu/) under Grant Agreement No. 115620 (COMBACTE-CARE).

The Use and Effectiveness of Ceftazidime-Avibactam in Real-World Clinical Practice: EZTEAM Study.

INTRODUCTION: Ceftazidime-avibactam has proven activity against multidrug-resistant (MDR) bacteria in clinical trials and real-world studies. This study was conducted to describe the patterns of use of ceftazidime-avibactam (including indications and associated antibiotics), and the effectiveness and safety of ceftazidime-avibactam in real-world clinical practice. METHODS: This non-interventional medical chart review study was conducted in 11 countries across the European and Latin American (LATAM) regions. Consecutive patients treated in clinical practice with at least one dose of ceftazidime-avibactam for an approved indication per country label since 01 January 2018 (or launch date in the country if posterior) were enrolled. Effectiveness analyses were conducted in patients treated with ceftazidime-avibactam for at least 72 h. RESULTS: Of the 569 eligible patients enrolled, 516 (90.7%) were treated for at least 72 h (354 patients from Europe and 162 patients from LATAM); 390 patients (75.7%) had switched from another antibiotic line for Gram-negative coverage. Infection sources were intra-abdominal, urinary, respiratory, bloodstream infections, and other infections (approximately 20% each). K. pneumoniae was the most common microorganism identified in the latest microbiological evaluation before starting ceftazidime-avibactam (59.3%). Two-thirds of microorganisms tested for susceptibility were MDR, of which 89.3% were carbapenem-resistant. The common MDR mechanisms for K. pneumoniae were carbapenemase (33.9%), oxacillinase 48 (25.2%), extended-spectrum beta-lactamase (21.5%), or metallo-beta-lactamase (14.2%) production. Without prior patient exposure, 17 isolates (mostly K. pneumoniae) were resistant to ceftazidime-avibactam. Treatment success was achieved in 77.3% of patients overall (88.3% among patients with urinary infection), regardless of first or second treatment line. In-hospital mortality rate was 23.1%. Adverse events were reported for six of the 569 patients enrolled. CONCLUSION: This study provides important real-world evidence on treatment patterns, effectiveness, and safety of ceftazidime-avibactam in clinical practice through its recruitment in the European and LATAM regions. Ceftazidime-avibactam is one of the antibiotics to consider for treatment of MDR bacteria. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03923426.

Ex Vivo Evaluation of Glutamine Treatment in Sepsis and Trauma in a Human Peripheral Blood Mononuclear Cells Model.

We aimed to assess the lipopolysaccharide (LPS), or heat shock (HS) induction, and glutamine-modulating effects on heat shock protein-90α (HSP90α) and cytokines in an ex vivo model using peripheral blood mononuclear cells (PBMCs). The PBMCs of patients with septic shock, trauma-related systemic inflammatory response syndrome (SIRS), and healthy subjects were incubated with 1 µg/mL LPS at 43 °C (HS). Glutamine 10 mM was added 1 hour before or after induction or not at all. We measured mRNA HSP90α, monocyte (m) and lymphocyte (l) HSP90α proteins, interleukin (IL)-1b, -6, -8, -10, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) supernatant levels. Heat shock increased the HSP90α mRNA and mHSP90α in all groups (10-fold in sepsis, p < 0.001 and p = 0.047, respectively). LPS induced the mHSP90α and lHSP90α in healthy (p < 0.001) and mHSP90α in SIRS (p = 0.004) but not in sepsis. LPS induced the cytokines at 24 and 48 h in all groups, especially in trauma (p < 0.001); HS only induced the IL-8 in healthy (p = 0.003) and septic subjects (p = 0.05). Glutamine at 10 mM before or after stimulation did not alter any induction effect of LPS or HS on HSP90α mRNA and mHSP90α protein in sepsis. In SIRS, glutamine before LPS decreased the mHSP90α but increased it when given after HS (p = 0.018). Before or after LPS (p = 0.049) and before HS (p = 0.018), glutamine decreased the lHSP90α expression in sepsis but increased it in SIRS when given after HS (p = 0.003). Regarding cytokines, glutamine enhanced the LPS-induced MCP-1 at 48 h in healthy (p = 0.011), SIRS (p < 0.001), and sepsis (p = 0.006). In conclusion, glutamine at 10 mM, before or after LPS and HS, modulates mHSP90α and lHSP90α in sepsis and SIRS differently and unpredictably. Although it does not alter the stimulation effect on interleukins, glutamine enhances the LPS induction effect on supernatant MCP-1 in all groups. Future research should seek to elucidate better the impact of glutamine and temperature modulation on HSP90α and MCP-1 pathways in sepsis and trauma.

Estimating the Clinical and Economic Impact of Introducing a New Antibacterial into Greek Clinical Practice for the Management of Hospital-Acquired Infections with Limited Treatment Options.

INTRODUCTION: Hospital-acquired infections (HAIs) and growing antimicrobial resistance (AMR) represent a significant healthcare burden globally. Especially in Greece, HAIs with limited treatment options (LTO) pose a serious threat due to increased morbidity and mortality. This study aimed to estimate the clinical and economic value of introducing a new antibacterial for HAIs with LTO in Greece. METHODS: A previously published and validated dynamic model of AMR was adapted to the Greek setting. The model estimated the clinical and economic outcomes of introducing a new antibacterial for the treatment of HAIs with LTO in Greece. The current treatment pathway was compared with introducing a new antibacterial to the treatment sequence. Outcomes were assessed from a third-party payer perspective, over a 10-year transmission period, with quality-adjusted life years (QALYs) and life years (LYs) gained considered over a lifetime horizon. RESULTS: Over the next 10 years, HAIs with LTO in Greece account for approximately 1.4 million hospital bed days, hospitalisation costs of more than €320 million and a loss of approximately 403,000 LYs (319,000 QALYs). Introduction of the new antibacterial as first-line treatment provided the largest clinical and economic benefit, with savings of up to 93,000 bed days, approximately €21 million in hospitalisation costs and an additional 286,000 LYs (226,000 QALYs) in comparison to the current treatment strategy. The introduction of a new antibacterial was linked to a monetary benefit of €6.8 billion at a willingness to pay threshold of €30,000 over 10 years. CONCLUSION: This study highlights the considerable clinical and economic benefit of introducing a new antibacterial for HAIs with LTO in Greece. This analysis shows the additional benefit when a new antibacterial is introduced to treatment sequences. These findings can be used to inform decision makers to implement policies to ensure timely access to new antibacterial treatments in Greece.

Antimicrobial resistance is a major issue for the Greek healthcare system. The overuse of antibacterial agents contributes to the growing resistance levels, making currently available treatment options less effective. As a result, there is an imperative need to address antimicrobial resistance in Greece. This study developed a mathematical model to investigate the clinical and economic benefits of introducing a new antibacterial to current treatment practice. The model uses regression equations to describe the relationships between inputs and outputs from a published and validated model, which describes the transmission and treatment of infections. The model is used to estimate the impact of a new treatment in Greece, considering differing treatment sequence scenarios. The largest health and financial benefits were seen when a new antibacterial was introduced at first line prior to currently used treatments. Over 10 years, savings of up to 93,000 hospital bed days and €21 million in hospitalisation costs could be achieved, as well as a gain of 286,000 patient life years and 226,000 patient quality-adjusted life years (QALYs), a measure of a patient's quality and length of life, over their remaining lifetime. The introduction of a new antibacterial into the current treatment pathway resulted in an overall monetary benefit of €6.8 billion over 10 years, when additional QALYs are valued at €30,000. This study demonstrates considerable health economic benefits of introducing a new antibacterial in Greece and can help inform decision makers when developing a national action plan to combat resistance and improve access to treatments.

Predictive score for patients with carbapenemase-producing enterobacterales colonization upon admission in a tertiary care hospital in an endemic area.

OBJECTIVES: Carbapenemase-producing Enterobacterales (CPE) comprise important nosocomial pathogens worldwide. Colonized patients are the source of further dissemination in healthcare settings. Considering that timely detection of CPE carriers is pivotal but universal screening is unfeasible, we aimed to develop and validate a prediction score to detect patients harbouring CPE on hospital admission. METHODS: The study was conducted in a tertiary care hospital located in a CPE endemic area. Rectal swabs were obtained from 2303 patients, screened shortly after hospital admission. The Enterobacterales isolated in cultures were examined for the presence of blaVIM, KPC, NDM, OXA-48 by PCR. Demographic data and patient history of the previous 6 months were recorded. Risk factors for CPE carriage were identified using a multivariable logistic regression model and a points-system risk score was developed. The discriminative ability of the risk score was assessed using the AUC and its predictive performance was validated in a second dataset of 1391 patients in a different time period. RESULTS: Seven predictors were identified: previous CPE colonization or infection, prior hospitalization, stay in a long-term health care facility, history of ≥2 interventions, renal replacement therapy, diabetes with end-organ damage and Karnofsky score. The developed risk score in the derivation dataset ranged between 0 and 79 points, with an AUC of 0.84 in the derivation and 0.85 in the validation dataset. CONCLUSIONS: This prediction tool may assist in identifying patients who are at risk of harbouring CPE on hospital admission in an endemic area and guide clinicians to implement prompt and appropriate infection control measures.

The Effect of Different Colistin Dosing Regimens on Nephrotoxicity: A Cohort Study.

(1) Background: It is not known whether different daily dosing schemes have different effects on colistin nephrotoxicity. We examined the effect of once- versus twice- or thrice-daily doses of colistin on renal function. (2) Methods: We performed a multicenter retrospective cohort study of hospitalized patients with a baseline glomerular filtration rate ≥ 50 mL/min who received intravenously the same colistin dose once (regimen A), twice (regimen B) or thrice daily (regimen C). The primary endpoint was acute kidney injury (AKI), defined as fulfilment of any of the RIFLE (Risk-Injury-Failure-Loss-End stage renal disease) criteria. (3) Results: We included 306 patients; 132 (43.1%) received regimen A, 151 (49.3%) regimen B, and 23 (7.5%) regimen C. Ninety-nine (32.4%) patients developed AKI; there was no difference between regimen A vs. B and C [45 (34.1%) vs. 54 (31.0%), p = 0.57]. In a propensity score−matched cohort, AKI was similar in patients receiving Regimen A, Regimen B, and Regimen C (31.6% vs. 33.3%, p = 0.78). On logistic regression analysis, diabetes was an independent predictor of AKI (OR = 4.59, 95% CI 2.03−10.39, p = 0.001) while eGFR > 80 mL/min (OR = 0.50, 95% CI 0.25−0.99, p = 0.048) was inversely associated with AKI. (4) Conclusions: Colistin once daily is not more nephrotoxic than the standard colistin regimens. The only independent predictor of nephrotoxicity was diabetes mellitus, while eGFR > 80 mL/min had a protective effect.

Molecular screening of cat and dog ectoparasites for the presence of Bartonella spp. in Attica, Greece.

The purpose of this study was the molecular detection of Bartonella spp. in fleas and ticks parasitizing cats and dogs from 39 locations in Attica, Greece. One hundred and forty five ectoparasites (104 fleas and 41 ticks) from 92 cats and 53 dogs were investigated individually using PCRs targeting the 16S-23S ribosomal RNA intergenic spacer (ITS) and the citrate synthase (gltA) genetic loci. Bartonella spp. were detected in 14 out of 104 fleas (13.5%) and in none of the ticks examined. Consequent sequence analysis of the amplicons from the two loci identified 3 strains as Bartonella henselae, and 11 as Bartonella clarridgeiae. Οur study demonstrates the presence of B. henselae and B. clarridgeiae in Ctenocephalides felis fleas from cat and dog in Greece. We also report a novel ITS sequence for B. clarridgeiae. Considering that fleas could pose a risk for human bartonellosis from their infected hosts, further studies on the public health risk of Bartonella presence in animal ectoparasites are warranted.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

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.

In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections.

OBJECTIVES: Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections. METHODS: Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 105 CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes. RESULTS: The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04-2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03-2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95-2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09-3.25). CONCLUSIONS: In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine).

SCOPE: These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy. METHODS: An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak). RECOMMENDATIONS: The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, ß-lactam/ß-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.

Pneumocystis jirovecii pneumonia in a X-linked chronic granulomatous disease female carrier.

The X-chromosome linked (XL) female carriers of chronic granulomatous disease (CGD) are considered to have no risk for infection. Herein we present a female CGD XL-carrier who developed Pneumocystis jirovecii pneumonia and Serratia marcescens infection associated with age-related skewing of X-chromosome inactivation.

Risk Factors for Surgical Site Infections in Patients Undergoing Emergency Surgery: A Single-centre Experience.

BACKGROUND/AIM: Surgical site infections (SSI) are associated with increased morbidity and mortality, and they occur more frequently during unplanned emergency surgical (ES) procedures rather than elective. Our aim was to determine the incidence of SSI within our ES cohort and to identify risk factors for SSI. PATIENTS AND METHODS: Data from consecutive patients undergoing ES in a single institution during a 5-year period were prospectively collected and analyzed. RESULTS: A total of 838 consecutive patients were included. The median age was 52 (IQR=25-71) years and some 368 (44%) were female. 157 (18.7%) of those patients developed SSI. The most commonly isolated pathogen was E. Coli (55.4%) followed by Staphylococcus Aureus (40.1%). The 30-day mortality rate of patients who presented SSIs was 14.6% compared to 6.8% of patients without SSI (p=0.002). Multivariable analysis showed that the type of wound, American Society of Anesthesiology score, severity and duration of surgery >90 min were independent risk factors for the occurrence of SSI. CONCLUSION: Identification of modifiable causative factors for SSI within an ES unit is paramount as they can critically impact postoperative outcomes.