Daptomycin Exposure Prediction With a Limited Sampling Strategy.

BACKGROUND: Daptomycin is a cyclic lipopeptide antibiotic used to treat serious infectious endocarditis caused by Staphylococcus aureus . The pharmacodynamic parameter correlating best with efficacy is the ratio of the estimated area under the concentration (AUC 0-24 )-time curve to the minimum inhibitory concentration. The aim of the study is to develop a limited sampling strategy to estimate AUC 0-24 using a reduced number of samples. METHODS: Sixty-eight daptomycin AUC 0-24 values were calculated for 50 White patients who underwent treatment for at least 5 consecutive days. Plasma concentrations were detected using a validated high-performance liquid chromatography-tandem mass spectrometry analytical method, with daptomycin-d5 as an internal standard. Multiple regression was used to evaluate the ability of 2 concentration-time points to predict the AUC 0-24 calculated from the entire pharmacokinetic profile. Prediction bias was calculated as the mean prediction error, whereas prediction precision was estimated as the mean absolute prediction error. The development and validation datasets comprised 40 and 10 randomly selected patients, respectively. RESULTS: The AUC 0-24 (mg*h/L) was best estimated using the daptomycin trough concentration and plasma concentrations detected 2 hours after dosing. We calculated a mean prediction error of 1.6 (95% confidence interval, -10.7 to 10.9) and a mean absolute prediction error of 11.8 (95% confidence interval, 5.3-18.3), with 73% of prediction errors within ±15%. CONCLUSIONS: An equation was developed to estimate daptomycin exposure (AUC 0-24 ), offering clinical applicability and utility in generating personalized dosing regimens, especially for individuals at high risk of treatment failure or delayed response.

Optimizing Antibiotic Therapy for Intravenous Drug Users: A Narrative Review Unraveling Pharmacokinetics/Pharmacodynamics Challenges.

Intravenous drug users (IVDUs) face heightened susceptibility to life-threatening gram-positive bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA). While the standard antibiotic dosing strategies for special patients, such as obese or critically ill individuals, are known to be inadequate, raising concerns about treatment efficacy, a similar sort of understanding has not been assessed for IVDUs yet. With this in mind, this review examines the pharmacokinetic/pharmacodynamic characteristics of antibiotics commonly used against gram-positive bacteria in IVDUs. Focusing on daptomycin, vancomycin, teicoplanin, aminoglycosides, and the novel lipoglycopeptide dalbavancin, the study reveals significant pharmacokinetic variations in IVDUs, suggesting the need for personalized dosing. Concomitant opioid substitution therapy and other factors, such as malnutrition, contribute to altered pharmacokinetics/pharmacodynamics, emphasizing the importance of targeted therapeutic drug monitoring. Overall, our study calls for increased awareness among clinicians regarding the unique pharmacokinetic/pharmacodynamic challenges in IVDUs and advocates for tailored antibiotic dosing strategies to enhance treatment outcomes in this marginalized population.

Concomitant Resistance to Cefiderocol and Ceftazidime/Avibactam in Two Carbapenemase-Producing Klebsiella pneumoniae Isolates from Two Lung Transplant Patients.

In this study, we present two cases of Klebsiella pneumoniae, one KPC-33- and one NDM-1-producing, showing resistance to cefiderocol and ceftazidime/avibactam, collected in the intensive care unit of a hospital in Northern Italy from two patients who had recently undergone lung transplantation. Whole-genome sequencing was performed to investigate the molecular features of these strains.

The possible role of serum bactericidal titres in long-term suppressive antibiotic treatment for infective endocarditis: report of three cases.

INTRODUCTION: long term suppressive antibiotic treatment may be the only feasible option for patients with infective endocarditis (IE) not suitable for surgery. CASE REPORTS: we present three cases of prosthetic valve endocarditis (PVE) caused by Enterococcus faecalis and Streptococcus gallolyticus which could not undergo surgical intervention due to high risk. Despite this, patients were successfully managed only by medical approach. Following intravenous targeted antimicrobial therapy, patients received chronic suppressive antimicrobial therapy (SAT) for at least twelve months with oral amoxicillin. In all cases, no further febrile episodes nor bacteraemia were observed and in two cases a complete positron emission tomography (PET) response was achieved. Due to a priori uncertainty about antimicrobial exposure during oral SAT, serum bactericidal titres (SBTs) were obtained and compared to those obtained during parenteral therapy. CONCLUSIONS: long term oral amoxicillin was effective and well-tolerated. SBTs after switch to oral therapy were quite heterogeneous, in some cases not reaching the conventionally established titre to assess bactericidal effect (1:8).Key pointsendovascular infection in non-suitable-for-surgery patients can be managed with long-term oral suppressive therapy.serum bactericidal assay confirmed high effectiveness of parenteral antibiotic therapy.serum bactericidal assay showed highly variable titres during oral therapy.

Efficacy of ceftazidime-avibactam in solid organ transplant recipients with bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae.

We aimed to compare the efficacy of ceftazidime-avibactam (CAZ-AVI) versus the best available therapy (BAT) in solid organ transplant (SOT) recipients with bloodstream infection caused by carbapenemase-producing Klebsiella pneumoniae (CPKP-BSI). A retrospective (2016-2021) observational cohort study was performed in 14 INCREMENT-SOT centers (ClinicalTrials.gov identifier: NCT02852902; Impact of Specific Antimicrobials and MIC Values on the Outcome of Bloodstream Infections Due to ESBL- or Carbapenemase-producing Enterobacterales in Solid Organ Transplantation: an Observational Multinational Study). Outcomes were 14-day and 30-day clinical success (complete resolution of attributable manifestations, adequate source control, and negative follow-up blood cultures) and 30-day all-cause mortality. Multivariable logistic and Cox regression analyses adjusted for the propensity score to receive CAZ-AVI were constructed. Among 210 SOT recipients with CPKP-BSI, 149 received active primary therapy with CAZ-AVI (66/149) or BAT (83/149). Patients treated with CAZ-AVI had higher 14-day (80.7% vs 60.6%, P = .011) and 30-day (83.1% vs 60.6%, P = .004) clinical success and lower 30-day mortality (13.25% vs 27.3%, P = .053) than those receiving BAT. In the adjusted analysis, CAZ-AVI increased the probability of 14-day (adjusted odds ratio [aOR], 2.65; 95% confidence interval [CI], 1.03-6.84; P = .044) and 30-day clinical success (aOR, 3.14; 95% CI, 1.17-8.40; P = .023). In contrast, CAZ-AVI therapy was not independently associated with 30-day mortality. In the CAZ-AVI group, combination therapy was not associated with better outcomes. In conclusion, CAZ-AVI may be considered a first-line treatment in SOT recipients with CPKP-BSI.

A worldwide survey on perioperative antimicrobial prophylaxis for heart transplantation: From theory to clinical practice.

BACKGROUND: The aim of our survey was to analyze the current attitudes toward antimicrobial prophylaxis in heart transplanting centers worldwide. METHODS: The survey was composed of a total of 50 questions, it consisted of four different sections as follows. The first section collected physicians' personal data and centers' general characteristics, second assessed the approach to patients colonized with multidrug-resistant organisms (MDROs), while the third consisted of the infection risk related to cardiovascular devices, and antimicrobial treatment data, the last focused on donor's colonization. RESULTS: A total of 56 answers from 26 different countries were collected, mostly from Europe (n = 30) and the USA (n = 16). A first-generation cephalosporin (58.9%) or a combination therapy with vancomycin (10.7%) were the most frequently prescribed antimicrobial prophylaxis. Roughly 30% of the centers used different antimicrobial prophylaxis,mostly including Gram negative bacteria coverage. The frequency of screening for multidrug resistant Gram-negative bacteria was higher in Europe, where the percentage of centers providing screening for extended spectrum beta-lactamase (46.7%) and carbapenem-resistant Enterobacteriaceae (CRE) (53.3%) was higher than in other geographic area (p = .019; p = .013, respectively). CONCLUSION: This survey highlights a heterogeneity of clinical practice concerning antimicrobial prophylaxis at transplant. The concern for potential Gram-negative bacteria infection was responsible for broader antimicrobial coverage in 30% of centers.

Reduction of BSI associated mortality after a sepsis project implementation in the ER of a tertiary referral hospital.

The emergency room (ER) is the first gateway for patients with sepsis to inpatient units, and identifying best practices and benchmarks to be applied in this setting might crucially result in better patient's outcomes. In this study, we want to evaluate the results in terms of decreased the in-hospital mortality of patients with sepsis of a Sepsis Project developed in the ER. All patients admitted to the ER of our Hospital from the 1st January, 2016 to the 31stJuly 2019 with suspect of sepsis (MEWS score ≥ of 3) and positive blood culture upon ER admission were included in this retrospective observational study. The study comprises of two periods: Period A: From the 1st Jan 2016 to the 31st Dec 2017, before the implementation of the Sepsis project. Period B: From the 1st Jan 2018 to the 31stJul 2019, after the implementation of the Sepsis project. To analyze the difference in mortality between the two periods, a univariate and multivariate logistic regression was used. The risk of in-hospital mortality was expressed as an odds ratio (OR) and a 95% confidence interval (95% CI). Overall, 722 patients admitted in ER had positive BC on admissions, 408 in period A and 314 in period B. In-hospital mortality was 18.9% in period A and 12.7% in period B (p = 0.03). At multivariable analysis, mortality was still reduced in period B compared to period A (OR 0.64, 95% CI 0.41-0.98; p = 0.045). Having an infection due to GP bacteria or polymicrobial was associated with an increased risk of death, as it was having a neoplasm or diabetes. A marked reduction in in-hospital mortality of patients with documented BSI associated with signs or symptoms of sepsis after the implementation of a sepsis project based on the application of sepsis bundles in the ER.

The WEST Study: A Retrospective and Multicentric Study on the Impact of Steroid Therapy in West Nile Encephalitis.

Background: The use of steroid therapy in potentially life-threatening neuroinvasive forms of West Nile infection (WNND) is controversial. The aim of this study is to assess the efficacy of steroid therapy in reducing intrahospital mortality, length of stay, and neurological sequelae at discharge. Methods: This was a multicenter, retrospective, observational study conducted in 5 hospitals in Northern Italy, headed by the Fondazione IRCSS Policlinico San Matteo (Pavia). We extracted all patient data with WNND diagnoses, comparing patients who received steroid treatment with patients who did not receive steroid treatment between January 2014 and January 2022. Comparisons between the 2 groups were performed using chi-square tests for categorical variables and Mann-Whitney tests for non-normal continuous data, and a generalized linear model for the binomial family was carried out. Results: Data from 65 WNND patients were extracted. Among these patients, 33 (50.7%) received steroid therapy at any point during their hospitalization. Receiving steroid therapy did not significantly reduce intrahospital mortality (odds ratio [OR], 1.70; 95% CI, 0.3-13.8; P = .89) or neurological sequelae at discharge (OR, 0.53; 95% CI, 0.16-1.76; P = .47). Conclusions: Steroid treatment is currently used on a single-case basis in severe WNND. More prospective data are needed to demonstrate a protective effect on mortality and neurological sequelae.

Sars-Cov 2 versus Flu: ECMO-associated bloodstream infections.

SARS-CoV-2 and flu may lead to severe acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO). The aim of the present study is to compare the incidence of bloodstream infections (BSIs) and outcome in patients with flu and SARS-CoV-2 infection hospitalized in ICU and undergoing ECMO. This study is a retrospective analysis of the San Matteo COVID-19 Registry (SMACORE) cohort. The study was conducted from January 2018 to April 2020. Demographic data and microbiological data were recorded during hospitalization. BSIs occurring during ECMO were analyzed. Eighteen patients treated with ECMO, 22 subjects with SARS-CoV-2 infection and 7 with flu, median age 61years for SARS-CoV-2 and 50 for flu (p=NS). Median ECMO duration was similar in the two pathologies. Median time to bloodstream infection from ECMO initiation was similar. Bloodstream infection incidence rate was 2.65 per 100 patients/days for flu and 2.2 per 100 patients/days for SARS-CoV-2. Global infection rate was 5 per 100 patients/days for SARS-CoV-2 patients and 5.3 per 100 patients/days for flu. Mortality during ECMO was 40.9% (5 out of 22 patients) for SARS-CoV-2 infection while none died among flu patients. ECMO-associated mortality was higher in SARS-CoV-2 infection compared with flu infection.

Immune Response to BNT162b2 in Solid Organ Transplant Recipients: Negative Impact of Mycophenolate and High Responsiveness of SARS-CoV-2 Recovered Subjects against Delta Variant.

The immunogenicity of severe acute respiratory syndrome 2 virus (SARS-CoV-2) vaccines in immunocompromised patients remains to be further explored. Here, we evaluated the immunogenicity elicited by complete vaccination with BNT162b2 vaccine in solid organ transplant recipients (SOTRs). A cohort of 110 SOTRs from Northern Italy were vaccinated with two doses of BNT162b2 mRNA vaccine and prospectively monitored at baseline and after 42 days. Both SARS-CoV-2 naïve and recovered subjects were included. Humoral response elicited by vaccination, including SARS-CoV-2 neutralizing antibodies (SARS-CoV-2 NT Abs), was evaluated; additionally, ex-vivo ELISpot assay was performed for the quantification of Spike-specific T-cell response. Results were compared with those obtained in a cohort of healthy subjects. In a subset of patients, humoral and T-cell responses against delta variant were also evaluated. Less than 20% of transplanted subjects developed a positive humoral and cell-mediated response after complete vaccination schedule. Overall, median levels of immune response elicited by vaccination were significantly lower with respect to controls in SARS-CoV-2 naïve transplant, but not in SARS-CoV-2 recovered transplanted patients. Additionally, a significant impairment of both humoral and cell-mediated response was observed in mycophenolate-treated patients. Positive delta-SARS-CoV-2 NT Abs levels were detected in almost all the SARS-CoV-2 recovered subjects but not in previously uninfected patients. Our study supports previous observations of a low level of seroconversion after vaccination in transplanted patients.

Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients.

The development and persistence of SARS-CoV-2-specific immune response in immunocompetent (IC) and immunocompromised patients is crucial for long-term protection. Immune response to SARS-CoV-2 infection was analysed in 57 IC and 15 solid organ transplanted (TX) patients. Antibody responses were determined by ELISA and neutralization assay. T-cell response was determined by stimulation with peptide pools of the Spike, Envelope, Membrane, and Nucleocapsid proteins with a 20-h Activation Induced Marker (AIM) and 7-day lymphoproliferative assays. Antibody response was detected at similar levels in IC and TX patients. Anti-Spike IgG, IgA and neutralizing antibodies persisted for at least one year, while anti-Nucleocapsid IgG declined earlier. Patients with pneumonia developed higher antibody levels than patients with mild symptoms. Similarly, both rapid and proliferative T-cell responses were detected within the first two months after infection at comparable levels in IC and TX patients, and were higher in patients with pneumonia. T-cell response persisted for at least one year in both IC and TX patients. Spike, Membrane, and Nucleocapsid proteins elicited the major CD4+ and CD8+ T-cell responses, whereas the T-cell response to Envelope protein was negligible. After SARS-CoV-2 infection, antibody and T-cell responses develop rapidly and persist over time in both immunocompetent and transplanted patients.

Propensity Score and Desirability of Outcome Ranking Analysis of Ertapenem for Treatment of Nonsevere Bacteremic Urinary Tract Infections Due to Extended-Spectrum-Beta-Lactamase-Producing Enterobacterales in Kidney Transplant Recipients.

There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.

Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy.

BACKGROUND AND OBJECTIVE: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. METHODS: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal ß-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. RESULTS: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 µg/mL (CV: 0.32) and 8.7 µg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 µg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers. CONCLUSIONS: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.

A Case Report of Disseminated Histoplasmosis in AIDS Diagnosed Through Peripheral Blood Smear.

BACKGROUND: Histoplasma capsulatum is an environmental fungus that causes opportunistic infections in AIDS patients in endemic areas but is uncommon in Europe. It shares clinical features with other opportunistic infections and lymphoproliferative disorders common in AIDS patients. The World Health Organization included Histoplasma antigen tests on the Lists of Essential In Vitro Diagnostics, however, they are not routinely available in non-endemic countries. Consequently, mycoses can be a great challenge for clinicians in non-endemic countries. CASE PRESENTATION: We report the case of a 42-year-old Colombian woman admitted to an Italian university hospital with diarrhea, acute renal failure, psychomotor impairment and fever. When a screening HIV test came back positive, she was screened for opportunistic infections with no results. Given the severity of her clinical condition a broad spectrum antibacterial and antifungal therapy was started in addition to HAART. A blood smear documented leucocytes inclusions, identified as capsular structures. On suspicion of Histoplasma capsulatum the patient was started on empiric amphotericin B. The diagnosis was confirmed by positive serology. Despite therapy, the patient died shortly after. In the following days, the mycology laboratory managed to grow Histoplasma capsulatum, thus confirming the diagnosis of invasive histoplasmosis in AIDS. CONCLUSION: The case highlights the need for a high index of suspicion for the diagnosis of endemic mycosis outside of endemic areas, and the necessity of expanding access to tests. Even if antigen/ antibody tests are not available, however, blood smear has worldwide feasibility and allows a rapid diagnosis.

An eight-year experience of Nocardia infection in Italy: does immunosuppression matter?

Nocardia has always been considered a pathogen of the immunocompromised host, but recent evidence has also highlighted its role as a pathogen in the immunocompetent. We aim to assess the role of immunosuppression in the disease. We reviewed all the cases of infections due to Nocardia spp. in our center that occurred from 1 January 2012 to 30 September 2019. Patients were divided into three groups: typical immunocompromised (PLWHIV, solid organ or hematopoietic cell transplant recipients, individuals under immunosuppressive drugs), atypical immunocompromised (ongoing chronic diseases involving the lung, kidney, liver and diabetes) and immunocompetent. We identified 53 patients with an infection by Nocardia spp. Thirty-four (60.4%) of them were immunocompromised, 22 (64.7%) typical and 12 (35.3%) atypical immunocompromised. Nineteen (35.8%) were immunocompetent. The two conditions most frequently associated with infection were chronic lung disease (41.5%) and ongoing treatment with immunosuppressive drugs (33.9%). In our cohort a remarkable prevalence of nocardiosis in immunocompetent and atypical immunosuppressed patients was observed.

A case of Corynebacterium striatum endocarditis successfully treated with an early switch to oral antimicrobial therapy.

Patients with Corynebacterium striatum endocarditis are usually managed with long-term intravenous antibiotic therapy and hospitalization. Here we describe a case of a 76-year-old woman with hepatitis C virus (HCV) related cirrhosis who developed endocarditis due to Corynebacterium striatum associated with severe aortic regurgitation. To our knowledge, this is the first case to be successfully treated with an early switch to oral linezolid after three weeks of vancomycin. We performed a literature review using the PubMed database and found 27 cases which showed the enhanced virulence of this pathogen especially for long-term hospitalized patients with a frequent need of surgical treatment (44.4%) and long course of parenteral antimicrobial therapy, with vancomycin as drug of choice. There are no studies confirming the possibility of using oral treatment in non-diphtheritic Corynebacteria infective endocarditis. This case report provides us with the evidence that once the patient is in a stable condition, the efficacy and safety of linezolid might be similar to vancomycin administration. New trials and prospective studies are needed to confirm the opportunity of an early switch to oral therapy in this specific setting.