Revolutionizing Daptomycin Dosing: A Single 7-11 Hour Sample for Pragmatic Application.

Precision daptomycin dosing faces clinical implementation barriers despite known exposure-safety concerns with the use of twice the regulatory-approved doses. We propose achieving a single 7-11 hour post-dose plasma target concentration of 30 mg/L to 43 mg/L to be a practical starting point to facilitate precision daptomycin dosing.

Cefditoren: a clinical overview.

Cefditoren is an oral third-generation cephalosporin with a large spectrum activity against Gram-negative and Gram-positive bacteria which are reported to be responsible for respiratory tract and skin and skin structure infections. In this work we reviewed the pharmacodynamics, pharmacokinetics, and the main clinical indications of cefditoren. Similarly to other beta-lactams, cefditoren is a time-dependent antibiotic, and its "best" PK/PD target is probably 40% dosing interval time > 4- 5-fold MIC and 40-70% dosing interval time > 4- 5-fold MIC for bacteriostatic and bactericidal effect, respectively. In fasting patients oral bioavailability is low and increases when the drug is taken with food. This cephalosporin has significant bactericidal activity against S. pneumoniae (both penicillin-susceptible and penicillin-resistant strains), S. pyogenes, H. Influenzae and M. catarrhalis, as well as methicillin-susceptible S. aureus (MSSA). Regarding Enterobacterales, cefditoren has very low MICs90 against K. pneumoniae andE. coli but is not active against AmpC-, ESBL- and carbapenemase-producer' strains. Licensed indications are treatment of exacerbations of chronic bronchitis,acute rhinosinusitis, otitis media, upper respiratory tract infections (pharyngitis/tonsillitis), lower community-acquired respiratory tract infections (LRTIs), and skin and skin-structure infections (SSTI). Cefditoren might have a role in switching from parenteral to oral therapy in acute pyelonephritis and LRTIs. with a reduction of adverse effects and hospital costs. Eventually, due to its supposed binding to enterococcal penicillin binding proteins (PBPs) cefditoren, in combination with other beta-lactams, might have a role in partial oral enterococcal endocarditis treatment..

Monkeypox virus transmission in tattoo parlor.

In monkeypox virus (MPXV) transmission caused by contaminated material, we have to consider that recently the outbreak of several MPXV cases was linked to tattoo parlors in Cadiz, Spain. These tattoo parlors did not cause a single outbreak, but instead are an established transmission route for MPXV, underscoring the need for increased awareness. We recommend increasing awareness among tattooists and piercers not only to protect their own safety and health, but also to prevent spreading the virus to their customers. Personal protective equipment such as gloves should be utilized and vaccination can be considered for those at risk of occupational exposure.

Lactococcus lactis blood products contamination resulting in fatal human case: insights from a forensic case.

Lactococcus species are micro-aerophilic Gram positive bacteria characterized by low virulence features and other biotechnological properties of industrial interest. They are thus widely employed in food fermentation processes. Despite its low pathogenic potential and food grade safety, L. lactis may, however, rarely cause infections, especially among immunocompromised hosts. Moreover, the growing complexity of patients implies increased detections of such infections. This said, there is a paucity of data concerning L. lactis infections from infusion of blood transfusion products. To our knowledge, this is the first case of L. lactis infection from transfusion of blood products, as observed in an 82-year-old Caucasian male undergoing weekly platelet and blood transfusion due to sustained severe thrombocytopenia. Albeit minimally pathogenic, L. lactis should be considered for thorough testing, especially in the case of human-derived infusion products such as platelets due to their storage requirements for extended times at room temperature and their use in immunocompromised and critically ill subjects.

Pragmatic overview on acute bacterial and fungal infections of the central nervous system: a holistic update from diagnosis to treatment.

Although progress has led to a drop in infections, meningitis still represents a threat worldwide, affecting some areas more than others. As a medical emergency, it requires prompt recognition and treatment. Moreover, diagnosis relies on invasive methods, while representing a tug-of-war with timely therapeutic interventions, since delays are burdened by mortality and life-long sequalae. While counterbalancing the overuse of antimicrobials, it is imperative to assess correct interventions in order to optimize treatments and reduce negative outcomes. Because the drop in mortality and consequences has been consistent, although not as impactful as with other vaccine-preventable diseases, the WHO has traced a roadmap detailing actions to reduce the meningitis burden by 2030. There are currently no updated guidelines, whereas novel diagnostic methods as well as pharmacological interventions are increasing, along with the shifting epidemiology. In light of the above, this paper wishes to summarize existing data and evidences and suggest potential novel solutions to a complex problem.

Comparison of Septic Shock Due to Multidrug-Resistant Acinetobacter baumannii or Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Intensive Care Unit Patients.

A significant cause of mortality in the intensive care unit (ICU) is multidrug-resistant (MDR) Gram-negative bacteria, such as MDR Acinetobacter baumannii (MDR-AB) and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp). The aim of the present study was to compare the clinical features, therapy, and outcome of patients who developed septic shock due to either MDR-AB or KPC-Kp. We retrospectively analyzed patients admitted to the ICU of a teaching hospital from November 2010 to December 2015 who developed septic shock due to MDR-AB or KPC-Kp infection. Data from 220 patients were analyzed: 128 patients (58.2%) were diagnosed with septic shock due to KPC-Kp, and 92 patients (41.8%) were diagnosed with septic shock due to MDR-AB. The 30-day mortality rate was significantly higher for the MDR-AB group than the KPC-Kp group (84.8% versus 44.5%, respectively; P < 0.001). Steroid exposure and pneumonia were associated with MDR-AB infection, whereas hospitalization in the previous 90 days, primary bacteremia, and KPC-Kp colonization were associated with KPC-Kp infection. For patients with KPC-Kp infections, the use of ≥2 in vitro-active antibiotics as empirical or definitive therapy was associated with higher 30-day survival, while isolation of colistin-resistant strains was linked to mortality. Patients with MDR-AB infections, age >60 years, and a simplified acute physiology score II (SAPS II) of >45 points were associated with increased mortality rates. We concluded that septic shock due to MDR-AB infection is associated with very high mortality rates compared to those with septic shock due to KPC-Kp. Analysis of the clinical features of these critically ill patients might help physicians in choosing appropriate empirical antimicrobial therapy.

Are there any reasons to change our behavior in necrotizing fasciitis with the advent of new antibiotics?

PURPOSE OF REVIEW: The treatment of necrotizing fasciitis requires a multifaceted approach, consisting of surgical source control with immediate surgical debridement along with life support, clinical monitoring, and antimicrobial therapy. Many drugs are now available for the treatment of this life-threatening infectious disease, and the purpose of this review is to provide the reader with an updated overview of the newest therapeutic options. RECENT FINDINGS: Because most necrotizing soft tissue infections are polymicrobial, broad-spectrum coverage is advisable. Acceptable monotherapy regimens include piperacillin-tazobactam or a carbapenem. However, drugs such as ceftolozane-tazobactam, ceftazidime-avibactam in association with an antianaerobic agent (metronidazole or clindamycin) are currently available as valuable alternatives. The new cephalosporins active against methicillin-resistant Staphylococcus aureus (MRSA), ceftaroline, and ceftobiprole share similar antibacterial activity against Gram-positive cocci, and they might be considered as an alternative to nonbetalactam anti-MRSA agents for necrotizing fasciitis management. Two new long-acting lypoglycopeptides - oritavancin and dalbavancin - share the indications for acute bacterial skin and skin structure infections and had similar activity against Gram-positive cocci including MRSA and streptococci. SUMMARY: Carbapenem-sparing agents are particularly suitable for antimicrobial stewardship strategy. The new long-acting lypoglycopeptides are very effective in treating necrotizing fasciitis and are uttermost attractive for patients requiring short hospital stays and early discharge.

Clinical features and outcome of patients with descending necrotizing mediastinitis: prospective analysis of 34 cases.

PURPOSE: We aimed to investigate clinical features of patients with descending necrotizing mediastinitis (DNM) in order to improve management and outcome. METHODS: We prospectively examined all patients with DNM admitted to the Intensive Care Unit (ICU) during the period from April 2007 to December 2013. Demographics, clinical features, microbiology, medical and surgical treatment data were recorded. Survivor and nonsurvivor groups were analyzed to identify factors associated with mortality. RESULTS: Overall, 34 patients with DNM have been included. The mean age was 46.8 ± 11.2 years (range 24-70). The male/female ratio was 3.25. DNM arose from odontogenic infection in 22 (65%) patients; from peritonsillar abscess in 9 (26%) patients and from paranasal sinus in 3 (9%) patients. Microbiological cultures revealed a high percentage of aerobic/anaerobic coinfection. Nonsurvivors were statistically more likely to have higher SAPS II score (mean difference 19.1, 95% CI 12.3-25.9 P < 0.01) and more severe disease (P < 0.01) than survivors. Positive correlation was found between time to ICU admission after head or neck infection diagnosis and SAPS II score (ρ = 0.5, P = 0.03). The same was true for ICU length of stay and time to ICU admission (ρ = 0.6, P < 0.01) and time to surgery (ρ = 0.5, P = 0.03). Surgical treatments consisted in: transcervical drainage in 14 cases, (42%); irrigation through subxiphoid and cervical incisions of the anterior mediastinum with additional percutaneous thoracic drainage when necessary in ten cases, (29 %); thoracotomy with radical mediastinal surgical debridement, excision of necrotic tissue and decortication in ten cases, (29%). We have found a mortality rate of 12%. Patients with DNM type IIB were admitted to the ICU later than patients with DNM type I and type IIA (mean difference 3.2 days, 95% CI 1.2-5.1, P 0.02). CONCLUSIONS: Prompt ICU admission in order to manage severe sepsis and/or septic shock, along with early and aggressive surgery and adequate antimicrobial therapy, could be key factors in reducing DNM mortality.

Severe community onset healthcare-associated Clostridium difficile infection complicated by carbapenemase producing Klebsiella pneumoniae bloodstream infection.

BACKGROUND: Clostridium difficile infection (CDI) and Klebsiella pneumoniae carbapenemase producing-Klebsiella pneumoniae (KPC-Kp) bloodstream infection (BSI) are emerging health-care associated (HCA) diseases of public health concern, in terms of morbidity, mortality, and insufficient response to antibiotic therapy. Both agents can be acquired in the hospital but clinical disease can develop in a community setting, after discharge. We report here a putative link between the above-mentioned healthcare associated infections that appeared as a dramatic community onset disease with a fulminant fatal outcome. CASE PRESENTATION: We describe the case of a 63 year old man affected by severe CDI. Even though the patient underwent 72 hours of standard CDI antibiotic treatment, the clinical course was complicated by toxic megacolon and KPC-Kp BSI. The patient died 24 hours after total colectomy. CONCLUSION: The impact of HCA-BSIs in complicating CDI is still unknown. Intestinal inflammatory injury and disruption of intestinal flora by standard antibiotic treatment could be responsible for promoting difficult-to-treat infections in CDI. By preserving intestinal flora, Fidaxomicin could have a crucial role in preventing BSIs complicating severe CDI.

A case report of treatment of a streptococcal brain abscess with ceftobiprole supported by the measurement of drug levels in the cerebrospinal fluid.

In this paper, we describe the case of a patient admitted to our hospital because of a brain abscess due to Streptococcus intermedius. The management of brain abscess is challenging given the limited potential drug options with effective penetration into both the central nervous system and the abscess capsule to achieve adequate therapeutic concentrations. Due to the high anti-streptococcal activity of ceftobiprole and the availability of ceftobiprole therapeutic drug monitoring in our hospital, we decided to treat the patient with ceftobiprole. To maximize the antimicrobial effect of ceftobiprole, we chose a prolonged intravenous infusion, and we monitored its concentrations in both plasma and cerebrospinal fluid.

The Subcutaneous Administration of Beta-Lactams: A Case Report and Literary Review-To Do Small Things in a Great Way.

The subcutaneous (s.c.) route is a commonly used method for delivering various drugs, although its application in the administration of antibiotics is relatively uncommon. In this case, we report a successful treatment of nosocomial pneumonia using piperacillin/tazobactam via continuous subcutaneous administration. Furthermore, this article provides an overview of the current literature regarding the s.c. administration of beta-lactam antibiotics. Based on our analysis, we identified only 15 studies that described the s.c. use of beta-lactam antibiotics in human subjects. Among these studies, cephalosporins were the most extensively investigated antibiotic class, with 10 available studies. According to the study findings, all three antibiotic classes (cephalosporins, penicillins, and carbapenems) demonstrated a similar pharmacokinetic profile when administered via the subcutaneous route. The subcutaneous route appears to be associated with a lower peak serum concentration (Cmax) but a comparable minimum blood concentration (Cmin) and an extended half-life (t1/2) when compared to conventional routes of antibiotic administration. Further research is necessary to determine whether subcutaneously administered beta-lactam antibiotics in human subjects achieve pharmacodynamic targets and demonstrate clinical efficacy.

An Aminoglycoside-Sparing Regimen with Double Beta-Lactam to Successfully Treat Granulicatella adiacens Prosthetic Aortic Valve Endocarditis-Time to Change Paradigm?

(1) Background: Granulicatella adiacens is a former nutritionally variant streptococci (NVS). NVS infective endocarditis (IE) is generally characterized by a higher rate of morbidity and mortality, partially due to difficulties in choosing the most adequate microbiological culture method and the most effective treatment strategy, and partially due to higher rates of complications, such as heart failure, peripheral septic embolism, and peri-valvular abscess, as well as a higher rate of valve replacement. Depending on the affected valve (native valve endocarditisNVE, or prosthetic valve endocarditisPVE), the American Heart Association (AHA) 2015 treatment guidelines (GLs) suggest penicillin G, ampicillin, or ceftriaxone plus gentamicin (2 weeks for NVE and up to 6 weeks for PVE), while vancomycin alone may be a reasonable alternative in patients who are intolerant of ß-lactam therapy. The European Society of Cardiology (ESC) 2023 GLs recommend treating NVE with penicillin G, ceftriaxone, or vancomycin for 6 weeks, suggesting combined with an aminoglycoside (AG) for at least the first 2 weeks only for PVE; likewise, the same recommendations for IE due to Enterococcus faecalis. (2) Methods: Starting from the case of a 51-year-old man with G. adiacens aortic bio-prosthesis IE who was successfully treated with aortic valve replacement combined with double beta-lactams, an AG-sparing regimen, we performed microbiology tests in order to validate this potential treatment change. (3) Results: As for E. faecalis IE, we found that the combination of ampicillin plus cephalosporines (like ceftriaxone or ceftobiprole) showed a synergistic effect in vitro, probably due to wider binding to penicillin-binding proteins (PBPs), thus contributing to enhanced bacterial killing and good clinical outcome, as well as avoiding the risk of nephrotoxicity due to AG association therapy. (4) Conclusions: Further studies are required to confirm this hypothesis, but double beta-lactams and an adequate sourcecontrol could be a choice in treating G. adiacens IE.

Meropenem PK/PD Variability and Renal Function: "We Go Together".

BACKGROUND: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, not limited to intensive care units. METHODS: From December 2021 to February 2022, we retrospectively analyzed 195 meropenem serum concentrations (Css). We characterized patients according to meropenem exposure, focusing on the renal function impact. RESULTS: A total of 36% (n = 51) of the overall observed patients (n = 144) were in the therapeutic range (8-16 mg/L), whereas 64% (n = 93) required a meropenem dose modification (37 patients (26%) underexposed; 53 (38%) overexposed). We found a strong relationship between renal function and meropenem concentrations (correlation coefficient = -0.7; p-value < 0.001). We observed different dose-normalized meropenem exposure (Css/D) among renal-impaired (severe and moderate), normal, and hyperfiltrating patients, with a median (interquartile range) of 13.1 (10.9-20.2), 7.9 (6.1-9.5), 3.8 (2.6-6.0), and 2.4 (1.6-2.7), respectively (p-value < 0.001). CONCLUSIONS: Meropenem TDM in clinical practice allows modification of dosing in patients inadequately exposed to meropenem to maximize antibiotic efficacy and minimize the risk of antibiotic resistance, especially in renal alterations despite standard dose adaptations.

Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections.

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.

Ampicillin and Ceftobiprole Combination for the Treatment of Enterococcus faecalis Invasive Infections: "The Times They Are A-Changin".

BACKGROUND: Enterococcus faecalis is responsible for a large variety of severe infections. This study is a case series reporting our experience in the treatment of E. faecalis invasive infections with ampicillin in combination with ceftobiprole (ABPR). METHODS: We retrospectively analyzed all the medical records of patients admitted to the University Hospital of Udine from January to December 2020 with a diagnosis of infective endocarditis or primary or non-primary complicated or uncomplicated bacteremia caused by E. faecalis. RESULTS: Twenty-one patients were included in the final analysis. The clinical success rate was very high, accounting for 81% of patients, and microbiological cure was obtained in 86% of patients. One relapse was recorded in one patient who did not adhere to the partial oral treatment prescribed. Therapeutic drug monitoring (TDM) was always performed for ampicillin and ceftobiprole, and serum concentrations of both drugs were compared to the MICs of the different enterococcal isolates. CONCLUSIONS: ABPR is a well-tolerated antimicrobial regimen with anti-E. faecalis activity. TDM can help clinicians optimize medical treatments to achieve the best possible efficacy with fewer side effects. ABPR might be a reasonable option for the treatment of severe invasive infections caused by E. faecalis due to the high level of enterococcal penicillin-binding protein (PBP) saturation.

Potential role of IgM-enriched immunoglobulin as adjuvant treatment in severe SARS-CoV-2 infection.

BACKGROUND: Severe COVID-19 patients are characterized by a dysregulated host response to an infection, with uncontrolled pro- and anti- inflammatory pathway activation. Consistent proportion of patients require admission in intensive care units and are at risk of progression to severe forms of disease. These patients are generally admitted during later stages of the disease, when effective antiviral and monoclonal antibody are not indicated. We aimed to assess the potential role of IgM-enriched intra venous immunoglobulins (IGAM) preparations in this setting. METHODS: This retrospective, observational case-controlled study was conducted at a single-center University Hospital of Udine in the Friuli Venezia Giulia Region of Italy. Patients referring to the center between March 2020 and April 2021 was included. During the study period, patient who received Pentaglobin® IGAM treatment (N.=56), administered as compassionate use, was compared with a control group (N.=169) to assess, by propensity score analysis, clinical outcome. RESULTS: Untreated controls required, respect to patient treated with IGAM therapy, longer time to hospitalization with no significant differences in death and orotracheal intubation requirement. Significant differences in the two cohort were in: SOFA was higher in treated, while D-dimer and P/F ratio was better in the treatment cohort. Multivariate logistic regression analysis performed on the "matched sample," obtained by a weighting propensity score approach, identify, as significant protective factor for death outcome, the Pentaglobin® treatment (0.820 [0.698-0.963], P=0.016) and low C-reactive protein (1.001 [1.000-1.002], P=0.031) value while the delay of onset hospitalization is associate with a worst outcome (0.983 [0.967-0.999], P=0.041). CONCLUSIONS: The present study offers a significant insight concerning the use of IgM-enriched immunoglobulin preparations in patients with SARS-CoV-2 severe infection and also could identifying the specific immunological and biochemical profile of the patient who can more benefit from this therapeutic option.

Safety and Efficacy of a Single Procedure of Extraction and Reimplantation of Infected Cardiovascular Implantable Electronic Device (CIED) in Comparison with Deferral Timing: An Observational Retrospective Multicentric Study.

(1) Background: Infections are among the most frequent and life-threatening complications of cardiovascular implantable electronic device (CIED) implantation. The aim of this study is to compare the outcome and safety of a single-procedure device extraction and contralateral implantation versus the standard-of-care (SoC) two-stage replacement for infected CIEDs. (2) Methods: We retrospectively included 66 patients with CIED infections who were treated at two Italian hospitals. Of the 66 patients enrolled in the study, 27 underwent a single procedure, whereas 39 received SoC treatment. All patients were followed up for 12 months after the procedure. (3) Results: Considering those lost to follow-up, there were no differences in the mortality rates between the two cohorts, with survival rates of 81.5% in the single-procedure group and 84.6% in the SoC group (p = 0.075). (4) Conclusions: Single-procedure reimplantation associated with an active antibiofilm therapy may be a feasible and effective therapeutic option in CIED-dependent and frail patients. Further studies are warranted to define the best treatment regimen and strategies to select patients suitable for the single-procedure reimplantation.