Dimitrios Themelidis

Background/Objectives: The rise of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales has led to an increased carbapenem use, raising concerns regarding selection pressure for carbapenem-resistant organisms. Ceftolozane–tazobactam (C/T) is a potential effective carbapenem-sparing alternative. This single-centre retrospective study evaluated the clinical effectiveness and mortality predictors of ceftolozane–tazobactam versus meropenem as definitive targeted therapy for ESBL-producing Enterobacterales bloodstream infections (BSIs). Methods: We conducted a single-center retrospective analysis of adult hospitalized patients between January 2022 and February 2024 who presented with BSIs caused by ESBL-producing Enterobacterales. Patients (N = 185) were included if they received either C/T (n = 73) or optimized high-dose meropenem (n = 112) for at least 48 h. The primary clinical endpoint was all-cause 30-day mortality. Secondary endpoints included clinical success (cure), in-hospital mortality, treatment duration, microbiological eradication, and infection recurrence rates. A multivariable logistic regression model was executed to determine independent predictors of 30-day mortality. Results: Escherichia coli (54.1%) and Klebsiella pneumoniae (35.1%) were the primary pathogens. The raw clinical success rate was higher with C/T than meropenem (83.6% vs. 71.6%, p = 0.078). Unadjusted 30-day mortality was 12.3% for C/T and 19.6% for meropenem (p = 0.342). Zero recurrences occurred with C/T compared to an 8.0% recurrence rate with meropenem (0/73 [0.0%] in C/T vs. 9/112 [8.0%] in meropenem, p = 0.015). In the multivariable logistic regression analysis, definitive targeted treatment with C/T was independently associated with lower odds of all-cause 30-day mortality (Adjusted Odds Ratio [aOR] 0.60; 95% Confidence Interval [CI] 0.33–0.92; p = 0.022). Conversely, independent clinical mortality risks included male gender (p = 0.027), baseline SOFA score (p = 0.001), septic shock (p = 0.001), and an unknown primary infection source (p = 0.001). Conclusions: In this single-center retrospective observational cohort, definitive targeted therapy with ceftolozane–tazobactam was associated with favorable clinical success and lower adjusted 30-day mortality compared to meropenem in patients with ESBL Enterobacterales BSIs. These observational data support further prospective evaluation of C/T as a potential carbapenem-sparing option. Prospective randomized controlled trials are required to confirm these findings before clinical practice algorithms are modified.

Background and Clinical Significance: Tenofovir disoproxil fumarate (TDF) is a widely prescribed nucleotide reverse transcriptase inhibitor (NtRTI) for HIV-1 infection. Though generally well-tolerated, proximal renal tubulopathy resulting in full-blown Fanconi syndrome remains a rare but severe complication (<0.1%). Case Presentation: We present the case of a 52-year-old female living with HIV-1 (diagnosed in 1999, CDC stage A3) who had been treated with a TDF-based antiretroviral regimen for 12 years. Upon admission, she complained of progressive bone pain and polyuria over the preceding six months. Laboratory investigations revealed profound hypokalemia, severe hypophosphatemia, hypouricemia, elevated alkaline phosphatase (ALP) and a decline in renal function (creatinine 1.3 mg/dL from a baseline of 0.7 mg/dL). Arterial blood gas (ABG) analysis showed a normal anion gap hyperchloremic metabolic acidosis alongside respiratory acidosis. Urinalysis demonstrated profound glycosuria in the setting of normal blood glucose levels, coupled with increased 24 h urinary excretion of potassium and phosphorus. A bone scintigraphy demonstrated a “super scan” pattern of metabolic etiology, establishing secondary osteomalacia driven by renal phosphate wasting. Secondary hyperparathyroidism and severe vitamin D3 deficiency were also recorded. The diagnosis of TDF-induced Fanconi syndrome was established. TDF was discontinued, and her antiretroviral regimen was modified to tenofovir alafenamide fumarate (TAF), emtricitabine (FTC), darunavir, and ritonavir, combined with vitamin D supplementation. Over a 6-month follow-up period, renal function normalized, electrolyte wasting resolved, and metabolic acidosis completely reversed. Conclusions: This case highlights that TDF-induced proximal tubulopathy can manifest even after a decade of uneventful therapy, particularly when co-administered with a boosted protease inhibitor.

LL-37 has attracted significant research attention as a multifunctional antimicrobial peptide which is implicated in a broad spectrum of activities. It is the only human cathelicidin and represents a key molecule in host defense. Hence, it is described as possessing antimicrobial activity against a wide range of pathogens, including Gram-negative and Gram-positive bacteria, numerous viral species, and various fungi. Though it is widely recognized for its direct antimicrobial activity, it is a multifaceted immunomodulatory and tissue-protective molecule. Beyond host defense, LL-37 actively regulates inflammatory signaling, cellular interactions within the immune system, and mechanisms of tissue repair. Its ability to fine-tune immune responses and simultaneous regeneration highlights its dual role in inflammation control and wound healing. These pleiotropic functions place LL-37 in the spotlight between innate immunity and tissue homeostasis. This review aims to compile LL-37’s antimicrobial and immunomodulatory activities and highlight its wide range of potential clinical applications.

In recent decades, the problem of resistant strains, which present resistance to different types of antimicrobials, has increased. Klebsiella pneumoniae is one of the most important species that exhibits an acquired resistance phenotype to at least one agent in three or more classes of antimicrobials and is thus characterized as a multidrug-resistant bacterium (MDR). 98 nosocomial strains of K. pneumoniae were isolated during the pre-COVID-19 period, and more specifically, from February 2015 to March 2019, were analyzed for the detection of class A, D, and B carbapenemase genes. The existence of KPC, OXA-48 like, IMP, VIM, and NDM carbapenemases has been examined. The immunochromatography showed that NDM carbapenemases are more frequently detected in the samples, reaching a percentage of 30.7%, while correspondingly the percentage for VIM carbapenemases was 7.68% among the strains with resistant phenotypes. No strain with carbapenemase IMP was found. Real-time multiplex polymerase chain reaction (PCR) showed, in contrast to immunochromatography kits, that a high percentage of bacterial isolates (94.26%) carry NDM and VIM carbapenemase genes, while no IMP carbapenemase genes were detected. Regarding the KPC enzymes, the immunochromatography kits showed that KPC positive strains are reaching 53.1%, and OXA-48 positive strains are reaching 3.1% among the strains with resistant phenotypes. Real-time multiplex polymerase chain reaction revealed a much higher percentage of 89.6% KPC positive isolates and a percentage of 14.6% OXA-48 carbapenemase producers. The aforementioned results indicate the dominance of the Multiplex Real-Time PCR as a “gold standard” method. This study could not fully support the usefulness of rapid immunochromatographic tests as a fast and useful diagnostic tool in the laboratory daily routine, as per the results of previous studies. Thus, more studies need to be conducted in this field to introduce these rapid tests safely into the daily laboratory workflow as a screening tool. Additionally, this study underlines the predominance of KPC enzymes from clinical isolates of ICUs and a significant shift over the OXA-48 like enzymes that are not limited to the ICU environment.

Legionella pneumophila (L. pneumophila) infection is characterized by a wide spectrum of manifestations, from influenza-like illness to life-threatening atypical pneumonia with multiorgan failure. The aim of our study was the assessment of in vitro and ex vivo neutrophil activation in L. pneumophila infections, as well as the role of neutrophils’ peptides such as LL-37 in infection. The ability of neutrophils to form ex vivo extracellular traps (NETs) in response to bacterial infection was examined by immunofluorescence. In parallel, patients’ sera, as well as opsonized standard L. pneumophila strains, were used for in vitro activation of neutrophils from healthy individuals. The serum levels of interleukins were assessed using the LEGENDplexTM Multi-Analyte Flow Assay Kit. Furthermore, citrullinated cf-DNA as a marker of neutrophil extracellular traps (NETs) was detected in the serum of patients with acute infection. It was demonstrated that neutrophils released NETs in vitro and ex vivo upon L. pneumophila (interaction in an autophagy-independent manner. Notably, IL-1b was detected on NETs, but an antimicrobial peptide LL-37 was absent. The lack of antimicrobial activity failed to inhibit bacterial proliferation. In addition, in vitro and ex vivo NETs formation was observed during the Clarithromycin treatment. Those NETs were decorated with bioactive antimicrobial peptide LL-37, which inhibits bacterial proliferation. The findings provide evidence that neutrophils release NETs in vitro and ex vivo by expressing the IL1β protein in them. The lack of expression of the antimicrobial peptide LL-37 on the NETs demonstrates the inability of the cells to inhibit proliferation, and consequently the elimination of L. pneumophila. Clarithromycin plays a dual role in the elimination.