Abstract Introduction: Prolonged infusion of β-lactam antibiotics is recommended for adults with sepsis, but whether this benefit applies specifically to piperacillin–tazobactam remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials comparing prolonged with intermittent infusion of piperacillin–tazobactam in critically ill adults. Methods: We searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials from inception to March 10, 2026. Eligible randomized controlled trials compared prolonged (continuous or extended) with intermittent infusion of piperacillin–tazobactam in critically ill adults. Primary outcomes were clinical cure and all-cause mortality. Secondary outcomes included intensive care unit length of stay and duration of antibiotic therapy. Random-effects meta-analyses were performed to calculate pooled risk ratios for dichotomous outcomes and mean differences for continuous outcomes. Results: Seven studies comprising 6,080 patients were included. For clinical cure, the pooled estimate favored prolonged infusion (risk ratio 1.23, 95% confidence interval 1.07–1.42, 6 trials, 585 participants; very low-certainty evidence). The effect on 28-day mortality was uncertain (risk ratio 0.47, 95% confidence interval 0.16–1.41, 2 trials, 104 participants; low-certainty evidence). There was no clear difference in 90-day mortality (risk ratio 0.92, 95% confidence interval 0.84–1.01, 2 trials, 5,532 participants; moderate-certainty evidence). BLING III contributed 99.3% of the weight in the analysis. The pooled mean difference in antibiotic treatment duration was −2.47 days (95% confidence interval −3.92 to −1.02, 2 trials, 120 participants; very low-certainty evidence), but the evidence was very uncertain. Conclusion: In this meta-analysis of randomized controlled trials, prolonged infusion of piperacillin–tazobactam may improve clinical cure in critically ill adults, but the evidence is very uncertain. The estimate for 90-day mortality was consistent with the direction of benefit reported for β-lactams overall, but the confidence interval included no effect. These findings are consistent with the class-level evidence but do not independently confirm a mortality benefit specific to piperacillin–tazobactam. The effects on 28-day mortality and antibiotic treatment duration remain uncertain.
Background: Multidrug-resistant (MDR) bacterial infections present significant challenges to the management of central nervous system (CNS) infections, particularly in neurosurgical patients and those with cerebrospinal fluid (CSF) diversion devices. Achieving adequate CNS exposure is complicated by variable blood-brain barrier permeability and physiological changes, and CSF concentrations are not reliably predicted by plasma concentrations. Several new antibiotics have been introduced in response to rising MDR rates. To date, none are licenced for CNS infections, and data on CSF penetration and clinical utility are limited. Summary: Evidence describing CSF penetration of new antibiotics is limited and largely derived from small pharmacokinetic studies and case reports, predominantly in post-neurosurgical meningitis and ventriculitis. β-Lactams (BL) such as cefiderocol, and the BL/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam, ceftolozane-tazobactam and sulbactam-durlobactam, have achieved target CSF concentrations in individual cases, particularly with meningeal inflammation and intensive dosing. Predictors of adequate penetration are poorly defined, limiting identification of patients most likely to benefit, and the role of therapeutic drug monitoring (TDM) remains uncertain. Lipoglycopeptides and newer tetracyclines generally demonstrate low CSF penetration after systemic administration, with sparse clinical data supporting their use. Key Messages: CSF exposure to new antibiotics is highly variable, inconsistently achieves pharmacodynamic targets, and cannot be reliably inferred from plasma concentrations. Limited evidence suggests that BLs and BL/BLI combinations may have utility, whereas newer lipoglycopeptides and tetracyclines do not. Prospective studies and multicentre registries are required to better define CNS exposure, clarify the role of TDM, and inform practice.
INTRODUCTION:Linezolid exhibits significant pharmacokinetic variability in hospitalized patients, which may lead to suboptimal exposure or toxicity. Therapeutic drug monitoring (TDM) has been proposed to optimize treatment, although real-world data under standardized dosing conditions remain limited. The objective was to evaluate linezolid exposure in routine clinical practice under standardized dosing conditions and to identify factors associated with overexposure, dose optimization, and hematological toxicity. METHODS:A retrospective observational study was conducted using a hospital-based TDM database. Only patients receiving linezolid 600 mg every 12 h were included. A single trough concentration (Cmin) per patient was analyzed, defined as the first determination obtained at ≥48 h after treatment initiation. Exposure was categorized as subtherapeutic (<2 µg/mL), therapeutic (2-10 µg/mL), or supratherapeutic (>10 µg/mL). Logistic regression analyses were performed to identify factors associated with overexposure and thrombocytopenia. RESULTS:A total of 76 patients were included. The mean Cmin was 4.75 ± 4.45 µg/mL (median 3.07; range 0.67-23.6). Subtherapeutic, therapeutic, and supratherapeutic exposure occurred in 26.3%, 60.5%, and 13.2% of patients, respectively, with 39.5% of patients outside the therapeutic range. Age was associated with higher exposure (odds ratio: 1.03 per year; p = 0.025), while renal function showed a nonsignificant trend. Thrombocytopenia occurred in approximately 5-6% of patients and showed a nonsignificant association with higher trough concentrations. TDM led to dose modification in a relevant proportion of patients. CONCLUSION:Linezolid exposure shows substantial interindividual variability in hospitalized patients despite standardized dosing. A considerable proportion of patients present subtherapeutic or supratherapeutic concentrations. TDM may help identify patients at risk of underexposure or toxicity and support individualized dosing strategies, particularly in elderly patients and those with renal impairment.
BACKGROUND:Monoclonal antibodies (mAbs) and their derivatives represent a central pillar of contemporary oncology, with expanding complexity in molecular design and clinical application. Beyond unconjugated mAbs, bispecific antibodies (bsAbs), trispecific antibodies (tsAbs), and antibody-drug conjugates (ADCs) introduce additional pharmacological dimensions that directly impact efficacy, toxicity, and resistance. BsAbs were developed as pharmacological matchmakers to simultaneously engage tumor antigens and immune receptors, physically bridging effectors and malignant cells to promote immunological synapse formation. TsAbs extend this concept by enabling coordinated engagement of three targets. ADCs exploit mAb specificity to deliver highly potent, otherwise intolerable cytotoxic payloads directly into tumor cells, expanding the therapeutic window in hematologic and solid tumors. SUMMARY:Clinical performance is tightly linked to molecular architecture: bsAb/tsAb activity depends on valency, target geometry, and Fc configuration, whereas ADC efficacy reflects a tripartite pharmacology integrating target engagement, intracellular payload release, and bystander cytotoxicity. Despite their remarkable potency, antibody-based platforms remain vulnerable to resistance, which may arise through target-dependent mechanisms, including antigen downregulation and epitope masking, or target-independent processes, such as altered intracellular trafficking, lysosomal dysfunction, payload efflux, and adaptive survival signaling. KEY MESSAGE:A comprehensive understanding of antibody architecture, target biology, pharmacokinetic/pharmacodynamic behavior, toxicity profiles, and resistance mechanisms is essential to optimize treatment selection and sequencing. Collectively, mAbs, bsAbs/tsAbs, and ADCs provide the mechanistic and technological basis for next-generation platforms, including peptide-drug conjugates and antibody-radionuclide conjugates.
INTRODUCTION:Pseudoprogression during immunotherapy (IO) - defined as clinical documentation of tumor growth or new lesions during treatment with immune checkpoint inhibitors, followed by disease regression - has been reported in ≤10% of cases. Its incidence appears to be lower in cutaneous squamous cell carcinoma (cSCC) patients (1.5-4%). CASE PRESENTATION:We report a rare case of pseudoprogression of an advanced cSCC during IO (cemiplimab). Following initial surgery for a cSCC of the left auricular area, the tumor recurred and infiltrated the ear cartilage and external auditory meatus. At the time of administration of the second IO, the tumor had rapidly grown with a fulminant pattern and doubled in size. Treatment with IO continued, as per protocol, and by the third infusion appointment, the tumor had disappeared, and complete re-epithelialization of the auricular area was observed, confirming pseudoprogression. So far, the patient has received ten cycles of IO without experiencing toxicity, and there has been no sign of disease recurrence. CONCLUSION:Awareness of potential pseudoprogression is crucial for clinicians managing advanced cSCC with cemiplimab.
