Intrathecal Route Research Articles

Successful Treatment of MDRAcinetobacter baumannii Meningitis in a Young Adult Patient With Intraventricular and Intravenous Polymyxin B‐Tigecycline Based Combinations: A Case Report

ABSTRACTMultiple drug resistance to Acinetobacter baumannii infection treatment is a great challenge for neuro‐intensivists due to poor drug penetration through the blood–brain barrier (BBB). Fortunately, the intraventricular administration of polymyxin‐B and tigecycline seems to be effective; there are few case reports demonstrating the effectiveness of such treatments. Here, we report the case of a 24‐year‐old male who presented with fever and neck rigidity after intracranial drainage following lung infection caused by MDR Acinetobacter baumannii. Due to the presence of turbid CSF, the administration of the intrathecal (ITH) route polymyxin‐B and tigecycline is not possible. In this situation, the neuro‐intensivist decided to start intraventricular tigecycline and polymyxin‐B administration along with IV tigecycline and polymyxin‐B via the intraventricular route, which was feasible because the patient had an external ventricular drain (EVD) due to obstructive hydrocephalus caused by the neurosurgeon after excision of the tumor.

Intrathecal ephedrine plus bupicaine for hernioraphy prophylaxis for hypotension and analgesic

Background Usually, hernia repair is performed under spinal anesthesia. Hypotension secondary to spinal anesthesia is a common problem and many protocols have been tested regarding their efficacy in preventing this oweful complication. Aim of the work Compare the efficacy of intrathecal ephedrine plus Bupivacaine as prophylaxis for prevention of hypotension in patient undergoing inguinal hernia repair as compared to intrathecal Bupivacaine alone.as well as Does it have analgesic effect or not?.Patients and methods Eighty-four patients who underwent unilateral hernial were randomized to receive intratcal bupivacaine combined with ephedrine or receive intrathecal bupivacaine alone. The primary outcome was the effect of ephedrine on the hemodynamic profile. The secondary outcomes were the analgesic efficacy and the associated complications. Results In the current study, there was statistically significant decrease in the heart rate in the control group at the following duration during the intraoperative period. No cases in the test group showed bradycardia or hypotension. In the control group bradycardia occurred in 4 cases (16.7%) and hypotension occurred in 1 case (4.2%). The VAS score at 4 hours, 6 hours, 12 hours and 24 hours postoperative, the pain score were statistically significantly lower in the ephedrine group. Conclusion The use of ephedrine by the intrathecal route during spinal anesthesia was associated with better control of the hemodynamic parameters and lower incidence of bradycardia. As shown by lower VAS scores of pain, lower rescue analgesia doses, and longer first analgesic recall, ephedrine had a strong analgesic effect.

Sex differences in PD-L1-induced analgesia in paclitaxel-induced peripheral neuropathy mice depend onTRPV1-based inhibition of CGRP.

Paclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel-induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions. Male and female C57BL/6 mice (5-6 weeks and 12 months, weighing 18-30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD-L1. On day 14 after PTX administration, PD-L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno-associated virus 9 (AAV9)-Trpv1-RNAi (5 μL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD-L1, TRPV1 and CGRP were measured via Western blotting, RT-PCR, and immunofluorescence staining. The levels of TNF-α and IL-1β were measured via RT-PCR. TRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX-induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD-L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717-fold and 2.303-fold, respectively. PD-L1 and CGRP were partly co-localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD-L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9-mediated spinal cord specific decreased TRPV1 expression. PTX-induced nociceptive behaviors and the analgesic effect of PD-L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex-specific therapeutic approaches.

Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment

Opioids are the gold standard for the treatment of chronic pain but are limited by adverse side effects. In our earlier work, we showed that Heat shock protein 90 (Hsp90) has a crucial role in regulating opioid signaling in spinal cord; Hsp90 inhibition in spinal cord enhances opioid anti-nociception. Building on these findings, we injected the non-selective Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice, showing that morphine anti-nociceptive potency was boosted by 1.9–3.5-fold in acute and chronic pain models. At the same time, tolerance was reduced from 21-fold to 2.9 fold and established tolerance was rescued, while the potency of constipation and reward was unchanged. These results demonstrate that spinal Hsp90 inhibition can improve the therapeutic index of morphine. However, we also found that systemic non-selective Hsp90 inhibition blocked opioid pain relief. To avoid this effect, we used selective small molecule inhibitors and CRISPR gene editing to identify 3 Hsp90 isoforms active in spinal cord (Hsp90α, Hsp90β, and Grp94) while only Hsp90α was active in brain. We thus hypothesized that a systemically delivered selective inhibitor to Hsp90β or Grp94 could selectively inhibit spinal cord Hsp90 activity, resulting in enhanced opioid therapy. We tested this hypothesis using intravenous delivery of KUNB106 (Hsp90β) and KUNG65 (Grp94), showing that both drugs enhanced morphine anti-nociceptive potency while rescuing tolerance. Together, these results suggest that selective inhibition of spinal cord Hsp90 isoforms is a novel, translationally feasible strategy to improve the therapeutic index of opioids.

Effect of Intraperitoneal Instillation of Dexmedetomidine With Local Anesthetics in Laparoscopic Cholecystectomy: A Systematic Review and Meta-analysis of Randomized Trials.

Dexmedetomidine (DEX) can strengthen the analgesic effects of local anesthetics (LAs) when used as an adjuvant through intrathecal, perineural, and intraperitoneal routes. Many studies have used intraperitoneal instillation of DEX with LAs in laparoscopic cholecystectomy (LC) to relieve postoperative pain. We performed a systematic review and meta-analysis to synthesize evidence of the efficacy and safety of intraperitoneal instillation of DEX as an adjuvant of LAs in patients undergoing LC. A comprehensive literature search of the MEDLINE, PubMed, EMBASE, and Cochrane Library databases was performed to identify randomized controlled trials in which patients received intraperitoneal instillation of DEX combined with LAs during LC. A meta-analysis and sensitivity analysis of the results were conducted. We also performed a subgroup analysis to investigate the source of heterogeneity. The Egger test was used to check for publication bias. Eleven randomized controlled trials involving 890 patients were analyzed. We found that the addition of DEX to LAs significantly decreased pain scores at six postoperative time points (0.5, 1, 2, 4, 12, and 24 h) and significantly prolonged the time to the first analgesic request by patients. In addition, 24-hour postoperative analgesic consumption was decreased in the experimental group, and no significant difference in the incidence of nausea and vomiting was observed. Our findings indicate that intraperitoneal instillation of DEX with LAs can reduce postoperative pain and prolong the time to first request analgesia after LC.

Clinical Studies that Initiated the Use of Spinal Opioids for the Treatment of Pain: A New Approach to Historical Review.

Opioids administered into the spinal space by intrathecal or epidural routes can provide potent and prolonged selective analgesia. Compared to the systemic administration of opioids, spinal administration can bring about analgesia with fewer central and systemic adverse effects. For the past 40 years, spinal opioid analgesia has achieved great popularity in various fields of pain treatment. The aim of this work is to identify clinical studies that initiated the use of spinal opioids for the treatment of pain. To determine the historical role of each of the review's studies, we used the combination of two factors: the study priority in terms of the time of its publication and the degree of its acknowledgement in the form of citation impact. The date of publication was regarded as the primary factor, but only if the count of citations indicated a sufficient acknowledgement by the other authors. The citation impact was assessed as the initial citation count - for a period of five years after the year of article publication - and the total count. Analysis of the related data shows that the clinical studies initiating the use of spinal opioids for the treatment of pain belong to two groups of authors - Wang et al. and Behar et al. Both studies were published in 1979 and described delivery of morphine into the spinal space, although the techniques of administration were different: Wang et al. injected morphine intrathecally, Behar et al. administered morphine epidurally. The response to these studies was overwhelming - close to a dozen reports on this topic were published in 1979 and more than a hundred - in 1980-1981. The total citation response to the Wang et al. article reached 699, and that to Behar et al. - 518. Two earlier records (1900-1901) of the use of intrathecal morphine, by Nicolae Racoviceanu-Pitesti and Otojiro Kitagawa, found no following in medical literature for more than three quarters of a century.

Concept for intrathecal delivery of brain recording and stimulation device.

Neurological disorders are common, yet many neurological diseases don't have efficacious treatments. The protected nature of the brain both anatomically and physiologically through the blood brain barrier (BBB) make it exceptionally hard to access. Recent advancements in interventional approaches, like the Stentrode™, have opened the possibility of using the cerebral vasculature as a highway for minimally invasive therapeutic delivery to the brain. Despite the immense success that the Stentrode™ has faced recently, it is limited to major cerebral vasculature and exists outside the BBB, making drug eluting configurations largely ineffective. The present study seeks to identify a separate anatomical pathway for therapeutic delivery to the deep brain using the ventricular system. The intrathecal route, in which drug pumps and spinal cord stimulators are delivered through a lumbar puncture, is a well-established route for delivering therapies to the spinal cord as high as C1. The present study identifies an extension of this anatomical pathway through the foramen of Magendie and into the brains ventricular system. To test this pathway, a narrow self-expanding electrical recording device was manufactured and its potential to navigate the ventricular system was assessed on human anatomical brain samples. While the results of this paper are largely preliminary and a substantial amount of safety and efficacy data is needed, this paper identifies an important anatomical pathway for delivery of therapeutic and diagnostics tools to the brain that is minimally invasive, can access limbic structures, and is within the BBB.

Biodistribution of Radioactively Labeled Splice Modulating Antisense Oligonucleotides After Intracerebroventricular and Intrathecal Injection in Mice.

Antisense oligonucleotides (AONs) are promising therapeutic candidates, especially for neurological diseases. Intracerebroventricular (ICV) injection is the predominant route of administration in mouse studies, while in clinical trials, intrathecal (IT) administration is mostly used. There is little knowledge on the differences in distribution of these injection methods within the same species over time. In this study, we compared the distribution of splice-switching AONs targeting exon 15 of amyloid precursor protein pre-mRNA injected via the ICV and IT route in mice. The AON was labeled with radioactive indium-111 and mice were imaged using single-photon emission computed tomography (SPECT) 0, 4, 24, 48, 72, and 96 h after injection. In vivo SPECT imaging showed 111In-AON activity diffused throughout the central nervous system (CNS) in the first hours after injection. The 111In-AON activity in the CNS persisted over the course of 4 days, while signal in the kidneys rapidly decreased. Postmortem counting in different organs and tissues showed very similar distribution of 111In-AON activity throughout the body, while the signal in the different brain regions was higher with ICV injection. Overall, IT and ICV injection have very similar distribution patterns in the mouse, but ICV injection is much more effective in reaching the brain.

Intracranial Gene Delivery Mediated by Albumin-Based Nanobubbles and Low-Frequency Ultrasound

Research in the field of high-intensity focused ultrasound (HIFU) for intracranial gene therapy has greatly progressed over the years. However, limitations of conventional HIFU still remain. That is, genes are required to cross the blood-brain barrier (BBB) in order to reach the neurological disordered lesion. In this study, we introduce a novel direct intracranial gene delivery method, bypassing the BBB using human serum albumin-based nanobubbles (NBs) injected through a less invasive intrathecal route via lumbar puncture, followed by intracranial irradiation with low-frequency ultrasound (LoFreqUS). Focusing on both plasmid DNA (pDNA) and messenger RNA (mRNA), our approach utilizes LoFreqUS for deeper tissue acoustic penetration and enhancing gene transfer efficiency. This drug delivery method could be dubbed as the “Spinal Back-Door Approach”, an alternative to the “front door” BBB opening method. Experiments showed that NBs effectively responded to LoFreqUS, significantly improving gene transfer in vitro using U-87 MG cell lines. In vivo experiments in mice demonstrated significantly increased gene expression with pDNA; however, we were unable to obtain conclusive results using mRNA. This novel technique, combining albumin-based NBs and LoFreqUS offers a promising, efficient, targeted, and non-invasive solution for central nervous system gene therapy, potentially transforming the treatment landscape for neurological disorders.

Intrathecal delivery of a bicistronic AAV9 vector expressing β-hexosaminidase A corrects Sandhoff disease in a murine model: A dosage study

The pathological accumulation of GM2 ganglioside associated with Tay-Sachs disease (TSD) and Sandhoff disease (SD) occurs in individuals who possess mutant forms of the heterodimer β-hexosaminidase A (Hex A) because of mutation of the HEXA and HEXB genes, respectively. With a lack of approved therapies, patients experience rapid neurological decline resulting in early death. A novel bicistronic vector carrying both HEXA and HEXB previously demonstrated promising results in mouse models of SD following neonatal intravenous administration, including significant reduction in GM2 accumulation, increased levels of Hex A, and a 2-fold extension of survival. The aim of the present study was to identify an optimal dose of the bicistronic vector in 6-week-old SD mice by an intrathecal route of administration along with transient immunosuppression, to inform possible clinical translation. Three doses of the bicistronic vector were tested: 2.5e11, 1.25e11, and 0.625e11 vector genomes per mouse. The highest dose provided the greatest increase in biochemical and behavioral parameters, such that treated mice lived to a median age of 56weeks (>3 times the lifespan of the SD controls). These results have direct implications in deciding a human equivalent dose for TSD/SD and have informed the approval of a clinical trial application (NCT04798235).

Unlocking the Intrathecal Route: A Comprehensive Review

The intrathecal route of administration, which involves the direct delivery of therapeutic agents into the cerebrospinal fluid (CSF) via lumbar or cervical puncture, has gained increasing prominence in the field of healthcare and neurology. This review provides a comprehensive overview of the intrathecal route as a mode of drug delivery, focusing on its applications, advantages, challenges, and safety considerations. Intrathecal administration offers a unique advantage by bypassing the blood-brain barrier, allowing for precise and targeted drug delivery to the central nervous system. This approach has proven effective in managing a variety of conditions, including chronic pain, spasticity, infections, and neoplastic diseases. Furthermore, it has shown promise in the treatment of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis. Despite its potential benefits, intrathecal therapy presents challenges related to its invasive nature, the risk of infection, and the need for specialized equipment and personnel. Careful patient selection and ongoing monitoring are essential to mitigate these risks. In addition, ongoing research is focused on improving drug formulations and delivery techniques to enhance the safety and efficacy of intrathecal therapy1 . This review consolidates key findings from recent studies, clinical trials, and expert opinions, shedding light on the current state of intrathecal administration and its evolving role in medical practice. By exploring the latest advancements and addressing critical considerations, this review aims to provide valuable insights to healthcare professionals, researchers, and clinicians working with intrathecal drug delivery. Key words: Intrathecal therapy, Cerebrospinal fluid (CSF), Drug delivery, Neurological disorders, Central nervous system, Blood-brain barrier.

Refinement of intrathecal catheter design to enhance neuraxial distribution

BackgroundDelivery of therapeutics via indwelling intrathecal catheters is highly efficacious for targeting of pain, spasticity, neuraxial cancer and neurodegenerative disorders. However, current catheter designs have some major limitations. Given limited CSF flow, fixed intrathecal volume and the large distance of the rostro-caudal spinal axis, current intrathecal delivery routes fail to achieve adequate drug distribution. Additionally open catheter systems are plagued with cellular ingrowth and debris accumulation if used intermittently. New method1.We addressed these issues by designing a new catheter that includes micro-valves2.Micro-valves distributed along the catheter open simultaneously upon adequate local transmural pressure, which is evenly distributed along the catheter fluid column.3.Buildup of transmural pressure, prior to microvalve opening, results in increased solute exit velocity.4.Micro-valves are closed when not in use, preventing anything from entering the system, and allowing for long-term intermittent use. Results/comparison with existing method(s)High speed imaging showed micro-valve catheters greatly increase fluid exit velocities compared to typical open-ended catheters, which prevents pooling of injectate proximal to the opening. When implanted intrathecally in rats, small injection volumes (7.5 μL) of dye or AAV9-RFP, resulted in an even rostro-caudal distribution along the spinal axis and robust transfection of neurons from cervical to lumbar dorsal root ganglia. In contrast, such injections with an open-ended catheter resulted in localized distribution and transfection proximal to the delivery site.Our poly micro-valve catheter design resulted in equivalent transfection rates of cervical DRG neurons using 100x lower titer of AAV9-RFP. Unlike open port catheters, no debris accumulation was observed in the lumen of implanted catheters, showing potential for long-term intermittent use. ConclusionsThis catheter platform, suitable for small animal models is easily scalable for human use and addresses many of the problems observed with common catheter systems.

Continuous Intrathecal Medication Delivery With the IRRA flow Catheter: Pearls and Early Experience.

Intrathecal (IT) medications are routinely introduced through catheterization of the intraventricular space or subarachnoid space. There has been sporadic use of IT medications delivered directly to the ventricle either by intermittent injection through an external ventricular drain (EVD) or by an Ommaya reservoir with a ventricular catheter. IT medication delivery through EVD has many drawbacks, including the necessary opening of a sterile system, delivery of medication in a bolus form, and requirements to clamp the EVD after medication delivery. Despite these setbacks, IT medications delivered through EVD have been used across a wide range of applications, including antibiotic delivery treatment of vasospasm with nicardipine and delivery of tissue plasminogen activator. We used a newly developed active fluid exchange device to treat various severe conditions involved in the cerebral ventricles. Here, we present our treatment protocols and advice on the techniques related to successful active fluid exchange therapy. Seventy patients have been treated with our system with various conditions, including subarachnoid hemorrhage, intraventricular hemorrhage, ventriculitis, and cerebral abscess. Total complication rate was 14% with only 1 catheter occlusion and low rates of hemorrhage, infection, and spinal fluid leak. Current continuous IT medication dosages and protocols are based on reports and consensus statements evaluating intermittent instillation of medication boluses. The pharmacokinetics of continuous dosing and the therapeutic and safety profiles of the medications need to be studied in a prospective manner to evaluate the true optimal dosing standards. Furthermore, the ability to deliver continuous, sterile medications directly through an IT route will open new avenues of pharmacotherapy that were previously closed. This report serves as a basic guide for the safe and effective use of the IRRA flow active fluid exchange catheter to deliver IT medications.

Tetanus, an infectious disease still topical in Lome (Togo)

Tetanus still remains a public health problem in Togo despite the existence of the Expanded Program on Immunization. A retrospective and descriptive cohort study was performed from January 1, 2008 to December 31, 2018 in the infectious and tropical diseases department of Sylvanus Olympio teaching hospital of Lome (Togo) on tetanus cases. We included 208 tetanus cases accounting for 6.5% of the whole hospitalizations in the infectious and tropical diseases department at this hospital. The median age of the patients was 23 [13-38 years] with male predominance (81.2%). The patients were workers (63.5%) and came mainly from urban areas (65.9%). Tetanus vaccination was only up to date in 9.3% of patients. Gateways were dominated by skin wounds (66.8%). Antitetanus serum was administered in 191 patients (91.8%) mainly through intrathecal route (189 patients (91.1%)). Complications were marked by superinfection of the wound (n=8), septic shock (n=3), acute respiratory failure and skin necrosis in 1 case respectively. The lethality was 27.4%. The morbidity of tetanus, in particular juvenile morbidity, remains high with significant lethality. It is therefore important to place particular emphasis on the vaccine booster component.

Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid.

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

Cell-Penetrating Peptides as Valuable Tools for Nose-to-Brain Delivery of Biological Drugs.

Due to their high specificity toward the target and their low toxicity, biological drugs have been successfully employed in a wide range of therapeutic areas. It is yet to be mentioned that biologics exhibit unfavorable pharmacokinetic properties, are susceptible to degradation by endogenous enzymes, and cannot penetrate biological barriers such as the blood-brain barrier (i.e., the major impediment to reaching the central nervous system (CNS)). Attempts to overcome these issues have been made by exploiting the intracerebroventricular and intrathecal routes of administration. The invasiveness and impracticality of these procedures has, however, prompted the development of novel drug delivery strategies including the intranasal route of administration. This represents a non-invasive way to achieve the CNS, reducing systemic exposure. Nonetheless, biotherapeutics strive to penetrate the nasal epithelium, raising the possibility that direct delivery to the nervous system may not be straightforward. To maximize the advantages of the intranasal route, new approaches have been proposed including the use of cell-penetrating peptides (CPPs) and CPP-functionalized nanosystems. This review aims at describing the most impactful attempts in using CPPs as carriers for the nose-to-brain delivery of biologics by analyzing their positive and negative aspects.

Device-associated Meningitis due to Elizabethkingia meningoseptica: A Therapeutic Challenge.

To the Editors: Elizabethkingia meningoseptica causes life-threatening infections in humans, especially in immunocompromised patients and infants with low birth weights. It is one of the main causes of meningitis in pediatric and immunocompromised patients in the context of nosocomial diseases associated with devices and is also related to low-birth-weight infants and prematurity1 Due to their resistance to many commonly used antibiotics (beta-lactams, carbapenemics, aminoglycosides, etc.), clinicians face treatment challenges.2 There are currently few publications on pediatric cases regarding E. meningoseptica device-associated meningitis with breakthrough resistance to trimethoprim-sulfamethoxazole (TMP/SMX) while treatment with dual intravenous (IV) therapy with TMP/SMX and high-dose ciprofloxacin requiring intraventricular ciprofloxacin for eradication. This letter is written to describe a case that posed a diagnostic challenge in our center. A 1-month-old female patient with hydrocephalus secondary to a history of myelomeningocele that required correction at birth with a ventriculoperitoneal (VP) shunt system presented during her prolonged hospitalization with device-associated meningitis due to E. meningoseptica initially susceptible to TMP/SMX MIC <16 µg/L, follow-up cerebrospinal fluid (CSF) cultures remained positive for the same pathogen with TMP/SMX breakthrough resistance acquired (MIC > 64 µg/L) (Table 1). Different antibiotics were tested in vitro and showed resistance to vancomycin, minocycline, and rifampicin, maintaining only susceptibility to ciprofloxacin without achieving eradication with systemic dual high-dose IV therapy. TABLE 1. - Cerebrospinal Fluid Culture Analyzed in Vitek2 System (Biomérieux) Initial Control Antibiotic Value/Interpretation Value/Interpretation Amikacin ≥64 µg/mL (R) ≥64 µg/mL (R) Aztreonam ≥64 µg/mL (R)) Cefazolin ≥64 µg/mL (R) Cefepime ≥64 µg/mL (R) ≥64 µg/mL (R) Ceftazidime ≥64 µg/mL (R) ≥64 µg/mL (R) Ceftriaxone ≥64 µg/mL (R) Ciprofloxacin ≥1 µg/mL (Susceptible) ≥1 µg/mL (S) Gentamicin ≥16 µg/mL (Resistant) ≥16 µg/mL (R) Meropenem ≥64 µg/mL (Resistant) ≥64 µg/mL (R) Piperacillin/tazobactam 32 µg/mL (Susceptible) ≥128 µg/mL (R) Tigecycline 1 µg/mL (S) ≥8 µg/mL (R) Trimethoprim/sulfamethoxazole (TMP/SMX) 40 µg/mL (S) ≥320 µg/mL (R) Colistin ≥16 µg/mL (R) Doripenem ≥8 µg/mL (R) Imipenem ≥16 µg/mL (R) (R), resistant; (S), susceptible. Intraventricular antimicrobial therapy with ciprofloxacin was proposed based on a case report in the literature: 21 days of systemic treatment combined with Intrathecal therapy, and another 21 days of systemic therapy alone. Negative CSF cultures were obtained after 6 days of dual therapy plus intraventricular ciprofloxacin with clinical improvement in the patient and replacement of the VP shunt. Although recent literature suggests that antibiotics such as fluoroquinolones can achieve good concentrations in the CSF fluid after IV administration and do not suggest their use in intraventricular or intrathecal routes,3 and that the FDA has not approved any antimicrobial agent for intraventricular use,3,4 when therapeutic options are limited due to multidrug-resistant pathogens in central nervous system infections, intraventricular/intrathecal antibiotic therapy with fluoroquinolones appears to be a viable option in the absence of other available treatments. More studies are required, particularly in cases, such as the one presented for antibiotics that theoretically achieve adequate CSF concentrations when only IV route is used.

A systematic review and meta-analysis of intrathecal versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

2034 Background: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous (IV), or intrathecally (IT) administered HER2-targeted therapy regimens for patients with HER2+ BCLM. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BCLM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (IT or IV), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (TDXd). The primary endpoint was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. To assess differences between groups, shared frailty Cox regression models were used to estimate the hazard ratio (HR), 95% confidence interval (CI) and p-value. Results: 7780 abstracts were screened, identifying 44 publications with 200 patients, corresponding to 257 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable (OS: HR=0.9, 95% CI: 0.64-1.4, P=0.76; PFS: HR=0.8, 95% CI: 0.57-1.2, P=0.35) and multivariable (OS: HR=1.4, 95% CI: 0.68-3.1, P=0.4; PFS: HR=0.8, 95% CI: 0.41-1.7, P=0.6) analyses, we observed no significant difference between IT, oral or IV administration of HER2-targeted therapy. Meanwhile, ECOG performance status remained independently associated with prolonged OS (HR=2.2, 95% CI: 1.5-3.2, P&lt;0.001) and PFS (HR=2.2, 95% CI: 1.5-3.2, P&lt;0.001 and HR=1.9, 95% CI: 1.4-2.8, P&lt;0.001) in the final multivariable model. ECOG status was not associated with route of trastuzumab delivery (P&gt;0.40). Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors (OS: P=0.647; PFS: P=0.983). In a cohort of 7 patients, TDXd demonstrated improved OS compared to other HER2-targeted therapies and compared to T-DM1 (P&lt;0.05). Conclusions: The results of this meta-analysis suggest that IT administration of HER2-targeted therapy for patients with HER2+ BCLM confers no additional benefit over oral and/or IV treatment regimens. We also present the first evidence supporting the efficacy of TDXd compared to alternative strategies for this patient population. Although the number of patients receiving TDXd in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

CNS RELAPSE OF DIFFUSE LARGE B‐CELL LYMPHOMA AND ROLE OF UPFRONT PROPHYLAXIS: A 10‐YEAR SINGLE CENTER EXPERIENCE

Introduction: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare event, occurring in about 5% of patients (pts) and correlating with a very dismal prognosis. Much debate has surrounded the use of strategies to avert CNS disease recurrence. Nowadays, CNS prophylaxis is mostly based on high-dose intravenous (iv) methotrexate (HD-MTX), but its effectiveness is controversial. Our study focuses on pts with CNS relapse of DLBCL in order to evaluate their clinical and biological features, the validity of known prognostic scores, the efficacy of CNS prophylaxis, prognosis and treatment at the time of relapse. Methods: All pts with DLBCL diagnosed between January 2010 and December 2021 at AOU Città della Salute e della Scienza di Torino and treated with curative intent were selected: 498 cases with at least 12 months of follow-up were identified. Pts with primary mediastinal lymphoma, primary testicular lymphoma or CNS disease at diagnosis were excluded. Results: The case series included 406 pts. Mean age was 67 years, 56/400 had ECOG PS ≥ 2 (14%), 231/400 elevated LDH levels (58%), 251/404 were stage IV (62%), 192/374 IPI score ≥ 3 (51%), 189/373 CNS-IPI 2–3 (51%), 91/373 CNS-IPI 4–6 (24%). 95/397 pts received CNS prophylaxis (24%): 59 by intrathecal (IT) route only (15%) (n 26 CNS-IPI 2-3; n 29 CNS-IPI 4-6), 25 by iv MTX only (6%) (n 17 HD-MTX ≥3 g/mq; n 6 CNS-IPI 2-3; n 16 CNS-IPI 4-6), and 11 by combined route (3%) (n 5 CNS-IPI 2-3, n 6 CNS-IPI 3–6). 12 pts experienced CNS relapse; 8/12 exclusively CNS and 4/12 along with systemic recurrence. The cumulative incidence at 3 years was 2.8%. In univariate analysis CNS relapse risk was significantly influenced by ECOG PS and elevated LDH levels, while the use of prophylaxis was not shown to impact the risk of CNS recurrence. However, none of the pts who received systemic MTX prophylaxis had subsequent CNS disease, while 2/59 pts who received exclusive IT prophylaxis had CNS relapse with an incidence superimposable to the whole cohort (3.3%). In multivariate analysis, only ECOG PS confirmed significant correlation with the risk of such disease recurrence (Figure 1). With a mean follow-up of 36 months, the 3-year overall survival for pts with SNC recurrence was 30%. Encore Abstract—previously submitted to EHA 2023 Keyword: aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Epidural and Intrathecal Drug Delivery in Rats and Mice for Experimental Research: Fundamental Concepts, Techniques, Precaution, and Application.

Epidural and intrathecal routes are the most effective drug administration methods for pain management in clinical and experimental medicine to achieve quick results, reduce required drug dosages, and overcome the adverse effects associated with the oral and parenteral routes. Beyond pain management with analgesics, the intrathecal route is more widely used for stem cell therapy, gene therapy, insulin delivery, protein therapy, and drug therapy with agonist, antagonist, or antibiotic drugs in experimental medicine. However, clear information regarding intrathecal and epidural drug delivery in rats and mice is lacking, despite differences from human medicine in terms of anatomical space and proximity to the route of entry. In this study, we discussed and compared the anatomical locations of the epidural and intrathecal spaces, cerebrospinal fluid volume, dorsal root ganglion, techniques and challenges of epidural and intrathecal injections, dosage and volume of drugs, needle and catheter sizes, and the purpose and applications of these two routes in different disease models in rats and mice. We also described intrathecal injection in relation to the dorsal root ganglion. The accumulated information about the epidural and intrathecal delivery routes could contribute to better safety, quality, and reliability in experimental research.