Poor Central Nervous System Penetration Research Articles

Management of a human immunodeficiency virus case with discordant antiviral drug resistance profiles in cerebrospinal fluid compared with plasma: a case report

BackgroundHuman immunodeficiency virus-1-associated neurocognitive disorder is a known complication in individuals treated with antiretroviral therapy. Cerebrospinal fluid escape, which is defined as discordant higher cerebrospinal fluid viremia than plasma, may occur in antiretroviral therapy-experienced individuals. Different cerebrospinal fluid versus plasma mutation patterns have been observed in individuals with cerebrospinal fluid escape.Case presentationA 46-year-old adult African male with human immunodeficiency virus-1 infection and acquired immunodeficiency syndrome based on cerebral toxoplasmosis and a chronic hepatitis B virus infection developed cerebrospinal fluid escape. A different human immunodeficiency virus-1 genotypic drug resistance profile was observed in plasma compared with cerebrospinal fluid. Brain biopsy and cerebral magnetic resonance imaging indicated the development of human immunodeficiency virus encephalopathy. A discordant protease inhibitor mutation/wild-type T74PT in plasma but not in cerebrospinal fluid indicated poor central nervous system penetration due to the selective pressure of drug therapy. An intensified antiretroviral therapy regimen including dolutegravir with good central nervous system penetration improved conditions.ConclusionsThis case shows the importance of measuring human immunodeficiency virus drug resistance in cerebrospinal fluid, which might differ from resistance detected in plasma samples and target effective antiretroviral therapy treatment accordingly.

Application of a high-resolution in vitro human MDR1-MDCK assay and in vivo studies in preclinical species to improve prediction of CNS drug penetration.

P‐glycoprotein (P‐gp, MDR1) is expressed at the blood–brain barrier (BBB) and restricts penetration of its substrates into the central nervous system (CNS). In vitro MDR1 assays are frequently used to predict the in vivo relevance of MDR1‐mediated efflux at the BBB. It has been well established that drug candidates with high MDR1 efflux ratios (ERs) display poor CNS penetration. Following a comparison of MDR1 transporter function between the MDR1‐MDCKI cell line from National Institutes of Health (NIH) and our internal MDR1‐MDCKII cell line, the former was found to provide better predictions of in vivo brain penetration than our in‐house MDR1‐MDCKII cell line. In particular, the NIH MDR1 assay has an improved sensitivity to differentiate the compounds with ERs of <3 in our internal cell line and is able to reduce the risk of false negatives. A better correlation between NIH MDR1 ERs and brain penetration in rat and non‐human primate (NHP) was demonstrated. Additionally, a comparison of brain penetration time course of MDR1 substrates and an MDR1 non‐substrate in NHP demonstrated that MDR1 interaction can delay the time to equilibrium of drug concentration in the brain with plasma. It is recommended to select highly permeable compounds without MDR1 interaction for rapid brain penetration to produce the maximal pharmacological effect in the CNS with a quicker onset.

Successful, Combined Long-term Treatment of Cerebral Candidiasis and Aspergillosis in a Liver Transplant Recipient: A Case Report

Invasive fungal infections, of which the most common are candidiasis and aspergillosis, are among the most important and fatal complications in solid organ transplantation. They continue to be a significant cause of morbidity and mortality in patients with involvement of the central nervous system (CNS) because of the poor CNS penetration of antifungal medications. Voriconazole yields fungicidal drug concentrations in the CNS, but its use is limited in solid organ transplant patients because of its metabolic interactions with immunosuppression. Here we report a case of invasive fungal infection in the CNS after an emergency liver transplantation due to hepatitis B virus-related acute liver failure. The patient was managed successfully with a long-term conservative medical treatment.

Central nervous system metastases and oligoprogression during treatment with tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer: how to treat and when?

Up to 70% of non-small cell lung cancer (NSCLC) patients develop central nervous system (CNS) metastases during the course of their disease, especially those with oncogenic drivers treated with a first-generation tyrosine kinase inhibitor (TKI), because of the relatively poor CNS penetration. CNS metastases are associated with a negative impact on quality of life and survival. As, with the introduction of newer generation TKIs, the survival rates are increasing in this particular population, treatment and/or prevention of CNS metastases becomes even more relevant and the TKI with the best CNS efficacy should be selected. Unfortunately, CNS efficacy data in clinical trials are not fully comparable. Furthermore, oligoprogression to the brain without extracranial progression regularly occurs in the oncogenic driver population and both local therapy and switch of systemic therapy are possible treatment options. However, the best order of systemic and local therapy is still not precisely known. In this narrative review, we will summarize incidence and treatment of CNS metastases in oncogene driven NSCLC, including the optimal treatment of CNS oligometastatic disease (synchronous as well as oligoprogressive).

New generation anaplastic lymphoma kinase inhibitors.

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3-7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting.

Characteristics and outcomes of non-Hodgkin\u2019s lymphoma patients with leptomeningeal metastases

BackgroundLeptomeningeal metastasis is an uncommon but devastating complication. The incidence of non-Hodgkin’s lymphoma has been increasing in recent decades, due to the poor central nervous system penetration of drugs and the prolonged overall survival of patients, leptomeningeal metastases has gradually increased over time. Patients with leptomeningeal metastases have short survival durations and poor quality of life; there are few studies about non-Hodgkin’s lymphoma with leptomeningeal metastases. We investigated characteristics and outcomes of non-Hodgkin’s lymphoma patients with leptomeningeal metastases.MethodsThis study included 27 non-Hodgkin’s lymphoma patients with leptomeningeal metastases diagnosed at Tianjin Medical University Cancer Institute and Hospital between 2013 and 2016. Statistical analysis was performed to investigate the overall survival of non-Hodgkin’s lymphoma with leptomeningeal metastases.ResultsDiffuse large B cell lymphoma was the most common cancer subtype (21/27, 78%), and more than half of the patients showed extranodal involvement (18/27, 67%). Survival analysis has shown extranodal involvement (P = 0.0205), International Prognostic Index (P = 0.0112), performance status (P < 0.0001), parenchymal involvement (P = 0.0330) and received radiotherapy (P = 0.0056) were predictive factors of prognosis for these patients with leptomeningeal metastases. Cox regression analysis has shown patients with concurrent parenchymal involvement and received radiotherapy are correlated with good prognosis.ConclusionsGiven the small number of patients who were included, this study exhibited limitations with respect to analytical power and the random selection of patients. Nevertheless, this investigation revealed characteristics of non-Hodgkin’s lymphoma patients with leptomeningeal metastases and suggested that such patients could benefit from multimodal therapy.

TRTH-18. COMBINED TOPOTECAN AND CARBOPLATIN THERAPY FOR DIPG SUPPRESSES CELL GROWTH IN VITRO AND IS WELL TOLERATED WHEN DELIVERED BY CONVECTION ENHANCED DELIVERY IN VIVO

AbstractDespite clinical advances, diffuse intrinsic pontine glioma (DIPG) remains universally fatal and urgently requires new treatment modalities to improve prognosis. Topotecan and carboplatin have formed treatment regimes for pediatric cancers as single agents with limited success. Both drugs have poor central nervous system penetration which may explain the lack of efficacy in the clinic when delivered systemically, furthermore, as single agents they have been administered to children with DIPG by convection enhanced delivery (CED) in early phase clinical trials and compassionate use programmes. Here, we describe the use of topotecan and carboplatin as combinatorial therapy for the treatment of DIPG in vitro and its tolerance when administered in vivo in a small animal model of intermittent CED. In this study, we assessed the in vitro cytotoxicity of combined topotecan and carboplatin in two ex vivo patient derived DIPG cell lines (SF7761 and SF8628). Combination therapy in vitro showed an additive effect on cell viability when compared to each single agent. Next, we determined the tolerance and toxicity of both drugs administered by CED using an implantable catheter system in juvenile wistar rats by clinical and neuropathological examination of infused brain 21 days after treatment. Results show that topotecan and carboplatin have an enhanced effect on DIPG cell viability in vitro when used in combination. This combination is currently being explored in a wider cohort of DIPG cell lines. In vivo assessment of sequential drug therapy in normal rat brain, shows this combination to be well tolerated and exhibited minimal CNS toxicity. Further work is required to see if this combination is effective in pre-clinical models of DIPG when administered by CED.

Quantitative Fluorescence Microscopy Measures Vascular Pore Size in Primary and Metastatic Brain Tumors.

Tumors residing in the central nervous system (CNS) compromise the blood-brain barrier (BBB) via increased vascular permeability, with the magnitude of changes dependent on the tumor type and location. Current studies determine penetrability of a cancer therapeutic by administering progressively larger molecules until cutoff is observed where little to no tumor accumulation occurs. However, decades-old experimental work and mathematical modeling document methods to calculate both the size of the vascular opening (pore) with solute permeability values. In this study, we updated this classic mathematical modeling approach with quantitative fluorescence microscopy in two preclinical tumor models, allowing simultaneous administration of multiple sized tracers to determine vascular permeability at a resolution of nearly one micron. We observed that three molecules ranging from 100 Da to 70 kDa permeated into a preclinical glioblastoma model at rates proportional to their diffusion in water. This suggests the solutes freely diffused from blood to glioma across vascular pores without steric restriction, which calculates to a pore size of >140 nm in diameter. In contrast, the calculated pore size of a brain metastasis of breast cancer was approximately 10-fold smaller than glioma vasculature. This difference explains why antibodies are effective against glioblastoma but generally fail in brain metastases of breast cancer. On the basis of our observations, we hypothesize that trastuzumab most likely fails in the treatment of brain metastases of breast cancer because of poor CNS penetration, while the similar sized antibody bevacizumab is effective in the same tumor type not because it penetrates the CNS degree better, but because it scavenges VEGF in the vascular compartment, which reduces edema and permeation. Cancer Res; 77(2); 238-46. ©2016 AACR.

Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases.

Neoplastic meningitis, a central nervous system (CNS) complication of cancer metastatic to the meninges and cerebrospinal fluid (CSF), is relevant to oncologists due to the impact of the disease on patient quality of life and survival rates. A review of the literature of articles published in English was conducted with regard to neoplastic meningitis. The incidence of neoplastic meningitis is increasing because patients with cancer are surviving longer in part because of the use of novel therapies with poor CNS penetration. Up to 5% of patients with solid tumors develop neoplastic meningitis during the disease course (breast cancer, lung cancer, and melanoma being the predominantly causative cancers). The rate of median survival in patients with untreated neoplastic meningitis is 1 to 2 months, although it can be as long as 5 months in some cases. Therapeutic options for the treatment of neoplastic meningitis include systemic therapy (cancer-specific, CNS-penetrating chemotherapy or targeted therapies), intra-CSF administration of chemotherapy (methotrexate, cytarabine, thiotepa) and CNS site-specific radiotherapy. Determining whom to treat with neoplastic meningitis remains challenging and, in part, relates to the extent of systemic disease, the neurological burden of disease, the available systemic therapies, and estimated rates of survival. The prognosis of neoplastic meningitis remains poor. The increasing use of novel, targeted therapies and immunotherapy in solid tumors and its impact on neoplastic meningitis remains to be determined and is an area of active research. Thus, well conducted trials are needed.

Intracranial activity of crizotinib: something to rely on?

Central nervous system (CNS) metastases remain a significant problem in the management of patients with ALK -rearranged non-small cell lung cancer (NSCLC). The frequency of CNS involvement in ALK -positive tumors is extremely high; it approaches 25% in treatment naive patients (1) and rises to 50% in patients treated with crizotinib (2,3). Crizotinib was previously reported to have only minor intracranial activity (4), with poor CNS penetration suggested as the underlying mechanism (5).

A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects

IntroductionWe conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. MethodsWe used stable isotope labeling kinetics (SILK-ApoE and SILK-Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C13-leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured. ResultsOral administration of bexarotene resulted in plasma levels of 1 to 2 μM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aβ peptides. DiscussionBexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aβ metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK-ApoE technology in measuring apoE kinetics in humans. Trial RegistrationThis trial is registered at clinicaltrials.gov (NCT02061878).

Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier.

BackgroundPoor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.MethodsTwenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.ResultsIn all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1–3 weeks before decreasing to baseline by 6 weeks.ConclusionsThe data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1–2 weeks after laser ablation and resolving by 4–6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.Trial RegistrationClinicalTrials.gov NCT01851733

Multiple Brain Hemorrhages on Presentation in a Patient with Accelerated Phase Chronic Myeloid Leukemia and Subsequent CNS Blast Crisis Despite Systemic Complete Molecular Response: Possible Role of CNS Bleed in Leukemia Proliferation

BackgroundChronic myeloid leukemia (CML) is a myeloproliferative disorder which can present in one of the three disease phases; chronic phase, accelerated phase or blast crisis. Central nervous system (CNS) as a site of extramedullary blast crisis in CML is rare and when affected, it usually occurs concurrently with systemic relapse. In extremely rare cases, the blast phase can affect the CNS without bone marrow involvement. Tyrosine kinase inhibitors (TKI) have become the treatment of choice for CML. However, there is poor penetration of CNS by some of these drugs or their active metabolites. Therefore, CNS may act as a sanctuary site for malignant cells in CML patients treated with TKIs. Here we describe an unusual case of CML who presented in accelerated-phase and multiple intracranial hemorrhages, and developed isolated CNS blast crisis after one year in spite of being in systemic remission.Clinical presentationA previously healthy 27-years-old male presented with10 days history of fatigue, abdominal pain and vomiting. He also complained of weight loss and low grade fever. Abdominal examination revealed huge splenomegaly. Investigations showed a white cell count of 538Í 109/l, hemoglobin 7.2 g/dl and platelets 47Í 109/l. Blood film showed marked leukocytosis with left shift, blasts 9% and thrombocytopenia, consistent with accelerated-phase CML. A bone marrow (BM) aspirate confirmed the above findings. Cytogenetic analysis of the bone marrow revealed100% Philadelphia chromosome and BCR/ABL positivity.After admission, the patient developed headache and vomiting. MRI of brain showed multiple small hemorrhages in the supratentorial and infratentorial compartments (figure). The patient was diagnosed with accelerated-phase CML and leukostasis. Emergency leukapheresis was performed (two sessions) resulting in a decrease in his WBC count.He was also started on hydroxurea, nilotinib and cytarabine 100mg, which led to improvement of his general condition and control of leukocyte count. He was continued on nilotinib 400 mg twice daily. He achieved complete molecular remission. Brain radiotherapy was considered because of brain hemorrhages and fear of lodging of blasts in the brain but not given because of opinion against it by expert colleagues. He was also referred for allogeneic stem-cell-transplant (SCT) because of the above concerns but not considered because of excellent response to nilotinib.After 1year of initial diagnosis, he was readmitted with headache and bilateral visional loss. Fundoscopy showed retinal hemorrhages. His CBC, BM biopsy and brain MRI were normal. Lumbar puncture showed markedly increased CSF pressure (55cm) and leukocyte infiltration with many blast cells (42%).Patient was diagnosed as CNS blast crisis of CML with BM in molecular remission. He was stareted on intrathecal chemotherapy (ITC), triple regime (methotrexate 6mg, ARA-C 30 mg, hydrocortisone 30 mg) and nilotinib was changed to dasatinib. His CSF cleared after multiple sessions of ITC; unfortunately, significant visual impairment persisted. Patient also received radiotherapy to the brain. He went on to have a sibling SCT and remains well 8 months post transplant.ConclusionWe describe a young male with accelerated-phase CML and multiple brain hemorrhages on presentation and subsequent isolated CNS blast crisis. We speculate that there was a possible link between the initial brain hemorrhages causing lodging and proliferation of blasts in the brain and subsequent isolated CNS blast crisis. We suggest that treatment options in such cases should include consideration of cranial irradiation initially, a tyrosine kinase inhibitor with better CNS penetration like dasatinib, and upfront allogeneic SCT as potential therapeutic modalities. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Central nervous system penetration of antiretroviral drugs: pharmacokinetic, pharmacodynamic and pharmacogenomic considerations.

The prevalence of HIV-associated neurocognitive disorder (HAND) is increasing despite the widespread use of combination antiretroviral therapy (ART). Initial reports suggest that the use of antiretrovirals with good central nervous system (CNS) penetration leads to better neurocognitive outcomes, but this has not yet been confirmed in a large cohort study or randomised controlled trial. There is emerging evidence that high CNS concentrations of some antiretrovirals are potentially neurotoxic and may be associated with the development of HAND. Antiretroviral CNS exposure is ideally determined by determining the ratio of cerebrospinal fluid (CSF):plasma area under the curve of unbound drug, but usually only total drug concentrations are measured and the ratio of CSF:plasma drug concentration is done at a single time point, which can result in misclassifying CNS penetration ability. Efavirenz was previously thought to have poor CNS penetration, measured by the CSF:plasma ratio (0.87%), but when unbound concentrations were measured it was found to have good CNS penetration (85%). Indinavir and efavirenz are the only antiretroviral drugs for which CNS area under the concentration-time curves using unbound plasma and CSF concentrations has been calculated. Patient data to support the contribution of blood-brain barrier transporter polymorphisms to CNS antiretroviral concentrations are currently limited and lack power to detect true associations. Correlations between CNS antiretroviral exposure and effect is multifaceted, and to accurately predict CNS effects there is a need to develop a sophisticated intra-brain pharmacokinetic-pharmacodynamic-pharmacogenetic model that includes transporters as well as the influence of HIV.

Convection-enhanced drug delivery for gliomas.

In spite of aggressive multi-modality treatments, patients diagnosed with anaplastic astrocytoma and glioblastoma continue to display poor median survival. The success of our current conventional and targeted chemotherapies are largely hindered by systemic- and neurotoxicity, as well as poor central nervous system (CNS) penetration. Interstitial drug administration via convection-enhanced delivery (CED) is an alternative that potentially overcomes systemic toxicities and CNS delivery issues by directly bypassing the blood–brain barrier (BBB). This novel approach not only allows for directed administration, but also allows for newer, tumor-selective agents, which would normally be excluded from the CNS due to molecular size alone. To date, randomized trials of CED therapy have yet to definitely show survival advantage as compared with today's standard of care, however, early studies appear to have been limited by “first generation” delivery techniques. Taking into consideration lessons learned from early trials along with decades of research, newer CED technologies and therapeutic agents are emerging, which are reviewed herein.

Pharmacokinetics of Antibacterial Agents in the CSF of Children and Adolescents

The adequate management of central nervous system (CNS) infections requires that antimicrobial agents penetrate the blood-brain barrier (BBB) and achieve concentrations in the CNS adequate for eradication of the infecting pathogen. This review details the currently available literature on the pharmacokinetics (PK) of antibacterials in the CNS of children. Clinical trials affirm that the physicochemical properties of a drug remain one of the most important factors dictating penetration of antimicrobial agents into the CNS, irrespective of the population being treated (i.e. small, lipophilic drugs with low protein binding exhibit the best translocation across the BBB). These same physicochemical characteristics determine the primary disposition pathways of the drug, and by extension the magnitude and duration of circulating drug concentrations in the plasma, a second major driving force behind achievable CNS drug concentrations. Notably, these disposition pathways can be expected to change during the normal process of growth and development. Finally, CNS drug penetration is influenced by the nature and extent of the infection (i.e. the presence of meningeal inflammation). Aminoglycosides have poor CNS penetration when administered intravenously. Intrathecal gentamicin has been studied in children with more promising results, often exceeding the minimum inhibitory concentration. There are very limited data with intrathecal tobramycin in children. However, in the few patients that have been studied, the CSF concentrations were highly variable. Penicillins generally have good CNS penetration. Aqueous penicillin G reaches greater concentrations than procaine or benzathine penicillin. Concentrations remain detectable for ≥ 12 h. Of the aminopenicillins, both ampicillin and parenteral amoxicillin reach adequate CNS concentrations; however, orally administered amoxicillin resulted in much lower concentrations. Nafcillin and piperacillin are the final two penicillins with pediatric data: their penetration is erratic at best. Cephalosporins vary greatly in regard to their CSF penetration. Few first- and second-generation cephalosporins are able to reach higher CSF concentrations. Cefuroxime is the only exception and is usually avoided due to its adverse effects and slower sterilization of the CSF than third-generation agents. Ceftriaxone, cefotaxime, ceftazidime, cefixime and cefepime have been studied in children and are all able to adequately penetrate the CSF. As with penicillins, concentrations are greatest in the presence of meningeal inflammation. Meropenem and imipenem are the only carbapenems with pediatric data. Imipenem reaches higher CSF concentrations; however, meropenem is preferred due to its lower incidence of seizures. Aztreonam has also demonstrated favorable penetration but only one study has been completed in children. Both chloramphenicol and sulfamethoxazole/trimethoprim (cotrimoxazole) penetrate into the CNS well; however, significant toxicities limit their use. The small size and minimal protein binding of fosfomycin contribute to its favorable CNS PK. Although rarely used, it achieves higher concentrations in the presence of inflammation and accumulation is possible. Linezolid reaches high CSF concentrations; however, more frequent dosing might be required in infants due to their increased elimination. Metronidazole also has very limited information but it demonstrated favorable results similar to adult data; CSF concentrations even exceeded plasma concentrations at certain time points. Rifampin (rifampicin) demonstrated good CNS penetration after oral administration. Vancomycin demonstrates poor CNS penetration after intravenous administration. When combined with intraventricular therapy, CNS concentrations are much greater. Of the antituberculosis agents, isoniazid, pyrazinamide and streptomycin have been studied in children. Isoniazid and pyrazinamide have favorable CSF penetration. Streptomycin appears to produce unpredictable CSF levels. No pediatric-specific data are available for clindamycin, daptomycin, macrolides, tetracyclines, and fluoroquinolones. Daptomycin, fluoroquinolones, and tetracyclines have demonstrated favorable CNS penetration in adults; however, data are limited due to their potential pediatric-specific toxicities and newness within the marketplace. Macrolides and clindamycin have demonstrated poor CNS penetration in adults and thus have not been studied in pediatrics.

Isolated central nervous system progression on Crizotinib

Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in this subset of NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.

Treatment of Refractory Cerebral Aspergillosis in a Liver Transplant Recipient With Voriconazole: Case Report and Review of the Literature

Extension of invasive aspergillosis to the central nervous system is associated with high mortality, in part because of poor central nervous system penetration of antifungal drugs. Voriconazole yields fungicidal drug concentrations within the central nervous system, but use of this drug is limited in liver transplant recipients because of hepatotoxicity and drug interactions. We reviewed medical records and antifungal treatment for all liver transplant recipients from 2007 to 2009 who had cerebral aspergillosis (Proven [2]; Probable [1]; Possible [1]) at week 3, 4, 6, and 12 after transplant. A 33-year-old white man underwent orthotopic liver transplant for acute liver failure that was caused by acetaminophen overdosage. Risk factors for fungal infection included major blood loss (8 L), prolonged surgery (9 h), and emergency revision transplant that was done because of nonfunctioning of the primary transplant at 48 hours. He developed postoperative aspergillus pneumonia and invasive aspergillosis of the kidneys, brain, and eye. Treatment with voriconazole and amphotericin B was successful, with moderate residual renal impairment. Voriconazole was effective and safe in the treatment of cerebral aspergillosis in this liver transplant recipient.

The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

Therapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity against Cryptococcus neoformans, the major causative agent of fungal meningitis. In in vitro assays, this neurotropic drug is fungicidal to all natural Cryptococcus isolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole against Cryptococcus. Importantly, consistent with our in vitro observations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency against Cryptococcus, sertraline is less effective against strains of Candida species and its interactions with fluconazole against Candida strains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection of Saccharomyces cerevisiae for altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation. In vitro translation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis.

Acinetobacter species meningitis in children: a case series from Karachi, Pakistan

Multidrug-resistant strains of Acinetobacter pose a serious therapeutic dilemma in hospital practice, particularly when they cause meningitis, as the few antimicrobial agents to which these isolates are susceptible have poor central nervous system (CNS) penetration. We retrospectively reviewed the clinical course and outcome of eight consecutive cases of meningitis due to Acinetobacter spp. in children ages 15 years or less, seen in a tertiary care medical center in Karachi, Pakistan. Of the eight cases of Acinetobacter meningitis, isolates from five patients were pan-resistant, and two were multidrug-resistant. A neurosurgical procedure was performed in five of eight patients followed by external ventricular drain insertion prior to the development of infection. Seven received intravenous (IV) polymyxin (mean; 12.8 days), while 5/8 also received intrathecal (IT) polymyxin (mean; 12.0 days). The mean length of hospitalization was 38.7 ± 19 days. All patients achieved cerebrospinal fluid (CSF) culture negativity by the end of treatment (mean; 5.4 days). Two patients died: one with pan-resistant Acinetobacter, and the second with a multi-drug resistant isolate. Post-neurosurgical multidrug-resistant and pan-resistant Acinetobacter meningitis can be successfully treated if appropriate antimicrobial therapy is instituted early. The role of IT polymyxin B administration alone versus combination therapy (IV and IT) needs further study.