Cerebral Spinal Fluid Cultures Research Articles

Cerebral Spinal Fluid Attenuates the Efficacy of Methotrexate Against Acute Lymphoblastic Leukemia Cells

The anti-folate methotrexate is a critical component of acute lymphoblastic leukemia (ALL) therapy. In addition to systemic administration, methotrexate is given intrathecally, or directly into the cerebral spinal fluid (CSF) via lumbar puncture, for central nervous system (CNS) leukemia treatment and prophylaxis. While IT methotrexate played a critical role in improving outcomes for ALL, CNS ALL relapse remains a major cause of treatment failure and therapy related morbidity. However, attempts to develop more efficacious and less toxic CNS ALL therapies have been largely unsuccessful and IT methotrexate has remained the standard of care for 60+ years. Based on our prior work showing that ALL cells are more poised to undergo apoptosis in nutrient poor CSF, we initially hypothesized that ALL chemosensitivity will be increased in CSF (Basile et al., 2020). While this was confirmed for several ALL drugs including cytarabine and anthracyclines, we strikingly found that methotrexate was significantly less efficacious and potent against ALL cells in CSF relative to standard tissue culture media or the more physiologically relevant human plasma-like media (HPLM). CSF also attenuated the sensitivity of ALL cells to other anti-folates including raltitrexed, trimetrexate, and pralatrexate. To define the mechanism(s) underlying this methotrexate resistance induced by CSF, we explored previously well-described mechanisms of methotrexate resistance in leukemia and other cancers. However, to date this work suggests that the molecular etiology of this CSF-induced relative methotrexate resistance is not entirely explained by diminished leukemia proliferation in CSF, altered methotrexate cellular influx/efflux, methotrexate metabolism, folate analog rescue, dysregulated expression of methotrexate target proteins, or compensation by nucleotide salvage pathways. To complement our work examining known mechanisms of methotrexate resistance, we also used a more discovery-based approach and compared the gene expression patterns of leukemia cells in CSF versus tissue culture media. Preliminary bioinformatic analyses identified dysregulation of multiple genes involved in the integrated stress response (ISR) and unfolded protein response (UPR) pathways in leukemia cells in CSF. The ISR/UPR are mechanisms by which cells adapt to diverse stress stimuli in the microenvironment, including potentially nutrient poor CSF which is low in glucose, proteins, and lipids relative to plasma. The hallmark event in this pathway is the phosphorylation of the translation initiation factor eIF2α, which inhibits global protein synthesis and enables the translation of selected genes that together enable cell survival. Supporting our gene expression data, ALL cells in CSF showed increased phosphorylation of eIF2α and a decrease in global protein synthesis. Intriguingly, it has been shown that activation of the UPR can divert metabolites from glycolysis to mitochondrial one-carbon metabolism with resulting resistance to anti-folates such as methotrexate (Reich et al., 2020). Accordingly, we next tested the effect of UPR/ISR activation on leukemia cell sensitivity to methotrexate in tissue culture media. Activation of the UPR with thapsigargin, a sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) inhibitor that triggers ER stress, increased methotrexate resistance in leukemia cells. Similarly, BtdCPU a small-molecule activator of heme regulated inhibitor (HRI) kinase that phosphorylates eIF2α and activates the ISR, also enhanced leukemia resistance to methotrexate. Building upon these results, current investigations are focused on testing the role of UPR/IST activation in methotrexate resistance in leukemia cells in CSF and modulating this pathway to overcome resistance. While methotrexate is clearly an efficacious and critical component of CNS leukemia treatment and prophylaxis, we have shown that CSF attenuates the overall efficacy of methotrexate in targeting leukemia cells. Moreover, we anticipate that our current work defining the mechanisms driving this resistance may identify novel approaches for maximizing methotrexate efficacy and more completely eradicating leukemia cells in CSF and the CNS. Finally, this work highlights the importance of critically evaluating even long-established standards of care.

Lung infection by Pseudomonas aeruginosa induces neuroinflammation and blood–brain barrier dysfunction in mice

BackgroundSevere lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood–brain barrier (BBB) leakage and behavioral impairment.MethodsLung infection in mice was induced by instilling Pseudomonas aeruginosa (PA) intratracheally. We determined bacterial colonization in tissue, microvascular leakage, expression of cytokines and leukocyte infiltration into the brain.ResultsLung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell–cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 h and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + CD45+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell–cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1β induced a significant reduction of barrier function coupled with tight junction (TJ) and adherens junction (AJ) diffusion and disorganization. Combined treatment with IL-1β and TNFα augmented the barrier injury.ConclusionsLung bacterial infection is associated with BBB disruption and behavioral changes, which are mediated by systemic cytokine release.

Penicillin-Susceptible Streptococcus pneumoniae Meningitis in Adults: Does the Ceftriaxone Dosing Matter?

The recommended empiric ceftriaxone dosing regimen for acute bacterial meningitis in adults is 2 g every 12 h. After penicillin-susceptible Streptococcus pneumoniae is isolated as a causative microorganism, the ceftriaxone dose may be continued or reduced to a single dose of 2 g every 24 h, per institutional preference. There is no clear guidance that indicates the superiority of one regimen over the other. The objective of this study was to evaluate the susceptibility of S. pneumoniae in the cerebral spinal fluid (CSF) of patients with meningitis and the relationship between ceftriaxone dose and clinical outcomes. We identified 52 patients with S. pneumoniae meningitis with positive CSF cultures who were treated at the University Hospital, Bern, Switzerland, over a 19-year period. We collected clinical and microbiological data for evaluation. Broth microdilution and Etest methods were performed to test penicillin and ceftriaxone susceptibility. All isolates were susceptible to ceftriaxone. Ceftriaxone was empirically used in 50 patients, with a starting dosing regimen of 2 g every 24 h in 15 patients and 2 g every 12 h in 35 patients. In 32 patients started on a twice-daily regimen (91%), doses were reduced to once daily after a median of 1.5 (95% CI 1-2) days. The overall in-hospital mortality was 15.4% (n = 8), and 45.7% of patients reported at least one sequela of meningitis at the last follow-up (median 375, 95% CI 189-1585 days). We found no statistical difference in outcome between the 2 g every 24 h and the 2 g every 12 h ceftriaxone dosing regimens. A ceftriaxone total daily dose of 2 g may be associated with similar outcomes to a 4 g total daily dose, provided that the causative organism is highly susceptible to ceftriaxone. The persistence of neurological and infection sequelae at the last follow-up underscores the need for optimal treatment of these complex infections.

Cryptococcal Cerebellitis In the Setting of Fingolimod Use for Multiple Sclerosis: Atypical Clinical Presentation of Dystonia and Imaging Finding Mimicking Subacute Ischemic Stroke (P1-10.004)

<h3>Objective:</h3> To describe a case of cryptococcal cerebellitis in a patient on Fingolimod with atypical findings of generalized dystonia and imaging findings mistaken for bilateral subacute cerebellar strokes. <h3>Background:</h3> Fingolimod is used for multiple sclerosis and is often associated with lymphopenia with prolonged use. Opportunistic infections, particularly cryptococcus neoformans in patients on Fingolimod, have been rarely described. <h3>Design/Methods:</h3> Case report and review of literature. <h3>Results:</h3> 44-year-old man with multiple sclerosis in remission treated with Fingolimod since 2014, and poorly controlled type-II diabetes mellitus (A1c 10.4), transferred to our facility for stroke work-up with brain MRI findings reportedly consistent with subacute bilateral cerebellar ischemic strokes. On physical exam, he was somnolent and intermittently followed simple commands. He also had nuchal rigidity and positive Kernig and Brudzinski signs. Meningitis was suspected and empiric treatment was initiated. MRI findings on DWI/ADC/FLAIR sequences were inconsistent with any vascular territory. Additionally, extensive leptomeningeal enhancement was noted in the cerebellar folia, basal cisterns, suprasellar cistern, and the surface of the brainstem. Labs were remarkable for lymphopenia (Lymphocyte count 250), and both cerebral spinal fluid (CSF) and blood culture grew cryptococcus neoformans so treatment with liposomal amphotericin B and flucytosine was started. On day 4 of admission, patient developed generalized dystonia that resolved with diphenhydramine. Unfortunately, patient did not respond to therapy as evident on repeat LP on day 6 of admission. His physical exam continued to worsen, and he was intubated 2 days after. Repeat MRI was consistent with tonsillar herniation and patient expired <h3>Conclusions:</h3> Cryptococcal cerebellitis is a rare opportunistic infection occurring in multiple sclerosis patients on Fingolimod. Early recognition is crucial given rapidly worsening neurological outcomes and atypical presentation of generalized dystonia. <b>Disclosure:</b> Dr. Singh has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Kakawand has nothing to disclose. Dr. Asif has nothing to disclose. Dr. Al-Awwad has nothing to disclose.

Visual Diagnosis: Abnormal Behavior in a 2-month-old Boy.

Visual Diagnosis: Abnormal Behavior in a 2-month-old Boy.

Prevalence of Co-Existing &lt;i&gt;E. coli&lt;/i&gt; Urinary Tract Infection With Meningitis in Children Under 2 Years: Are We Carrying Out Too Many Lumbar Punctures?

Background/Objectives: Our objectives were to determine the prevalence of co-existing bacterial meningitis (BM) and sterile cerebral spinal fluid (CSF) pleocytosis in the presence of Escherichia coli urinary tract infection (UTI) in children age zero days to two years, with the addition of CSF E. coli Polymerase Chain Reaction (PCR) analysis. Subjects/Methods: A retrospective study was conducted at a tertiary referral paediatric hospital from 1/1/2014 to 30/4/2019. Co-existing E. coli BM with UTI was defined as a pure growth E. coli from urine and a CSF culture with pure growth of E. coli and/or positive E. coli PCR. All children with a pure growth of E. coli from a urine sample and a CSF sample taken 48 hours before or after a positive urine culture were included. Further PCR analysis was carried out in cases with CSF pleocytosis. Results: There were 1911 patients that met the definition for an E. coli UTI, of which 314 had a CSF taken within 48 hours. No cases of co-existing E. coli meningitis were identified. Overall, there were 71 (23%) cases of pleocytosis, 57 (80%) of these had further PCR analysis, all of which were E. coli PCR not detected.­ Conclusion: The risk of E. coli UTI and co-existing E. coli BM is low. Routine lumber punctures (LPs) could be avoided in well-appearing infants with a diagnosis of E. coli UTI with the greatest impact seen in children up to 6 months of age. CSF E. coli PCR can help to further reduce the post-test probability of meningitis in the setting of pleocytosis. Funding Statement: None. Declaration of Interests: All authors declare that they have no conflicts of interest. Ethics Approval Statement: The study was reviewed and approved by the CHI Temple Street Scientific and Ethics Committee [REC Reference 19·007].

Late-onset Neonatal Infections 1997 to 2017 Within a Cohort in Western Sweden-The Last 21 Years of a 43-Year Surveillance.

The objective of the study was to assess the epidemiology of late-onset (LO) neonatal invasive infections with surveillance covering 43 years, starting from 1975. Observational epidemiologic, retrospective study including a cohort of infants born in western Sweden in 1997-2017, who had a positive blood and cerebral spinal fluid culture between 3 and 120 days of age. A comparison was made of the incidence between 1997-2007 and 2008-2017. Data on LO infections during 3-27 days of life were assessed from 1975. A total of 473 cases of LO infections were registered in 437 patients. The incidence increased from 2.0 to 3.1/1000 live births (LB) between 1997-2007 and 2008-2017 (P < 0.001). The increase in incidence was most pronounced among infants born <28 weeks gestation (from 255 to 398/1000 LB, P < 0.001). The most frequent pathogens were Staphylococcus aureus (25%), coagulase-negative staphylococci (17%), and Escherichia coli (13%). Infections due to group B Streptococci rose from 0.16/1000 LB to 0.33 (P = 0.03). During the whole surveillance period from 1975 to 2017, there were 579 cases between 3 and 27 days of life. Although the incidence increased in 2008-2017 to 1.9/1000 LB after first declining in 1997-2007, the case-fatality rate continued to decline from 27/284 (9.5%) between 1975 and 1996 to 6/182 (3.3%) in 2008 and 2017 (P = 0.01). The incidence of LO neonatal invasive infections increased during the study period (1997-2017), but the case-fatality rate remained lower than in the previous surveillance period (1975-1996). Further surveillance and interventions with focus on prevention is critical to counteract the increasing incidence among high-risk infants.

A Case Report of Widely Disseminated Tuberculosis in Immunocompetent Adult Male.

IntroductionDisseminated tuberculosis (TB) is rare, affects any organ system, and presents mainly in immunocompromised populations. Typical presentation is non-specific, posing a challenge for diagnosis.Case ReportThis case presents an immunocompetent male presenting with severe headaches with meningeal signs. Lab and lumbar puncture results suggested bacterial meningitis, yet initial cerebral spinal fluid cultures and meningitis/encephalitis polymerase chain reaction were negative. A chest radiograph (CXR) provided the only evidence suggesting TB, leading to further tests showing dissemination to the brain, spinal cord, meninges, muscle, joint, and bone.DiscussionThis case stands to acknowledge the difficulty of diagnosis in the emergency department (ED), and the need for emergency physicians to maintain a broad differential including disseminated TB as a possibility from the beginning of assessment. In this case, emergency physicians should be aware of predisposing factors of disseminated TB in patients presenting with non-specific symptoms. They should also acknowledge that TB may present atypically in patients with minimal predisposing factors, rendering the need to further investigate abnormal CXR images despite lab results inconsistent with TB.ConclusionWhile this diagnosis is easily missed, early identification in the ED can lead to optimal treatment.

Neonatal meningitis, endocarditis, and pneumonitis due to Streptococcus gallolyticus subsp. pasteurianus: a case report

BackgroundStreptococcus pasteurianus is a rare cause of neonatal infection, with only 3 cases reported in the USA and 18 cases reported in other countries within the past decade. Neonatal S. pasteurianus infection typically presents as meningitis. This case report describes the first neonatal case of S. pasteurianus endocarditis in the literature, in addition to a neonatal case of S. pasteurianus infection presenting as pneumonitis without meningitis. The S. pasteurianus infections in these two cases are unusual not only because of how rare this particular pathogen is, but also because of the atypical clinical manifestations.Case presentationThe first patient is a full-term male infant admitted to NICU at 20 h of life due to respiratory distress. He was empirically started on ampicillin and gentamicin for presumed sepsis. Laboratory analysis of cerebral spinal fluid obtained after initiation of antibiotics was suggestive of partially treated meningitis. Blood cultures came back positive for S. pasteurianus. The neonate was transitioned from ampicillin to cefepime, while gentamicin was continued. Echocardiograph showed a possible tricuspid valve vegetation concerning for endocarditis. Due to the unusual complication of endocarditis, the patient remained on IV cefepime for 28 days rather than the more conventional duration of 14–21 days reported in the literature. The baby clinically improved with no evidence of thrombi or vegetations on repeat cardiac echo.The second patient is a full-term male infant who required intubation at birth for respiratory distress. Chest X-ray findings were concerning for meconium aspiration with pneumonitis. The baby went into septic shock and was empirically started on ampicillin and gentamicin. Blood cultures came back positive for S. pasteurianus, while cerebral spinal fluid and urine cultures were negative. Ampicillin and gentamicin were discontinued after 3 days and the baby was started on cefepime and clindamycin for a total 14-day course. The baby clinically recovered and was discharged from NICU without any sequelae.ConclusionsThese two cases highlight the importance of recognizing S. pasteurianus as a potential cause of neonatal sepsis and the importance of recognizing endocarditis and pneumonitis as possible clinical manifestations of this infection.

344. Post Malaria Neurological Syndrome: A Rare Complication of Malaria

BackgroundPost malaria neurological syndrome (PMNS) is a rare neurological complication that can occur after recovery from malaria, usually following severe Plasmodium falciparum malaria. A total of 43 cases have been previously reported in the literature.MethodsWe report a patient with neurological symptoms following 1 month of clinical and microbiological resolution of severe falciparum malaria following treatment consistent with PMNS.ResultsA 24-year-old male presented with fever, confusion, dysarthria, and grand mal seizure. His recent medical history was significant for severe falciparum malaria with multiorgan dysfunction, including acute kidney injury after being noncompliant with antimalarial prophylaxis while working for the Peace Corps in Togo prior to falling ill. He fully recovered but still required dialysis, and returned to the United States. He presented to the hospital 1 month after his initial malaria infection. On physical examination, the patient was febrile to 38.9°C, lethargic and responsive only to painful stimuli. Signs of meningismus were absent. Computed tomography of head, abdomen and thorax were unrevealing. Magnetic resonance imaging of the brain revealed a nonspecific focus of signal abnormality in right internal capsule. Cerebral spinal fluid (CSF) analysis revealed WBC of 75/μL, with lymphocytic pleocytosis and elevated protein of 65 mg/dL. CSF bacterial and viral polymerase chain reaction pane and cryptococcal antigen were negative. CSF VDRL was nonreactive. HIV antigen/antibody serology was negative. Blood, CSF, and urine cultures were all negative for growth. Two malaria smears were negative. Initially, he was started on broad spectrum antibiotics, Acyclovir and Coartem which were discontinued following negative laboratory results, and a steroid taper was initiated. His mental status began improving on the second day of the initiation of the steroid taper, and he fully recovered by day 5 of steroid therapy.ConclusionIn patient with recent medical history of malaria who presents with neuropsychiatric symptoms, clinicians must have a high index of suspicion for PMNS.Figure 1.MRI of brain showing nonspecific focus of signal abnormality in the posterior limb of the right internal capsule.Disclosures All authors: No reported disclosures.

Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis.

Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. NCT01802385.

Antibiotic Stewardship in the Neonatal Intensive Care Unit: Effects of an Automatic 48-Hour Antibiotic Stop Order on Antibiotic Use.

Meeting antibiotic stewardship goals in the neonatal intensive care unit (NICU) is challenging because of the unique nature of newborns and the lack of specificity of clinical signs of sepsis. Antibiotics are commonly continued for 48 hours pending culture results and clinical status. The goal of this study was to examine if the implementation of a 48-hour automatic stop (autostop) order during NICU admissions would decrease antibiotic use at UnityPoint Health-Meriter. An observational double-cohort study was performed in a level 3 NICU. Antibiotic use was evaluated before and after the autostop initiative. The admission order set included 48 hours of ampicillin and gentamicin coverage. After the autostop initiation, total doses given per patient decreased by 35% and doses per patient-day decreased by 25% (P < .0001). The greatest effect was a 66% decrease in the use of vancomycin, an antibiotic not included in the admission order set. Providers proactively continued antibiotics for infants in whom they had high suspicion for sepsis and in those with positive blood or cerebral spinal fluid culture results. An admission-order autostop was highly effective at decreasing antibiotic usage with no doses intended for a pathogen missed. Fewer doses of certain antibiotics outside of the admission order set were administered, particularly vancomycin, which results in our speculation that provider awareness of the antibiotic stewardship initiative might have altered prescribing practices.

Congenital Nephrotic Syndrome: A Cases Report

Congenital nephrotic syndrome (CNS) can be caused by neonatal infections and renal diseases that usually occur in early infancy. The most common CNS is the Finnish type, which is an autosomal recessively inherited disease characterized by intrauterine onset of massive proteinuria. In this study, we presented a preterm neonate confirmed as the first case of CNS in Iran by genetic study, who was admitted to the Neonatal Intensive Care Unit of Imam Reza Hospital, Mashhad, Iran. The patient’s mother had gestational diabetes mellitus and a history of intrahepatic cholestasis of pregnancy. The newborn was hospitalized at birth because of hypoglycemia. Upon admission, repeat seizure, intraventricular hemorrhage, intracerebral hemorrhage, and edema (specific gravity of more than 58 and sever protein urea) were detected. Furthermore, hypoalbuminemia was observed. The result of the blood culture and cerebral spinal fluid culture were negative. In addition, TORCH and venereal disease research laboratory tests were negative. Finally, genetic study showed a mutation in C3250 DUPG.

A Tertiary Care Center's Experience with Novel Molecular Meningitis/Encephalitis Diagnostics and Implementation with Antimicrobial Stewardship.

Novel molecular techniques, such as the Biofire FilmArray Meningitis/Encephalitis (ME) panel, are increasingly used to improve pathogen detection and time to detection (TtD). The Brooke Army Medical Center antibiotic stewardship program evaluated the impact of the ME panel on empiric antimicrobial usage. Negative ME panels were analyzed for days of therapy (DOT). The ME panel became available at Brooke Army Medical Center on January 1, 2016 and a retrospective chart review was performed on all hospitalized patients tested by ME panel through April 30, 2016. Demographic data, cerebral spinal fluid (CSF) leukocyte count, immunocompromised status, and intensive care unit admission status were collected. TtD by ME panel and CSF culture were compared and DOT for common antimicrobials were quantified. Positive ME panels were analyzed for same demographic data, diagnoses, and microbiologic workup including CSF cultures and send out polymerase chain reactions. Of the 77 ME panels performed during the study period, 54 (70%) were conducted on inpatients and included in the analysis. The majority of patients were males (n = 29, 54%) and the median age was 24 yr (interquartile range [IQR] 45; range 1 d to 83 yr). A total of eight (15%) patients were immunocompromised and 17 (31%) required intensive care unit level of care. The median TtD with the ME panel and CSF culture was 2.75 (IQR 2.16, 3.64) and 68.5 (IQR 63.87, 78.37) h, respectively. For negative ME panels, the overall median DOT for antimicrobials was 3 (IQR 1.5, 4.0) d, whereas the median DOT for individual agents was 2 (IQR 1.0, 4.0) d for vancomycin (n = 15), 1.5 (IQR 1.0, 2.25) d for ceftriaxone (n = 16), 3 (IQR 3.0, 4.0) d for ampicillin (n = 15), 3.5 (IQR 2.75, 4.0) d for gentamicin (n = 8), 3.5 (IQR 2.25, 4.0) d for cefotaxime (n = 6), and 5 (IQR 3.0, 5.5) d for acyclovir (n = 7); the median CSF leukocyte is of 2 cells/mm3 (IQR 1.0, 7.5). DOT excluded cases of positive ME panels: human herpes virus-6 (n = 2), herpes simplex virus-2 (n = 3), enterovirus (n = 1), and Streptococcus pneumoniae (n = 1). Of these, there were two discordance diagnoses between ME panel and convention microbiologic methods. S. pneumonia was detected on the ME panel and not on the CSF culture. One bone marrow transplant recipient had symptoms of encephalitis caused by human herpes virus-6 detected only by the ME panel, the send out human herpes virus-6 polymerase chain reaction was negative. The ME panel appears to improve diagnostic yield in our facility, and there is potential for improvement in decreasing empiric antimicrobial usage, particularly in patients with a negative ME panel and absence of CSF pleocytosis. This demonstrates the need for antibiotic stewardship program involvement to assist in implementation of rapid diagnostic tests through methods such as education, clinical guidelines, and prospective audit and feedback to improve meningitis and encephalitis management.

The Disputed Champion: Ampicillin and Gentamicin for Febrile Young Infants.

The distribution of pathogens and approach to empirical antibiotics in febrile infants aged <90 days has been debated for decades. There is increasing disagreement as to whether the combination of those timeless workhorses ampicillin and gentamicin (A&G) remains appropriate empirical therapy given the changing epidemiology of bacteremia and meningitis in young infants.1–8 In the article by Feldman et al, researchers used the Pediatric Health Information System to describe regional differences in both pathogens and empirical antibiotic use in previously healthy infants <90 days old who were seen in 1 of 8 US pediatric children’s hospital emergency departments and had a positive urine, blood, or cerebral spinal fluid (CSF) culture.9 Not surprisingly, urinary tract isolates (urinary tract infection [UTI] alone or with associated bacteremia) made up 87% of infections. There was no regional difference in UTI pathogens. Blood and CSF pathogens differed by hospital, but susceptibilities remained constant and Escherichia coli and group B Streptococcus were the most common organisms. Third-generation cephalosporins (3GCs) were used for empirical therapy in the majority of infants, either alone (43%) or with ampicillin (39%). The combination of A&G was used in only 11% of infants. We struggle to understand why providers are not using A&G empirically in febrile infants <90 days of age. This choice flies in the face of data. In previous studies, researchers have consistently demonstrated equal, or in some cases superior, efficacy of A&G compared with 3GCs.3,10 In this study by Feldman et al, for example, A&G …

Management of Intracranial Ventriculitis caused by Multidrug Resistant Acinetobacter Baumannii: Case Report and Literature Review

Background: We report a case of a male patient in our hospital who developed associated multidrug-resistant Acinetobacter baumanii (MDRAB) intracrainial ventriculitis and treated using intraventricular (IVT) plus intrathecal (IT) colistin.&#x0D; Objective: The purpose of our case report is to show case the effectiveness and safety of using intraventricular (IVT) plus intrathecal(IT) colistin in the management of potentially fatal MDRAB associated intracrainial ventriculitis.&#x0D; Materials and methods: Patient was diagnosed with MDRAB after developing associated symptoms and conducting cerebral spinal fluid (CSF) culture and sensitivity analysis. Colistin 250,000 IU once daily administered via intraventricular plus intrathecal routes for 14 days was prescribed.&#x0D; Result: Cerebrospinal fluid was collected on the 14th day post commencement of colistin and sterilization was attained.&#x0D; Conclusion: Colistin is a potentially effective and safe therapy for the treatment of MDRAB intracrainial ventriculitis.

Management of intracranial ventriculitis caused by multidrug resistant Acinetobacter baumannii : case report and literature review

Background: We report a case of a male patient in our hospital who developed associated multidrug-resistant Acinetobacter baumanii (MDRAB) intracrainial ventriculitis and treated using intraventricular (IVT)plus intrathecal(IT) colistin. Objective: The purpose of our case report is to show case the effectiveness and safety of using intraventricular (IVT) plus intrathecal(IT) colistin in the management of potentially fatal MDRAB associated intracrainial ventriculitis. Materials and methods: Patient was diagnosed with MDRAB after developing associated symptoms and conducting cerebral spinal fluid(CSF) culture and sensitivity analysis. Colistin 250,000 IU once daily administered via intraventricular plus intrathecal routes for 14 days was prescribed. Result: Cerebrospinal fluid was collected on the 14th day post commencement of colistin and sterilization was attained. Conclusion: Colistin is a potentially effective and safe therapy for the treatment of MDRAB intracrainial ventriculitis. Keywords: Acinetobacter baumannii , colistin, ventriculitis, intraventricular, intrathecal

Invasive meningococcal disease with pericarditis and pneumonia: A rare presentation in childhood

Previously healthy 2-year-old boy presented with a 3-day history of fever, irritability and vomiting. There was no cutaneous rash. Ceftriaxone (100 mg/kg/day) and Dexamethasone 5.5 mg 6/6 h (on the first 3 days) were started and lumbar puncture was performed. Cerebral spinal fluid (CSF) showed 3.696 WBCs/μL with 99% neutrophils, glucose 1 mg/dL and total protein 578.0 mg/dL. CSF Gram stain showed extracellular and intracellular Gram-negative diplococci. Latex agglutination was reactive for N. meningitidis group C. The CSF culture was negative. After 6-day of antibiotic treatment patient started with dyspnea, dry cough and hypotension. Cardiorespiratory examination revealed an elevated jugular venous pressure, normal heart sounds, with no pericardial rub, coarse sounds with crackles over left base were heard. New CSF analyses showed 336 WBCs/μL with 61% neutrophils, 39% lymphocytes, protein 99.5 g/L and glucose 26 mg/dL (serum glucose 75 mg/dL). The CSF and blood cultures were negative. Chest X-ray showed an enlarged cardiac silhouette, consolidation in the left lung and pleural effusion. The antimicrobial treatment was changed to meropenem. Computed tomography of the chest showed moderate pleural effusion, consolidation in the left lobe. The cardiac echography revealed a pericardial effusion. There was no sign of imminent cardiac tamponade. Pericardiocentesis was performed and a total of 115 ml hemorrhagic pericardial fluid was aspirated. The fluid analysis demonstrated 1.460 WBC/mm3, with 85% polymorphonuclear neutrophils and 15% lymphocytes, total proteins of 4.5 g/dL, 836 U/L LDH and glucose 60 mg/dL. No microorganism was observed by Gram and Ziehl-Nielsen stain. The pericardial fluid culture to aerobic and mycobacteria was negative. Methylprednisolone was administered for five days. Patient was discharged after 14 days of antibiotic therapy with full recovery. We present a case of meningococcal meningitis that developed two rare manifestations associated in children: pericarditis and pneumonia (Fig. 1, Fig. 2, Fig. 3). Occurrence of cardiac tamponade in reactive pericarditis is most often associated in serogroup C infections [1], [2], serogroup predominant in Amazon [3]. Meningococcal pneumonia is more associated with serogroup Y [4]. The forms of presentation of pericardial involvement include: disseminated meningococcal infection with pericardial, primary meningococcal pericarditis and reactive meningococcal pericarditis [1]. The hypersensitivity reaction type 3 tends to occur during the convalescent period (4–10 days after the start of antibiotic therapy) [5]. Thought to be due to a hypersensitivity reaction to previously damaged pericardial tissue, which acts as an antigen stimulus to antibody formation [5]. If the effusion is large treatment is done with high doses corticoids [1]. Fig. 1 Chest X-ray showed an enlarged cardiac silhouette, consolidation in the inferior lobe of left lung and pleural effusion. Fig. 2 Computed tomography of the chest (CTC) showed left lung atelectasis, moderate pleural effusion and consolidation in the left upper lobe. CTC mediastinal window shows moderate pericardial effusion. Fig. 3 The cardiac echography revealed a pericardial effusion. There was no sign of cardiac tamponade.

Procalcitonin as a Marker of Serious Bacterial Infections in Febrile Children Younger Than 3 Years Old

There is no perfectly sensitive or specific test for identifying young, febrile infants and children with occult serious bacterial infections (SBIs). Studies of procalcitonin (PCT), a 116-amino-acid precursor of the hormone calcitonin, have demonstrated its potential as an acute-phase biomarker for SBI. The objective of this study was to compare performance of serum PCT with traditional screening tests for detecting SBIs in young febrile infants and children. This was a prospective, multicenter study on a convenience sample from May 2004 to December 2005. The study was conducted in four emergency departments (EDs): one pediatric ED and three EDs with pediatric units, all with academic faculty on staff. A total of 226 febrile children 36months old or younger who presented to the four participating EDs and were evaluated for SBI by blood, urine, and/or cerebral spinal fluid (CSF) cultures were included. The test characteristics (with 95% confidence intervals [CIs]) of the white blood cell (WBC) counts including neutrophil and band counts were compared with PCT for identifying SBI. Thirty children had SBIs (13.3%, 95% CI=8.85 to 17.70). Four (13.3%) had bacteremia (including one with meningitis), 18 (60.0%) had urinary tract infections (UTIs), and eight (26.6%) had pneumonia. Children with SBIs had higher WBC counts (18.6×10(9) ± 8.6×10(9) cells/L vs. 11.5×10(9) ± 5.3×10(9) cells/L, p<0.001), higher absolute neutrophil counts (ANCs; 10.6×10(9) ± 6.7×10(9) cells/L vs. 5.6×10(9) ± 3.8×10(9) cells/L, p=0.009), higher absolute band counts (0.90×10(9) ± 1.1×10(9) cells/L vs. 0.35×10(9) ± 0.6×10(9) cells/L, p=0.009), and higher PCT levels (2.9 ± 5.6 ng/mL vs. 0.4 ± 0.8 ng/mL, p=0.021) than those without SBIs. In a multivariable logistic regression analysis, the absolute band count and PCT were the two screening tests independently associated with SBI, although the area under the receiver operating characteristic (ROC) curve for PCT was the largest (0.80, 95% CI=0.71 to 0.89). Procalcitonin is a more accurate biomarker than traditional screening tests for identifying young febrile infants and children with serious SBIs. Further study on a larger cohort of young febrile children is required to definitively determine the benefit of PCT over traditional laboratory screening tests for SBIs.

Appropriateness of Testing for Serious Bacterial Infection in Children Hospitalized With Bronchiolitis

The goal of this study was to evaluate provider practice patterns for evaluation of serious bacterial infection (SBI) in patients hospitalized with bronchiolitis and to assess the association of SBI testing with length of stay and antibiotic use. This was a retrospective chart review of hospitalized patients <24 months of age with a discharge diagnosis of bronchiolitis from 2 separate study sites during 2004 to 2008. Patient characteristics, laboratory testing, antibiotic use, and clinical outcomes were assessed in relation to SBI testing. A total of 1233 charts met inclusion criteria. The incidence of urinary tract infections in patients who underwent urine testing was 2.3%. Of the 367 patients undergoing blood culture testing, all 13 positive-result blood cultures were contaminated specimens. There were no cases of meningitis. In total, 64.5% of patients tested for SBI had a blood culture obtained, 45.0% had an urinalysis or urine culture, and 16.3% had a cerebral spinal fluid culture obtained. Of those patients who underwent SBI testing, 53.8% received antibiotics versus 19.1% who did not (P < .0001). Length of stay for patients undergoing SBI testing was 3.4 days versus 2.3 days for those without SBI testing (P < .0001). There was no significant difference in readmission rates. SBI is uncommon in children hospitalized for bronchiolitis, and urinary tract infection is the most common diagnosis. In the evaluation of SBI in bronchiolitis, providers more frequently obtain blood cultures than urinalysis and/or urine cultures. Evaluation for SBI is associated with increased antibiotic use and increased LOS.