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Rapport og anbefaling vedrørende lumbalpunktur, blodfortyndende behandling og akut bakteriel meningitis. Udarbejdet af en arbejdsgruppe nedsat af Dansk Selskab for Infektionsmedicin vedrørende neuroinfektioner.
Udgiver: Dansk Selskab for Infektionsmedicin 2018
Arbejdsgruppe: Anne-Mette Lebech, Birgitte Rønde Hansen, Christian Brandt, Hans Rudolph von Lüttichau, Jacob Bodilsen, Jannik Helweg-Larsen, Lothar Wiese, Lykke Larsen, Trine Mogensen.
Udgiver: Dansk Selskab for Infektionsmedicin
Arbejdsgruppe: Anne-Mette Lebech, Birgitte Rønde Hansen, Christian Brandt, Hans Rudolf von Lüttichau, Jacob Bodilsen, Lothar Wiese, Lykke Larsen, Trine Mogensen.
Udgiver: Dansk Selskab for Infektionsmedicin
Arbejdsgruppe: Anne-Mette Lebech, Birgitte Rønde Hansen, Christian Brandt, Hans Rudolph von Lüttichau, Jacob Bodilsen, Jannick Helweg-Larsen, Lothar Wiese, Lykke Larsen, Trine Mogensen.
Klinik, diagnostik og behandling af Lyme Borreliose i Danmark.
Forfattergruppen er nedsat af Dansk Selskab for Klinisk Mikrobiologi, Dansk Selskab for Infektionsmedicin og Dansk Neurologisk Selskab.
Tværregional vejledning vedrørende akut bakteriel (purulent) meningitis hos voksne
Vejledning om forebyggelse ved tilfælde af Meningokoksygdom
To estimate long term survival, health, and educational/social functioning in patients with Lyme neuroborreliosis compared with the general population.
To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark.
To examine clinical characteristics and outcome of patients with late diagnosis of community-acquired bacterial meningitis (CABM).
The purpose of this review is to give an overview of viral meningitis and then focus in on some of the areas of uncertainty in diagnostics, treatment and outcome.
The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment.
To describe the clinical manifestations, cerebrospinal fluid (CSF) characteristics, imaging studies and prognostic factors of adverse clinical outcomes (ACO) among adults with herpes simplex virus (HSV) or varicella zoster virus (VZV) CNS infections.
Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research.
Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2-4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings.
Lyme borreliosis, caused by spirochaetes of the Borrelia burgdorferi genospecies complex, is the most commonly reported tick-borne infection in Europe and North America. The non-specific nature of many of its clinical manifestations presents a diagnostic challenge and concise case definitions are essential for its satisfactory management. Lyme borreliosis is very similar in Europe and North America but the greater variety of genospecies in Europe leads to some important differences in clinical presentation. These new case definitions for European Lyme borreliosis emphasise recognition of clinical manifestations supported by relevant laboratory criteria and may be used in a clinical setting and also for epidemiological investigations.
Mortality and morbidity rates are high among adults with acute bacterial meningitis, especially those with pneumococcal meningitis. In studies of bacterial meningitis in animals, adjuvant treatment with corticosteroids has beneficial effects.
Lyme disease is the most common vector-borne infection in some temperate regions of the Northern Hemisphere. However, for most areas of endemic disease reliable epidemiologic data are sparse.
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Mizrahi, A., Marvaud, J. C., Pilmis, B., Nguyen Van, J. C., Couzigou, C., Bruel, C., Engrand, N., Le Monnier, A., Lambert, T.
We report a case of a 62-year old man treated for a Streptococcus pneumoniae meningitis by ceftriaxone and dexamethasone. After a neurological improvement, neurological degradation by vasculitis occurred, despite effective concentrations of ceftriaxone in serum and CSF. S. pneumoniae with increased MICs to third-generation-cephalosporins (3GC) was isolated from the ventricular fluid ten days after the isolation of the first strain. Isolates analysis showed that a mutation of penicillin-binding proteins in PBP2x has occurred under treatment.
Streptococcus oralis belongs to the Streptococcus mitis group and is part of the normal flora of the nasal and oropharynx (Koneman et al., The Gram-positive cocci part II: streptococci, enterococci and the ‘Streptococcus-like’ bacteria. Color atlas and textbook of diagnostic microbiology, 1997). Streptococcus oralis is implicated in meningitis in patients with decreased immune function or from surgical manipulation of the central nervous system. We report a unique case of meningitis by Streptococcus oralis in a 58-year-old patient with cerebral spinal fluid leak due to right sphenoid meningoencephalocele.
A 58-year-old female presented in the emergency department due to altered mental status, fevers, and nuchal rigidity. Blood cultures were positive for Streptococcus oralis. Magnetic resonance stereotactic imaging of head with intravenous gadolinium showed debris in lateral ventricle occipital horn and dural thickening/enhancement consistent with meningitis. There was also a right sphenoidal roof defect, and meningoencephalocele with cerebrospinal fluid leak as a result. The patient was treated with ceftriaxone and had endoscopic endonasal repair of defect. She had complete neurologic recovery 3 months later.
Cerebrospinal fluid leak puts patients at increased risk for meningitis. Our case is unique in highlighting Streptococcus oralis as the organism implicated in meningitis due to cerebrospinal fluid leak.
Vimal Kumar Paliwal, Animesh Das, Sucharita Anand and Prabhakar Mishra
Intravenous (IV) dexamethasone is recommended for 14 days in stage 1 and 28 days in stage 2/3 tuberculous meningitis (TBM). We used a different steroid protocol. We shifted TBM patients to oral steroids after 48 hours of sustained improvement on IV steroids (oral group). Patients who worsened after shifting to oral steroids were reinitiated on IV steroids. Once they showed a consistent improvement for 48 hours, the IV steroids were overlapped with oral steroids for 7–10 days to taper off IV steroids (overlap group). We compared total IV steroid days in our patients with the recommended treatment and identified predictors that favored the oral group. This was a retrospective study. We included 98 patients with TBM (66 in the overlap group and 32 in the oral group) from January 2013 to July 2018. The median IV steroid days were 9 days (interquartile range of 4–12; 2–3.5 days in the oral group and 10–11.5 days in the overlap group). The mortality rate was 6.1%. The logistic regression model showed that TBM patients with basal exudate, tuberculoma, and modified Rankin scale (mRS) < 3 had a higher probability for going to the oral group. We conclude that total IV steroid days can be reduced in TBM patients by our method of steroid use. Presence of basal exudates and tuberculoma may favor early shifting from IV to oral steroid, whereas higher mRS may require a relatively longer course of IV steroid.
Svensson E, Dian S, te Brake L, et al.
AbstractBackgroundIntensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis.MethodsAn individual patient meta-analysis was performed on data from three Indonesian randomized controlled phase II trials comparing oral rifampicin 450mg (~10mg/kg) to intensified regimens including 750-1350mg orally, or a 600mg intravenous infusion. Pharmacokinetic data from plasma and CSF was analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models.ResultsPharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured two disposition-compartments, saturable clearance and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5% [95%CI 4.4-6.4]) and half-life for distribution plasma to CSF (2.1 h [1.3-2.9]). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 drop-outs) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from ~50% to ~70% upon increasing the oral rifampicin dose from 10 to 30mg/kg, and that higher doses would further increase survival.ConclusionsHigher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30mg/kg to be investigated in phase III clinical trials.
Invasive meningococcal disease (IMD) presenting with meningitis causes significant mortality and morbidity. Suppurative complications of serogroup B meningococcal sepsis are rare and necessitate urgent multidisciplinary management to mitigate long-term morbidity or mortality.
We present a rare case of invasive meningococcal disease in a 28-month old boy complicated by multiple abscess formation within a pre-existing antenatal left middle cerebral artery territory infarct. Past history was also notable for cerebral palsy with right hemiplegia, global developmental delay and West syndrome (infantile spasms). Two craniotomies were performed to achieve source control and prolonged antimicrobial therapy was necessary. The patient was successfully discharged following extensive multidisciplinary rehabilitation.
Longstanding areas of encephalomalacia in the left MCA distribution may have facilitated the development of multiple meningococcal serogroup B abscess cavities in the posterior left frontal, left parietal and left temporal lobes following an initial period of cerebritis and meningitis. A combination of chronic cerebral hypoperfusion and some degree of pre-existing necrosis in these areas, may also have facilitated growth of Neisseria meningitidis, leading ultimately to extensive cerebral abscess formation following haematogenous seeding during meningococcemia. In this case report we review similar cases of cerebral abscess or subdural empyema complicating serogroup B meningococcal meningitis.
Fiona Cresswell, Christoph Lange, Reinout van Crevel
Tuberculosis (TB) is the leading infectious cause of death globally. Meningitis accounts for 1-2% of TB cases (more in HIV-endemic settings), but kills or disables up to 50% or more of those affected . Tuberculous meningitis (TBM) is notoriously difficult to diagnose with conventional microbiological techniques due to the scarcity of bacilli and Mycobacterium tuberculosis DNA.
Cryptococcal meningitis is most commonly found in HIV-infected patients. In HIV-negative patients, its low incidence can lead to prolonged time to diagnosis. Detailed case reports of chronic cryptococcal meningitis are scarce, but could provide clues for earlier diagnosis in this patient category.
A 60-year old man presented June 2015 with intermittent headaches for several months without any fever. Initial work-up showed a leukocytosis, raised CSF opening pressure and raised leukocytes and protein in the CSF. An MRI revealed leptomeningeal contrast enhancement and cerebellar oedema. While malignancy and various infectious causes were excluded, the patient had a spontaneous clinical and radiological recovery. One year later, the patient returned with complaints of headaches. Also, cerebellar oedema and leptomeningeal contrast enhancement had recurred. Eventually in March 2017, the novel cryptococcal antigen lateral flow assay (CrAg LFA) was positive on CSF, and one colony of Cryptococcus neoformans was cultured from CSF. The patient was treated with the standard antifungal regimen which resulted in resolution of his headaches. In retrospect, the cryptococcal antigen test was already positive on a serum sample from June 2015. Interestingly, post-treatment immunological analysis revealed both a low mannose-binding lectin (MBL) concentration and low naïve CD4 counts.
We present a patient with cryptococcal meningitis in an HIV-negative patient with low MBL and low naïve CD4 count suffering a chronic relapsing meningo-encephalitis with relatively mild symptoms for around 2 years. In patients with an unexplained meningo-encephalitis such as this case, early performance of CrAg LFA on serum and/or CSF is an inexpensive and rapid method to reduce time-to diagnosis.
Ying Liu, Xiaohua Peng, Weizhen Weng, Jianyun Zhu, Hong Cao, Shibin Xie
A. J. Henningsson et al.
Non-typhoidal salmonellae (NTS) have been associated with invasive disease, notably meningitis, in immunocompromised individuals. Infections of this nature carry high rates of morbidity and mortality. Colistin resistance in salmonellae is a rare finding, more so in an invasive isolate such as cerebrospinal fluid (CSF). Colistin resistance has important infection control implications and failure to manage this phenomenon may lead to the loss of our last line of defence against multi-drug resistant Gram-negative organisms. To our knowledge, this is the first reported clinical case of colistin-resistant Salmonella Enteritidis meningitis in South Africa.
We report a case of a young male patient with advanced human immunodeficiency virus (HIV) infection who presented to hospital with symptoms of meningitis. Cerebrospinal fluid (CSF) cultured a Salmonella Enteritidis strain. Antimicrobial susceptibility testing (AST) of the isolate, revealed the strain to be colistin resistant. Despite early and aggressive antimicrobial therapy, the patient succumbed to the illness after a short stay in hospital. Subsequent genomic analysis of the isolate showed no presence of the mcr genes or resistance-conferring mutations in phoPQ, pmrAB, pmrHFIJKLME/arnBCADTEF, mgrB, and acrAB genes, suggesting the presence of a novel colistin resistance mechanism.
Invasive non-typhoidal salmonellae infection should be suspected in patients with advanced immunosuppression who present with clinical features of meningitis. Despite early and appropriate empiric therapy, these infections are commonly associated with adverse outcomes to the patient. Combination therapy with two active anti-Salmonella agents may be a consideration in the future to overcome the high mortality associated with NTS meningitis. Colistin resistance in clinical Salmonella isolates, although a rare finding at present, has significant public health and infection control implications. The causative mechanism of resistance should be sought in all cases.
Ana Helena A. Figueiredo, Matthijs C. Brouwer, Merijn W. Bijlsma, Arie van der Ende, Diederik van de Beek
Pneumonia is considered a focus of infection in patients presenting with community-acquired bacterial meningitis but the impact on disease course is unclear. The aim was to study presenting characteristics, clinical course and outcome of meningitis patients with co-existing pneumonia on admission.
Brink, M., Glimaker, M., Sjölin, J., Naucler, P.
Objectives Cefotaxime, alone or with ampicillin, is frequently used as empirical treatment of acute bacterial meningitis (ABM). Meropenem is a less investigated alternative. The aim of the study was to investigate the effects of empirical treatment with meropenem compared to cefotaxime plus ampicillin on outcome in ABM.Methods The study was based on data from the Swedish quality register for ABM between January 2008 and December 2016. A propensity score matching was performed to adjust for baseline differences between the groups. Mortality within 30-days was the primary outcome.Results The treatment regimens of interest were administered to 623 patients; 328 were given cefotaxime plus ampicillin whereas 295 received meropenem. After propensity score matching the 30-day mortality was 3.2% in the cefotaxime plus ampicillin group and 3.6% in the meropenem group. For matched cases the OR for 30-day mortality for meropenem vs. cefotaxime plus ampicillin was 1.15 (CI: 0.41–3.22; p=0.79). The OR for 90-day mortality was 1.47 (CI: 0.62–3.52; p=0.38), and for unfavorable outcome 1.10 (CI: 0.75–1.63; p=0.62).Conclusions The findings of our study indicate that meropenem is an effective empirical treatment option for adults with community-acquired ABM. However, to spare carbapenems, guidelines should continue to recommend third-generation cephalosporins as empirical treatment for the majority of patients with ABM.
Skipper C, Schleiss M, Bangdiwala A, et al.
AbstractBackgroundCryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced HIV/AIDS. Cytomegalovirus (CMV) viremia may be associated with increased mortality in HIV-infected persons with tuberculosis. It is unknown if concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections.MethodsWe prospectively enrolled HIV-infected Ugandans with cryptococcal meningitis from 2010–2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival among those with and without CMV viremia.ResultsOf 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL; IQR, 259–2390). All samples tested were positive on IgG serology. The median CD4+ T cell count was 19 cells/µL (IQR, 9–70) and did not differ by the presence of CMV viremia (P=.47). The 10-week mortality was 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (Hazard Ratio=2.19; 95%CI, 1.07–4.49; P=.03), which remained significant after multivariate adjustment for known risk factors of mortality (adjusted Hazard Ratio=3.25; 95%CI, 1.49–7.10; P=.003). Serum and CSF cytokine levels were generally similar, and cryptococcal antigen-specific immune stimulation responses did not differ.ConclusionHalf of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with over two-fold higher mortality. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect underlying immune dysfunction (i.e. cause vs. effect).
Zhang Z, Zhao S, Lian D, et al.
AbstractBackgroundStreptococcus pneumonia meningitis (PM) is a major cause of childhood neurological deficits. Although the Notch1 signalling pathway regulates neurogenesis and neuroinflammation, we know little about its expression or influence on hippocampal neurogenesis and gliogenesis during PM.MethodsWe used immunofluorescence and western blots to detect Notch1 signalling expression during experimental PM. Through double-labelling immunofluorescence, we investigated proliferation and differentiation in the dentate gyrus (DG) in PM before and after treatment with exogenous Notch1 activator (Jagged1) and inhibitor (IMR-1).ResultsOur results showed that Notch1 was activated after 24 h in PM. Compared with the PBS control, Jagged1 increased the proliferation of neural stem cells and progenitor cells (NS/PCs) in DG. After 14 and 28 d of meningitis, astrocyte differentiation increased compared with control. Astrocyte differentiation was higher in the Jagged1 versus the PBS group. In contrast, IMR-1 increased neuronal differentiation but decreased astrocyte differentiation compared with DMSO treatment.ConclusionUnder PM, Notch1 signalling promotes NS/PC proliferation and astrocyte differentiation in DG, while decreasing neuronal differentiation. Transient activation of the Notch1 signalling pathway explains the reactive gliogenesis and limited neuronal differentiation observed in PM.
G. Oligbu et al.
Management of partially-treated, community-acquired bacterial meningitis (PCBM) is commonly compromised by lack of microbiological diagnosis. We aimed to analyze the impact of FilmArray Meningitis-Encephalitis (FA-ME) PCR on the management of PCBM.
Comparison of treatment variables of PCBM cases between two periods, before (6.5 years, control group) and after (2 years, study group) the application of FA-ME PCR assay.
The total duration of antimicrobial treatment in the study group (n = 8) was significantly shorter than the control group (n = 23) (9.5 ± 3.7 days vs. 15.2 ± 5 days, p = 0.007). The percentage of narrow-spectrum regimens was significantly higher in the study group (78 ± 11% vs. 40 ± 9%, p = 0.03). There was a significant difference in implementation of antimicrobial chemoprophylaxis for close contacts (4/8 (50%) vs. 1/23 (4%), p = 0.01).
The use of FA-ME PCR provides significant benefits in the management of PCBM by shortening duration of antibiotic treatment, increasing the use of narrow-spectrum regimens, and allowing proper administration of antimicrobial chemoprophylaxis.
The study was approved and retrospectively registered by the Tel-Aviv Sourasky Medical Center (0378–17-TLV, 10/17/2017) and Rabin Medical Center (0270–18-RMC, 11/11/2018) Ethics committees and conforms to recognized standards.
Ravi Shekhar Jaipuriar, Ravindra Kumar Garg, Imran Rizvi, Hardeep Singh Malhotra, Neeraj Kumar, Amita Jain, Rajesh Verma, Praveen Kumar Sharma, Shweta Pandey and Ravi Uniyal
Most deaths in tuberculous meningitis occur in the early part of the illness. We assessed the determinants of early deaths, occurring within 2 months of intensive therapy. We prospectively included consecutive newly diagnosed adults with HIV-negative tuberculous meningitis. Patients were given WHO-recommended antituberculosis treatment and were followed up for 9 months. We enrolled 152 patients. A total of 26 deaths were recorded during 2 months. The logistic regression analysis revealed that papilledema (P = 0.029, odds ratio (OR) = 4.8 [1.2–19.8]), increasing age (P = 0.001, OR = 1.07 [1.03–1.1]), stage-III disease (Glasgow coma scale score ≤ 10; P = 0.01, OR = 4.2 [1.4–12.3]), and hydrocephalus (P = 0.003, OR = 8.4 [2.1–33.6]) were independently associated with death. In addition, cerebral infarcts (P = 0.012, OR = 5.6 [1.5–21.3]), paraparesis (P = 0.004, OR = 8.8 [2.02–38.1]), and age (P = 0.005, OR = 1.05 [1.02–1.09]) were associated with poor functional outcome. In conclusion, disease severity predicts early deaths in tuberculous meningitis.
Ji-Soo Kwon, Joung Ha Park, Ji Yeun Kim, Hye Hee Cha, Min-Jae Kim, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Jun Hee Woo, Yong Seo Koo, Sang-Beom Jeon, Sang-Ahm Lee and Sung-Han Kim
In this study, we investigated the diagnostic utility of the cytokine profile of the cerebrospinal fluid (CSF) and enzyme-linked immunospot (ELISPOT) assays of patients with suspected tuberculous meningitis (TBM). We prospectively enrolled adult patients with suspected TBM, and CSF specimens were analyzed for 18 cytokines/chemokines and soluble programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1). Enzyme-linked immunospot assays were performed on mononuclear cells from the CSF (CSF-MCs) and peripheral blood (PBMCs). A total of 87 patients with meningitis, including 42 TBM-suspected patients and 45 non-TBM patients, were enrolled. Excluding the 32 patients with possible TBM, 10 patients with TBM and 45 patients with non-TBM were finally analyzed. Levels of adenosine deaminase (ADA), interleukin 12 subunit β (IL-12p40), IL-13, macrophage inflammatory protein α (MIP-1α), and soluble PD-1 and PD-L1 in the CSF were significantly higher in the TBM group than in the non-TBM group (P < 0.05). The optimal cutoff values for the sensitivities and specificities of the test methods for diagnosing TBM with small samples of 10 cases of definite or probable TBM were as follows: ADA > 6.95 U/L, 70% and 81%; IL-12p40 > 52.04 pg/mL, 80% and 73%; IL-13 > 0.44 pg/mL, 90% and 47%; MIP-1α > 8.83 pg/mL, 80% and 62%; soluble PD-1 > 35.87 pg/mL, 80% and 63%; soluble PD-L1 > 24.19 pg/mL, 80% and 61%; CSF-MC ELISPOT > 13.5 spots/250,000 CSF-MC, 30% and 91%; and PBMC ELISPOT > 14 spots/250,000 PBMCs, 50% and 78%, respectively. Therefore, CSF IL-12p40, IL-13, MIP-1α, and soluble PD-1 and PD-L1 concentrations appear to be useful adjuncts for diagnosing TBM.
Tucker, E. W., Pieterse, L., Zimmerman, M. D., Udwadia, Z. F., Peloquin, C. A., Gler, M. T., Ganatra, S., Tornheim, J., Chawla, P., Caoili, J. C., Ritchie, B., Jain, S. K., Dartois, V., Dooley, K. E.
Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug (MDR-) and extensively drug resistant-tuberculous meningitis (TBM), specifically, is nearly uniformly fatal, with little information to guide treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated TB drug with a low minimal inhibitory concentration (1-12 ng/mL) against Mycobacterium tuberculosis. It is used for pulmonary MDR-TB, but CNS pharmacokinetic (PK) data in TBM are not available. In the present study, we measured DLM concentrations in the brain and cerebrospinal fluid (CSF) of six rabbits, with and without experimentally-induced TBM, receiving single-dose DLM. We report steady-state CSF concentrations from three patients receiving DLM as part of multidrug-treatment who underwent therapeutic drug monitoring. Drug was quantified using LCMS/MS. In rabbits and humans, mean CSF concentrations (rabbit [1.26 ng/mL at 9h, 0.47 ng/mL at 24h]; human [48 ng/mL at 4h]) were significantly lower than plasma (rabbits [124 ng/mL at 9h, 14.5 ng/mL at 24h]; human [726 ng/mL at 4h]), but estimated free CSF/plasma ratio were >1. In rabbits, brain DLM concentrations were 5-fold higher than in plasma (mean 518 ng/mL at 9h, 74.0 ng/mL at 24h). All patients with XDR-TBM receiving DLM experienced clinical improvement and survival. Collectively, these results suggest that DLM achieves adequate concentrations in brain tissue. Despite relatively low total CSF drug levels, free drug may be sufficient and DLM may have a role in treating TBM. More studies are needed to develop a fuller understanding of its distribution over time with treatment, and clinical effectiveness.
Definitive diagnosis of meningitis is made by analysis of cerebrospinal fluid (CSF) culture or polymerase chain reaction (PCR) obtained from a lumbar puncture (LP), which may take days. A timelier diagnostic clue of meningitis is pleocytosis on CSF analysis. However, meningitis may occur in the absence of pleocytosis on CSF.
Areas of Uncertainty: A diagnosis of meningitis seems less likely without pleocytosis on CSF, leading clinicians to prematurely exclude this. Further, there is little available literature on the subject.
Ovid/Medline and Google Scholar search was conducted for cases of CSF culture-confirmed meningitis with lack of pleocytosis. Inclusion criterion was reported cases of CSF culture-positive or PCR positive meningitis in the absence of pleocytosis on LP. Exclusion criteria were pleocytosis on CSF, cases in which CSF cultures/PCR were not performed, and articles that did not include CSF laboratory values.
A total of 124 cases from 51 articles were included. Causative organisms were primarily bacterial (99 cases). Outcome was reported in 86 cases, 27 of which died and 59 survived. Mortality in viral, fungal and bacterial organisms was 0, 56 and 31%, respectively. The overall percentage of positive initial CSF PCR/culture for viral, fungal and bacterial organisms was 100, 89 and 82%, respectively. Blood cultures were performed in 79 of the 124 cases, 56 (71%) of which ultimately cultured the causative organism. In addition to bacteremia, concomitant sources of infection occurred in 17 cases.
Meningitis in the absence of pleocytosis on CSF is rare. If this occurs, causative organism is likely bacterial. We recommend ordering blood cultures as an adjunct, and, if clinically relevant, concomitant sources of infection should be sought. If meningitis is suspected, empiric antibiotics/antifungals should be administered regardless of initial WBC count on lumbar puncture.
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