Continuous evaluation of single-dose moxifloxacin concentrations in brain extracellular fluid, cerebrospinal fluid, and plasma: a novel porcine model.

BACKGROUND: Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. OBJECTIVE: (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. METHODS: Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (Cmax):MIC ratio >8. RESULTS: We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. Cmax and AUC0-8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound Cmax:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. CONCLUSION: A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.

Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations in brain abscess patients: a nationwide, population-based matched cohort study.

OBJECTIVES: The extent of hereditary haemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformations (PAVMs) as a risk factor for brain abscess is unknown. METHODS: Nationwide and population-based registries were used to identify persons with first-time hospitalization for brain abscess (index date) and population controls matched by age, sex and residence (1:10). Accounting for competing risks, cumulative incidence curves of new diagnosis of HHT/PAVM after brain abscess were constructed. Next, Cox regression was used for computation of cause-specific hazard rate ratios (HRRs) adjusted for severe liver disease and congenital heart disease as potential confounders. RESULTS: HHT/PAVM was prevalent before the index date in 2/1384 (0.1%; 95% CI 0.02-0.52) brain abscess patients and 6/13 838 (0.04%; 95% CI 0.02-0.09) matched population controls. After the index date, a new diagnosis of hereditary haemorrhagic telangiectasia or pulmonary arteriovenous malformations was made in 15/1384 brain abscess patients (range 0 days to 17 years) compared with 7/13 812 population controls yielding an adjusted hazard rate ratio of 31.4 (95% CI 9.95-98.9). Cumulative incidence was 1.5% for brain abscess patients and 0.1% for population controls. DISCUSSION: HHT/PAVM should be considered in patients with cryptogenic brain abscess, although absolute risk is low.

The cause of death in bacterial meningitis.

BACKGROUND: Death from bacterial meningitis is rarely attributed to the actual event causing death. The present study therefore categorized and characterized the cause and time of death due to bacterial meningitis. METHODS: In a cohort of patients > 15 years of age with community acquired bacterial meningitis the medical records were reviewed, and a clinical cause of death categorized into six main categories: 1) CNS complications, 2) Systemic complications, 3) Combination of systemic and CNS complications, 4) Sudden death, 5) Withdrawal of care, or 6) Unknown. RESULTS: We identified 358 patients of which 84 (23%) died in-hospital. Causes of death were ascribed to CNS complications in 43%, Systemic complications in 39%, Combined CNS and systemic complications in 4%, Sudden death in 7% and withdrawal of care in 5%. Brain herniation, circulatory failure, intractable seizures and other brain injury were the most common specific causes of death within 14 days from admission (55%). CONCLUSION: Fatal complications due to the primary infection - meningitis - is most common within 14 days of admission. The diversity of complications causing death in meningitis suggest that determining the clinical cause of death is essential to the evaluation of novel treatment strategies.

Incidence and mortality of brain abscess in Denmark: a nationwide population-based study.

OBJECTIVES: To examine the incidence and mortality of brain abscesses. METHODS: We accessed nationwide population-based medical registries to obtain data for patients with first-time brain abscesses in Denmark from 1982 through 2016. Annual age- and sex-standardized incidence rates with 95% confidence intervals were calculated and compared by direct standardization. We used Cox regression to compute mortality rate ratios adjusted for age and year groups, sex and Charlson comorbidity index score. RESULTS: We identified 1384 patients (37% female). The overall standardized incidence rate of brain abscess was 0.76 per 100 000 person-years (95% confidence interval 0.70-0.81). The incidence rates gradually increased from 0.60 during 1982-88 to 0.90 per 100 000 person-years during 2010-16, yielding an incidence rate ratio of 1.50 (95% confidence interval 1.26-1.79). This increase in incidence was most pronounced in the proportions of brain abscess patients >40 years of age and those with immuno-compromise. The 1-year mortality declined from 29% during 1982-88 to 20% during 2010-16, yielding an adjusted mortality rate ratio of 0.44 (95% confidence interval 0.31-0.63). Risk factors for death were advanced age, Charlson comorbidity index >0, immuno-compromised status and congenital heart disease. CONCLUSIONS: The incidence of brain abscess in Denmark is low but increasing, especially in the elderly, along with an increasing proportion of brain abscess patients with immuno-compromise. The prognosis has improved during the last decades, but mortality remains high. Risk factors for death in our study were advanced age, presence of comorbidity, immuno-compromised status and congenital heart disease.

Infectious meningitis and encephalitis in adults in Denmark: a prospective nationwide observational cohort study (DASGIB).

OBJECTIVES: To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark. METHODS: Nationwide prospective observational study of all cases of proven community-acquired infectious meningitis and encephalitis in adults treated in all infectious diseases departments in Denmark from 1 January 2015 to 30 June 2016. We included data on symptoms, aetiology, treatment and outcome assessed by the Glasgow Outcome Scale (GOS) 30 days after discharge. GOS 1-4 was categorized as unfavourable outcome. RESULTS: During 18 months of observation, we identified 252 cases of viral meningitis (3.6/100 000/year), 214 cases of bacterial meningitis (3.1/100 000/year) and 96 cases of infectious encephalitis (1.4/100 000/year). In bacterial meningitis, Streptococcus pneumoniae was the most frequent infectious agent (n = 101) followed by Staphylococcus aureus (n = 24) and ß-haemolytic streptococci (n = 14). Meningococcal meningitis was rare (n = 11). In encephalitis, herpes simplex virus type 1 was most common (n = 37) followed by varicella zoster virus (n = 20), whereas varicella zoster virus (n = 61) was most common in viral meningitis followed by enterovirus (n = 50) and herpes simplex virus type 2 (n = 46). Case fatality and unfavourable outcome occurred in 31/214 (15%) and 96/214 (45%) with bacterial meningitis and in 5/96 (5%) and 55/89 (62%) with encephalitis. For viral meningitis, unfavourable outcome occurred in 41/252 (17%). CONCLUSIONS: The epidemiology and clinical presentation of the examined central nervous system infections differed considerably and bacterial meningitis was more frequent than previously estimated. Overall prognosis remains poor for bacterial meningitis and encephalitis. Prospective nationwide clinical databases of central nervous system infections may be superior to epidemiological monitoring based on notifications or laboratory systems.

Early versus late diagnosis in community-acquired bacterial meningitis: a retrospective cohort study.

OBJECTIVES: To examine clinical characteristics and outcome of patients with late diagnosis of community-acquired bacterial meningitis (CABM). METHODS: We conducted a chart review of all adults with proven CABM in three centres in Denmark from 1998 through to 2014. Patients were categorized as early diagnosis of CABM immediately on admission, or late diagnosis if CABM was not listed in referral or admission records and neither lumbar puncture nor antibiotic therapy for meningitis was considered immediately on admission. We used modified Poisson regression analysis to compute adjusted relative risks with 95% CIs for predictors of late diagnosis and in-hospital mortality. RESULTS: A total of 113/358 (32%) patients were categorized as late diagnosis demonstrating a variety of tentative diagnoses of which 81/113 (72%) were non-infectious. We observed several statistically significant baseline differences (p <0.05) in patients with late versus early diagnosis including age >65 years (56/113, 50% versus 67/245, 27%), neck stiffness (35/97, 36% versus 183/234, 78%), concomitant pneumonia (26/113, 23% versus 26/245, 11%), and meningococcal meningitis (6/113, 5% versus 52/245, 21%). These variables remained statistically significant in multivariate analysis. Moreover, late diagnosis was associated with increased in-hospital mortality (41/113, 36% versus 43/245, 18%; adjusted relative risk 1.7, 95% CI 1.2-2.5). CONCLUSIONS: Late diagnosis of CABM was common and patients were admitted with mostly non-infectious diagnoses. Absence of neck stiffness did not rule out CABM and special attention should be given to patients with pneumonia and the elderly. Late diagnosis was associated with incorrect patient management and increased mortality.