Caspofungin Cerebral Penetration and Therapeutic Efficacy in Experimental Cerebral Aspergillosis.

Despite best available therapy, cerebral aspergillosis is an often-lethal complication of disseminated aspergillosis. There is an urgent need to expand the currently limited therapeutic options. In this study, we assessed cerebral drug exposure and efficacy of caspofungin (CAS) using a lethal infant rat model of cerebral aspergillosis. Eleven-day-old Wistar rats were infected by intracisternal injection of Aspergillus fumigatus conidia. Treatment started after 22 h and was continued for 10 days. Regimens were CAS 1 mg/kg/day intraperitoneally (i.p.), liposomal amphotericin B (L-AmB) 5 mg/kg/day i.p., and both drugs combined at the same dose i.p. Infected controls were given NaCl 0.85% i.p. Primary endpoints assessed were survival, cerebral fungal burden, galactomannan index, and drug concentrations in brain homogenate at 2, 3, 5, and 11 days after infection. Compared to those of controls (4.4 ± 2.7 days), survival times were increased by treatment with CAS alone (10.3 ± 1.7 days; P < 0.0001) and CAS combined with L-AmB (9.3 ± 2.8 days; P < 0.0001). In contrast, survival time of L-AmB-treated animals (4.3 ± 3.1 days) was not different from that of controls. Cerebral fungal burden and galactomannan index declined in all animals over time, without significant differences between controls and treated animals. CAS trough levels in brain tissue were between 0.84 and 1.4 μg/g, concentrations we show to be associated with efficacy. AmB trough levels in brain tissue were higher than the MIC of the A. fumigatus isolate. In summary, CAS concentrations in brain tissue suggest it may be therapeutically relevant and it significantly improved survival in this lethal model of cerebral aspergillosis in nonneutropenic rats. The clinical efficacy of CAS treatment for cerebral aspergillosis merits further study. IMPORTANCE Treatment options for cerebral aspergillosis, an often-lethal disease, are limited. The echinocandins (caspofungin is one of them) are not recommended treatment because their brain tissue penetration is often considered insufficient. In a nursing rat model of cerebral aspergillosis that mimics human disease, we found potentially therapeutically relevant concentrations of caspofungin in brain tissue and prolonged survival of caspofungin-treated animals. The efficacy of caspofungin in the treatment of cerebral aspergillosis documented here, if confirmed in other animal models (especially immunosuppressed murine models) and by using additional Aspergillus isolates across a range of CAS minimal effective concentrations (MECs), would suggest that caspofungin merits further study as a treatment option for patients suffering from aspergillosis disseminated to the brain

Predictive Value of Cerebrospinal Fluid (CSF) Lactate Level Versus CSF/Blood Glucose Ratio for the Diagnosis of Bacterial Meningitis Following Neurosurgery

The value of cerebrospinal fluid (CSF) lactate level and CSF/blood glucose ratio for the identification of bacterial meningitis following neurosurgery was assessed in a retrospective study. During a 3-year period, 73 patients fulfilled the inclusion criteria and could be grouped by preset criteria in one of three categories: proven bacterial meningitis (n = 12), presumed bacterial meningitis (n = 14), and nonbacterial meningeal syndrome (n = 47). Of 73 patients analyzed, 45% were treated with antibiotics and 33% with steroids at the time of first lumbar puncture. CSF lactate values (cutoff, 4 mmol/L), in comparison with CSF/blood glucose ratios (cutoff, 0.4), were associated with higher sensitivity (0.88 vs. 0.77), specificity (0.98 vs. 0.87), and positive (0.96 vs. 0.77) and negative (0.94 vs. 0.87) predictive values. In conclusion, determination of the CSF lactate value is a quick, sensitive, and specific test to identify patients with bacterial meningitis after neurosurger

Predictive Value of Cerebrospinal Fluid (CSF) Lactate Level Versus CSF/Blood Glucose Ratio for the Diagnosis of Bacterial Meningitis Following Neurosurgery

The value of cerebrospinal fluid (CSF) lactate level and CSF/blood glucose ratio for the identification of bacterial meningitis following neurosurgery was assessed in a retrospective study. During a 3-year period, 73 patients fulfilled the inclusion criteria and could be grouped by preset criteria in one of three categories: proven bacterial meningitis (n = 12), presumed bacterial meningitis (n = 14), and nonbacterial meningeal syndrome (n = 47). Of 73 patients analyzed, 45% were treated with antibiotics and 33% with steroids at the time of first lumbar puncture. CSF lactate values (cutoff, 4 mmol/L), in comparison with CSF/blood glucose ratios (cutoff, 0.4), were associated with higher sensitivity (0.88 vs. 0.77), specificity (0.98 vs. 0.87), and positive (0.96 vs. 0.77) and negative (0.94 vs. 0.87) predictive values. In conclusion, determination of the CSF lactate value is a quick, sensitive, and specific test to identify patients with bacterial meningitis after neurosurger

Der internistische Check-up

Zusammenfassung: Viele präventive Maßnahmen bei gesunden Erwachsenen werden in zunehmendem Maße durch Evidenz gestützt oder verworfen. Dabei sind v.a. die Beratung bezüglich Tabakabstinenz, indizierte Impfungen und das Screening in Bezug auf Übergewicht, hohen Blutdruck, Hyperlipidämie, Zervixkarzinom, kolorektales Karzinom und Mammakarzinom bewiesenermaßen wichtig und sinnvoll. Nicht empfohlen wird ein Screening für Bronchial-, Pankreas- und Ovarialkarzinom. Ein Screening für Diabetes mellitus beim jüngeren Erwachsenen, Schilddrüsenerkrankungen und Prostatakarzinom wird nicht routinemäßig empfohlen, sollte aber je nach persönlichem Risikoprofil im Sinne eines sog. "Case findings" erwogen werden. Aus ärztlicher Sicht ist es auch wichtig, auf mögliche nicht deklarierte Beweggründe für eine Check-up-Untersuchung einzugehen, um so mögliche "Hidden Agendas" der Konsultationen aufzudecke

Eosinophilia in patients infected with the human immunodeficiency virus

The prevalence and significance of peripheral blood eosinophilia in patients infected with the human immunodeficiency virus (HIV) were evaluated. Fifteen of 119 consecutive patients had absolute eosinophil counts of > 450/mm3. During a mean follow-up period of 419 days eosinophilia could be identified as secondary to a parasitic infection in only one patient. Correlation with disease stage showed a higher rate of advanced disease in patients with absolute eosinophilia. In a multivariate regression analysis, only low CD4+ cell counts, not the CDC disease stage or the use of antiretroviral therapy or primary prophylaxis, contributed significantly to the prevalence of eosinophilia. It is concluded that expen-sive laboratory investigations in asymptomatic patients with advanced-stage HIV disease are neither necessary nor cost effectiv

Toll-Like Receptor 2-Deficient Mice Are Highly Susceptible to Streptococcus pneumoniae Meningitis because of Reduced Bacterial Clearing and Enhanced Inflammation

Toll-like receptor-2 (TLR2) mediates host responses to gram-positive bacterial wall components. TLR2 function was investigated in a murine Streptococcus pneumoniae meningitis model in wild-type (wt) and TLR2-deficient (TLR2−/−) mice. TLR2−/− mice showed earlier time of death than wt mice (P<.02). Plasma interleukin-6 levels and bacterial numbers in blood and peripheral organs were similar for both strains. With ceftriaxone therapy, none of the wt but 27% of the TLR2−/− mice died (P<.04). Beyond 3 hours after infection, TLR2−/− mice had higher bacterial loads in brain than did wt mice, as assessed with luciferase-tagged S. pneumoniae by means of a Xenogen-CCD (charge-coupled device) camera. After 24 h, tumor necrosis factor activity was higher in cerebrospinal fluid of TLR2−/− than wt mice (P<.05) and was related to increased blood-brain barrier permeability (Evans blue staining, P<.02). In conclusion, the lack of TLR2 was associated with earlier death from meningitis, which was not due to sepsis but to reduced brain bacterial clearing, followed by increased intrathecal inflammatio

A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case-control study

Purpose: Rifampin combination therapy plays an important role in the management of staphylococcal periprosthetic joint infection (PJI). However, the emergence of rifampin resistance is a feared complication. We retrospectively analysed predetermined potential risk factors in patients with rifampin-resistant staphylococcal PJI in a multicentre case-control study. Methods: Cases (n=48) were defined as PJI caused by rifampin-resistant staphylococci. Rifampin-susceptible controls (n=48) were matched for microorganism and type of prosthetic joint. Uni- and multivariable conditional logistic regression analyses were performed to estimate odds ratios (OR) with 95% confidence intervals (95% CI). Results: Forty-eight cases (31 men; median age 67years; age range 39-88years) with hip- (n=29), knee- (n=13), elbow- (n=4), shoulder- (n=1) or ankle-PJI (n=1) were enrolled in the study. Staphylococcus aureus and coagulase-negative staphylococci were isolated in ten and 38 episodes, respectively. Most of the cases (n=44, 92%) had a previous PJI, and 93 % (n=41) of these had been treated with rifampin. There was an independent association of emergence of rifampin resistance with male sex (OR 3.6, 95% CI 1.2-11),≥3 previous surgical revisions (OR 4.7, 95% CI 1.6-14.2), PJI treatment with high initial bacterial load (inadequate surgical debridement, <2weeks of intravenous treatment of the combination medication; OR 4.9, 95% CI 1.6-15) and inadequate rifampin therapy (OR 5.4, 95% CI 1.2-25). Conclusions: Based on our results, extensive surgical debridement and adequate antibiotic therapy are needed to prevent the emergence of rifampin resistanc