Extracerebral Infection Research Articles

Reply to Gatti and Pea, "Are the pharmacokinetic data of meropenem studied in CSF of a mixed population composed of patients with cerebral infections and patients with extracerebral infections really helpful for clinicians treating CNS infections?"

Reply to Gatti and Pea, "Are the pharmacokinetic data of meropenem studied in CSF of a mixed population composed of patients with cerebral infections and patients with extracerebral infections really helpful for clinicians treating CNS infections?"

Linezolid brain penetration in neurointensive care patients.

Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients. Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe. The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L. Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.

Infective endocarditis with Osler’s nodule in a patient with Osler’s disease: a case report and review of the literature

BackgroundHereditary hemorrhagic telangiectasia, also known as Osler–Weber–Rendu disease, induces arteriovenous malformations in visceral organs. Arteriovenous malformations increase the risk of severe infections and are a common complication associated with hemorrhagic telangiectasia. However, cases of endocarditis associated with hemorrhagic telangiectasia are rarely reported. Although hemorrhagic telangiectasia causes erythematous macules on the extremities, these macules are usually painless. We encountered a rare case of infective endocarditis in a patient with Osler–Weber–Rendu disease.Case presentationA 52-year-old Japanese woman who was diagnosed with hemorrhagic telangiectasia 5 years prior presented to our hospital with fever and muscular pain. She had erythematous nodules and tenderness on the finger, heel, and toe, suggestive of Osler’s nodes. A physical examination revealed tachycardia with a 3/6 pansystolic murmur. A transesophageal echocardiogram showed vegetations along the atrial side of the mitral valve and mild mitral regurgitation because of prolapse of the anterior commissure. Methicillin-sensitive Staphylococcus aureus was identified in the blood cultures. Detection of distinctive skin lesions, so-called Osler’s nodes, was the symptomatic key to early diagnosis, and the patient was treated without surgery. She was discharged with negative blood cultures after a 6-week intravenous antibiotic administration.ConclusionsOur report highlights the importance of considering the risk of extracerebral infections including endocarditis in hemorrhagic telangiectasia. This rare case effectively demonstrates the importance of proper diagnosis of skin lesions.

Meropenem concentrations in brain tissue of neurointensive care patients exceed CSF levels.

Inadequate antibiotic exposure in cerebral infections might have detrimental effects on clinical outcome. Commonly, antibiotic concentrations within the CSF were used to estimate cerebral target levels. However, the actual pharmacological active unbound drug concentration beyond the blood-brain barrier is unknown. To compare meropenem concentrations in blood, CSF and cerebral microdialysate of neurointensive care patients. In 12 patients suffering subarachnoid haemorrhage, 2000 mg of meropenem was administered every 8 h due to an extracerebral infection. Meropenem concentrations were determined in blood, CSF and cerebral microdialysate at steady state (n = 11) and following single-dose administration (n = 5). At steady state, the free AUC0-8 was 233.2 ± 42.7 mg·h/L in plasma, 7.8 ± 1.9 mg·h/L in CSF and 26.6 ± 14.0 mg·h/L in brain tissue. The brain tissue penetration ratio (AUCbrain/AUCplasma) was 0.11 ± 0.06, which was more than 3 times higher than in CSF (0.03 ± 0.01), resulting in an AUCCSF/AUCbrain ratio of 0.41 ± 0.16 at steady state. After single-dose administration similar proportions were achieved (AUCbrain/AUCplasma = 0.09 ± 0.08; AUCCSF/AUCplasma = 0.02 ± 0.00). Brain tissue concentrations correlated well with CSF concentrations (R = 0.74, P < 0.001), but only moderately with plasma concentrations (R = 0.51, P < 0.001). Bactericidal thresholds were achieved in both plasma and brain tissue for MIC values ≤16 mg/L. In CSF, bactericidal effects were only reached for MIC values ≤1 mg/L. Meropenem achieves sufficient bactericidal concentrations for the most common bacterial strains of cerebral infections in both plasma and brain tissue, even in non-inflamed brain tissue. CSF concentrations would highly underestimate the target site activity of meropenem beyond the blood-brain barrier.

The expression of TLR2 and TLR4 in the kidneys and heart of mice infected with Acanthamoeba spp.

BackgroundAcanthamoeba spp. are cosmopolitan protozoans that cause infections in the brain, as well as extracerebral infections in the cornea, lungs and skin. Little is known about the mechanisms of the immunological response to these parasites in organs which are not their main biotope. Therefore, the purpose of this study was to determine the expression of TLR2 and TLR4 in the kidneys and heart of Acanthamoeba spp.-infected mice, with respect to the host’s immunological status.MethodsThe mice were grouped into four groups: immunocompetent control mice; immunosuppressed control mice; immunocompetent Acanthamoeba spp.-infected mice; and immunosuppressed Acanthamoeba spp. infected mice. In the study, we used the amoebae T16 genotype which was isolated from a patient. The TLRs expressions in the kidneys and heart of mice were assessed by quantitative real-time polymerase chain reaction. Moreover, we visualized TLR2 and TLR4 proteins in the organs by immunohistochemical staining.ResultsIn the kidneys, we observed a higher TLR2 expression in immunosuppressed mice at 24 days post-Acanthamoeba spp. infection (dpi) compared to the uninfected mice. There were no statistically significant differences in TLR4 expression in the kidneys between the immunocompetent and immunosuppressed mice, both of infected and uninfected mice. In the heart, we observed a difference in TLR2 expression in immunocompetent mice at 24 dpi compared to immunocompetent mice at 8 dpi. The immunocompetent Acanthamoeba spp.-infected mice had higher TLR4 expression at 8 dpi compared to the immunocompetent uninfected mice.ConclusionsOur results indicate that TLR2 is involved in response to Acanthamoeba spp. infection in the kidneys, whereas in the heart, both studied TLRs are involved.

"Proposals for Amendments in the Diagnosis and Treatment of Encephalitis caused by Free-living Amoebae".

Encephalitis caused by Free-living amoebae (FLA) has a mortality rate of around 95- 98%, a fraction that has not changed in the past decades. Pathogenic FLA include Acanthamoeba, Balamuthia mandrillaris, and Naegleria fowleri that are known to target the brain after an extra cerebral infection in the case of Acanthamoeba and Balamuthia mandrillaris, or directly the brain, as in the case of the Naegleria fowleri. The Acanthamoeba spp. and Balamuthia mandrillaris cause granulomatous amoebic encephalitis (GAE) while Naegleria fowleri, the so termed "brain eating amoeba" causes primary amoebic meningoencephalitis (PAM). The attempts to obtain a speedy diagnosis and an aggressive treatment protocol are the areas where advances can make a difference and reduce the mortality rates. At first, we highlight the reasons behind the diagnostic delays and treatment failures and provide proposals to establish a quick diagnosis in both PAM and GAE. Secondly, we emphasize the use of a transcribrial device, and a prompt, but vigilant surgical reduction of the intracranial pressure in these patients which could be life-saving. We also debate that an exudate obtained from the olfactory region by irrigation via a modified transcribrial device or by conventional methods, instead of a cerebrospinal fluid sample, could serve as a source of obtaining amoeba in PAM for a real-time polymerase chain reaction-based definitive diagnosis of PAM. Also, introduced is the rationale that has the potential to deliver the drugs to the brain in patients with PAM and the GAE localized to the frontal lobe of the brain, by bypassing the blood brain barrier. We put forward these proposals for debate and deliberation to our fellow colleagues in order to spot the potential of their application to reduce the mortality rates caused by the rare but fatal encephalitis caused by these FLA.

Cytomegalovirus infection in pregnancy.

Due to the severe risk of long-term sequelae, prenatal cytomegalovirus infection is of particular importance amongst intrauterine viral infections.This review summarizes the current knowledge about CMV infection in pregnancy. A search of the Medline and Embase database was done for articles about CMV infection in pregnany. We performed a detailed review of the literature in view of diagnosis, epidemiology and management of CMV infection in pregnancy. The maternal course of the infection is predominantly asymptomatic; the infection often remains unrecognized until the actual fetal manifestation. Typical ultrasound signs that should arouse suspicion of intrauterine CMV infection can be distinguished into CNS signs such as ventriculomegaly or microcephaly and extracerebral infection signs such as hepatosplenomegaly or hyperechogenic bowel. Current treatment strategies focus on hygienic measures to prevent a maternal CMV infection during pregnancy, on maternal application of hyperimmunoglobulines to avoid materno-fetal transmission in case of a maternal seroconversion, and on an antiviral therapy in case the materno-fetal transmission have occurred. CMV infection in pregnancy may result in a severe developmental disorder of the newborn. This should be taken into account in the treatment of affected and non-affected pregnant women.

Hemorrhagic Hereditary Telangiectasia (Rendu-Osler Disease) and Infectious Diseases: An Underestimated Association

Among 353 patients with hereditary hemorrhagic telangiectasia retrospectively analyzed during the period 1985-2005, we identified 67 cases of severe infection that affected 48 patients (13.6%). Extracerebral infections accounted for 67% of all infections, and most involved Staphylococcus aureus and were associated with prolonged epistaxis. Cerebral infections accounted for 33% of all infections, were mainly due to multiple and anaerobic bacteria, and were associated with the presence of pulmonary arteriovenous malformations and a short duration of epistaxis.

Levofloxacin disposition in cerebrospinal fluid in patients with external ventriculostomy.

In vitro levofloxacin exhibits both potent or intermediate activity against most of the pathogens frequently responsible for acute bacterial meningitis and synergistic activity with some beta-lactams. Since levofloxacin was shown to penetrate the cerebrospinal fluid (CSF) during meningeal inflammation both in animals and in humans, the disposition of levofloxacin in CSF was studied in 10 inpatients with external ventriculostomy because of communicating hydrocephalus related to subarachnoid occlusion due to cerebral accidents who were treated with 500 mg of levofloxacin intravenously twice a day because of extracerebral infections. Plasma and CSF concentration-time profiles and pharmacokinetics were assessed at steady state. Plasma and CSF levofloxacin concentrations were analyzed by high-pressure liquid chromatography. The peak concentration of levofloxacin at steady state (C(max ss))was 10.45 mg/liter in plasma and 4.06 mg/liter in CSF, respectively, with the ratio of the C(max ss) in CSF to the C(max ss) in plasma being 0.47. The areas under the concentration-time curves during the 12-h dosing interval (AUC(0-tau)s) were 47.69 mg. h/liter for plasma and 33.42 mg. h/liter for CSF, with the ratio of the AUC(0-tau) for CSF to the AUC(0-tau) for plasma being 0.71. The terminal-phase half-life of levofloxacin in CSF was longer than that in plasma (7.02 +/- 1.57 and 5.51 +/- 1.36 h, respectively; P = 0.034). The ratio of the levofloxacin concentration in CSF to the concentration in plasma progressively increased with time, from 0.30 immediately after dosing to 0.99 at the end of the dosing interval. In the ventricular CSF of patients with uninflamed meninges, levofloxacin was shown to provide optimal exposure, which approximately corresponded to the level of exposure of the unbound drug in plasma. The findings provide support for trials of levofloxacin with twice-daily dosing in combination with a reference beta-lactam for the treatment of bacterial meningitis in adults. This cotreatment could be useful both for overcoming Streptococcus pneumoniae resistance and for enabling optimal exposure of the CSF to at least one antibacterial agent for the overall treatment period.

Value of PCR for evaluating occurrence of parasitemia in immunocompromised patients with cerebral and extracerebral toxoplasmosis

PCR was used to evaluate the occurrence of Toxoplasma gondii parasitemia by detection of the B1 gene in blood samples in two groups of immunosuppressed patients (148 subjects) suspected of having cerebral or extracerebral infection, respectively. Group I consisted of 52 patients with AIDS with suspected cerebral toxoplasmosis. The diagnosis was clinically proven in 15 cases. Parasitemia was detected by PCR in only two of these patients (13.3%), both showing evidence of disseminated infection. Group II consisted of 96 immunocompromised patients, either with AIDS or receiving iatrogenic immunosuppressive therapy. Of these patients, 65 (34 with AIDS and 31 others) showed abnormalities only in chest radiography and were first screened for the presence of Toxoplasma DNA in bronchoalveolar lavage fluid. Blood was then analyzed when the parasite was detected in the bronchoalveolar lavage fluid. The remaining 31 subjects (22 with AIDS and 9 others) were suspected of having extracerebral, pulmonary, or disseminated toxoplasmosis, and blood was studied directly in these cases. Among the nine patients with clinically diagnosed extracerebral infection in group II, the parasite was detected by PCR in the blood of five patients (55.5%), all having pulmonary toxoplasmosis. If all patients with clinical manifestations of extracerebral toxoplasmosis (from both groups) who had not received antitoxoplasma therapy when the samples were collected are considered, PCR detected parasitemia in seven of the nine cases (77.8%). The present study indicates that examination of blood by PCR may be valuable in cases of extracerebral toxoplasmosis because of the disseminated nature of the disease. Since most cases of cerebral toxoplasmosis result from the local reactivation of latent brain cysts, detection of parasitemia by PCR is useful only in cases associated with severe cerebral infection or dissemination of this disease.

Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges

Cefotaxime and ceftriaxone have proven to be effective in pyogenic infections of the central nervous system. Since in some bacterial central nervous system infections the blood-cerebrospinal fluid (CSF) barrier is either minimally impaired or recovers in the course of the illness, we studied the penetration of both antibiotics in the absence of inflamed meninges. Patients who had undergone external ventriculostomies for noninflammatory occlusive hydrocephalus received either cefotaxime (2 g/30 min) or ceftriaxone (2 g/30 min) to treat extracerebral infections. Serum and CSF were drawn repeatedly after the first dose. With ceftriaxone, they were also drawn after the last dose. The concentrations of cefotaxime, its metabolite desacetylcefotaxime, and ceftriaxone were determined by high-performance liquid chromatography with UV detection. Maximum concentrations of cefotaxime in CSF were reached 0.5 to 8 h (median = 3 h; n = 6) after the end of the infusion and ranged from 0.14 to 1.81 mg/liter (median = 0.44 mg/liter; n = 6). Maximum levels of ceftriaxone in CSF ranging from 0.18 to 1.04 mg/liter (median = 0.43 mg/liter; n = 5) were seen 1 to 16 h (median = 12 h; n = 5) after the infusion. The elimination half-life of cefotaxime in CSF was 5.0 to 26.9 h (median = 9.3 h; n = 5), and that of ceftriaxone was 15.7 to 18.4 h (median = 16.8 h; n = 3). It is concluded that after a single dose of 2 g, maximal concentrations of cefotaxime and ceftriaxone in CSF do not differ substantially. The long elimination half-lives guarantee uniform concentrations in CSF. These concentrations reliably inhibit highly susceptible bacteria but cannot be relied on to inhibit staphylococci and penicillin G-resistant Streptococcus pneumoniae.

Optic Neuropathy and Paratrigeminal Syndrome Due to Aspercillus Fumigatus.

\s=b\Chronic Aspergillus meningitis and cerebral vasculitis occurred in a 67-year\x=req- old man. He experienced periorbital pain that increased in severity during a tenmonth period. Although no focal neurologic deficits were initially present, oculosympathetic paresis, corneal hypesthesia, and optic neuropathy developed. This is the first report, to our knowledge, of paratrigeminal syndrome with optic neuropathy due to aspergillosis. The case was also unusual because it was chronic and there was no extracerebral infection

Febrile convulsions and blood-cerebrospinal fluid barrier.

Three single CSF proteins with different molecular size (albumin, immunoglobulin G, and alpha2-macroglobulin) were determined by the method of electroimmunoassay in 61 children with febrile convulsions (FC) in order to evaluate the permeability of the blood-CSF barrier (B-CSF-B). Forty-two children with acute extracerebral infection served as controls. In contrast to a group of 22 children who suffered from acute meningoencephalitis or encephalitis, the CSF values of 48 children with FC were within normal limits. Thus even a very mild form of inflammatory encephalopathy-undetectable with conventional CSF investigation-was excluded in the majority of the children with FC. In 11 patients, however, CSF concentrations of albumin and alpha2-macroglobulin were abnormally raised, indicating a B-CSF-B distrubance. Elevated albumin values were found most frequently. In several children with FC lasting more than 20-30 min, B-CSF-B damage was probably caused by prolonged seizure activity since there is a linear correlation between albumin concentration and duration of convulsions. Several other factors known to raise the children's risk of developing epilepsy in later life were associated with the protein pattern of B-CSF-B disturbance in some of the children. In these cases, the cause of abnormal permeability of B-CSF-B is unknown and the condition might have existed prior to the occurrence of seizures.