In vitro efficacy of nitro- and bromo-thiazolyl-salicylamide compounds (thiazolides) against Besnoitia besnoiti infection in Vero cells

Nitazoxanide (NTZ) and its deacetylated metabolite tizoxanide (TIZ) exhibit considerable in vitro activity against Besnoitia besnoiti tachyzoites grown in Vero cells. Real-time-PCR was used to assess B. besnoiti tachyzoite adhesion, invasion, and intracellular proliferation in vitro. A number of NTZ-derivatives, including Rm4822 and Rm4803, were generated, in which the thiazole-ring-associated nitro-group was replaced by a bromo-moiety. We here show that replacement of the nitro-group on the thiazole ring with a bromo (as it occurs in Rm4822) does not impair the efficacy of the drug, but methylation of the salicylate ring at the ortho-position in a bromo-derivative (Rm4803) results in complete abrogation of the antiparasitic activity. Treatment of extracellular B. besnoiti tachyzoites with NTZ has an inhibitory effect on host cell invasion, while treatments with TIZ, Rm4822 do not. TEM demonstrates that the effects of Rm4822 treatment upon the parasites are similar to the damage induced by NTZ. This includes increased vacuolization of the parasite cytoplasm, and loss of the structural integrity of the parasitophorous vacuole and its membrane. Thus, Rm4822, due to the absence of a potentially mutagenic nitro-group, may represent an important potential addition to the anti-parasitic arsenal for food animal production, especially in cattle.

Impact of variation in acute virulence of BVDV1 strains on design of better vaccine efficacy challenge models

Due to antigenic differences between BVDV1 and BVDV2 strains, both pestivirus species are included in U.S. vaccines. The efficacy of these vaccines in preventing acute infections is evaluated based on reduction of clinical disease. While high virulence BVDV2 strains are used in U.S. vaccine efficacy studies, the BVDV1 strain used (NY-1) produces very little in the way of clinical disease. In order to identify a BVDV1 strain that generates a more pronounced clinical presentation, three field strains were compared to NY-1. Infection with two of the field strains resulted in significantly more pronounced clinical disease compared to NY-1. Decreasing the inoculation of a field strain by two logs did not significantly change clinical presentation.

Delivery mode and efficacy of BMP-2 in association with implants

Bone healing may be improved in implant patients by the administration of osteogenic agents, such as bone morphogenetic protein 2 (BMP-2). But the efficacy of BMP-2 depends upon its mode of application. We hypothesized that BMP-2 is capable of a higher osteogenic efficacy when delivered physiologically, viz., when incorporated into a calcium-phosphate carrier that mimics mineralized bone matrix, than when administered via simple pharmacological modes, such as by adsorption onto a carrier surface. Using an ectopic rat model, we compared the osteoinductive efficacies of calcium-phosphate implant-coatings bearing either incorporated, adsorbed, or incorporated and adsorbed BMP-2. When adsorbed directly onto the naked implant surface, BMP-2 was not osteogenic. When adsorbed onto a calcium-phosphate coating, it was osteoinductive, but not highly efficacious. When BMP-2 was incorporated into calcium-phosphate coatings, it was a potent bone-inducer, whose efficacy was compromised, not potentiated, by the additional deposition of an adsorbed pool.

Reduced neuronal efficacy in progressive mild cognitive impairment: a prospective fMRI study on visuospatial processing

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimer's disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI.

Efficacy and safety of intravenous meropenem and tobramycin versus ceftazidime and tobramycin in cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic bacterial broncho-pulmonary infection. Although intravenous (IV) antibiotic therapy is regarded as standard treatment in CF, only few randomised trials comparing different antibiotic compounds exist. METHODS: We report on a prospective multicenter interventional trial of IV meropenem (120 mg/kg/day) or IV ceftazidime (200-400 mg/kg/day), each administered together with IV tobramycin (9-12 mg/kg/day). Outcome measures were changes in lung function, microbiological sputum burden and blood inflammatory marker. Liver and renal function values were measured to assess safety. RESULTS: One hundred eighteen patients (59/59) were included into the study with the following indications: first infection of P. aeruginosa (n=6), acute pulmonary exacerbation (n=34) and suppression therapy of chronic P. aeruginosa colonization (n=78). Both treatments improved lung function measures, bacterial sputum burden and CRP levels with no differences between treatment groups observed. A significant higher elevation for alkaline phosphatase (p<0.0001) was observed for patients in the meropenem/tobramycin group. CONCLUSIONS: IV antibiotic therapy in CF patients with meropenem/tobramycin is as effective as with ceftazidime/tobramycin regarding lung function, microbiological sputum burden and systemic inflammatory status. Hepato-biliary function should be monitored carefully during IV treatment, possibly important in CF patients with pre-existing liver disease.

[Fixed-combination of losartan/hydrochlorothiazide 100 mg/25 mg. Tolerability and efficacy on blood pressure measured in the practice and for 24 hours]

BACKGROUND: A high proportion of patients with essential hypertension need a combination therapy to reach the therapeutic goal. In the present study, the tolerability and efficacy of a fixed, once daily combination of the AT1 blocker Losartan (100 mg) and the diuretic hydrochlorothiazide (HCTZ) (25 mg) for patients in the real-life situation was investigated. Special consideration was given to the results of ambulatory 24-hourblood pressure (ABP) measurements. METHODS: The open label, prospective non-interventional surveillance study took place from October 2005 to June 2006. A total of 1139 patients over 18 years in age were included whose blood pressures could not be adequately treated with HCTZ alone and for whom an individual dose titration for Losartan and HCTZ had already been performed. RESULTS: The average age (+/- standard deviation) of the patients was 61.2 +/- 11.6 years; 55.8% were men. Comorbidities were common. Specifically, left ventricular hypertrophy was present in 3.1% of the patients, coronary heart disease in 30.1%, chronic heart failure in 11.8% and status post myocardial infarction in 10.5%, respectively. In addition to the Losartan/HCTZ treatment, 61.0% of the patients received a second antihypertensive medicine. After an average treatment duration of 50.4 +/- 17.2 days, the base line systolic blood pressure of 160.8 +/- 16.3 mmHg decreased by 24.0 +/- 17.0 mmHg (-14.4%) and the diastolic blood pressure of 94.4 +/- 9.9 mmHg decreased by 11.8 +/- 10.2 mmHg (-11.8%). For the ABP measurements, the overall average systolic and diastolic blood pressures fell by 16.9 +/- 14.2 mmHg and 8.8 +/-10.3 mmHg, the day average by 17.3 +/- 14.8 mmHg and 9.0 +/- 10.2 mmHg and the night average by 15.1 +/- 17.6 mmHg and 7.8 +/- 11.7 mmHg, respectively. In twelve of the 1139 patients (1.1%), a total of 15 adverse events occurred. A causal connection with the medication was suspected in only in one case (one patient with three). CONCLUSION: The combination of Losartan/HCTZ 100/25 mg, as the exclusive therapy or in addition to other antihypertensive medicines, was for patients, many of whom who had comorbidities, in the real-life situation well tolerated and effective. The efficacy was demonstrated also during the night through ABP.

Microalbuminuria in diabetes mellitus: efficacy of a new screening method in comparison with timed overnight urine collection

Diabetic nephropathy and end-stage renal failure are still a major cause of mortality amongst patients with diabetes mellitus (DM). In this study, we evaluated the Clinitek-Microalbumin (CM) screening test strip for the detection of microalbuminuria (MA) in a random morning spot urine in comparison with the quantitative assessment of albuminuria in the timed overnight urine collection ("gold standard"). One hundred thirty-four children, adolescents, and young adults with insulin-dependent DM Type 1 were studied at 222 outpatient visits. Because of urinary tract infection and/or haematuria, the data of 13 visits were excluded. Finally, 165 timed overnight urine were collected in the remaining 209 visits (79% sample per visit rate). Ten (6.1%) patients presented MA of > or =15 microg/min. In comparison however, 200 spot urine could be screened (96% sample/visit rate) yielding a significant increase in compliance and screening rate (P<.001, McNemar test). Furthermore, at 156 occasions, the gold standard and CM could be directly compared. The sensitivity and the specificity for CM in the spot urine (cut-off > or =30 mg albumin/l) were 0.89 [95% confidence interval (CI) 0.56-0.99] and 0.73 (CI 0.66-0.80), respectively. The positive and negative predictive value were 0.17 (CI 0.08-0.30) and 0.99 (CI 0.95-1.00), respectively. Considering CM albumin-to-creatinine ratio, the results were poorer than with the albumin concentration alone. Using CM instead of quantitative assessment of albuminuria is not cost-effective (35 US dollars versus 60 US dollars/patient/year). In conclusion, to exclude MA, the CM used in the random spot urine is reliable and easy to handle, but positive screening results of > or =30 mg albumin/l must be confirmed by analyses in the timed overnight collected urine. Although the screening compliance is improved, in terms of analysing random morning spot urine for MA, we cannot recommend CM in a paediatric diabetic outpatient setting because the specificity is far too low.

Vagus nerve stimulation for depression: efficacy and safety in a European study

Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression.

Limited efficacy of adjuvant therapy with dexamethasone in preventing hearing loss due to experimental pneumococcal meningitis in the infant rat

Sensorineural hearing loss (SNHL) is the most common sequel of bacterial meningitis (BM) and is observed in up to 30% of survivors when the disease is caused by Streptococcus pneumoniae. BM is the single most important origin of acquired SNHL in childhood. Anti-inflammatory dexamethasone holds promises as potential adjuvant therapy to prevent SNHL associated with BM. However, in infant rats, pneumococcal meningitis (PM) increased auditory brainstem response (ABR) thresholds [mean difference = 54 decibels sound pressure level (dB SPL)], measured 3 wk after infection, irrespective to treatment with ceftriaxone plus dexamethasone or ceftriaxone plus saline (p < 0.005 compared with mock-infected controls). Moreover, dexamethasone did not attenuate short- and long-term histomorphologic correlates of SNHL. At 24 h after infection, blood-labyrinth barrier (BLB) permeability was significantly increased in infected animals of both treatment groups compared with controls. Three weeks after the infection, the averaged number of type I neurons per square millimeter of the Rosenthal's canal dropped from 0.3019 +/- 0.0252 in controls to 0.2227 +/- 0.0635 in infected animals receiving saline (p < 0.0005). Dexamethasone was not more effective than saline in preventing neuron loss (0.2462 +/- 0.0399; p > 0.05). These results suggest that more efficient adjuvant therapies are needed to prevent SNHL associated with pediatric PM.

Gentamicin increases the efficacy of vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model

In experimental meningitis a single dose of gentamicin (10 mg/kg of body weight) led to gentamicin levels in around cerebrospinal fluid (CSF) of 4 mg/liter for 4 h, decreasing slowly to 2 mg/liter 4 h later. The CSF penetration of gentamicin ranged around 27%, calculated by comparison of areas under the curve (AUC in serum/AUC in CSF). Gentamicin monotherapy (-1.24 log(10) CFU/ml) was inferior to vancomycin monotherapy (-2.54 log(10) CFU/ml) over 8 h against penicillin-resistant pneumococci. However, the combination of vancomycin with gentamicin was significantly superior (-4.48 log(10) CFU/ml) compared to either monotherapy alone. The synergistic activity of vancomycin combined with gentamicin was also demonstrated in vitro in time-kill assays.

Efficacy of gatifloxacin alone and in combination with cefepime against penicillin-resistant Streptococcus pneumoniae in a rabbit meningitis model and in vitro

Gatifloxacin penetrated well into cerebrospinal fluid (CSF) (49 +/- 11%), measured by comparison of AUC(CSF)/AUC(serum), and showed good bactericidal activity (leading to a decrease of 0.75 +/- 0.17 log10 cfu/mL/h) in the treatment of experimental meningitis in rabbits caused by a penicillin-resistant pneumococcal strain (MIC 4 mg/L). It was significantly more effective than the standard regimen, ceftriaxone with vancomycin, which led to a decrease of 0.53 +/- 0.17 log10 cfu/mL/h. The addition of cefepime to gatifloxacin slightly improved the killing rates (giving a decrease of 0.84 +/- 0.14 log10 cfu/mL/h). In vitro, synergy was demonstrated between cefepime and gatifloxacin by the chequerboard method (fractional inhibitory concentration index = 0.5) and by viable counts over 8 h.

Comparative efficacy of trovafloxacin in experimental endocarditis caused by ciprofloxacin-sensitive, methicillin-resistant Staphylococcus aureus

The new fluoroquinolone trovafloxacin was tested against a ciprofloxacin-sensitive, methicillin-resistant Staphylococcus aureus strain in the rabbit model of endocarditis. Trovafloxacin was more effective than vancomycin (CFU/g of vegetation, 2.65 +/- 1.87 versus 4.54 +/- 2.80 [mean +/- standard deviation]; P < 0.05) or ampicillin-sulbactam plus rifampin (4.9 +/- 1.1 CFU/g). The addition of ampicillin-sulbactam to trovafloxacin tended to reduce titers further.

A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate

PURPOSE: The primary purpose of the clinical trial was to assess the safety and efficacy of once-a-day compared with three-times-a-day gentamicin in patients with serious infections who had protocol-determined peak serum aminoglycoside concentrations. PATIENTS AND METHODS: A total of 249 hospitalized patients with suspected or proven serious infections were randomized in a 2:2:1 ratio to gentamicin given three times a day with ticarcillin-clavulanate (TC), gentamicin once a day with TC, or ticarcillin-clavulanate (TC) alone. The gentamicin once-a-day dosage for patients with estimated creatinine clearance values of > or =80 mL/min was 5.1 mg/kg. With lower creatinine clearance estimates, the mg/kg dosage of gentamicin was decreased, and the dosage intervals (once daily or three times a day) were maintained. Evaluability required documentation of achievement of protocol-defined peak serum gentamicin levels. RESULTS: Of the total 175 evaluable patients, there were no significant differences found between treatment regimens with respect to clinical or microbiologic efficacy. Bedside audiometry proved impractical due to the frequency of altered mental state in ill patients. Based on the traditional increase in serum creatinine values from baseline values, no differences in renal toxicity between the treatment groups was identified. When changes in renal function were reanalyzed based on maintaining, as opposed to worsening, of renal function, preservation of renal function was better in the gentamicin once-a-day patients as opposed to the gentamicin three-times-a-day patients, P <0.01. CONCLUSIONS: Gentamicin once a day plus TC, gentamicin three times a day plus TC, and TC alone had similar effects in seriously ill hospitalized patients. The incidence of nephrotoxicity was similar in the three treatment groups. Using a nonvalidated post-hoc analysis, renal function was better preserved in gentamicin once-a-day + TC and TC-only patients as opposed to gentamicin three-times-a-day + TC.

Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin

We examined the effect of azithromycin (CP-62,993), a new oral macrolide-like antibiotic, alone and in combination with rifampin, as treatment for experimental staphylococcal osteomyelitis. Clindamycin was used as a comparison drug. Rats (n = 10 to 15 per group) were infected by direct instillation of Staphylococcus aureus into the tibial medullary cavity. After 10 days, 21-day treatments with azithromycin (50 mg/kg of body weight, once daily, by the oral route), rifampin (20 mg/kg, once daily, subcutaneously), or clindamycin (90 mg/kg, three times daily, by the oral route) were started. The drugs were used singly or in combination (azithromycin plus rifampin or clindamycin plus rifampin). Peak azithromycin concentrations in bone were > 30 times higher than levels in serum, but the drug had little effect on final bacterial titers (5.13 +/- 0.46 log10 CFU/g of bone; for controls, 6.54 +/- 0.28 log10 CFU/g). Clindamycin was more active than azithromycin (3.26 +/- 2.14 log10 CFU/g of bone; 20% of sterilized bones), but rifampin was the most active single drug (1.5 +/- 1.92 log10 CFU/g; 53% of sterilized bones). Therapy with rifampin or clindamycin alone was associated with the emergence of resistance. Rifampin plus azithromycin (0.51 +/- 1.08 log10 CFU/g of bone; 80% of sterilized bones) and rifampin plus clindamycin (0.87 +/- 1.34 log10 CFU/g of bone; 66% of sterilized bones) were the most active regimens. Thus, azithromycin is ineffective as a single drug for the treatment of experimental staphylococcal osteomyelitis, despite high levels in bone that markedly exceeded the MIC, but it may be an attractive partner drug for rifampin.

Therapeutic efficacy of teicoplanin in experimental enterococcal endocarditis

The antimicrobial activities of teicoplanin and ampicillin, alone and in combination with gentamicin, were compared in experimental Streptococcus faecalis endocarditis. Bacterial titers in vegetations of rabbits treated with teicoplanin were significantly lower than those of untreated controls (P less than 0.01) and were equivalent to titers in ampicillin-treated animals. Gentamicin increased the activities of both drugs to a comparable degree.