R207910 (TMC207) : un nouvel antibiotique pour le traitement de la tuberculose

A new class of antibacterials, diarylquinolines, was identified. The lead compound, R207910 (TMC207), was able to inhibit Mycobacterium tuberculosis in vitro, in mice and in patients. R207910 targets the mycobacterial ATP synthase. In vitro, it displayed potent activities against both drug-sensitive and multidrug-resistant strains of M. tuberculosis. It was also strongly active against dormant bacilli in the Wayne's dormancy culture system, hypoxia and nitric oxide models. In the murine model, when used alone, it was as active as the triple combination of rifampicin + isoniazid + pyrazinamide. When added to the previous combination or substituted for isoniazid or rifampicin, the treatment including the combinations containing R207910 led to culture conversion after 2 months of therapy. When added to the combination used to treat MDR-TB or substituted for moxifloxacin or ethionamide, the combinations containing R207910 led to culture conversion after 2 months of therapy. In MDR-TB infected patients, R207910 combined with second line drugs was able to convert more sputum cultures (47.6%) than the placebo combined to second line drugs regimen (8.7%).     

Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration

The objective of the present study was to identify the optimal R207910-containing regimen to administer to patients who cannot receive rifampin (RIF) and isoniazid (INH) because of multidrug-resistant tuberculosis (MDR-TB), concomitant use of antiretroviral drugs, or toxicity. Mice were infected intravenously with 5 x 10(6) CFU of the H37Rv strain and treated five times per week with R207910 alone or various combinations of R207910 with the second-line drugs amikacin (AMK), pyrazinamide (PZA), moxifloxacin (MXF), and ethionamide (ETH). All R207910-containing regimens were significantly more active than the non-R207910-containing regimens after 1 month of therapy. When given for 2 months, R207910 alone was more active than the WHO standard first-line regimen RIF-INH-PZA. When R207910 was combined with second-line drugs, the combinations were more active than the currently recommended regimen of MDR-TB AMK-ETH-MXF-PZA, and culture negativity of both the lungs and spleen was reached after 2 months of treatment in almost every case.     

Detection of hypovascular hepatic metastases at triple-phase helical CT: sensitivity of phases and comparison with surgical and histopathologic findings

PURPOSE: To compare the respective sensitivities of unenhanced, arterial-dominant, and portal-dominant phase helical computed tomography (CT) in the preoperative depiction of hypovascular hepatic metastases by using intraoperative ultrasonographic (US) and histopathologic findings as the standard of reference. MATERIALS AND METHODS: In this prospective study, 32 patients with 59 surgically and histopathologically proved hypovascular hepatic metastases underwent triple-phase helical CT of the liver, which included unenhanced, arterial-dominant, and portal-dominant phase scanning. Images from each phase were separately analyzed by three readers, and disagreements were resolved with consensus readings. The findings on CT images were compared with intraoperative US and histopathologic findings on a lesion-by-lesion basis to determine the sensitivity of each imaging phase. Statistical review of the lesion-by-lesion analysis was performed by using the Wilcoxon rank sum test. RESULTS: Among 59 hepatic metastases, unenhanced, arterial-dominant, and portal-dominant phase helical CT imaging depicted 39 (66.1%; 95% CI: 53.3%, 76.8%), 44 (74.5%; 95% CI: 62.2%, 83.9%), and 54 (91.5%; 95% CI: 81.6%, 96.3%) metastases, respectively. Portal-dominant phase imaging depicted significantly more hypovascular hepatic metastases than did unenhanced (P <.001) or arterial-dominant (P <.01) phase imaging (Wilcoxon test). CONCLUSION: Preoperative use of triple-phase helical CT in patients with hypovascular hepatic metastases may not be warranted. Portal-dominant phase helical CT imaging allows depiction of significantly more hypovascular hepatic metastases than does imaging during any of the other phases.     

Hepatic involvement in hereditary hemorrhagic telangiectasia: helical computed tomography features in 24 consecutive patients

OBJECTIVE: Among the various organs that may be affected by hereditary hemorrhagic telangiectasia (HHT), the liver can show various degrees of vascular and parenchymal involvement. The purpose of this prospective study comprising a large series of patients was to reassess the computed tomography (CT) features of hepatic involvement in HHT using helical CT. METHODS: Twenty-four consecutive patients with HHT had prospective helical CT of the liver, including noncontrast, arterial-dominant, and portal-dominant phases. The CT images were analyzed by 2 readers in consensus to determine the presence of vascular and parenchymal abnormalities. The diameter of the proper hepatic artery in these 24 patients was compared with that in 24 healthy subjects (Student t test). RESULTS: Helical CT was normal in 5 patients (21%) and abnormal in 19 patients (79%). Vascular abnormalities were found in 16 patients (67%), consisting of marked dilatation of the hepatic artery (n = 16), intrahepatic telangiectases (n = 12), arteriovenous shunting (n = 5), and arterioportal shunting (n=3). The diameter of the proper hepatic artery was greater in the patients with HHT than in control subjects (6.12 +/- 2.52 mm vs. 3.29 +/- 0.65 mm, respectively; P < 0.05). Helical CT showed nodular hyperplasia in 1 patient with vascular and parenchymal abnormalities, cavernous hemangiomas in 2 patients (1 in a patient with an enlarged hepatic artery, intrahepatic telangiectases, and arteriovenous shunting and 1 in a patient with an isolated enlarged hepatic artery), and biliary cysts in 3 patients (2 biliary cysts were present in 2 patients with an enlarged hepatic artery and intrahepatic telangiectases, and 1 biliary cyst was present without any manifestations in the third patient). CONCLUSION: Liver involvement in HHT is associated with a constellation of findings on helical CT, including significant dilatation of the proper hepatic artery, telangiectases, arteriovenous shunting, and focal liver lesions. Familiarity with these findings will result in more accurate diagnosis and allows better therapeutic options if necessary.     

ATP Synthase Inhibition of Mycobacterium avium Is Not Bactericidal

The efficacy of ATP synthase inhibitor TMC207 was assessed in early and late Mycobacterium avium infections in mice. In contrast to what was earlier observed for M. tuberculosis, a bacteriostatic effect was obtained. In vitro, the minimal bactericidal concentration (MBC)/MIC ratio was very high. The MBC was more relevant for assessment of pharmacokinetic/pharmacodynamic relationships than the MIC.Mycobacterium avium is a pathogen that causes disseminated disease in immunocompromised individuals and pulmonary disease in immunocompetent adults (15) and is far less susceptible than Mycobacterium tuberculosis to most antimicrobial agents; treatment options are very limited (7, 10). The most efficacious drugs are clarithromycin (CLA), the azalide antibiotic azithromycin, and amikacin (AMK). They are generally part of a multidrug regimen including rifamycins and ethambutol (10) and need to be administered daily for up to 24 months (10). These regimens are expensive and poorly tolerated (2, 6). TMC207 (also known as R207910) is a diarylquinoline ATP synthase inhibitor with potent activity against M. tuberculosis (1, 3, 13). It has broad antimycobacterial activity, with MICs against several clinical isolates of M. avium ranging from 0.007 to 0.25 μg/ml (1, 8).Female C57BL/6J mice aged 6 to 7 weeks (Janvier Breeding, France) were infected intraperitoneally with 0.5 ml of a bacterial suspension containing 2.3 × 10⁷ CFU of M. avium 101. In a first group of 20 animals (Table ​(Table1),1), treatment started the day after infection (early infection model) and included a negative control, a positive control (CLA), and two test groups (TMC207 or CLA plus TMC207). Mice were sacrificed after 1 month of treatment. A second group of 165 mice was kept untreated for 1 month (late infection model) and then was treated with CLA alone, AMK alone, TMC207 alone, CLA plus AMK, CLA plus TMC207, AMK plus TMC207, or CLA plus AMK plus TMC207 for 4 months (Table ​(Table1).1). Five animals from each group were sacrificed at monthly intervals. All drugs were given five times weekly at the following doses: 25 mg/kg body weight TMC207 orally, 200 mg/kg CLA orally, and 150 mg/kg AMK subcutaneously. Treatment effects were assessed by CFU counts, determined by plating three serial 10-fold dilutions of homogenized spleen suspensions onto Löwenstein-Jensen plates. The Student t test with Bonferroni correction of the P value was used to analyze CFU counts. As four and seven groups were compared, P values were adjusted to 0.0083 and 0.0024, respectively.

TABLE 1.

Experimental design

Chronic intestinal pseudo-obstruction in adult patients: multidetector row helical CT features

Chronic intestinal pseudo-obstruction (CIPO) is a rare condition due to severe gastrointestinal motility disorder. Adult patients with CIPO experience symptoms of mechanical obstruction, but reliable clinical signs that may help distinguish between actual mechanical obstruction and CIPO are lacking. Additionally, abdominal plain films that commonly show bowel dilatation with air-fluid levels do not reach acceptable degrees of specificity to exclude actual obstruction. Therefore, most adult patients with CIPO usually undergo multiple and often fruitless surgery, often leading to repeated bowel resections before diagnosis is made. In these patients who present with abdominal signs mimicking symptoms that would warrant surgical exploration, multidetector-row helical CT (MDCT) is helpful to resolve this diagnostic dilemma. MDCT shows a diffusely distended bowel and helps to rule out a mechanical cause of obstruction, thus suggesting CIPO and obviating the need for unnecessary laparotomy. In adult patients with CIPO, MDCT may show pneumatosis intestinalis, pneumoperitoneum or intussusception. However, these conditions generally do not require surgery in patients with CIPO. This pictorial essay presents the more and less common MDCT features of CIPO in adult patients, to make the reader more familiar with this disease.     

Celiac disease in adults: evaluation with MDCT enteroclysis

OBJECTIVE: The purpose of this article is to present the MDCT enteroclysis features of the multiple complications of celiac disease and illustrate why this technique is helpful to adult patients with celiac disease. CONCLUSION: MDCT enteroclysis findings can suggest the diagnosis in adult patients with unknown celiac disease, and many complications of celiac disease can be recognized because of their characteristic appearance. Familiarity with these signs can help in appropriate planning of further diagnostic procedures.     

Effectiveness of Once-Weekly Rifapentine and Moxifloxacin Regimens against Mycobacterium tuberculosis in Mice

Mice infected with 1.6 x 10(7) CFU of Mycobacterium tuberculosis were treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis.     

L’hémodiafiltration online en mode prédilutionnel : quelle dose d’anticoagulation ?

IntroductionPatients in end stage renal disease on hemodialysis are in higher risk of bleeding related to the anticoagulation used during a session, so only the lowest effective dose of anticoagulation must be used. The aim of this study was to evaluate the efficacy of predilution in hemodiafiltration with reduced dose of anticoagulation compared to hemodialysis in preventing coagulation of circuits.Patients and methodsThis study was conducted in stable hemodialysis patients without high bleeding risk. All patients were treated by two different treatments: (A) conventional hemodialysis, (B) predilution hemodiafiltration with the half dose of anticoagulation used during treatment (A). Other confounding parameters were kept constant during the study. The primary endpoint was the incidence of major thrombotic events judged on a subjective visual score.ResultsTwenty-one patients were included (105 sessions for each treatment). Major incidents are occurring more frequently in predilution hemodiafiltration with reduced dose of anticoagulation (P = 0.03). The premature discontinuation of sessions was more frequent in predilution hemodiafiltration, this difference was not significant (P = 0.07). Duration of sessions was significantly shorter in predilution hemodiafiltration (P = 0.03). The higher frequency of thrombotic events in predilution hemodiafiltration has no effect on net ultrafiltration volume achieved in both treatments.ConclusionPredilution hemodiafiltration with a lower dose of anticoagulation did not prevent major clotting of extracorporeal circuit manner at least equivalent to a reference method.