f Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3-and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3-and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine > clofazimine > rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further. N ovel oral regimens composed mostly or entirely of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for tuberculosis (TB), including multidrugresistant and extensively drug-resistant tuberculosis (DR-TB). Several new drugs in clinical development have demonstrated the potential to shorten TB treatment in animal models (16,23,26,27,32,44) and even in clinical trials (6,11,34). We recently reported promising results in a murine model of TB with a regimen comprised of two new drugs in clinical development, TMC207 (TMC) and PA-824, plus moxifloxacin (MXF), and this regimen was at least as sterilizing as the first-line regimen of rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA) (36). Combinations of TMC plus MXF or TMC plus PA-824 with PZA had even greater treatment-shortening abilities, suggesting that a 4-drug combination of TMC plus PZA plus MXF plus PA-824 may offer potential as a shorter (i.e., Յ4-month) regimen against PZA-susceptible isolates yet still constitute an effective short-course regimen (i.e., Յ6 months) against isolates resistant to PZA (36). However, because PZA and MXF are unlikely to be active against extensively DR-TB strains and both PZA and fluoroquinolone resistance are on the rise in DR-TB patients (1, 11, 12, 25), replacement of one or both of these agents with one or more new drugs having novel mechanisms of action may lead to short-course regimens active against virtually all forms of DR-TB. Additionally, PA-824 has shown some potential in antagonizing the initial bacterial kill when added to TMC or TMC plus PZA, although the impact on the sterili...

New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.

Umbilical cord accidents preceding labor are rare. Single and multiple nuchal cords, and true knot(s) of the umbilical cord, are often incidental findings noted at delivery of nonhypoxic non-acidotic newborns without any evidence of subsequent adverse neonatal outcome. In contrast to single nuchal cords, true knots of the umbilical cord, which occur in between 0.04% and 3% of all deliveries, have been associated with a reported 4 to 10 fold increased risk of stillbirth. First reported with real-time ultrasound, current widespread application of color Doppler, power Doppler and three-dimension sonography, has enabled increasingly more accurate prenatal sonographic diagnoses of true knot(s) of the umbilical cord. Reflecting the inability to visualize the entire umbilical cord at prenatal ultrasound assessment, despite detailed second and third-trimester scanning, many occurrences of incidental true knot of the umbilical cord remain undetected and are noted only at delivery. Although prenatal sonographic diagnostic accuracy is increasing, false positive sonographic diagnosis of true knot of the umbilical cord cannot be ruled out with certainty, and must continue to be considered clinically. Notwithstanding the inability to diagnose all true knots, currently there is a clear absence of clinical management guidelines by governing bodies regarding patients in whom prenatal sonographic diagnosis of true knot(s) of the umbilical cord is / are suspected. As a result, in many prenatal ultrasound units, suspected sonographic findings suggestive of or consistent with true knot of the umbilical cord are often disregarded, not documented, and patients are not uniformly informed of this potentially life-threatening condition, which carries an associated considerable risk of stillbirth. This commentary will address current perspectives of prenatal sonographic diagnostic and management challenges associated with true knot(s) of the umbilical cord in singleton pregnancies.