The steady-state concentrations of omadacycline and tigecycline in the plasma, epithelial lining fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0–24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0–24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0–12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0–12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

SUMMARY Electrophysiological studies in suicidal patients with organophosphate poisoning are reported. Patients often developed muscular weakness of variable severity owing to diplorisation block at nicotinic receptors. During such paralysis nerve conduction velocity and distal latencies were normal even in severely paralysed patients. The amplitude of the compound action potential was smaller than in controls and often showed a repetitive response. The amplitude tended to be lower in those more severely affected. On repetitive stimulation there was usually no decrement with three stimuli per second and only occasional decrement at 10 per second. At 30Hz several cases showed a decrement even in the absence of paralysis. This response to repetitive stimuli is thus quite distinct from that seen in either myasthenia or Eaton Lambert syndrome. On three occasions after poisoning with dichlorovos there was first anticholinesterase insecticide poisoning and later delayed neurotoxicity as seen with triorthocresylphosphate. These cases showed all the features of a severe pure motor axonal degeneration neuropathy.Organosphosphate insecticide poisoning is the commonest mode of suicidal poisoning in India today.'The drug is usually ingested and the patients are commonly admitted with miosis, fasciculations, pulmonary oedema and froth at the mouth due to the muscarinic, nicotinic and central manifestations of cholinergic poisoning. We have described before the neurological manifestations seen in 200 consecutive cases.2 We divided the signs into Type I, that is, those present on admission and responding promptly to atropine therapy and Type II as those appearing sometime after commencement of treatment and basically not influenced by atropine. Type I signs are believed to be cholinergic effects at muscarinic receptors and include bilateral pyramidal signs and impairment of consciousness and miosis. Type II are believed to be due to acetylcholine excess at nicotinic receptors. Type II paralysis appears from 12-72 hours after poisoning and lasts up to 5-6 days. This Type II paralysis is clearly different from delayed neurotoxicity, which appears only after 8-12 days and lasts much longer.3 Delayed neurotoxicity after a prior episode of clinical organophosphate anticholinesterase poisoning is furthermore very uncom-

The incidence of nontuberculous mycobacterial diseases in the US is rising and has surpassed tuberculosis. Most notable among the nontuberculous mycobacteria is Mycobacteroides abscessus , an emerging environmental opportunistic pathogen capable of causing chronic infections. M. abscessus disease is difficult to treat and the current treatment recommendations include repurposed antibiotics, several of which are associated with undesirable side effects. In this study, we have evaluated the activity of omadacycline, a new tetracycline derivative, against M. abscessus using in vitro and in vivo approaches. Omadacycline exhibited an MIC 90 of 0.5 μg/ml against a panel of 32 contemporary M. abscessus clinical isolates several of which were resistant to antibiotics that are commonly used for treatment of M. abscessus disease. Omadacycline when combined with clarithromycin, azithromycin, cefdinir, rifabutin or linezolid also exhibited synergism against several M. abscessus strains and did not exhibit antagonism when combined with an additional nine antibiotics also commonly considered to treat M. abscessus disease. Concentration-dependent activity of omadacycline was observed in time-kill assessments. Efficacy of omadacycline was evaluated in a mouse model of lung infection against four M. abscessus strains. A dose equivalent to the 300 mg standard oral human dose was used. Compared to the untreated control group, within four weeks of treatment, 1 to 3 log 10 fewer M. abscessus colony forming units were observed in the lungs of mice treated with omadacycline. Treatment outcome was biphasic, with bactericidal activity observed after the first two weeks of treatment against all four M. abscessus strains.

Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 μg · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 μg · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 μg · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 μg/ml when it was administered after dialysis and 2.33 μg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 μg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.

Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines but is structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300-mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline at 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was ∼50% higher than that on day 1. Omadacycline plasma concentrations on day 1 of 450-mg dosing were similar to those on day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.