Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram‐negative bacteria including multidrug‐resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000‐mg intravenous 1‐hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end‐stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function. The effect of hemodialysis on the clearance of cefiderocol was also assessed. Total drug clearance from plasma (CL) and terminal half‐life (t1/2) correlated with renal function. Ratios (90% confidence intervals) of area under the plasma concentration‐time curve from 0 to infinity (AUC) in mild, moderate, severe, and ESRD groups compared to those with normal renal function were 1.0 (0.8‐1.3), 1.5 (1.2‐1.9), 2.5 (2.0‐3.3), and 4.1 (3.3‐5.2), respectively. Maximum plasma concentration (Cmax) was similar between renal‐impairment groups and the normal‐renal‐function group. Approximately 60% of cefiderocol was removed by hemodialysis for 3 to 4 hours. The plasma‐protein‐unbound fraction was similar between various renal function groups. The incidence of adverse events did not appear to have any correlation with the degree of renal impairment. Single 1000‐mg intravenous doses of cefiderocol were generally well tolerated in subjects with impaired renal function except for 1 subject who discontinued due to urticaria. In conclusion, renal impairment impacted AUC, CL, and t1/2 without affecting Cmax. Cefiderocol was significantly removed by intermittent hemodialysis.

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.)

Systolic anterior motion (SAM) of the mitral valve, once considered to be pathognomonic of hypertrophic cardiomyopathy, has been reported in the absence of asymmetric septal hypertrophy. Of the 1,000 open heart operations performed with intraoperative two-dimensional epicardial echocardiography monitoring, four patients developed intraoperative dynamic left ventricular outflow obstruction associated with systolic anterior motion of the mitral valve that was not present preoperatively: three cases of mitral valve annuloplasty with Carpentier ring insertion and one of coronary artery bypass grafting. Though no patient had asymmetric septal hypertrophy or echocardiographic evidence of outflow obstruction by either preoperative cardiac catheterization or echocardiography, intraoperative two-dimensional epicardial echocardiography revealed SAM, and hyperdynamic left ventricles with three of these patients having documented left ventricular outflow tract gradients causing hemodynamic compromise. (Case 4 was hemodynamically stable following mitral valve repair, but had SAM and significant residual mitral regurgitation [MR] requiring reinstitution of cardiopulmonary bypass and re-repair). Measurement of mitral annular dimension demonstrated a normal decrease in size from diastole to systole in control operative subjects but not in the patients who developed outflow obstruction. The pathophysiology, treatment, and role of intraoperative echocardiography of dynamic left ventricular outflow tract obstruction are discussed.