Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment.

WCK 5222 is a novel ß-lactam-ß-lactam-enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel ß-lactam enhancer with a dual action of binding to Gram-negative penicillin-binding protein 2 (PBP2) and ß-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogen infections. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in 48 subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR). We enrolled mild (n = 6; CLCR, 60 to <90 ml/min), moderate (n = 6; CLCR, 30 to <60 ml/min), and severe (n = 6; CLCR, <30 ml/min; not on dialysis) impairment, end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR, ≥90 ml/min). Healthy control subjects and mild and moderate renal impairment subjects received a single 60-min intravenous (i.v.) infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min i.v. infusion of 1.5 g WCK 5222 (1 g FEP plus 0.5 g ZID). Body and renal clearance decreased, and plasma half-life (t1/2) and the area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞ [h µg/ml]) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT02942810.).

Outcomes of minority patients with very severe hypertension (>220/>120 mmHg).

OBJECTIVES: Acute severe hypertension is a common problem among inner-city ethnic minority populations. Nevertheless, the effects of currently employed treatment regimens on blood pressure have not been determined in a clinical practice setting. We determined the SBP responses to acute antihypertensive drug protocols and the 2-year natural history of patients presenting with severe hypertension. METHODS: Retrospective cohort investigation in consecutive patients with SBP at least 220 mmHg and/or DBP at least 120 mmHg during 3-month enrollment in 2014 with 2-year follow-up. Primary outcomes were SBP versus time for the first 5 h of emergency treatment and 2-year follow-up including repeat visits, target organ events, and hospitalizations. RESULTS: One hundred and fifty-six unique patients met criteria with 69% Black; 34% Hispanic; 56% had previous visits for severe hypertension; 31% had preexisting target injury. Acute management: Acute antihypertensive regimens resulted in grossly unpredictable and often exaggerated effects on SBP. Treatment acutely reduced SBP to less than 140 mmHg in 30 of 159 patients. Clonidine reduced SBP to less than 140 mmHg in 19/61. Two-year follow-up: We observed 389 repeat visits for severe hypertension, 99 new target events, and 76 hospitalizations accounting for 620 hospital days. CONCLUSION: Acute treatment of severe hypertension produced unpredictable and potentially dangerous responses in SBP. Two-year follow-up demonstrated extraordinary rates of recurrent visits, target organ events, and hospitalizations. Our findings indicate a need to develop effective management strategies to lower blood pressure safely and to prevent long-term consequences. Our findings may apply to other hospitals caring for ethnic minority populations.

Prehypertension is real and can be associated with target organ damage.

Prehypertension (systolic blood pressure 120-139 or diastolic blood pressure 80-89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors.