Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

Serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae isolates from a Phase III community-acquired bacterial pneumonia (CABP) trial.

OBJECTIVES: To report Streptococcus pneumoniae serotyping and susceptibility data from a recent clinical trial (ML-3341-306) comparing delafloxacin with moxifloxacin in the treatment of adults with community-acquired bacterial pneumonia (CABP). METHODS: Serotyping and susceptibility testing were conducted on 142 baseline S. pneumoniae isolates recovered from subjects participating in a CABP clinical trial. RESULTS: Overall, 113/142 (79.6%) isolates were vaccine serotypes. 76.8% (109/142) of serotyped isolates were PPSV23 serotypes and 59.9% (85/142) of isolates were PCV13 serotypes. 15.5% (22/142) of serotyped isolates were serotypes not covered by either vaccine; 4.9% (7/142) of tested isolates were non-typeable. The most common serotypes were serotypes 3 (19.0%; 27/142), 19F (9.9%; 14/142) and 23F (7.0%; 10/142). All of the 142 isolates were susceptible to delafloxacin and moxifloxacin, 76.1% were susceptible to azithromycin and 71.8% were susceptible to penicillin. Multidrug resistance was found among 19A (4/5; 80%), 6A (1/4; 25%), 6B (1/4; 25%), 14 (1/4; 25%), 19F (1/14; 7.1%), and 23F serotypes (2/10; 20%), and among non-typeable S. pneumoniae isolates (1/7; 14.3%). CONCLUSIONS: S. pneumoniae vaccine-targeted serotypes were the main cause of CABP in this Phase 3 CABP study. Fluoroquinolones including delafloxacin remain a good treatment option for CABP in adults caused by S. pneumoniae.

Attenuation of oxidant-induced lung injury by 21-aminosteroids (lazaroids): correlation with the mRNA expression for E-selectin, P-selectin, ICAM-1, and VCAM-1.

We compared the effects of treatment with methylprednisolone or the 21-aminosteroids, U-74389 and U-74006F (Tirilizad mesylate), on hyperoxic lung injury and the associated expression of mRNA for several adhesion molecules in rats. Inhalation of > 95% oxygen for up to 72 hr in Sprague-Dawley rats produced a marked increase in lung weight and an accumulation of fluid in the thorax when compared with air-breathing controls. Hyperoxia also induced a marked neutrophil-rich influx of inflammatory cells into the bronchial lumen as measured by bronchoalveolar lavage. Neutrophil numbers in bronchoalveolar lavage fluid peaked after 60 hr of exposure to s 95% oxygen; this was associated with a marked upregulation of mRNA for the adhesion molecules P-selectin and E-selectin but not VCAM-1. mRNA for ICAM-1 was constitutively expressed at high levels in both air-breathing controls and in the lungs of rats exposed to high concentrations of oxygen. Pretreatment with the 21-aminosteroids reduced hyperoxic lung damage and improved survival times in animals exposed to > 95% oxygen. However, treatment with methylprednisolone significantly decreased survival times. Treatment with U-74389 did not significantly (p > 0.05) inhibit the BAL neutrophilia and did not significantly (p > 0.05) reduce hyperoxia-induced increases in mRNA expression for P-selectin and E-selectin. The inhibition of hyperoxic lung damage coupled with improved survival seen in treated animals suggests that 21-aminosteroids may provide valuable treatments for pulmonary disorders in which oxidant damage has been implicated.

Chylothorax after childbirth.

We report a case of chylothorax which appeared in a mother after childbirth. Disruption of the thoracic duct occurred with the high intrathoracic pressures generated by the Valsalva maneuver used by the patient during labor to "push." No evidence of other trauma or malignancy were found and the patient did well after use of total parenteral nutrition, thoracotomy with thoracic duct ligation, and pleurodesis.