An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam.

Carbapenem-resistant gram-negative pathogens remain an urgent public health threat, and safe, effective treatment options are limited. Although several agents are now available to combat these infections, meropenem-vaborbactam was the first to combine a novel, cyclic, boronic acid-based, ß-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate ß-lactamase inhibitors with biochemical, microbiologic, and pharmacologic properties optimized for use in conjunction with a carbapenem. Meropenem was selected as the ideal carbapenem given its broad-spectrum in vitro activity, well established safety profile, and proven efficacy in the treatment of serious gram-negative infections. The combination has demonstrated potent in vitro activity against resistant gram-negative pathogens, particularly KPC-producing Klebsiella pneumoniae (MIC50 values typically ≤ 0.06 mg/l). Importantly, the pharmacokinetic (PK) profiles of the two agents are well matched, and the approved optimized dosing regimen of 4 g every 8 h (Q8h) as a 3-h infusion provides reliable probability of target attainment against the majority of commonly encountered carbapenem-resistant Enterobacteriaceae (CRE). Robust in vitro and in vivo PK/pharmacodynamic (PD) data support the ability of this dosing regimen to achieve specified PK/PD targets for both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. This concerted effort into optimizing the PK and PD parameters of both the ß-lactam and ß-lactamase inhibitor alone and in combination contributed to the clinical success of meropenem-vaborbactam demonstrated in phase 3 trials in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections. As the use of meropenem-vaborbactam increases concomitantly with the prevalence of KPC-producing CRE, continued pharmacovigilance and antimicrobial stewardship efforts will be of upmost importance to ensure that these PK/PD efforts translate into improved patient outcomes.

Carbapenem-resistant gram-negative pathogens, specifically, Enterobacteriaceae, remain an urgent public health threat, and safe, effective treatment options are limited. The antibiotic agents meropenem and vaborbactam were selected to be combined to leverage their individual properties for efficacy against carbapenem-resistant gram-negative pathogens, the most prevalent being Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae.Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are associated with high morbidity and mortality and excess healthcare costs and have traditionally required treatment with low-efficacy, high-toxicity antimicrobials such as the polymyxins.The authors present a review of the pre-clinical, clinical, pharmacokinetic (PK), and pharmacodynamic (PD) data on meropenem-vaborbactam, and data on difficult to treat organisms, and on special patient populations obtained post-marketing.Pre-clinical in vitro and in vivo PK/PD data support this optimized combination of these agents with meropenem-vaborbactam demonstrating low MIC50/MIC90 values against KPC-producing Enterobacteriaceae. Phase 1 PK trials confirmed the PK parameters, including in subjects with renal impairment and in target extravascular body sites such as the pulmonary epithelial lining fluid. In vitro, the combination of meropenem-vaborbactam has shown potent activity against resistant gram-negative pathogens; importantly, this includes KPC-producing Klebsiella pneumoniae. The approved optimized dosing regimen [4 g every 8 h (Q8h) as a 3-h infusion] achieves the PK/PD targets to achieve both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. Phase 3 trials showed the clinical success of meropenem-vaborbactam in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections.

Real-World Use of Oritavancin for the Treatment of Osteomyelitis.

Osteomyelitis is a difficult-to-treat disease that can require both surgical debridement and a prolonged course of antimicrobial therapy. Current standard of care for the antimicrobial treatment of osteomyelitis is fraught with multiple challenges and limitations. Patients typically require the insertion of an indwelling catheter for single or multiple daily intravenous antibiotic infusions for up to 6 weeks. Currently, there are treatment guidelines for only vertebral osteomyelitis, indicating the complexity of the condition. Oritavancin is a long-acting, second-generation lipoglycopeptide, administered intravenously once per week, which has potential to be a useful alternative in the treatment of osteomyelitis. This article reviews occurrence and outcomes of off-label oritavancin use for treatment of osteomyelitis as described in case reports. Analysis included 23 patients treated for osteomyelitis with single- or multiple-dose oritavancin. Overall, clinical cure or improvement was achieved in 87% of patients, and adverse events were mild and reported in only two patients. Clinical efficacy was demonstrated in 81.8% of methicillin-resistant Staphylococcus aureus (MRSA), 71.4% of methicillin-sensitive S. aureus (MSSA), 50% of vancomycin-resistant Enterococcus (VRE), and in the single case of Streptococcus pyogenes. Oritavancin has shown efficacy against Gram-positive pathogens in osteomyelitis, and offers a possible outpatient treatment option for osteomyelitis patients. Future studies are needed to determine dosing frequency in osteomyelitis patients.

Post Hoc Assessment of Time to Clinical Response Among Adults Hospitalized with Community-Acquired Bacterial Pneumonia Who Received Either Lefamulin or Moxifloxacin in 2 Phase III Randomized, Double-Blind, Double-Dummy Clinical Trials.

Time to clinical response, a proxy for hospital "discharge readiness," was compared between CABP inpatients who received lefamulin or moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) trials. The analysis included 926 inpatients. A short and comparable median time to clinical response (4 days) was observed in both treatment groups.

Hospital-level high-risk antibiotic use in relation to hospital-associated Clostridioides difficile infections: Retrospective analysis of 2016-2017 data from US hospitals.

OBJECTIVE: Antibiotics are widely used by all specialties in the hospital setting. We evaluated previously defined high-risk antibiotic use in relation to Clostridioides difficile infections (CDIs). METHODS: We analyzed 2016-2017 data from 171 hospitals. High-risk antibiotics included second-, third-, and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and lincosamides. A CDI case was a positive stool C. difficile toxin or molecular assay result from a patient without a positive result in the previous 8 weeks. Hospital-associated (HA) CDI cases included specimens collected >3 calendar days after admission or ≤3 calendar days from a patient with a prior same-hospital discharge within 28 days. We used the multivariable Poisson regression model to estimate the relative risk (RR) of high-risk antibiotic use on HA CDI, controlling for confounders. RESULTS: The median days of therapy for high-risk antibiotic use was 241.2 (interquartile range [IQR], 192.6-295.2) per 1,000 days present; the overall HA CDI rate was 33 (IQR, 24-43) per 10,000 admissions. The overall correlation of high-risk antibiotic use and HA CDI was 0.22 (P = .003), and higher correlation was observed in teaching hospitals (0.38; P = .002). For every 100-day (per 1,000 days present) increase in high-risk antibiotic therapy, there was a 12% increase in HA CDI (RR, 1.12; 95% CI, 1.04-1.21; P = .002) after adjusting for confounders. CONCLUSIONS: High-risk antibiotic use is an independent predictor of HA CDI. This assessment of poststewardship implementation in the United States highlights the importance of tracking trends of antimicrobial use over time as it relates to CDI.

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. METHODS: Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. RESULTS: After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 µg/ml and 299 µg/ml; AUClast: 10,850 µg·h/ml and 22,679 µg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. CONCLUSIONS: Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.