Eric Wenzler

Meropenem-RPX7009 Concentrations in Plasma, Epithelial Lining Fluid, and Alveolar Macrophages of Healthy Adult Subjects

ABSTRACT The steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: Cmax = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, Vss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0–8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.

Telavancin: The Long and Winding Road From Discovery to Food and Drug Administration Approvals and Future Directions

Telavancin (TD-6424) was discovered in 2000 and became the first marketed semisynthetic lipoglycopeptide in 2009. This parenteral antibacterial agent has a dual mechanism of action and potent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and isolates with reduced vancomycin susceptibility. Pharmacokinetic and pharmacodynamic analyses support the concentration-dependent activity and once-daily dosing regimen of telavancin. A changing regulatory approval process, manufacturing obstacles, and the termination of a commercialization partnership have challenged the development and marketing of telavancin. The commercial operations for telavancin have been restored, a new manufacturer has been secured, and reliable product supplies are available for clinical use. In addition, telavancin continues to be supported by ongoing clinical research with the recent launch of the Telavancin Observational Use Registry (TOUR; NCT02288234) in the United States and an international phase 3, randomized trial comparing telavancin with standard therapy for the treatment of patients with complicated S. aureus bacteremia, including endocarditis (NCT02208063).

Inhaled Antibiotics for Gram-Negative Respiratory Infections

SUMMARY Gram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects, in vitro and microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

Impact of rapid identification of Acinetobacter Baumannii via matrix-assisted laser desorption ionization time-of-flight mass spectrometry combined with antimicrobial stewardship in patients with pneumonia and/or bacteremia

We evaluated the clinical and economic outcomes of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) with stewardship intervention in patients with Acinetobacter baumannii (AB) pneumonia and/or bacteremia. 66 patients were included in the pre-intervention group and 53 in the intervention group. The combination of AB identification via MALDI-TOF MS and ID PharmD intervention significantly reduced the median time to effective therapy compared to conventional identification without intervention [77.7 (95% CI: 73.1-84.8) to 36.6 (95% CI: 25.9-50.9) hours (P < 0.0001)]. Rapid organism identification along with ID PharmD intervention was also associated with a 19% increase in clinical cure (15% versus 34%, P = 0.016) and a decreased length of stay during antibiotic therapy (13 [8-18] versus 11 [7-15] days, P = 0.021). No difference in 14-day mortality was observed (20% versus 25%, P = 0.526). Median costs during infection were approximately

An Automated, Pharmacist-Driven Initiative Improves Quality of Care for Staphylococcus aureus Bacteremia

6500 less in the intervention group (

Synergistic activity of ceftazidime-avibactam and aztreonam against serine and metallo-β-lactamase-producing gram-negative pathogens

49,402 [35,307-86,566] versus

Controversies in Antimicrobial Stewardship: Focus on New Rapid Diagnostic Technologies and Antimicrobials

42,872 [26,966-74,506]; P = 0.243). AB identification via MALDI-TOF MS combined with stewardship intervention allows for timely, effective antimicrobial therapy and is associated with increased clinical cure.

Anticipating the Unpredictable: A Review of Antimicrobial Stewardship and Acinetobacter Infections

Background Infectious diseases (ID) consultation and antimicrobial stewardship intervention have been shown to improve the management of Staphylococcus aureus bacteremia (SAB). As the workload of antimicrobial stewardship programs (ASPs) continues to increase, ASPs must find a way to maximize the efficiency of the program while optimizing patient outcomes. The objective of this study was to evaluate the impact of incorporating health informatics into the management of SAB via a pharmacist-driven initiative. Methods Retrospective, single-center quasi-experimental study of hospitalized patients with SAB. During the intervention period, pharmacists were alerted to patients with SAB via a patient scoring tool integrated into the electronic medical record. Pharmacists utilized the scoring tool and the institutions evidence-based practice guideline to make standardized recommendations to promote adherence to SAB quality-of-care measures and encourage ID consultation. The primary outcome was overall compliance along with adherence to individual quality-of-care components. Secondary clinical outcomes were also analyzed. Results In sum, 84 patients were identified for study inclusion, 45 in the pre-intervention and 39 in the intervention group. As a whole, all 4 quality-of-care components for the management of SAB were significantly more frequently adhered to in the intervention group (68.9% vs 92.3%; P = .008). The incidence of ID consult improved significantly by almost 20% in the intervention group (75.6% vs 94.9%, P = .015). No statistically significant differences in duration of bacteremia, length-of-stay, infection-related length-of-stay, or readmission were observed between the groups. The incidence of all-cause mortality was 6-fold higher in the pre- intervention group compared to the intervention group (15.6% vs 2.6%, P = .063). Conclusion An automated, pharmacist-driven intervention for the management of patients with SAB demonstrated a significant improvement in patients receiving an ID consult, targeted antimicrobial therapy, and adherence to all SAB quality-of-care measures. As antimicrobial stewardship becomes a mandatory aspect of healthcare in all hospitals in the United States, ASPs will be forced to find ways to provide more efficient, impactful, disease state-based patient care. Our study provides the framework for and data to support this intervention in one of the most clinically important infectious diseases.

Severe Sepsis Secondary to Persistent Lysinibacillus sphaericus, Lysinibacillus fusiformis and Paenibacillus amylolyticus Bacteremia

This study assessed the in vitro synergy between ceftazidime, aztreonam, and ceftazidime-avibactam against serine and metallo-β-lactamase (MBL)-producing pathogens via the Etest MIC:MIC ratio and Agar-Etest synergy methods. The combination of aztreonam and ceftazidime-avibactam was synergistic against all Enterobacteriaceae. None of the tested combinations were consistently synergistic against IMP-producing P. aeruginosa.

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers

Antimicrobial stewardship programs (ASPs) are challenged with ensuring appropriate antimicrobial use while minimizing expenditures. ASPs have consistently demonstrated improved patient outcomes and significant cost reductions but are continually required to justify the costs of their existence and interventions due to the silo mentality often adopted by hospital administrators. As new technologies and antimicrobials emerge, ASPs are in a constant tug-of-war between providing optimal clinical outcomes and ensuring cost containment. Additionally, robust data on cost-effectiveness of new rapid diagnostic technologies and antimicrobials with subsequent ASP interventions to provide justification are lacking. As the implementation of an ASP will soon be mandatory for acute care hospitals in the United States, ASPs must find ways to justify novel interventions to align themselves with healthcare administrators. This review provides a framework for the justification of implementing a rapid diagnostic test or adding a new antimicrobial to formulary with ASP intervention, reviews approaches to demonstrating cost-effectiveness, and proposes methods for which ASPs may reduce healthcare expenditures via alternative tactics.