rpx7009 and Klebsiella-Infections

Vaborbactam (VAB; formerly RPX7009) is a novel beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Ambler class A and C beta-lactamases. It has been co-formulated with meropenem to restore its activity against Klebsiella pneumoniae carbapenemases (KPC). VAB does not inhibit class B or D carbapenemases, nor does it improve the activity of meropenem against multidrug-resistant nonfermenting gram-negative bacilli, notably Acinetobacter spp. and Pseudomonas aeruginosa. The purpose of this article is to review existing data pertaining to the biochemistry, mechanism of action, pharmacokinetics/pharmacodynamics, in vitro activity, and current progress in clinical trials of meropenem and VAB (MV). Phase 1 studies have demonstrated single and multiple doses of VAB up to 2000 mg, alone or in combination with meropenem 2000 mg administered as a prolonged infusion over 3 hours, are well tolerated with an adverse effect profile similar to that of meropenem monotherapy. The available data suggest preexisting resistance among KPC-producing isolates is rare. Strains with elevated MICs have been characterized by multiple resistance determinants including porin defects, increased drug efflux, and increased blaKPC expression. It remains uncertain whether multifactorial resistance will emerge during MV treatment and with more widespread use. Early data are positive for complicated urinary tract infections and MV compared with best available therapy in patients with serious carbapenem-resistant Enterobacteriaciae (CRE) infections. As clinicians contemplate how to incorporate MV into CRE treatment strategies, it will be important to track and understand resistance, discern the role, if any, of combination therapy in enhancing efficacy and/or preserving activity, and define the specific therapeutic niche of MV among the expanding anti-CRE armamentarium.

Topics: Anti-Bacterial Agents; Area Under Curve; Bacterial Proteins; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Bacterial; Klebsiella Infections; Meropenem; Metabolic Clearance Rate; Microbial Sensitivity Tests; Porins; Urinary Tract Infections

Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations.. Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested.. Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance.. Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.

Topics: Agar; Ceftazidime; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem

Topics: Anti-Bacterial Agents; Aztreonam; beta-Lactamases; Drug Combinations; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Critical Illness; Drug Combinations; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated

In February 2022, a critically ill patient colonized with a carbapenem-resistant K. pneumoniae producing KPC-3 and VIM-1 carbapenemases was hospitalized for SARS-CoV-2 in the intensive care unit of Policlinico Umberto I hospital in Rome, Italy. During 95 days of hospitalization, ceftazidime/avibactam, meropenem/vaborbactam, and cefiderocol were administered consecutively to treat 3 respiratory tract infections sustained by different bacterial agents. Those therapies altered the resistome of K. pneumoniae sequence type 512 colonizing or infecting the patient during the hospitalization period. In vivo evolution of the K. pneumoniae sequence type 512 resistome occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore gene, resulting in high levels of cefiderocol resistance. Cross-selection can occur between K. pneumoniae and treatments prescribed for other infective agents. K. pneumoniae can stably colonize a patient, and antimicrobial-selective pressure can promote progressive K. pneumoniae resistome evolution, indicating a substantial public health threat.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cefiderocol; Ceftazidime; Humans; Italy; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Boronic Acids; Ceftazidime; Drug Combinations; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Concerns regarding carbapenem-resistant Klebsiella pneumoniae (CR-Kp), especially in bloodstream infections (BSIs), are continuing to increase worldwide. Several novel agents with activity against BSI CR-Kp have been approved or are in late-stage clinical development. In this study, the antibacterial effects of ceftazidime/avibactam (CZA), aztreonam/avibactam (AZA), meropenem/vaborbactam (MEV), imipenem-cilastatin/relebactam (ICR) and eravacycline (ERV) against three colistin-resistant CR-Kp (COLR-Kp) and four CZA-resistant CR-Kp (CZAR-Kp) were tested by time-kill assay. Klebsiella pneumoniae ATCC® BAA-1705TM was used as a control strain. Two COLR-Kp isolates carried the blaKPC-2 gene and four CAZR-Kp isolates carried metallo-β-lactamase genes. The results revealed that ERV resulted in re-growth of seven tested isolates. CZA and MEV showed a bactericidal effect against isolates harbouring blaKPC-2. ICR reduced the population of six isolates to >5 log10 CFU/mL compared with the initial count. AZA showed a bactericidal effect (>5 log10 CFU/mL) against seven isolates and a bacteriostatic effect (<3 log10 CFU/mL) against one CZAR-Kp isolate. Therefore, AZA and ICR are effective therapeutic candidates for COLR-Kp and CZAR-Kp isolates.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Bacteremia; beta-Lactamase Inhibitors; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Cilastatin; Colistin; Drug Combinations; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Tetracyclines

Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of

Topics: Animals; Bacteria; beta-Lactamase Inhibitors; Borinic Acids; Boronic Acids; Carboxylic Acids; Drug Discovery; Klebsiella Infections; Mice; Microbial Sensitivity Tests; Structure-Activity Relationship

Resistance to ceftazidime-avibactam due to mutations in KPC genes has been reported both

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Boronic Acids; Cefepime; Ceftazidime; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections

Meropenem-vaborbactam resistance in

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Down-Regulation; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Mutation; Porins

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Meropenem-vaborbactam is a new β-lactam/β-lactamase inhibitor combination designed to target Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae. Meropenem-vaborbactam was United States Food and Drug Administration-approved for complicated urinary tract infections in patients 18 years of age or older. An understanding of the pharmacokinetics of meropenem when given in combination with vaborbactam is important to understanding the dosing of meropenem-vaborbactam. In addition, the safety and efficacy of meropenem-vaborbactam in a pediatric patient have yet to be described in the literature. The authors conducted a retrospective single-patient chart review for a 4-year-old male patient with short bowel syndrome, colostomy and gastrojejunal tube, bronchopulmonary dysplasia, and a central line for chronic total parenteral nutrition and hydration management, complicated with multiple central line-associated bloodstream infections (BSIs). The patient was brought to our medical center with fever concerning for a BSI. On day 2, the patient was started on meropenem-vaborbactam at a dosage of 40 mg/kg every 6 hours infused over 3 hours for KPC-producing K. pneumoniae BSI. Meropenem serum concentrations obtained on day 5 of meropenem-vaborbactam therapy, immediately following the completion of the infusion and 1 hour after the infusion, were 51.3 and 13.6 μg/ml, respectively. Serum concentrations correlated to a volume of distribution of 0.59 L/kg and a clearance of 13.1 ml/min/kg. Repeat blood cultures remained negative, and meropenem-vaborbactam was continued for a total of 14 days. A meropenem-vaborbactam regimen of 40 mg/kg every 6 hours given over 3 hours was successful in providing a target attainment of 100% for meropenem serum concentrations above the minimum inhibitory concentration for at least 40% of the dosing interval and was associated with successful bacteremia clearance in a pediatric patient.

Topics: Anti-Bacterial Agents; Boronic Acids; Child, Preschool; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Treatment Outcome