A Phase 1 Study to Evaluate the Safety and Pharmacokinetics following Administration of Single and Multiple Doses of the Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an anti-staphylococcal lysin, was administered intravenously as a 6 mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein.

Optimized loading dose strategies for bedaquiline when restarting interrupted drug-resistant tuberculosis treatment

Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT-prolongation) were simulated for 5000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety respectively of the reloading strategies. Bedaquiline weekly AUC and M2 Cmax deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than two weeks, no new loading dose is needed. For interruptions with durations between two weeks and one month, one month and one year, and longer than one year, reloading periods of three days, one week, and two weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with -16.4% to -59.8% without reloading for interruptions of two weeks and one year respectively, without increasing M2 Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.

Pseudomonas aeruginosa Oligoribonuclease Controls Susceptibility to Polymyxin B by Regulating Pel Exopolysaccharide Production

Polymyxins are considered as the last resort antibiotics to treat infections caused by multidrug-resistant Gram negative pathogens. Pseudomonas aeruginosa is an opportunistic pathogen that causes various infections in humans. Proteins involved in lipopolysaccharide modification and maintaining inner and outer membrane integrities have been found to contribute to the bacterial resistance to polymyxins. Oligoribonuclease (Orn) is an exonuclease that regulates the homeostasis of intracellular (3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), thereby regulating the production of extracellular polysaccharide in P. aeruginosa . Previously, we demonstrated that Orn affects the bacterial resistance to fluoroquinolone, β-lactam and aminoglycoside antibiotics. In this study, we found that mutation of orn increased the bacterial survival following polymyxin B treatment in a wild type P. aeruginosa strain PA14. Overexpression of c-di-GMP degradation enzymes in the orn mutant reduced the bacterial survival. By using a fluorescence labeled polymyxin B, we found that mutation of orn increased the bacterial surface bound polymyxin B. Deletion of the Pel synthesis genes or treatment with a Pel hydrolase reduced the surface bound polymyxin B and bacterial survival. We further demonstrated that Pel binds to extracellular DNA (eDNA), which traps polymyxin B and thus protects the bacterial cells. Collectively, our results revealed a novel defense mechanism against polymyxin in P. aeruginosa .

Treatment, clinical outcomes, and predictors of mortality among a national cohort of admitted patients with Acinetobacter baumannii infection

Objectives: To analyze treatment, clinical outcomes, and predictors of mortality in hospitalized patients with Acinetobacter baumannii infection. Methods: Retrospective cohort study of inpatients with A. baumannii cultures and treatment from 2010-2019. Patients who died during admission were compared to those who survived to identify predictors of inpatient mortality, using multivariable unconditional logistic regression models. Results: We identified 4,599 inpatients with A. baumannii infection; 13.6% died during admission. Fluoroquinolones (26.8%), piperacillin/tazobactam (24%) and carbapenems (15.6%) were used for treatment. Tigecycline (3%) and polymyxins (3.7%) were not used often. Predictors of inpatient mortality included current acute respiratory failure (adjusted odds ratio [aOR] 3.94), shock (aOR 3.05), and acute renal failure (aOR 2.01); blood (aOR 1.94) and respiratory (aOR 1.64) infectious source; multidrug-resistant A. baumannii (MDRAB) infection (aOR 1.66); liver disease (aOR 2.15); and inadequate initial treatment (aOR 1.30). Inpatient mortality was higher in those with MDRAB vs. non-MDRAB (aOR 1.61) and in those with CRAB vs. non-CRAB infection (aOR 1.68). Length of stay >10 days was higher among those with MDRAB vs. non-MDRAB (aOR 1.25) and in those with CRAB vs. non-CRAB infection (aOR 1.31). Conclusions: In our national cohort of inpatients with A. baumannii infection, clinical outcomes were worse among those with MDRAB and/or CRAB infection. Predictors of inpatient mortality included several current conditions associated with severity, infectious source, underlying illness, and inappropriate treatment. Our study may assist healthcare providers in the early identification of admitted patients with A. baumannii infection who are at higher risk of death.

Analysis of the clinical pipeline of treatments for drug resistant bacterial infections: despite progress, more action is needed

There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

A novel plasmid entry exclusion system in pKPC_UVA01, a promiscuous conjugative plasmid carrying the bla KPC carbapenemase gene

Conjugative plasmids are the principal mediator in the emergence and spread of antibiotic resistance genes in Enterobacterales. Plasmid entry-exclusion (EEX) systems can restrict their transfer into the recipient bacteria carrying closely related plasmids. In this study, we have identified and characterized a novel plasmid entry exclusion system in a carbapenem resistance plasmid pKPC_UVA01, responsible for widespread dissemination of the bla KPC carbapenemase gene among Enterobacterales in the United States. The identified eex gene in the recipient strain of different Enterobacterales species inhibits the conjugation transfer of pKPC_UVA01 plasmids at a range of 200-400 fold, and this inhibition was found to be a dose-dependent function of the EEX protein in recipient cells. The C-terminus truncated version of eex or eex with an early termination codon at the C-terminus region alleviates inhibition of conjugative transfer. Unlike the strict specificity of plasmid exclusion by the known EEX protein, the newly identified EEX in the recipient strain can inhibit the transfer of IncP and IncN plasmids. The eex gene from the plasmid pKPC_UVA01 is not required for conjugative transfer but is essential in the donor bacteria for entry exclusion of this plasmid. This is a novel function of a single protein that is essential in both donor and recipient bacteria for entry exclusion of a plasmid. This eex gene is found to be distributed in multi-drug resistance plasmids similar to pKPC_UVA01 in different Enterobacterales species and may contribute to the stability of this plasmid type by controlling its transfer.

Genome analysis of Klebsiella oxytoca complex for antimicrobial resistance and virulence genes

Klebsiella oxytoca complex comprises nine closely-related species causing human infections. We curated genomes labeled Klebsiella (n=14,256) in GenBank and identified 588 belonging to the complex, which were examined for precise species, sequence types, K- and O-antigen types, virulence and antimicrobial resistance genes. The complex and Klebsiella pneumoniae share many K- and O-antigen types. Of the complex, K. oxytoca and Klebsiella michiganensis appear to carry more virulence genes and be more commonly associated with human infections.

A multiplex molecular assay for detection of six penA codons to predict decreased susceptibility to cephalosporins in Neisseria gonorrhoeae

The emerging cephalosporin-resistant Neisseria gonorrhoeae poses an urgent threat to the continued efficacy of the last-line monotherapy for gonorrhea. Consequently, high-throughput, accurate, and reasonable molecular assays are urgently needed for strengthening antimicrobial-resistance surveillance in N. gonorrhoeae . In this study, we designed a high-throughput multiplex method that incorporates high-resolution melting technology and is based on a 6-codon assay (among the most parsimonious assays) developed following comprehensive and systematic reviews. The results showed that our method can precisely distinguish specific single-nucleotide polymorphisms in resistance-associated genes with a specificity and sensitivity of 100% and a detection limit as low as 10 copies per reaction. This method can be directly applied to clinical samples without cumbersome culture and successfully predicted all cephalosporin-resistant isolates (sensitivity: 100%). The method presented here represents a technique for rapid testing of antimicrobial resistance and will serve as a valuable tool for tailor-made antimicrobial therapy and for monitoring the transmission of cephalosporin-resistant strains.

Antifungal Resistance Trends of Candida auris Clinical Isolates, New York-New Jersey, 2016-2020

About 55% of U.S. Candida auris clinical cases were reported from New York and New Jersey from 2016 through 2020. Nearly all New York-New Jersey clinical isolates (99.8%) were fluconazole resistant, and 50% were amphotericin B resistant. Echinocandin resistance increased from 0% to 4% and pan-resistance increased from 0 to <1% for New York C. auris clinical isolates but not for New Jersey, highlighting the regional differences.

In vitro Time Kill of Trimethoprim/Sulfamethoxazole against Stenotrophomonas maltophilia versus Escherichia coli using Cation Adjusted Muller Hinton Broth and ISO-Sensitest Broth

Trimethoprim/sulfamethoxazole (TMP/SMZ) is considered the treatment of choice for infections caused by Stenotrophomonas maltophilia , but limited pharmacodynamic data are available to support current susceptibility breakpoints or guide optimal dosing. Time-kill studies using a TMP/SMZ concentration of 4/40 μg/mL were conducted to compare 4 S. maltophilia with 4 Escherichia coli having the same MICs (0.25/4.75-4/76 μg/mL) in cation adjusted Mueller Hinton Broth (CAMHB) and ISO-Sensitest™ broth (ISO). With the exception of the resistant isolates (4/76 μg/mL), which resulted in regrowth approaching control, TMP/SMZ displayed significantly greater killing for E. coli compared with S. maltophilia at each MIC. Against E. coli , mean changes at 24 hour were -4.49, -1.73, -1.59, and +1.83 log 10 colony forming units (CFU) for isolates with MICs of 0.25/4.75, 1/19, 2/39, and 4/74 μg/mL, respectively. The f AUC/MIC required for stasis, 1-log 10 , and 2-log 10 CFU reductions were 40.7, 59.5, and 86.3, respectively. In contrast, TMP/SMZ displayed no stasis or CFU reductions against any S. maltophilia regardless of MIC, and no pharmacodynamic thresholds were quantifiable. Observations were consistent in both CAMHB and ISO broth. These data add increasing evidence that current TMP/SMZ susceptibility breakpoints against S. maltophilia should be reassessed.