Stephen P. Hawser

The investigational β-lactam/β-lactamase inhibitor combination cefepime-taniborbactam is intended as therapy for serious infections caused by Gram-negative pathogens resistant to third-generation cephalosporins and carbapenems. Establishing a susceptibility testing reference method for cefepime-taniborbactam that conforms to the Clinical Laboratory Standards Institute (CLSI) M07 and International Standards Organization 20776-1:2019 standards is necessary to inform patient care. This study describes the reference broth microdilution MIC method for cefepime-taniborbactam (taniborbactam fixed at 4 µg/mL). In a CLSI M23 Tier 2 study that included nine clinical microbiology laboratories, the CTX-M-15-producer Escherichia coli NCTCC 13353 was determined to be appropriate for routine quality control (QC) as ranges for cefepime (≥64 µg/mL) and cefepime-taniborbactam (0.12 to 1 µg/mL) were non-overlapping, thereby simultaneously controlling for cefepime antibacterial activity and taniborbactam β-lactamase inhibition. Of the cefepime-taniborbactam MIC results obtained, 99.6% (269/270) were within the identified QC range; similarly, 100% (79/79) and 98.0% (98/100) of the QC values from a surveillance study and from the two central microbiology laboratories of the CERTAIN-1 Phase 3 clinical study (clintrials.gov identifier NCT03840148) were in range, respectively. Modifications to the standard medium (pH, cation content, or supplementation with human serum, albumin, polysorbate-80, or pulmonary surfactant) or assay parameters (inoculum density, incubation duration, and atmosphere) revealed that only inoculum titers (e.g., ≥5 × 10 ⁶ CFU/mL) exceeding the CLSI M07 standard (2–8 × 10 ⁵ CFU/mL) increased MIC values above the QC range. These results demonstrate the robustness and reliability of the cefepime-taniborbactam broth microdilution MIC reference method when performed following the approved standards. IMPORTANCE: This study focuses on a new antibiotic combination called cefepime-taniborbactam that is being developed to treat serious infections caused by bacteria that are often resistant to current treatments. To make sure this new antibiotic combination can be used safely and effectively once it has been approved for clinical use, we developed a standardized laboratory method to measure its activity against certain bacteria that are widely used during quality control testing. The method was assessed in multiple labs and proved to be reliable, accurate, and consistent. It also held up well under different testing conditions, showing that it is a dependable tool for guiding treatment decisions. This is an important step in meeting the challenge of antibiotic-resistant infections since it will help clinicians evaluate cefepime-taniborbactam as a potential treatment option as they strive to improve the care of patients suffering from serious infections.

This study determined the in vitro activity of finafloxacin against panels of bacterial strains, representative of those associated with infection in cystic fibrosis patients and predominately isolated from clinical cases of respiratory disease. Many of these isolates were resistant to various antimicrobials evaluated including the aminoglycosides, cephalosporins, carbapenems and fluoroquinolones. Broth microdilution assays were performed at neutral and acidic pH, to determine antimicrobial activity. Finafloxacin demonstrated superior activity at reduced pH for all of the bacterial species investigated, highlighting the requirement to determine the activity of antimicrobials in host-relevant conditions.

The rapid worldwide spread of antimicrobial resistance highlights the significant need for the development of innovative treatments to fight multidrug-resistant bacteria. This study describes the potent antimicrobial activity of the novel peptide OMN6 against a wide array of drug-resistant Acinetobacter baumannii clinical isolates. OMN6 prevented the growth of all tested isolates, regardless of any pre-existing resistance mechanisms. Moreover, in vitro serial-passaging studies demonstrated that no resistance developed against OMN6. Importantly, OMN6 was highly efficacious in treating animal models of lung and blood infections caused by multidrug-resistant A. baumannii. Taken together, these results point to OMN6 as a novel antimicrobial agent with the potential to treat life-threatening infections caused by multidrug-resistant A. baumannii avoiding resistance.

Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings.

Mecillinam is a β-lactam antibiotic that exerts its antibacterial activity by binding to penicillin-binding protein 2. In the USA, intravenous (IV) mecillinam is in development for the treatment of complicated UTIs in the hospital setting and as step-down therapy transitioning from IV mecillinam to oral pivmecillinam so that patients can continue treatment at home. To support the clinical development of mecillinam in the USA for the treatment of both complicated and uncomplicated UTI, this observational study investigated the activity of mecillinam against Enterobacterales isolates from patients with UTI in the USA, collected during 2019. This study evaluated the activity of mecillinam and other antimicrobial agents against 1075 selected Enterobacterales clinical isolates collected from patients with UTI in the USA during 2019. Antibiotic activity (minimum inhibitory concentration [MIC]) was determined by Clinical & Laboratory Standards Institute (CLSI) agar dilution methodology, and susceptibility was interpreted according to CLSI guidelines. Among the selected 1075 isolates, producers of extended-spectrum beta-lactamase (ESBL) represented 9.6% of Escherichia coli and 50% of Klebsiella pneumoniae. Ninety-five percent of the isolates tested were susceptible to mecillinam (Table 1). The MIC₅₀ and MIC₉₀ values for mecillinam were 0.25 and 2 µg/mL, respectively. Fosfomycin MIC₅₀ and MIC₉₀ were 1 and 32 µg/mL, respectively (97.6% of isolates were susceptible). Mecillinam showed the lowest MIC₉₀ value of all single antibiotics tested. The highest MIC₉₀ was 128 µg/mL for both nitrofurantoin and cefotaxime. The lowest percentage of resistance was obtained with fosfomycin (1.7%), followed by mecillinam (4%). Table 1: Summary MIC and susceptibility data for all isolates tested (n=1075) Overall, mecillinam showed excellent activity and a comparable resistance profile to fosfomycin. Resistance rates to ceftazidime, cefotaxime, ciprofloxacin and trimethoprim/sulfamethoxazole of greater than 20% are concerning due to the frequent use of these antibiotics in clinical practice to treat UTIs. Taken together, these data demonstrate that mecillinam has promising activity, with low resistance observed in Enterobacterales species causing UTIs in the USA. Clinical development of mecillinam in the USA is ongoing. Stephen Hawser, PhD, Utility Therapeutics (Grant/Research Support) Ian Morrissey, Utility Therapeutics (Grant/Research Support) Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant)

Eravacycline (ERV) is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for the treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The purpose of this study was to further monitor the in vitro activity of ERV against Gram-positive pathogens, such as Staphylococcus aureus (including methicillin-resistant S. aureus, MRSA), Enterococcus spp. (including vancomycin-resistant Enterococcus, VRE) and Streptococcus spp. Isolates were collected globally during 2018 from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using the most recent CLSI breakpoints (30^th ed CLSI M100 document), except for ERV and tigecycline (TGC) where FDA breakpoints from 2018 and 2005, respectively, were applied. Summary MIC data for ERV and select comparators are shown in the Table. ERV MIC_50/90 for Enterococcus spp were 0.06/0.12 μg/mL and were not affected by the presence of vancomycin resistant mechanisms. The MIC₉₀ of ERV against VRE was 2-fold lower than TGC, at a value of 0.12 μg/mL. ERV MIC₉₀ values for methicillin-susceptible S. aureus (MSSA) was 0.12 μg/mL and for MRSA was 0.25 μg/mL. Generally, for all pathogens, ERV MIC₉₀ values were 2- to 4-fold lower than TGC. Table ERV in vitro activity was demonstrated for clinically important Gram-positive pathogens, including resistant isolates. Overall, ERV demonstrated lower MIC₉₀ values than comparators for all organisms. This 2018 global surveillance highlights ERV’s utility against Gram-positive organisms and further underscores its role in cIAI, where these pathogens play a causative role. Steven Morgan, PharMD, Tetraphase Pharmaceuticals (Employee) Sara Hwang, PharMD, Tetraphase Pharmaceuticals (Employee) Ekaterina Efimova, PharMD, Tetraphase Pharmaceuticals (Employee) Stephen Hawser, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator) Virgil Lijfrock, PharMD, Tetraphase (Employee)