1065. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits

Abstract Background Stenotrophomonas maltophilia causes lethal pneumonia, bacteremia, and sepsis in immunocompromised patients. As a standard of care, trimethoprim-sulfamethoxazole (T/S) is considered to be the first-line therapy for Stenotrophomonas pneumonia. Cefiderocol (CFDC) is a new parenteral siderophore cephalosporin that is transported through the outer cell membrane as a siderophore mimic that then inhibits Gram-negative cell wall biosynthesis. CFDC has potent activity in vitro against S. maltophilia; however, little is known about its in vivo activity against Stenotrophomonas pneumonia in immunocompromised hosts. We therefore studied CFDC in comparison to TS in the persistently neutropenic rabbit model of Stenotrophomonas pneumonia. This rabbit model, in contrast to conventional murine models, reflects the human pattern of infection more accurately over time. Methods We initially studied the plasma pharmacokinetics of CFDC in non-infected and infected animals. Stenotrophomonas pneumonia was established by direct endotracheal inoculation of S. maltophilia 1×1010 CFUs for tracheobronchial colonization that evolved into bronchopneumonia. Experimental groups consisted of CFDC, T/S, and untreated controls (UC). Rabbits received CFDC at 120 mg/kg IV Q8h and T/S at 5 mg/kg IV Q12h. Profound persistent neutropenia was maintained with cytosine arabinoside. Treatment was continued for 10 days. Results There were no significant differences between non-infected and infected rabbits in CFDC pharmacokinetics. Rabbits treated with CFDC and T/S demonstrated significant decreases of residual pulmonary and BAL bacterial burden vs UC (p≤0.001). CFDC achieved full clearance of S. maltophilia from lung tissue and BAL. This antibacterial activity coincided with significant reduction of lung weights (marker of organism-mediated pulmonary injury) in the CFDC group vs T/S and UC (p< 0.01). Survival was prolonged in the CFDC treatment group with 87% survival in comparison to that of T/S (25%) and UC (0%) (p< 0.01). Table 1. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistency Neutropenic Rabbits Conclusion Cefiderocol is highly active in treatment of experimental S. maltophilia pneumonia in persistently neutropenic rabbits, thus laying the foundation for future clinical investigations against this lethal infection. Disclosures Naoki Ishibashi, MD, Shionogi, Inc. (Employee) Benjamin Georgiades, n/a, Shionogi, Inc. (Consultant) Roger Echols, MD, Shionogi (Consultant) Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support) Yoshinori Yamano, PhD, Shionogi (Employee) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support)


Treatment Success in Reducing Recurrent Clostridioides difficile Infection with Investigational Live Biotherapeutic RBX2660 Is Associated with Microbiota Restoration: Consistent Evidence from a Phase 3 Clinical Trial
Ken Blount, PhD 1 ; Dana M. Walsh, PhD 1 ; Carlos Gonzalez, MS 2 ; Bill Shannon, PhD MBA 2 ; 1 Rebiotix, Inc., Roseville, Minnesota; 2 BioRankings, LLC, St. Louis, Missouri Session: P-61. Novel Agents Background. Several investigational microbiota-based live biotherapeutics are in clinical development for reducing recurrence of Clostridioides difficile infection (rCDI), including RBX2660 a liquid suspension of a broad consortium of microbiota, which includes Bacteridetes and Firmicutes. RBX2660 has been evaluated in >600 participants in 6 clinical trials. Here we report that RBX2660 induced significant shifts to the intestinal microbiota of treatment-responsive participants in PUNCH CD3-a Phase 3 randomized, double-blinded, placebo-controlled trial.
Methods. PUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. Samples were extracted and sequenced using shallow shotgun methods. Operational taxonomic unit (OTU) data were used to calculate relative taxonomic abundance, alpha diversity, and the Microbiome Health Index (MHI)-a biomarker of antibiotic-induced dysbiosis and restoration.
Results. Clinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). From before to after treatment, RBX2660-treated clinical responders' microbiome diversity shifted significantly (Mann-Whitney), and so did microbiome composition (Generalized Wald Test). Post-treatment changes were characterized by increased Bacteroidia and Clostridia and decreased Gammaproteobacteria and Bacilli, changes and were durable to at least 6 months. Repeated measures analysis confirmed that shifts were greater among RBX2660 responders compared to placebo responders (DMRepeat). The majority of responders' MHI values shifted from a range common to antibiotic dysbiosis to a range common in healthy populations. Figure 1 Left panel. Mean relative abundance taxonomic class level at timepoints for participants in PUNCH CD3 before and after RBX2660 treatment, and for doses of RBX2660 administered in PUNCH CD3. The four taxonomic classes that change most from before to after treatment are shown with the mean and confidence intervals based on fitting OTU data to a Dirichlet multinomial distribution. Right panel, MHI biomarker for the same time points and investigational product groups, shown as median (red) and individual samples. A previously calculated threshold of MHI = 7.2 is shown (dotted line), above which MHI values predict healthy, below which MHI values predict antibiotic-induced dysbiosis.
Conclusion. Among PUNCH CD3 clinical responders, RBX2660 significantly restored microbiota from less to more healthy compositions, and this restoration was durable to at least 6 months. These clinically-correlated microbiome shifts are highly consistent with results from multiple prior trials of RBX2660.

Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits
Vidmantas Petraitis, MD 1 ; Ruta Petraitiene, MD 1 ; Povilas Kavaliauskas, MSc 1 ; Ethan Naing, MD 2 ; Andrew Garcia, MS 1 ; Naoki Ishibashi, MD 3 ; Benjamin Georgiades, n/a 4 ; Roger Echols, MD 5 ; Robert A. Bonomo, MD 6 ; Yoshinori Yamano, PhD 7 ; Thomas J. Walsh, MD, PhD (hon)  Background. Stenotrophomonas maltophilia causes lethal pneumonia, bacteremia, and sepsis in immunocompromised patients. As a standard of care, trimethoprim-sulfamethoxazole (T/S) is considered to be the first-line therapy for Stenotrophomonas pneumonia. Cefiderocol (CFDC) is a new parenteral siderophore cephalosporin that is transported through the outer cell membrane as a siderophore mimic that then inhibits Gram-negative cell wall biosynthesis. CFDC has potent activity in vitro against S. maltophilia; however, little is known about its in vivo activity against Stenotrophomonas pneumonia in immunocompromised hosts. We therefore studied CFDC in comparison to TS in the persistently neutropenic rabbit model of Stenotrophomonas pneumonia. This rabbit model, in contrast to conventional murine models, reflects the human pattern of infection more accurately over time.
Methods. We initially studied the plasma pharmacokinetics of CFDC in non-infected and infected animals. Stenotrophomonas pneumonia was established by direct endotracheal inoculation of S. maltophilia 1×10 10 CFUs for tracheobronchial colonization that evolved into bronchopneumonia. Experimental groups consisted of CFDC, T/S, and untreated controls (UC). Rabbits received CFDC at 120 mg/kg IV Q8h and T/S at 5 mg/kg IV Q12h. Profound persistent neutropenia was maintained with cytosine arabinoside. Treatment was continued for 10 days.
Results. There were no significant differences between non-infected and infected rabbits in CFDC pharmacokinetics. Rabbits treated with CFDC and T/S demonstrated significant decreases of residual pulmonary and BAL bacterial burden vs UC (p≤0.001). CFDC achieved full clearance of S. maltophilia from lung tissue and BAL. This antibacterial activity coincided with significant reduction of lung weights (marker of organism-mediated pulmonary injury) in the CFDC group vs T/S and UC (p< 0.01). Survival was prolonged in the CFDC treatment group with 87% survival in comparison to that of T/S (25%) and UC (0%) (p< 0.01).