630. Emergence of Colistin Resistance in the OVERCOME Trial: Impact of Combination Therapy with Meropenem

Abstract Background Colistin (COL) remains an important therapeutic option for carbapenem-resistant (CR) Gram-negative bacilli (GNB). COL is often utilized in combination with meropenem (MEM), in part due to concerns regarding the development of COL resistance with monotherapy. We recently completed a randomized controlled trial comparing outcomes in patients receiving COL + placebo to those receiving COL + MEM; herein we present data on the emergence of COL resistance in this trial. Methods OVERCOME was an international, multicenter, randomized, double-blind, placebo-controlled study comparing COL and COL + MEM for the treatment of bloodstream infection and/or pneumonia due to CR GNB. Subjects were included in the modified intent to treat population (mITT) if their enrollment pathogen had a COL MIC ≤2 mg/L, as determined by broth microdilution (BMD). Daily blood and/or respiratory samples were obtained in patients per protocol until two consecutive negatives were obtained or the end of study treatment. All subsequent isolates were evaluated for COL resistance via BMD, defined as MIC ≥ 4 mg/L. Results Of the 425 patients in the mITT population, 380 (191 COL; 189 COL + MEM) were evaluable for the endpoint of COL resistance development. The median age of the cohort was 70, 38% were female, 47% were white, and 45% were Asian. 70% had an index infection of pneumonia, 68% were in the intensive care unit at the onset of their infection, and A. baumannii was the most common pathogen (78% of patients). Baseline characteristics, infection type, severity of illness, and index pathogen were similar amongst treatment arms. No significant difference in resistance development was seen between the COL and COL + MEM groups overall (12% vs. 8%; p = 0.31), or in any subgroup (Table). In patients with A. baumannii, there was a trend towards decreased resistance development with COL + MEM (13.3% vs 7.5%; p = 0.13). Conclusion We were unable to identify a significant difference in resistance emergence between treatment arms, but given the low incidence of this outcome, were underpowered to do so. The impact of COL + MEM on preventing emergence of COL resistance in A. baumannii warrants further clinical study. Disclosures Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Michael J. Rybak, PharmD, MPH, PhD, Paratek Pharmaceuticals (Research Grant or Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor)


Session: P-28. Clinical Trials
Background. Increase of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam.
Methods. A randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/ MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations.
Results. Profiles of C max , t max , AUC 0-8 , AUC 0-∞ and t 1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of C trough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of C max and AUC 0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as "Not related to study drug".

Conclusion.
In conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development. Background. BRAAVE 2020 demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among African American adults with suppressed HIV through Week (W) 48 ( Figure 1). We present resistance, viral blips, adherence, and virologic outcomes through W72. Methods. Enrollment criteria permitted NNRTI resistance (-R), PI-R, and certain NRTI-R (M184V/I allowed; K65R/E/N, ≥3 thymidine analog mutations [TAMs], or T69-insertions excluded) and excluded known primary INSTI-R. Preexisting drug resistance was assessed with historical genotypes and retrospective baseline proviral DNA genotyping. Adherence was calculated by pill count. Viral blips (transient HIV-1 RNA ≥50 copies/mL) and outcomes based on last available on-treatment HIV-1 RNA were assessed.
Methods. OVERCOME was an international, multicenter, randomized, double-blind, placebo-controlled study comparing COL and COL + MEM for the treatment of bloodstream infection and/or pneumonia due to CR GNB. Subjects were included in the modified intent to treat population (mITT) if their enrollment pathogen had a COL MIC ≤2 mg/L, as determined by broth microdilution (BMD). Daily blood and/or respiratory samples were obtained in patients per protocol until two consecutive negatives were obtained or the end of study treatment. All subsequent isolates were evaluated for COL resistance via BMD, defined as MIC ≥ 4 mg/L.

Results.
Of the 425 patients in the mITT population, 380 (191 COL; 189 COL + MEM) were evaluable for the endpoint of COL resistance development. The median age of the cohort was 70, 38% were female, 47% were white, and 45% were Asian. 70% had an index infection of pneumonia, 68% were in the intensive care unit at the onset of their infection, and A. baumannii was the most common pathogen (78% of patients). Baseline characteristics, infection type, severity of illness, and index pathogen were similar amongst treatment arms. No significant difference in resistance development was seen between the COL and COL + MEM groups overall (12% vs. 8%; p = 0.31), or in any subgroup (Table). In patients with A. baumannii, there was a trend towards decreased resistance development with COL + MEM (13.3% vs 7.5%; p = 0.13).
Conclusion. We were unable to identify a significant difference in resistance emergence between treatment arms, but given the low incidence of this outcome, were underpowered to do so. The impact of COL + MEM on preventing emergence of COL resistance in A. baumannii warrants further clinical study. Background. Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) is associated with high rates of morbidity and mortality; this is often worse among patients who experience a delay in receiving appropriate therapy. Initial treatment choice and early adjustment occurs prior to pathogen susceptibility results and may be based on suspicion of a resistant infection and/ or clinical deterioration. This study assesses the cost effectiveness of Imipenem/ cilastatin/relebactam (IMI/REL) in an early adjustment prescribing scenario compared to PIP/TAZ for patients with high risk of resistant infection from a US perspective.

Disclosures. Jason M Pogue, PharmD, BCPS, BCIDP, Merck
Methods. Although early adjustment data was not directly available, pathogen susceptibility data derived from 2017-19 Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program was applied to estimate patients who may have clinical worsening, likely due to a resistant infection. The efficacy and safety data for IMI/REL and PIP/TAZ were informed by the modified intent-to-treat population of a phase III trial (RESTORE-IMI 2). Our analysis comprised a decision tree (reflecting hospitalization period) followed by a yearly Markov model (capturing lifetime impact). The decision tree captured short-term outcomes (clinical cure, allcause mortality, and hospital resource use). The Markov model translated short term outcomes into quality-adjusted life years (QALYs). Results were expressed as an incremental cost-effectiveness ratio (ICER). Sensitivity analyses were conducted to test the robustness of model results.
Results. Compared with PIP/TAZ, IMI/REL in the early adjustment setting was associated with increased costs ($10,087 per patient) but a higher cure (+7%) and lower mortality (-3%) rate. The resulting ICER ($12,173/QALY) falls well below typical US willingness to pay thresholds. Model drivers were the SMART-based susceptibility profiles and RESTORE-IMI 2 response and mortality rates.
Conclusion. Our results suggest that IMI/REL, used as an early adjustment option, could be considered cost effective for patients with worsening HABP/VABP in a US setting, when compared against PIP/TAZ.