Study on the efficacy of ceftriaxone versus azithromycin for the treatment of uncomplicated enteric fever among the patients admitted in a tertiary level hospital

Background: Typhoid fever is a severe debilitating and potentially life threating illness. In Bangladesh, typhoid fever is a round the year problem which sometimes take epidemic proportions. The reasons behind such occurrences are unsafe water supply, defective sewage system and unhygienic food handling practice. This study aimed to compare the efficacy of ceftriaxone and azithromycin in the treatment of uncomplicated enteric fever.Methods: An observational study was conducted at the department of pharmacology in Dhaka medical college, Dhaka, Bangladesh. Data were collected from blood culture positive patients for Salmonella typhi and Salmonella paratyphi, who admitted in the Dhaka medical college and hospital, Dhaka during the period of July 2015 to June 2016. Data was collected by using a structured questioner, face to face interview, physical examination and investigation reports. Patients were hospitalized during the entire treatment period and at admission evaluation was made by history and physical examination in a structured format. Subjects ware asked regarding changes in symptoms and possible adverse effects of the study drugs. All patients were asked to return two weeks after completion of treatment for follow up. Blood culture of Salmonella typhi or Salmonella paratyphi were done in all cases. Total 91 patients were culture positive for either S. typhi or S. paratyphi which were finally studied.Results: During the study period out of 91 patients, 51 were receiving ceftriaxone and 40 were receiving azithromycin. Clinical cure was achieved in 46 patients (90%) of ceftriaxone group and in 31 patients (78%) in the azithromycin group. There were no significant differences of clinical cure between both treatment groups (p>0.05). Mean fever clearance time in ceftriaxone group was 3±1.4 days and was 4±1.6 days for azithromycin group. Difference in fever clearance time was statistically significant (p<0.05). No clinical relapses were detected in any study subject. No major side effects of both drugs occurred in any subject.Conclusions: These results indicated that both ceftriaxone and azithromycin were effective against enteric fever caused by sensitive organisms and multi drug resistant S. typhi and S. paratyphi. It is concluded that ceftriaxone is more effective and can be a convenient alternative for the treatment of enteric fever, especially in developing countries like us where medical resources are scarce.

Symptomatic atherosclerotic plaque progression in a first-generation carotid stent—case report: Management and 5-year clinical and imaging outcome

Background Restenosis in first-generation (single-layer, nitinol) carotid stents (FGS) is believed to represent an exaggerated healing response of (neo)intimal hyperplasia (NIH) formation. Rather than NIH, we describe symptomatic in-FGS unstable plaque (neo)atherosclerosis mandating re-revascularization. To halt continued plaque evolution, we propose a novel treatment strategy involving a micronet-covered stent to sequestrate the plaque from the vessel lumen. A durable long-term result is documented using multi-modal imaging. Case summary With a seemingly optimal result of FGS (Precise) symptomatic carotid lesion revascularization followed by optimal medical therapy, a late (≥3 years) progressive ISR arose. At year 11, crescendo ipsilateral transient ischaemic attacks occurred. Angiography showed an ulcerated tight lesion throughout stent length. Intravascular ultrasound (IVUS) revealed thin-cap fibroatheroma. Re-intervention was performed under distal protection. Undersized balloon predilatation caused symptomatic no-flow, and aspiration catheter was used to reduce the filter load. A micronet-covered stent (CGuard) was implanted and post-dilated to ensure full lumen gain; IVUS confirmed complete plaque sequestration. The optimal anatomic result remained unchanged throughout 5 years (ultrasound and computed tomography verification); this was accompanied by clinical cure. Discussion This is the first demonstration of in-FGS (neo)atherosclerosis resolution using a micronet-covered stent to sequestrate and insulate the atherosclerotic plaque. We show that ISR may be underlined by late atherosclerotic plaque progression via the FGS single-layer stent struts that may show vulnerable plaque phenotype and may be associated with cerebral ischaemia. The anatomically and clinically effective exclusion of the atherosclerotic plaque by a micronet-covered stent enabled lasting, optimal endovascular reconstruction and clinical cure.

Effectiveness of Nifurtimox Eflornithine Combination Therapy (NECT) in T. b. gambiense second stage sleeping sickness patients in the Democratic Republic of Congo: Report from a field study

Background Nifurtimox-eflornithine combination therapy (NECT) for the treatment of second stage gambiense human African trypanosomiasis (HAT) was added to the World Health Organization’s Essential Medicines List in 2009 after demonstration of its non-inferior efficacy compared to eflornithine therapy. A study of NECT use in the field showed acceptable safety and high efficacy until hospital discharge in a wide population, including children, pregnant and breastfeeding women, and patients with a HAT treatment history. We present here the effectiveness results after the 24-month follow-up visit. Methodology/Principal findings In a multicenter, open label, single arm phase IIIb study, second stage gambiense HAT patients were treated with NECT in the Democratic Republic of Congo. Clinical cure was defined 24 months after treatment as survival without clinical and/or parasitological signs of HAT. Of the 629 included patients, 619 (98.4%) were discharged alive after treatment and were examined for the presence of trypanosomes, white blood cell count in cerebro-spinal fluid, and disease symptoms. The clinical cure rate of 94.1% was comparable for all subpopulations analyzed at the 24-month follow-up visit. Self-reported adverse events during follow-up were few and concerned mainly nervous system disorders, infections, and gastro-intestinal disorders. Overall, 28 patients (4.3%) died during the course of the trial. The death of 16 of the 18 patients who died during the follow-up period was assessed as unlikely or not related to NECT. Within 24 months, eight patients (1.3%) relapsed and received rescue treatment. Sixteen patients were completely lost to follow-up. Conclusions/Significance NECT treatment administered under field conditions was effective and sufficiently well tolerated, no major concern arose for children or pregnant or breastfeeding women. Patients with a previous HAT treatment history had the same response as those who were naïve. In conclusion, NECT was confirmed as effective and appropriate for use in a broad population, including vulnerable subpopulations. Trial registration The trial is registered at ClinicalTrials.gov, number NCT00906880.

1143. Safety and Efficacy of Ceftolozane/Tazobactam Versus Meropenem in Neonatal and Pediatric Participants With Complicated Urinary Tract Infection, Including Pyelonephritis: A Phase 2, Randomized, Clinical Trial

Background Ceftolozane/tazobactam (C/T) is a cephalosporin–β-lactamase inhibitor combination approved to treat complicated urinary tract infections (cUTI), complicated intra-abdominal infections, and nosocomial pneumonia in adults. Safety and efficacy of C/T in neonatal and pediatric participants with cUTI was assessed. Methods This phase 2, randomized, double-blind study (NCT03230838) compared C/T with meropenem (MEM) for treatment of cUTI, including pyelonephritis in participants from birth to 18 years of age. Treatment duration was 7-14 days. After 3 days of intravenous therapy, optional oral step-down therapy was allowed. Participants were stratified and dosed by age group (Table 1). The primary objective was to evaluate the safety and tolerability of C/T compared with MEM, and key secondary end points included clinical response and per-participant microbiologic response at end of treatment (EOT) and test of cure (TOC). Results Participants were randomized 3:1 and treated with C/T (n=100) or MEM (n=33). The microbiologic modified intent-to-treat population (mMITT) included 95 participants in the C/T (n=71) and MEM (n=24) arms; the most common reason for mMITT exclusion was lack of a qualifying baseline uropathogen (28.4%). Pyelonephritis was the most common baseline diagnosis (83.2%), and Escherichia coli was the most common qualifying baseline uropathogen (77.9%). Overall mean treatment duration was comparable in both arms (C/T, 10.2 days; MEM, 10.7); a total of 50 (70.4%) and 20 (83.3%) participants switched to optional oral step-down therapy in the C/T and MEM arms, respectively, both for a mean of approximately 6 days. The overall incidence of adverse events (AE; all and drug related), serious AE (SAE), and AE leading to discontinuation was comparable between C/T and MEM arms. There were no AE leading to death, drug-related SAE, or discontinuations due to drug-related AE or SAE (Table 2). For C/T and MEM, rates of clinical cure and microbiologic eradication at EOT and TOC were high (Figure). Conclusion In this study, C/T was well tolerated with a safety profile comparable to MEM and to the previously reported safety profile for C/T in adults with cUTI. C/T achieved high clinical cure and microbiologic eradication rates and is a potential new treatment option for children with cUTI. Disclosures Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Negar Ashouri, MD, Merck Sharp & Dohme Corp. (Grant/Research Support) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Julia Lonchar, MSc, Merck Sharp & Dohme Corp. (Employee, Shareholder) Feng-Hsiu Su, MPH, MBA, Merck Sharp & Dohme Corp. (Employee, Shareholder) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Myra W. Popejoy, PharmD, Merck Sharp & Dohme Corp. (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Carisa S. De Anda, PharmD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Elizabeth G. Rhee, MD, Merck Sharp & Dohme Corp (Employee, Shareholder) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

Background In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants. Methods This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%. Results A total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). Conclusion C/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile. Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

613. Clinical Outcomes Following Dalbavancin Administration during Outpatient Parenteral Antimicrobial Therapy

Background Dalbavancin, a lipoglycopeptide with prolonged half-life targeting Gram-positive organisms, is approved for treatment of acute bacterial skin and soft tissue infection. It reduces hospital duration in patients with barriers to short-term rehabilitation or outpatient parenteral antimicrobial therapy (OPAT). Increasing evidence supports the off-label use of dalbavancin to treat other types of infection. We conducted a quality improvement study to evaluate outcomes following dalbavancin administration. Methods We performed a cohort study of recipients of ≥1 dose of dalbavancin from 1/31/2016-1/31/2021 at the Veterans Affairs Connecticut Healthcare System. Demographic, comorbidity, microbiological, antibiotic duration prior to dalbavancin, indication for dalbavancin, and type of infection data were collected. Outcomes included 1) lab abnormalities: hepatotoxicity within 2 weeks of dalbavancin; 2) clinical cure: resolution of symptoms of infection within 90 days; 3) all-cause readmission within 90 days; and 4) all-cause mortality within 90 days. Results 42 patients met criteria. Median age was 69 years (range, 32-91), 100% were male, 55% (n=23) had diabetes, 31% (n=13) had liver disease, 36% (n=15) had other immunosuppressive conditions, and 12% (n=5) had substance use disorder (SUD). All received their first dose as inpatients. Median hospital duration was 8 days (range, 1-32). 4 (10%) required critical care. Median antibiotic duration prior to dalbavancin was 7 days (range, 1-42). Indications included ineligibility for OPAT (n=21, 50%), pharmacologic reasons (n=10, 24%), ineligibility for peripherally inserted central catheter (n=6, 14%), or SUD (n=5, 12%). Common microorganisms were Staphylococcus spp. (n=22, 52%), polymicrobial (n=13, 31%), and Corynebacterium spp. (n=10, 24%). 93% (n=39) had clinical cure of infection; readmissions and mortality were rare (Table 1). Conclusion Dalbavancin was associated with clinical cure for diverse infections with low rates of adverse events, readmission and mortality in patients ineligible for traditional OPAT. Although confirmatory data are needed from larger studies, dalbavancin appears to be a versatile therapeutic agent for Gram-positive infections. Disclosures All Authors: No reported disclosures

762. Real-World Utilization of C. difficile Drug Treatments and Associated Clinical Outcomes in a US Hospital System

Background IDSA recommends use of fidaxomicin or oral vancomycin for treatment of initial episode or first recurrence of Clostridioides difficile infection (CDI). This study aimed to evaluate impact of a clinical decision support order set driving appropriate use of fidaxomicin on utilization of CDI drug treatments and associated clinical outcomes. Methods This was a retrospective, quasi-experimental study evaluating CDI therapies pre- (8/2016-11/2017) and post- (5/2018-1/2020) CDI order set implementation at a level-one trauma center located in Virginia. Admitted adult patients were included if CDI testing was positive for a 1st or 2nd episode and received active CDI treatment. Exclusions included fulminant CDI and CDI diagnosis by PCR with &lt; 3 bowel movements or laxative use within 24 hours. The primary outcome was CDI recurrence within 30 days of completing therapy in patients who achieved clinical cure. Secondary outcomes were evaluated at 30 and 90 days and included sustained response and CDI-related readmissions. Results After screening, 186 patients in the pre-group and 187 in the post-group were included. Median age was 68 [59-77], most patients had an initial CDI episode (88.2%) and were diagnosed with severe CDI (50.7%). Baseline characteristics were similar between each group on Charlson comorbidity index, ICU admission, CDI risk factors, and concomitant antibiotic use. Primary treatment options in the pre-group were most commonly metronidazole 47.9% and oral vancomycin 50.5%, and in the post-group were fidaxomicin 56.7% and oral vancomycin 41.7% (Figure 1). CDI recurrence rates at 30 days post-index medication (17.2% vs. 6.3%, p=0.004) were lower in the post-group (Table 1). Clinical cure (84.4% vs. 94.1%, p=0.002) and sustained response at 90 days (55.9% vs. 73.3%, p&lt; 0.001) were higher in the post-group. CDI recurrence rates at 90 days and CDI-related readmissions at 30 and 90 days were also lower in the post group. Figure 1. CDI Treatment Utilization Table 1. Clinical Outcomes Conclusion Implementation of the CDI order set increased fidaxomicin use and was associated with a decrease in CDI recurrences and CDI-related readmissions and increase in clinical cure and sustained response. Findings suggest increased first-line use of fidaxomicin results in better clinical outcomes. Disclosures Lauren McDaniel, Pharm.D., BCIDP, Merck Sharp & Dohme Corp (Grant/Research Support) Nathan Everson, Pharm.D., BCIDP, AAHIVE, Merck & Co. (Grant/Research Support) Melissa White, PharmD, Merck Sharpe & Co (Grant/Research Support) Engels N. Obi, PhD, Merck & Co. (Employee, Shareholder) Yiyun Chen, PhD, Merck & Co., Inc (Employee) Rose Kohinke, PharmD, Merck Sharpe & Co (Research Grant or Support)

1257. Re-Evaluation of Cefepime or Piperacillin-Tazobactam to Decrease Use of Carbapenems in ESBL-Producing Enterobacterales Urinary Tract Infections (REDUCE-UTI)

Background Carbapenems (CBP) are considered first-line for infections caused by extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E). However, recent literature suggests that cefepime (FEP) and piperacillin-tazobactam (TZP) may produce similar outcomes vs. CBPs for the treatment of ESBL-E urinary tract infections (UTIs). The goal of this study was to determine if non-carbapenem (NCBP) therapy with FEP or TZP is as effective as CBPs for the treatment of ESBL-E UTIs. Methods This was a retrospective observational study of patients admitted to the hospital from January 1st, 2016 to June 30th, 2020 with a urine culture positive for ESBL-E. Patients were included if they received a study antibiotic (meropenem, ertapenem, TZP, or FEP). Patients were excluded if they had any of the following: absence of pyuria, prior receipt of study antibiotic, CBP-resistant organism isolated in urine culture, polymicrobial urine culture, end-stage renal disease, or concomitant gram-negative infection. The primary outcome was clinical cure defined as complete resolution of signs and symptoms of infection. Secondary outcomes included in-hospital mortality, recurrence within 30 days, and resistance within 30 days. Results A total of 133 patients were included based on definitive therapy received; 69 (52%) received CBP and 64 (48%) received NCBP therapy. Of the total patient population, 17 (13%) were admitted to the intensive care unit, 84 (63%) had a complicated UTI, and 64 (48%) had pyelonephritis. Baseline characteristics were similar between the two groups. There was no difference in clinical cure between the CBP and NCBP therapy groups (96% vs. 97%, p = 1.0). Additionally, no differences in secondary outcomes were observed. Subgroup analyses were performed in patients with specific pathogens, uncontrolled genitourinary source, complicated UTI, and pyelonephritis. These analyses did not reveal any differences in primary or secondary outcomes between the two groups. Conclusion FEP and TZP may be reasonable CBP-sparing alternatives for the treatment of ESBL-E UTIs as clinical and microbiological outcomes were similar with these NCBP agents vs. CBPs in this study population. Disclosures Venugopalan Veena, PharmD, Melinta (Other Financial or Material Support, Received a stipend for participation in a drug registry)Merck (Other Financial or Material Support, Received a stipend for participation in a drug registry)

701. An Open-label Phase 2a Study of Ibezapolstat, a Unique Gram-positive Selective Spectrum (GPSS) Antibiotic, for Patients with Clostridioides difficile Infection

Background Ibezapolstat, a DNA polymerase IIIC inhibitor, currently in Phase 2 clinical development for treatment of C. difficile infection (CDI). Its unique mechanism of action targets low G+C content Gram-positive bacteria primarily Firmicutes including C. difficile. Phase I healthy volunteer results demonstrated a favorable microbiome profile suggestive of an anti-recurrence effect. The purpose of this study was to report clinical outcomes, pharmacokinetics, and microbiome changes from this Phase 2a clinical study and to continue to test for anti-recurrence microbiome properties. Methods Ibezapolstat 450 mg was given twice daily for 10 days to patients with mild-moderate CDI defined as diarrhea plus a positive C. difficile toxin test. Test of cure was evaluated at day 12 and sustained clinical cure at day 38. Stool samples were evaluated for C. difficile cultures and microbiome changes. Results Ten subjects (female: 50%) aged 50 ±15 years were enrolled. All ten subjects experienced a clinical cure by the test of cure visit at day 12 and all 10 subjects experienced a sustained clinical cure at the day 38 visit. Ibezapolstat was well tolerated with 1 adverse event (nausea) probably related to drug. Ibezapolstat systemic exposure was minimal with no plasma level reaching 1 ug/mL any time during therapy. Ibezapolstat colonic concentrations averaged 400 ug/g stool at day 3 and greater than 1,000 ug/g by day 10 of dosing. Six of the seven available baseline stool samples grew toxigenic C. difficile of various ribotypes including RT078-226 and RT014-020 (Ibezapolstat MIC range: 0.25-1 ug/mL). Follow-up cultures were no growth starting from day 3 stool cultures. Microbiome changes included overgrowth of Actinobacteria and/or Firmicute phylum species while on therapy. Conclusion Favorable clinical efficacy and safety results were observed in ibezapolstat patients with CDI including 100% clinical cure and sustained clinical cure. These results begin to validate our approach to ibezapolstat development in that the favorable microbiome effects seen in healthy Phase 1 volunteers may be predictive of beneficial patient outcomes, including low rates of recurrence. These results support the continued clinical development of ibezapolstat. Disclosures Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support) Michael Silverman, MD, Acurx Pharmaceuticals (Consultant)